CME FOR PHYSICIANS AND OTHER HEALTH CARE PROVIDERS

InforMed is Accredited With Commendation by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

2019 WISCONSINMEDICAL LICENSURE PROGRAM

TARGETED SERIES OF CME FOR LICENSE RENEWAL

WI.CME.EDU

PROGRAM INCLUDES:

BOARD-APPROVED2 CREDITSRESPONSIBLE OPIOID PRESCRIBING*

6 TOTALAMA PRA CATEGORY 1 CREDITSTM

*OPIOID CME REQUIREMENT:2 CREDIT HOURS OF BOARD-APPROVED EDUCATION ON RESPONSIBLE OPIOID PRESCRIBING

ONLINE MAIL FAXWI.CME.EDU

1015 Atlantic Blvd #301Jacksonville, FL 32233 1.800.647.1356

*This course is approved by the Wisconsin Medical Examining Board to satisfy the mandatory requirement for two (2) AMA PRA Category 1 CreditsTM or equivalent on opioid prescribing for all licensed physicians (MD/DO) with a current DEA registration.

2019 WISCONSIN

PROGRAM PRICE

$50.00

01

42

81

SATISFIES OPIOID CME REQUIREMENT

PRESCRIBER EDUCATION FOR OPIOID ANALGESICSCOURSE ONE | 2 CREDITS*

EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTIONCOURSE TWO | 4 CREDITS

SELF-ASSESSMENT & EVALUATION SURVEYREQUIRED TO RECEIVE CREDIT

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Disclaimer: The above information is provided by InforMed and is intended to summarize state CE/CME license requirements for informational purposes only. This is not intended as a comprehensive statement of the law on this topic, nor to be relied upon as authoritative. All information should be verified independently.

Wisconsin Medical Examining BoardDSPS

PO Box 8366Madison, WI 53708-8366

P :(608) 266-2112F :(608) 267-3816

INFORMED TRACKSWHAT YOU NEED,WHEN YOU NEED IT

Wisconsin Professional License Requirements

What This Means For You:

PHYSICIANS MANDATORY CONTINUING MEDICAL EDUCATION REQUIREMENT FOR LICENSE RENEWAL

The Wisconsin Medical Examining Board requires all physicians (MD/DO) maintaining a current license to complete 30 credit hours of continuing medical education (CME) during the current two (2) year CME cycle (11/1/2017 to 10/31/2019) which are AMA PRA Category 1 CreditsTM or equivalent.

MANDATORY CME ON PRESCRIPTION OF OPIOID MEDICATION

All physicians (MD/DO) licensed by the Wisconsin Medical Examining Board that have a current DEA registration to prescribe controlled substances must earn a minimum of two (2) AMA PRA Category 1 CreditsTM or equivalent via a board-approved course on opioid prescribing.

If you are licensed by the Wisconsin Medical Examining Board as a physician (MD/DO), and have a current DEA registration to prescribe controlled substances, then you must earn two (2) credit hours on opioid prescribing through a board-approved course by October 31, 2019. These credits earned will also count toward your overall CME requirements for license renewal.

COMPLETION DEADLINE:

10/31/2019LICENSE TYPES:

MD’S & DO’S

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WI.CME.EDU

For more than 45 years InforMed has been providing high level education activities to physicians and other healthcare professionals. Through our level of engagement with a wide variety of stakeholders, including our physician association, we have become the foremost public health policy continuing medical education organization in the United States. We are recognized as the leading provider of mandatory CME activities to physicians as a means of updating knowledge, improving competencies and fulfilling requirements for federal, state, regulatory and license renewal

1015 Atlantic Blvd #301Jacksonville, FL 32233

Dear Wisconsin Medical Professional,

InforMed is pleased to offer this collection of CME activities for physicians that are licensed by the state of Wisconsin. The uniquely tailored curriculum is customized to the educational needs of Wisconsin medical professionals. Participants earn AMA PRA Category 1 CreditTM through these self-directed, on-demand courses.

The CME series is designed to streamline the education requirements of the Wisconsin Medical Examining Board. Licensees who complete this program optimize their learning path while satisfying professional credentialing requirements including a board-approved course to fulfill the mandatory two (2) credit hour requirement on opioid prescribing.

Thank you for choosing InforMed as your CME provider. Please do not hesitate to contact us with any questions, concerns or suggestions.

-InforMed CME Team

Visit WI.CME.EDU, select NETPASS to begin.

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Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation, and payment to InforMed by mail, phone, fax or complete online at course website under NETPASS.

Completion of this course will better enable the course participant to:1. Discuss the fundamental concepts of pain management, including definitions and mechanisms of pain.2. Identify the range of therapeutic options for managing pain, including nonpharmacologic approaches and pharmacologic

(non-opioid and opioid analgesics) therapies.3. Explain how to integrate opioid analgesics into a pain treatment plan individualized to the needs of the patient, including

counseling patients and caregivers about the safe use of opioid analgesics.4. Describe how to safely and effectively manage patients on opioid analgesics in the acute and chronic pain settings,

including initiating therapy, titrating, and discontinuing use of opioid analgesics.5. Discuss recommendations on incorporating emergency opioid antagonists into prescribing practice, utilizing best

practices for co-prescribing emergency antagonists and training family members and loved ones on the use of naloxone. 6. Recognize the risks of addiction following all stages of treatment in the management of pain, identify strategies to

mitigate these risks, and discuss therapeutic options for treatment of opioid addiction.

LEARNING OBJECTIVES

TARGET AUDIENCE

This course is designed for all physicians and health care providers involved in the treatment and monitoring of patients prescribed controlled substances.

COURSE OBJECTIVE

The purpose of this course is to educate prescribers about Risk and Mitigation Strategies (REMS) in accordance with the Food and Drug Administration (FDA) blueprint of prescriber education related to opioid analgesics.

Release Date:06/2018 Exp. Date: 05/2021

Enduring Material(Self Study)

2 AMA PRACategory 1 Credits™

PRESCRIBER EDUCATIONFOR OPIOID ANALGESICS

ACCREDITATION STATEMENT:InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

DESIGNATION STATEMENT:InforMed designates this enduring material for a maximum of 2 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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FACULTY

Paul J. Christo, MD, MBAAssociate Professor of Anesthesiology and Critical Care MedicineDivision of Pain MedicineThe Johns Hopkins University School of Medicine

Beth DoveMedical WriterDove Medical Communications

ACTIVITY PLANNER

Elizabeth ThomasMSN, WHNP-BC, NP-C

DISCLOSURE OF INTEREST:In accordance with the ACCME Standards for Commercial Support of CME, InforMed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

STAFF AND CONTENT REVIEWERS:

InforMed staff, input committee and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

DISCLAIMER

*2019. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought.

• Paul J. Christo, MD, MBA has received honoraria from GlaxoSmithKline Consumer Healthcare.

FACULTY/PLANNING COMMITTEE DISCLOSURE:

The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:

The following faculty and/or planning committee members have indicated that they have relationship(s) with industry to disclose:

• Elizabeth Thomas, MSN, WHNP-BC, NP-C • Beth Dove

This activity is approved by the Wisconsin Medical Examining Board and satisfies the education requirement in

Responsible Opioid Prescribing.

RESPONSIBLE OPIOID

PRESCRIBING

WISCONSIN SPECIAL APPROVAL

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The Wisconsin Medical Examining Board requires all physicians (MD/DO’s) with a current DEA registration to complete a minimum of 2 AMA PRA Category 1 CreditsTM or equivalent on opioid prescribing through a

board approved course.

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Introduction

Overview of Pain ManagementThe practice of pain management requires an understanding of two competing public health problems: the high prevalence and burden of pain and the risks associated with opioid analgesics and other controlled substances often used to treat pain. All healthcare providers (HCPs) who treat pain with opioids are called upon to familiarize themselves with best practices to increase patient and societal safety while boosting patient outcomes for pain relief, function, and quality of life.

Close to 100 million Americans suffer from some type of ongoing pain.1 In National Health Interview Survey Data, 25 million respondents reported living with daily pain, and more than 14 million reported the highest level of pain.2 The higher the impact and severity of pain, the greater the costs in terms of disability, health status, quality of life, and use of health care services.3

Pain is even more common in military veterans, particularly those who have served in recent conflicts: 66% reported pain in the previous 3 months and 9% had the most severe pain.4 Certain populations are more vulnerable than others to developing more severe chronic pain and disability, including women, older adults, and racial and ethnic minorities.5 Members of some groups, including racial and ethnic minorities and children are also at risk for having their pain undertreated.5

Pain care is most effective when it combines multiple disciplines and utilizes a broad range of evidence-based pharmacologic and nonpharmacologic treatment options.1,6 For acute pain and for some chronic pain, unresponsive to nonopioid therapies, opioids may form part of a customized treatment plan. Some patients report improved pain and quality of life with opioids.7 However, opioids also bring well-documented risks that include misuse, abuse, opioid-use disorder (OUD), and overdose death. Approximately 11.5 million Americans, or 4.3 percent of the population, misused prescription opioids in 2016.8 Furthermore, of 42,000 opioid-related deaths in 2016, 40% involved prescription opioids.9

This educational activity follows national and state guidelines for the safe prescribing of opioids with the purpose of reducing adverse outcomes with opioids while preserving analgesia for patients who require opioids, particularly when pain is chronic. The goal is for HCPs to acquire the necessary knowledge to consider all available therapies and to create a comprehensive treatment plan, prescribing opioids only when the benefits outweigh the risks.

When a trial of potentially long-term opioids is selected, HCPs should be better equipped to recognize and manage any adverse events that may arise during the course of opioid therapy.

Pain Definitions and MechanismsThe International Association for the Study of Pain (IASP) defines pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”1 As such, pain is protective and essential for survival, serving as a useful warning signal that something has gone wrong. Pain is also a subjective experience with an emotional component. There are no precise clinical markers for pain, which is experienced by the individual as a constellation of biological, psychological, and social factors. Pain varies by type and mechanism:1

• Acute pain has a sudden onset and expected short duration, though episodes may recur

• Chronic pain lasts longer than normal healing and is generally diagnosed after persisting from 3-6 months

• Nociceptive pain is the normal response to any type of stimulus that results in tissue damage

• Visceral pain is nociceptive pain that arises from the body’s organs (may be cramping, throbbing, vague)

• Somatic pain, whether superficial or deep, is nociceptive pain that results from issues within the body’s bone, joints, muscles, skin, or connective tissue (may be localized and stabbing, aching, throbbing)

• Neuropathic pain results from damage to or abnormal processing of the peripheral or central nervous system (CNS) (may be sharp, stabbing, burning, tingling, numb)

• Referred pain spreads beyond the initial injury site

Chronic pain’s many possible causes include injuries, malignancies, diseases that flare up, medical treatments or surgeries, or inflammation that appears as a result of injury or chronic disease. Chronic pain may even occur in the absence of a defined injury or cause.

Ongoing pain can modify the CNS, through which pain is sensed, transmitted, modulated, and interpreted.1 When the nociceptors, or sensory receptors, become sensitized, they discharge more frequently. In peripheral sensitization, this state of heightened neuron excitability occurs at the site where the pain impulse originated in the body; in central sensitization, it occurs in the spinal neurons, which begin to fire spontaneously, resulting in pain that intensifies and lasts far longer

than the stimulus applied.1 Sensitization can result in hyperalgesia, where response to pain-causing stimuli is intensified, and allodynia, a pain response to stimuli that normally are not painful.1 Therefore, the resulting pain comes not just from an injury site but from neural impulses. The pathologies created by central sensitization can persist and continue to generate pain impulses indefinitely, far outlasting pain’s usefulness as a warning signal.

Chronic pain may be primarily nociceptive, neuropathic, or have mixed nociceptive-neuropathic characteristics. Examples of nociceptive or inflammatory pain include postoperative pain, arthritis, mechanical low back pain, sickle cell crises, and pain from traumatic injuries. Causes of peripheral neuropathic pain include postherpetic neuralgia and diabetic neuropathy. Central neuropathic pain triggers include spinal cord injury, trigeminal neuralgia, and multiple sclerosis.

Creating a Treatment PlanAcute pain is generally manageable with rest, over-the-counter (OTC) medications or a short course of stronger analgesics, and resolution of the underlying cause (e.g., trauma, surgery, illness). Prompt management of acute pain is necessary to prevent progression to a chronic state.

With chronic (as well as acute) pain, it is essential to treat the cause of pain, whenever a cause can be diagnosed, in addition to managing the pain. Addressing the underlying cause of the pain condition to the extent possible is the primary aim and top priority of care, while also keeping the patient comfortable. Specialist consultation is advised if the pain condition lies outside the scope of treatment for the HCP. Patients who refuse or resist treatment of the cause of their pain may be poor candidates for opioid therapy and, if opioids are necessary, their prescription should be accompanied by a clear rationale documented in the patient record. When the pain is moderate-to-severe in intensity, it requires a biopsychosocial model of comprehensive treatment in recognition of its complex contributors.1 The complexity of the pain experience involves emotions, attitudes, presence of confounding psychiatric and anxiety conditions, history of response to pain, current living conditions, and many other factors. The presence of a psychiatric condition does not mean the pain the patient is experiencing is not real. Chronic pain affects relationships, work, sleep, function, overall health, and quality of life. This complexity is why a comprehensive approach to pain management should factor in the many contributors from the biological, psychological, and social domains.1 It is also why patients often respond better to a combination of therapeutic modalities rather than a unimodal medication regimen.

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A number of guidelines have been developed by professional medical societies, states, and federal agencies to assist HCPs in setting and executing treatment plans for prescribing opioids for chronic pain.10-14

Common recommendations include:

• Conduct a physical exam targeted to the pain condition

• Collect pain history, medical history, and family/social history

• Consider all treatment options, weighing benefits and risks of opioid therapy, and prescribe opioids only when nonpharmacologic or nonopioid treatments are ineffective

• Obtain informed consent and implement pain treatment agreements

• Start patients on the lowest effective dose • Conduct urine drug testing (UDT), when

appropriate • Check prescription drug monitoring programs

(PDMPs) to identify past and present opioid prescriptions at initial assessment and during the monitoring phase

• Monitor pain and treatment progress with documentation, using greater vigilance at higher doses

• Use safe and effective methods for discontinuing opioids (e.g., tapering, making appropriate referrals to substance abuse treatment or other services)

• Pay close attention to drug-drug and drug-disease interactions

• Recognize special risks with fentanyl patches and methadone

• Titrate slowly and cautiously• Consider using an opioid-specific risk

assessment

The goals of treatment should be meaningful to the patient and contain pain relief and functional components.13,14 Even patients with pain conditions or injuries that make complete cessation of pain unlikely can set goals such as sleeping through most nights, returning to work, walking a set distance, or participating more fully in family activities. The self-efficacy involved in collaborating on these goals can help patients gain greater control over their pain and their lives.

Informed consent is critical to a treatment plan containing a trial or continuation of opioid therapy.12,13,15 Treatment plans should be revisited and adjusted frequently to ensure goals are being met and any adverse effects of therapy are addressed.

Nonpharmacologic ApproachesA number of nonpharmacologic and self-management treatment options are available, which may be used alone or as part of a comprehensive pain management plan.

Evidence-based nonpharmacologic options for acute and chronic pain, include:16

• Acupuncture therapy• Chiropractic and osteopathic manipulation• Massage therapy• Physical therapy• Exercise• Mind/body therapies (e.g., mindfulness-

based-stress reduction, cognitive-behavioral therapy)

• Movement therapies (e.g., yoga, Tai chi)• Injection treatments

Patients may find helpful a combination of approaches that include nutritional support, healthy lifestyle changes, patient education, sleep hygiene instruction, and relaxation and visualization techniques. Interventional techniques range from the less invasive such as injections (nerve blocks, trigger point injections, epidural steroid injections, joint blocks), transcutaneous electrical nerve stimulation, and various approved medical devices to the more invasive such as surgeries, implantable spinal pumps, and implantable spinal electronic stimulators or peripheral nerve stimulators.

Rather than thinking of these treatments as “alternatives” to conventional treatment, HCPs are encouraged to review the evidence base16 and consider a trial of 1 or more nonpharmacologic therapies. Unfortunately, barriers are common in obtaining insurance coverage and reimbursement for nonpharmacologic therapies, and access to trained professionals in these care options is sometimes limited.11 The modalities of cognitive-behavioral therapy, physical therapy, certain injections, exercise and electrical stimulation are generally recognized and covered as having benefit for chronic pain.16

Less invasive measures for pain management should be considered first.13 Education can be an effective means to patient self-management; for example, instruction in proper posture and movement techniques along with advice to remain active are recommended for the treatment of persistent low-back pain.

Nonopioid Pharmacologic Analgesic TherapyNonopioid pharmacologic treatments for pain include:

Acetaminophen (ACET) for pain without inflammation. All ACET products carry an FDA-required black box warning highlighting the potential for severe liver damage and potential for allergic reactions.17

Dose levels from all medication sources should be evaluated to avoid exceeding the recommended daily dosage.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which includes cyclooxygenase-2 (Cox-2) inhibitors, for pain and inflammation. Risks are elevated with NSAIDs for heart attack, stroke, gastrointestinal bleeding or perforation, and renal and cardiovascular abnormalities, particularly at higher doses and longer duration of use.13 An FDA-required black box warning for all marketing NSAIDs highlights the potential for increased risk of cardiovascular events and serious, potentially life-threatening gastrointestinal bleeding associated with their use.

Skeletal muscle relaxants for pain and muscle spasm for short-term use. Sedation is a common adverse effect. Particular CNS risks are notable with carisoprodol (toxicity) and benzodiazepines (substance dependence and respiratory depression leading to overdose) when prescribed in combination with opioids.16

Antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and tricyclics) used in low doses for insomnia and neuropathic pain. Depending on class, risks may include anticholinergic effects, sexual dysfunction, weight gain, emotional blunting, and suicidal thoughts.16

Anticonvulsants, such as gabapentin and pregabalin, have mild-to-moderate benefit for neuropathic pain and adverse effects that include drowsiness and cognitive slowing.16

Topical medications include lidocaine, ketamine, capsaicin, and anti-inflammatory drugs such as ketoprofen and diclofenac. Anti-inflammatory topicals are proven beneficial for musculoskeletal pain as is capsaicin for neuropathic pain.16

Many guidelines recommend NSAIDs and ACET as first-line therapies for low-back pain and osteoarthritis, and anticonvulsants and antidepressants as first- and second-line therapies for neuropathic pain with appropriate risk mitigation.13

Analgesic Effects of OpioidsUnderstanding the variety of opioid products, delivery systems, and formulations that are available to treat pain can assist HCPs in drug selection to maximize analgesia and minimize or prevent adverse effects. Opioids achieve an analgesic effect primarily by inhibiting nociceptive transmission in the CNS. They do this by binding to and activating receptors within the endogenous opioid system.

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Mu, kappa, and delta are the 3 primary opioid receptor types that mediate analgesia. Drugs that bind to these receptors are classified as full agonists, partial agonists, mixed agonist-antagonists, and antagonists (Table 1). Opioids used in clinical practice are typically full mu-agonists that bind selectively to the mu-opioid receptor. When an antagonist occupies the receptor, it displaces the agonist, and is associated with abstinence syndrome (withdrawal). Partial agonists, such as buprenorphine, have high receptor occupancy, some antagonistic effects, and low intrinsic activity at the site. In addition to use in pain treatment, methadone and buprenorphine are used to treat OUD, a process known as medication-assisted treatment (MAT) when combined with behavioral therapy.18 Kappa opioid receptor agonists (including levorphanol, pentazocine, and butorphanol) have been used clinically but are associated with side effects such as dysphoria and hallucinations.

Initiating Opioids: Acute Pain SettingFor acute pain, the therapeutic goal is to prescribe the lowest dose and fewest number of pills that control pain for the shortest duration, lasting only as long as the acute phase. Most prescriptions should not need to exceed 3 days,13 beyond 5 days are rarely indicated, and even severe episodes rarely need more than 7-14 days.13,14 When a larger amount of medication is necessary, HCPs can take steps to limit leftover opioids that may later be

diverted for illicit use by writing 2 prescriptions for smaller quantities with specific refill dates with the understanding that many patients will never fill the second prescription. Be aware also that localities and states may have strict regulations governing maximum duration of prescriptions.

Nonopioids (such as acetaminophen, anti-inflammatories, and nonpharmacologic treatments) should be utilized first and preferentially, LAOs should be avoided, and opioids are not recommended for nonspecific back pain, headaches, or fibromyalgia.12 In addition, acute exacerbations of chronic pain should not be treated with intravenous or intramuscular opioid injections in emergency or urgent care settings if it can be avoided. If it is clear from the patient’s condition that opioids will be needed, nonopioids may be prescribed simultaneously.

Nonopioids should be optimized in patients preoperatively as well. Pain from trauma and chronic degenerative diseases often can be managed without opioids prior to surgery, and HCPs should be aware that opioids used before spine surgery have been associated with higher complication rates, lower patient satisfaction rates with poorer outcomes, and greater opioid requirements after surgery, according to an information statement from the American Academy of Orthopedic Surgeons.19,20

If pain persists beyond the expected

healing period, HCPs should rule out complications, reevaluate the diagnosis and treatment plan, and – if complications are absent – transition to nonopioid pain management if possible.

Initiating Opioids: Chronic Pain SettingTreatment of patients who have active cancer or who need palliative or end-of-life care is not addressed in this activity. For patients with chronic noncancer pain (CNCP) in the outpatient setting, opioids are not considered first-line therapy and should not be routinely used.12,13 The HCP should weigh and discuss with the patient certain issues regarding expectation of benefit vs. risk when initiating LTOT. While opioids can reduce pain during short-term use, there is scant high-quality evidence that opioids improve pain or function with long-term use, the risk of harms can increase at higher doses, and complete relief of pain is unlikely.90

Furthermore, some evidence indicates that opioids may not be superior to other pharmacologic and nonpharmacologic therapies for chronic pain.16,91

The HCP may consider a trial of long-term opioid therapy (LTOT) as 1 therapeutic option if the patient’s pain:11

• Is severe and ongoing or recurs frequently• Diminishes function or quality of life• Is unrelieved or likely to be unrelieved by

nonopioid therapies

Table 1. Opioid Analgesic Classifications Type Generic Name Notes/Cautions

Pure agonists Codeine Dihydrocodeine Fentanyl Hydrocodone Hydromorphone Levorphanol Meperidine* Methadone Morphine Oxycodone Oxymorphone Propoxyphene

*Not recommended for long-term treatment or in patients with renal compromise due to toxicity risks

Agonist-antagonists Partial agonist: Buprenorphine Mixed agonist-an-tagonists: Butorphanol Dezocine Nalbuphine Pentazocine

May produce abstinence with physical dependence

Pure antagonists NaloxoneNaltrexone

Administered to reverse opioid effects

Other Tramadol Tapentadol

Dual action mu-agonist and serotonin–norepinephrine reuptake inhibitorDual action mu-agonist and norepinephrine reuptake inhibitor

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The HCP should consider the following questions:

• Is a medical condition present that would be expected to cause pain severe enough to require an opioid? (consider nonopioid treatment if questionable)

• Do medical comorbidities increase risk of side effects?

• Do other therapies have better or equal evidence for the particular pain type and condition?

• Do reasonable alternatives to LTOT exist? Are they available?

• Do anticipated therapeutic benefits of LTOT outweigh known risks?

• Does thorough patient evaluation indicate the patient is likely to adhere to the treatment plan?

The patient’s pain type and previous treatments tried should be evaluated to see if opioid therapy is likely to be effective. For example, one might first try an anticonvulsant for trigeminal neuralgia, a disease-modifying antirheumatic drug for rheumatoid arthritis, a corticosteroid for polymyalgia rheumatica, or various rescue and preventive medications for migraine and stress-related headache.11

Opioids, if administered, are best when used at the lowest effective dose and combined with modalities from other disciplines.11,13 Patients who refuse any treatment except opioids or who provide questionable reasons for not trying nonopioid treatments should not be treated with opioids.

Assessing Patients in PainInitial patient evaluation includes taking a medical and pain history, performing a physical exam, and conducting appropriate diagnostic testing when indicated. The evaluation should include chief complaint, prior diagnostic findings, results and analyses of laboratory tests and screenings, all previous treatments tried and response, and comorbid conditions (including medical, psychiatric, mood and sleep disorders). Medical conditions that may complicate treatment include renal disease, sleep apnea, and chronic obstructive pulmonary disease. One should obtain a complete history of current and past substance use and misuse to include prescription drugs, illegal substances, alcohol, and tobacco. Social history is also relevant to include employment, marital history, and family status.11 Women should be screened for contraceptive use and pregnancy or breastfeeding status or intent.13

Pain is assessed by onset, location, intensity, quality, duration, radiation, and variations. Patients should be asked what relieves or increases the pain, how it affects their daily lives and functioning, and what goals they have for pain relief and improved function. Pain is subjective, and HCPs are called upon to accept the patient’s report of pain while also evaluating whether the pain complaint aligns with causative factors that have been adequately evaluated in the past and treated with nonopioid therapies. Although HCPs are largely reliant upon patient self-report of pain severity, a number of pain assessment tools are available to be incorporated into routine clinical practice. The Visual Analogue Scale (VAS) and Numerical Rating Scale (NRS) are sensitive, validated, and widely-used, quick tools to measure pain severity.19 The Brief Pain Inventory (BPI) has good sensitivity, reliability, and validity for pain severity and interference-with-function items, including assessments of mood and sleep.20,21 The McGill Pain Questionnaire (MPQ), also available as a short form, assesses additional pain descriptors (sensory, evaluative, and affective).19 With good validity and reliability, the MPQ is useful for facilitating description of the subjective pain experience but requires a good vocabulary when self-administered. An instrument to assess how well patients cope with chronic pain is the Multidimensional Pain Inventory (MPI), which categorizes patients into 3 coping styles: Adaptive, Dysfunctional, and Interpersonally Distressed and has been validated for multiple chronic pain conditions.22,23

Patients also should be evaluated for psychosocial, psychiatric, and social factors that can impact pain and vice versa, including anxiety, post-traumatic stress disorder (PTSD), bipolar disorder, attention deficit disorders, sociopathic disorders, borderline personality disorder, and untreated or severe depressive symptoms or disorders. The 9-item Patient Health Questionnaire (PHQ-9) and its variations are brief, reliable, and valid measures to identify depression.13,24 One PHQ-9 item addresses suicidal ideation, an important assessment for patients with chronic pain.25 The Generalized Anxiety Disorder (GAD)-7 and GAD-2 are validated and recommended to assess for generalized, panic, and social anxiety disorders and PTSD.13,26

Additional helpful screening tools are the reliable and valid Beck Depression Inventory II (BDI-II) self-report measure of depression severity,27 and the Beck Anxiety Inventory (BAI),28 which emphasizes somatic components of anxiety. Even more in-depth pain assessment is offered through newer systems such as the Stanford-developed vented Collaborative Health Outcomes Information Registry through the use of item banks that capture many physical, psychological, and social functioning domains.29

Patients who are under consideration for a trial of opioid therapy or who are currently taking opioids should have additional initial screening to be described under the section Screening for Risk.

Risks and warnings with opioidsEven at prescribed doses, opioid analgesics carry the risks of misuse, abuse, OUD, respiratory depression, overdose, and death.

Terminology related to opioid use and misuse is shown in Table 2. The risks apply to all brand-name and generic extended release/long-acting (ER/LA) (See Table 8) and immediate-release (IR) opioids (guidance forthcoming).18,30 Opioid combination products containing acetaminophen also carry warnings of the potential for severe liver damage.17 Particular care and increased monitoring are essential during opioid dose initiation, upward titration, rotation, and addition of other CNS-depressant medications. Studies show patients are particularly vulnerable to respiratory depression at these times.31,32 In addition, patients may suffer harm that includes abstinence syndrome, increased pain, and distress if opioids are suddenly discontinued or tapered too rapidly. An FDA boxed warning details the risks of prescribing opioids and benzodiazepines together, a combination of medications that has increased in recent years but which is associated with extreme sleepiness, respiratory depression, coma, and death.33

Common adverse drug reactions with opioids include lightheadedness, dizziness, sedation, nausea and vomiting, drowsiness, mental clouding, constipation, hormonal deficiencies, pruritis, and myoclonus.13

The disease of OUD is diagnosed using DSM-5 criteria: A minimum of 2–3 criteria are required for a mild substance-use disorder (SUD) diagnosis, while 4–5 is moderate, and 6–7 is severe;37 OUD is specified instead of SUD, if opioids are the drugs of abuse. Addiction, while not a DSM-5 diagnosis, is still a term that is used and generally describes a severe OUD. The presence of tolerance and physical dependence are not in themselves indicators that an OUD has developed.

Before moving on to the next section, please spend the allotted time on Exercise 1.

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Table 2. Definitions Related to Opioid Use and Misuse Term Definition

Tolerance34 A physiologic state of adaptation in which exposure to the opioid results in diminution of its effects over time In patients with “analgesic tolerance,” increased doses of opioid are needed to maintain pain relief

Physical dependence34 A physiologic state characterized by abstinence syndrome (withdrawal) if treatment with an opioid is stopped or decreased abruptly, or if an antagonist is administered

Abuse35 The intentional, non-therapeutic use of a drug product or substance, even once, to achieve a desirable psychological or physiological effect

Misuse35 The intentional therapeutic use of a drug product in an inappropriate way and specifically excludes the definition of abuse

Addiction36 Chronic disease characterized by compulsive, or uncontrollable, drug seeking and use despite harmful consequences and long-lasting changes in the brain

Criteria for Opioid-Use Disorders from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition37*

1. Opioid taken in larger amounts or over a longer period than intended 2. Persistent desire or unsuccessful efforts to cut down or control opioid use 3. A lot of time spent obtaining, using, or recovering from the effects of the opioid 4. Craving or a strong desire to use opioids 5. Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home 6. Continued use despite persistent or recurring social or interpersonal problems caused or

exacerbated by opioid use 7. Stopping or reducing important social, occupational, or recreational activities due to opioid use 8. Recurrent use of opioids in physically hazardous situations 9. Continued use despite knowledge of having persistent or recurrent physical or psychological

problems cause or worsened by opioid use 10. Tolerance as defined by either a need for markedly increased amounts to achieve intoxication or

desired effect or by markedly diminished effect with continued use of the same amount. (Does not apply when used appropriately under medical supervision)

11. Withdrawal manifesting as either characteristic syndrome or the substance is used to avoid withdrawal (Does not apply when used appropriately under medical supervision)

Jan, 28, presents with low-back pain of 2 months duration. Pain is intermittent and aching. Pain intensity is typically 5-10 VAS but spikes to 7-10 after shifts in the call center where she works. The pain came on suddenly without an instigating trauma. She has no radicular symptoms. The pain is helped by yoga stretching and occasional OTC ACET and worsened by periods of prolonged sitting. Her sleep is interrupted by the need to change position in the night, and she reports sleeping 2 uninterrupted hours on average before waking; 5 hours total sleep per night is usual. She awakes unrefreshed and feels her ability to cope with stress is suffering as a result. She has a husband and 3-year-old son but does not join them for dinner as she used to, because she feels the need to lie down in the evening from the pain and fatigue. She has a history of major depression (1 episode in college) and smokes 1 pack of cigarettes daily. She reports no recreational drug use and drinks beer only on the weekends.

EXERCISE 1On her initial visit, which of the following therapies would you be likely to discuss/recommend?

A. IR opioid plus muscle relaxantB. ER opioid plus IR opioid for breakthrough painC. Exercise/physical therapy, option for standing desk, NSAIDD. Antidepressant for pain and benzodiazepine for insomnia

Nonpharmacologic remedies and treatment plans that address underlying causes are preferred. Trialing an NSAID that helps with inflammation, plus adding gentle movement therapies and addressing work-related triggers, may help the patient manage her pain. A CNS-depressant such as a benzodiazepine is not a first-line therapy for insomnia that appears to have an underlying cause (pain) that should be addressed. The best answer is C.

Instructions: Take 5 minutes to read the case below and answer the question as it relates to the case presented.

Notes:

8

Screening for RiskIf a trial of opioid therapy is warranted, the patient should be screened for the risk of developing an OUD or other drug abuse behavior that threatens patient wellbeing and precludes successful pain therapy. Initiation of the therapy should be considered to be on a trial basis to be discontinued or tapered if previously set objective symptom and function goals are not met; patients should be advised of this. A number of available screening tools are shown in Table 3. Tools recommended as having good content, face, and construct validity include the revised Screener and Opioid Assessment for Patients with Pain (SOAPP-R),38 the Opioid Risk Tool (ORT),39 and the Diagnosis, Intractability, Risk, Efficacy (DIRE) instrument.40 The DIRE is clinician-administered and is designed to assess for potential harms of opioid therapy as well as whether or not the patient is a good candidate. The SOAPP-R and ORT are patient self-report questionnaires to stratify patient risk of aberrant drug-related behaviors (ADRBs) into categories of low, moderate, or high risk. Of these, the SOAPP-R has the best sensitivity for predicting risk with opioid management but may also have more false positives.41 The Current Opioid Misuse Measure (COMM) is an assessment for patients already on ongoing opioid therapy.42 None have been fully validated in a variety of clinical settings. Such tools are generally chosen by evaluating length, time available, and expertise within the clinic. Treating HCPs may also apply a less formal set of questions that address patient risk factors if they do so consistently, treating assessment as routine and encouraging patients to share information honestly. Patient risk factors for ADRBs, pulled from the scientific literature, include but are not limited to the following:38-40,46-53

• Nonfunctional status due to pain• Exaggeration of pain• Unclear etiology for pain• History of rapid opioid dose escalation • Young age• Smoking• Poor social support• Personal history of substance abuse• Family history of substance abuse• Psychological stress• Psychological trauma• Psychological disease• Psychotropic substance use• Focus on opioids• Sexual abuse• History of legal problems• History of substance-abuse treatment• Craving for prescription drugs• Mood swings• Childhood adversity• Social environments that encourage illicit

substance use

Patient and prescriber roles and responsibilities should be delineated and documented in the patient record. A baseline UDT and query of the

state PDMP should also take place before opioids are initiated or continued.11-13 Wisconsin law requires prescribers to review PDMP data before issuing any controlled-substance prescription for greater than a 3-day supply. The PDMP is an important tool to inform clinical decisions and to help stop the spread of abuse and diversion as a public health problem. If results indicate unauthorized prescriptions or there are other clinical signs of abuse, results should be discussed with the patient and a specialist referral given. Patients with a history of running out of or losing prescriptions or of otherwise violating previous treatments agreements are questionable candidates for LTOT.

Clinicians may consider or continue LTOT for patients with CNCP and histories of drug abuse and psychiatric issues only if a strong rationale exists and they are able to implement more frequent and stringent monitoring parameters.13 In such situations, clinicians should strongly consider consultation and co-management with a mental health or addiction specialist.11,13 Prescription of opioids may not be appropriate until the comorbidity has been addressed.11

Opioid therapy in patients with untreated SUD or current abuse of illicit drugs is unlikely to achieve therapeutic aims, and initiating it is not recommended.12 For patients exhibiting active SUD already on LTOT (review criteria for SUD shown in

Table 2), the clinician should refer for addiction management and initiate slow, careful tapering with close monitoring of response and suicide risk.12 Sudden discontinuation or tapering that is accomplished too quickly or without MAT may put patients with OUD or other SUD at risk.

Healthcare providers also should remain alert to the risk of respiratory depression leading to overdose. A number of factors have been observed in opioid-related overdose deaths involving patients and people taking opioids nonmedically. The factors include:31,32,54-56

• Middle age • History of substance abuse • Comorbid mental and medical disorders • High opioid dose • Recent upward titration• Recent opioid rotation• Methadone • Benzodiazepines • Antidepressants • Unemployment • Polysubstance abuse• Recent release from prison• Recent release from abstinence-based

addiction treatment • Sleep apnea• Heart or pulmonary complications (e.g.,

respiratory infections, asthma)• Pain intensity

Before moving on to the next section, please spend the allotted time on Exercise 2.

How would you structure his therapy?A. Trial an ER opioid at its lowest dose,

request that he discontinue alcohol consumption, and assess in one month

B. Offer topical lidocaine C. Increase the frequency of IR hydrocodoneD. Add a benzodiazepine for relaxation

EXERCISE 2Instructions: Take 5 minutes to read the case below and answer the question as it relates to the case presented.

Joe, 72, presents with disabling osteoarthritis pain in both knees of some years duration. He is taking 40 mg daily of IR hydrocodone/ACET, but pain relief is inconsistent and lasts 2 hours on average. The pain is 5/10 on average, but he experiences spikes to 8/10 that last for days at a time. He has successfully tried physical therapy in the past but feels his ability to participate is now limited by pain. He has had 3 corticosteroid injections, which provided relief that was short lived. His BMI is 33. He no longer works, does not smoke, and has no history of illegal drug use. He drinks 1-2 alcoholic drinks 3 times per week. Depression and PTSD screens are negative, and his SOAPP-R score indicates he is at low risk for abuse behaviors. He takes OTC ibuprofen for times he expects to be active. More often, however, he remains home. His goals include more frequent visits to his daughter’s home, 45 minutes away, and to attend church twice a week. He has many friends in his church and misses socializing with them. The orthopedic surgeon indicates that the patient is not a surgical candidate

The patient experiences inconsistent and inadequate, short-term pain relief on his current IR regimen and may benefit with an around-the-clock ER opioid trial with appropriate risk mitigation that includes managing alcohol intake. Frequently reassessing the patient for progress in meeting functional goals is an important part of monitoring for chronic pain management and one in which the patient should actively participate. Although the patient is currently at low risk for abusing prescribed opioids, it is necessary to remain alert to changes in the patient’s social environment, pain control, and other stressful factors that could increase risk. The best answer is A.

9

Initial Dosing and Dose TitrationFor outpatient chronic pain management, opioids are typically administrated through the oral, transmucosal, and transdermal routes. Each route has advantages and disadvantages and safety concerns, some of which are intrinsic to all opioids and some of which are specific the route.

Short-acting opioids (SAOs) are preferred and considered safer when initiating a therapeutic trial of opioids for acute or chronic pain.11

Commonly prescribed SAOs include IR morphine, hydromorphone, oxymorphone, codeine, fentanyl, hydrocodone, and oxycodone.57 Codeine, hydrocodone, and oxycodone are also available in combination with ACET or an NSAID, which limit daily dose due to risk for liver and gastrointestinal toxic effects.57 In pain management, IR opioids, are indicated for pain severe enough to need opioid treatment and for which nonopioid treatments are ineffective or not tolerated.18 They have a short half-life and duration of action (typically 2 to 4 hours), and are often prescribed to take as needed every 4 to 6 hours.18 Patients with no or limited exposure to opioids should be initiated at the lowest dose and titrated slowly to minimize adverse effects.11

If patients require long-term maintenance and pain is severe enough to require around-the-clock analgesia that is not adequately relieved by SAOs or other therapies, consider a transition to ER/LA opioids with scheduled dosing.30 ER/LA opioids are not indicated for acute pain and are for use only in patients who are already tolerant to opioids, with rare exceptions.58 It is critical also that HCPs be aware that all transdermal fentanyl and hydromorphone ER products are for use only in opioid-tolerant patients and never for acute or short-term pain.58 Transmucosal IR fentanyl is also for use only in opioid-tolerant patients.

Adult patients are considered opioid tolerant if they have received the following dosages of opioids (or equianalgesic dosages of other opioids) for at least 1 week:13,58

• 60 mg daily of oral morphine• 25 mcg per hour of transdermal fentanyl• 30 mg daily of oral oxycodone• 8 mg daily of oral hydromorphone• 25 mg daily of oral oxymorphone

Product information for individual formulations contain guidance on degree of opioid tolerance necessary for administration and minimum titration intervals.

Dose titration is individualized depending on efficacy, tolerability, and presence of adverse effects. Patients should be monitored carefully, particularly within 24 to 72 hours of opioid initiation or upward titration. Patients who require repeated dose escalations to achieve sufficient pain relief should be reevaluated for the cause, and the risk-to-harm benefit of LTOT should be reconsidered.11

Altering oral ER/LA opioids by cutting, chewing, or dissolving in liquids can release a potentially toxic dose of active ingredient.58 Transdermal systems and buccal films should not be cut, torn, or damaged before use.

Methadone for pain presents special clinical challenges due to a long and variable half-life, risk for toxicity due to accumulation in plasma concentrations during the longer time (several days) necessary to achieve steady-state, and risk for cardiac toxicities due to prolongation of the QTc interval.11,59,60 Methadone-related deaths have occurred in disproportionate numbers relative to the frequency with which it is prescribed for pain.13 Methadone is only for patients whose severe

pain is unrelieved by other opioids. Methadone administration requires close monitoring during initiation and dose changes, and caution in patients with heart disease or taking medications with concurrent QTc interval effects. If deemed necessary, methadone should be started at a very low dose (e.g., ≤15 mg/day in divided doses) and slowly titrated (e.g., by no more than 25%-50%, no more frequently than weekly.11,59 Bear in mind pain relief from a methadone dose lasts only 4 to 8 hours, but methadone remains in the body much longer (8 to 59 hours).60 Patients should be counseled never to exceed prescribed dose, and methadone doses are scheduled, not taken as needed. Practitioners without experience and knowledge of methadone should seek expert consultation before prescribing or avoid prescribing it altogether.59 Most opioids fall into Category C, indicating evidence of potential harm to the fetus from animal studies. Oxycodone is an exception, listed as a Category B medication with no evidence of harm to the fetus from animal studies.61 Codeine and tramadol should be avoided in breastfeeding women due to risks to the infant from ultra-rapid CYP2D6 metabolism in some women.13 In CYP2D6 ultra-rapid metabolizers, codeine changes to morphine and tramadol to M1 faster than in other people, which can result in high and unsafe levels of morphine and M1 in blood and breast milk.62

Considerations with opioids in special populationsWomen should be given information on the potential effects of LTOT for current or future pregnancies, including the risks of life-threatening neonatal opioid withdrawal syndrome (NOWS).13 Babies born to women who are taking opioids are at risk for birth defects (including neural tube defects, congenital heart defects, and gastroschisis), preterm delivery, poor fetal growth, and stillbirth.13

Table 3. Examples of Opioid-Use Disorder Risk Assessment ToolsTool # of items Administered Approximate Time to Complete

Initial Screen Prior to Initiating Opioid Therapy

Opioid Risk Tool (ORT)39 5 Patient 1 min

Revised Screener and Opioid Assessment for Pa-tients with Pain (SOAPP-R)38

24* Patient 5 min

Diagnosis, Intractability, Risk, Efficacy (DIRE)40 7 Clinician 2 min

Pain Medication Questionnaire (PMQ)43 26 Patient 10 min

For Use During Opioid Therapy

Current Opioid Misuse Measure (COMM)42 17 Patient 10 min

Patient Version Prescription Drug Use Questionnaire (PDUQp)44

31 Patient 20 min

Brief Initial Drug Screening Not Specific toPain Population

CAGE-AID (Adapted to Include Drugs)45 4 Clinician 1 min

*4- and 12-item SOAPP formats available

10

During pregnancy, HCPs and patients together should carefully weigh risks and benefits when making decisions about whether to initiate opioid therapy.13 When caring for pregnant women who are taking opioids, HCPs should arrange for delivery at a facility prepared to evaluate and treat NOWS.13 In pregnant women with OUD, the risk of opioid exposure from MAT should be discussed and balanced against the risk of untreated OUD, which might lead to illicit opioid use associated with outcomes such as low birth weight, preterm birth, or fetal death.63

Several states pain management guidelines recommend the following measures when treating women of child-bearing age: 64

• Every woman with reproductive capacity should discuss with the HCP a method to prevent unintended pregnancy when initiated on opioids

• Agreement should be obtained to inform the HCP if the woman becomes or intends to become pregnant while taking opioids

• Women who plan to become pregnant should be counseled on the risks of opioid exposure to the fetus and referred to an obstetrician

• The obstetrician and HCP should work together to encourage compliance with chronic pain management and prenatal care

• All newly pregnant women should have a urine drug test administered by the appropriate women’s health provider

• If a urine result is positive for unprescribed controlled substances or illicit drugs during a prenatal visit, the woman should have another upon admission for delivery to help identify the infant at risk for NOWS

Patients with renal and hepatic impairment need extra caution in initiation and titration of opioid doses and increased monitoring.13 In patients with renal compromise, accumulation resulting in toxicity has been observed in case studies; monitoring for opioid toxicity and use of nonopioids when possible are advised.65

Avoid LTOT in children and adolescents for most chronic pain problems.14 Accidental exposure to and ingestion of opioids can result in death.

Genetic and phenotypic variations influence how quickly or well individuals metabolize opioids and other drugs.66 Medical conditions, including kidney and liver disease, also cause variations in opioid metabolism.66 Pharmacogenetic testing is available to help guide clinical decision making. For example, the FDA has approved tests to determine whether a patient is a CYP2D6 ultra-rapid metabolizer.62

However, little data exist to inform the practice

of pain management, and these tests are not routinely performed.67 Testing may help HCPs make individual treatment decisions while keeping in mind genetics is only one of many factors affecting drug metabolism and responses.

Older adults (≥65 years) require cautious opioid dosing and management as they may have numerous co-occurring medical problems with treatments that increase the risk for polypharmacy and harmful drug interactions.11 Their risk for falls and cognitive effects with sedating medications and their sensitivity to analgesic effects are increased. In addition, prescription drug or other substance abuse may be difficult to spot, mimicking symptoms of common conditions such as dementia, diabetes, and depression. Initial doses should be 25–50% lower than in those who are younger.14

Cancer survivors should be evaluated for a recurrence or secondary malignancy with any new or worsening pain symptoms.14

Sleep disorders co-occur frequently with chronic pain. For patients with moderate or severe sleep-disordered breathing, avoid LTOT whenever possible.13 Some clinicians recommend that all patients who are considered for LTOT receive a sleep study prior to therapy or when higher dosages are considered.59

For patients who experience a nonfatal opioid overdose during pain management, it is recommended to work to reduce opioid dose and discontinue opioids whenever possible.13

Ensure that the patient is optimally treated for depression and other mental health disorders: Consider using tricyclic or SNRI antidepressants for combined analgesic and antidepressant effects.13

Absolute contraindications for LTOT include:12

• Known hypersensitivity to active ingredients or other components of opioid analgesics

• Significant respiratory depression or compromise

• Acute or severe bronchial asthma• Known or suspected paralytic ileus and

gastrointestinal obstruction • Evidence for or history of diversion

of controlled substances (e.g., forged prescriptions, pharmacy robberies, selling own prescription drugs, theft of others’ drugs)

The Department of Veterans Affairs/Department of Defense (VA/DoD) practice guideline lists concomitant use of benzodiazepines as a contraindication to initiating LTOT.12 Wisconsin guidelines strongly discourage prescribing

opioids in patients taking benzodiazepines or other respiratory depressants due to heightened risks for respiratory depression. If opioids and benzodiazepines are concurrently prescribed, a clear clinical rationale must exist.

Pharmacokinetics (PK) influence the bioavailability of a drug, the production and elimination of metabolites, and the activity of metabolic enzymes.66 Most opioids are metabolized through the liver microsomal cytochrome P-450 (CYP) system with CYP2D6 or CYP3A4 being responsible for much metabolism of opioids and many other drugs. Certain clinical applications are relevant. Slow metabolizers of CYP2D6 may gain little benefit from codeine, for example. Opioids metabolized through the CYP450 system, including codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone, may have heightened or reduced CYP450-associated effects with drug combinations, while morphine, oxymorphone, and hydromorphone are not as prone to such interactions.68

Drug interactions and other safety issuesThe risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid.66 Interactions with inhibitors or inducers of certain enzymes may produce clinically relevant effects.66

Potential drug–drug interactions raise great concern when prescribing opioids as follows:58

• CNS-depressants including alcohol, benzodiazepines, sedatives, hypnotics, tranquilizers, and tricyclic antidepressants can potentiate sedation and respiratory depression caused by opioids.

• Alcohol exposure can rapidly release or increase drug level of some ER opioid formulations

• Combining opioids with monoamine oxidase inhibitors (MAOIs) increase respiratory depression effect; may cause serotonin syndrome with certain opioids

• Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone

• Initiating CYP 3A4 inhibitors or discontinuing CYP 3A4 inducers can result in higher than expected opioid blood levels leading to overdose

To prescribe safely, one should also comprehend a drug’s effects within the body or pharmacodynamics, such as binding action to opioid and other receptors and the location of the binding action.66 Essentially, all opioid drugs have similar pharmacodynamic actions, although individual response may vary. Both PK and PD contribute to the onset and duration of various effects, such as analgesia, as well as the vulnerability to toxicity.

11

Daily dosage thresholds are now common and may be part of state law. Some states have limits ranging between ≥50 morphine milligram equivalents (MME)/day to ≥90 MME/day. The CDC recommends prescribing opioids only if nonopioids are ineffective, exercising caution at any dose, prescribing the lowest effective dose, reassessing risk vs. benefit at ≥50 morphine milligram equivalents (MME)/day, and avoiding increasing dosage to ≥90 MME/day or carefully considering and documenting rationale.13 It must be reemphasized that these recommended ceiling doses do not remove the necessity of exercising caution at any dose or the importance of individualizing the dose.

Medication errors may result from miscommunication, packaging design, confusion caused by similar drug names, and other sources.

Abuse-deterrent formulationsA number of abuse-deterrent formulations (ADFs) of opioid analgesics are available and numerous additional technologies are in development. The FDA defines abuse-deterrent (AD) properties as those that deter but do not prevent all abuse.35

These formulations generally incorporate physical barriers designed to deter crushing and chewing, chemical barriers to resist extraction of the opioid in common solvents for injection, or opioid antagonists to block euphoria when a pill is altered. If a product has AD properties, the risk of abuse is lower than it would be without these properties. However, because AD technologies aim to frustrate manipulation of the pill, the FDA cautions that abuse by swallowing intact capsules is not addressed.

An ADF may be useful for a person who needs an opioid to manage pain but is at high risk for abuse through routes of administration that include manipulation of the pill, such as chewing, crushing, snorting, or injecting. When prescribing these formulations, HCPs should counsel patients that an ADF may not prevent all forms of overuse and abuse, that addiction to an ADF is still a risk as with any other opioid, and that overdose by ingesting too many pills may still occur. Thus, ADF products still carry a boxed warning.

Data on AD properties are included in the Drug Abuse and Dependence section of the Prescribing Information under 9.2 Abuse and, if missing or located elsewhere, the FDA does not consider the product an ADF. The label contains information on the types of studies conducted and routes of abuse the ADF is expected to deter (e.g., oral, intranasal, insufflation, intravenous).

Common opioid side effects with suggested management strategies are listed in Table 4.11

Opioid RotationA patient who suffers inadequate analgesia or intolerable side effects from one opioid may benefit from rotation to a different opioid, because individual opioid response varies from one drug to another.66 Because mu-agonists produce varied effects, switching a patient to a different drug may allow for pain control at lower doses. Care must be taken in switching to a different opioid, because tolerance to a particular opioid drug does not translate to tolerance to another – a concept known as incomplete cross-tolerance. Patients should be monitored especially closely during any dose or formulation changes.

Equianalgesic dosing tables, conversion charts, and calculators allow for the conversion of any opioid dose to the standard value of morphine, referred to as morphine milligram equivalents (MME) or morphine equivalent doses (MED). Equianalgesic dose tables have limitations in that supporting studies were conducted on single doses in patients with limited opioid exposure and did not incorporate needs for chronic dosing.69 When using equianalgesic dosing tables as a starting point for opioid rotation, HCPs are advised to reduce the dose (≥25% to 50% is advised, more with methadone) when converting to the new opioid.11 A greater reduction is advised in patient who are older or medically frail. A 75% to 90% reduction70 or considering the patient opioid naïve is advised for rotating to methadone followed by careful monitoring.11 Conversions to transdermal routes of fentanyl and buprenorphine require special considerations: HCPs should closely follow instructions in the prescribing information.

Informed Consent and Treatment AgreementsPatients started on LTOT should be informed of the potential risks and benefits, which should be reassessed throughout therapy. Meta-analyses show limited evidence of weak benefit for pain with no high-quality trials lasting beyond 6 months. The most serious risk with any opioid is respiratory depression leading to death. Therefore, the risk/benefit ratio can be considered poor in comparison to other medical treatments. Patients who have never taken opioids or whose medications or doses will be changed should be counseled to expect short-lived or lasting sedation or other cognitive effects. In addition, it is recommended to include product-specific risks (such as dangers of chewing an ER formulation) in the informed consent document.

An informed consent form should be signed by the patient and retained in the medical record. Items recommended in informed consent include:11,12,71

• Potential risks and benefits of opioid therapy • Risks of OUD, overdose, and death even at

prescribed doses• That evidence for benefit of opioids for LTOT

in CNCP is limited• Nonpharmacological and nonopioid

therapeutic options for pain treatment• Potential side effects (both short and long

term) such as cognitive impairment and constipation

• The likelihood that tolerance and physical dependence will develop

• Risks of drug interactions and over-sedation • Risks of impaired motor skills affecting driving,

operating machinery, and other tasks • Serious adverse effects• Signs and symptoms of overdose• Risks when combining opioids with other CNS-

depressants, including benzodiazepines and alcohol

• The importance of disclosing all medications and supplements

• How to handle missed doses

Table 4. Common Opioid Side Effects and Suggested Management StrategiesSide Effect Management

Respiratory depression Screen for sleep apnea Avoid sedatives, benzodiazepines, barbiturates and alcohol

Constipation Increase fiber and fluids; start prophylactic laxative treatment, particularly in elderly

Nausea or vomiting Antiemetic therapy; symptoms tend to diminish

Hormonal deficiencies Screen symptomatic patients (fatigue, sexual dysfunction)

Sedation, mental clouding Counsel as to home, work and driving safety and concomitant CNS depressant risks; symptoms tend to diminish

Pruritis Treatments largely anecdotal (may include reducing dose, changing medication)

Hyperalgesia Reduce dose or change medication

12

Opioid treatment agreements (OTAs) that spell out patient and provider expectations and responsibilities are recommended by most opioid guidelines.11,14 Recommendations of what an OTA should contain include:71

• Treatment goals in terms of pain management, restoration of function, and safety

• Patient’s responsibility for safe medication use (not taking more than prescribed; dangers of using in combination with alcohol, cannabis, or other substances like benzodiazepines; not altering pills)

• Instructions for secure storage and safe disposal

• Patient’s responsibility to obtain prescribed opioids from only 1 clinician or practice

• Patient’s responsibility of getting the prescriptions filled at only 1 pharmacy

• Patient’s agreement to periodic drug testing • Prescribing policies, including handling of

early refills and replacement of lost or stolen medications

• Reasons for which drug therapy may be changed or discontinued, including violation of the treatment agreement

• Statement that treatment may be discontinued without agreement by the patient

• HCPs availability policy, including responsibility to make available a covering clinician to care for unforeseen problems and to prescribe scheduled refills

• Education of the patient that the complete elimination of pain should not be expected

Patients should be counseled never to share opioids with any other person. Leftover opioids in the household pose dangers to children and pets, who may ingest them accidentally, and are frequent sources for illicit use in teenagers and young adults. Opioids that are unsecured may be stolen by family members or visitors. Opioids should be stored in a locked area or safe that is not available or visible to family members or visitors.11 Leftover opioids, including transdermal fentanyl patches, should not be placed in the trash but should be taken to an authorized drug take-back facility or, if one is not available, flushed down the toilet or washed down the drain immediately.72 Call 1-800-882-9539 or visit the website (https://www.deadiversion.usdoj.gov/drug_disposal/index.html) of the Drug Enforcement Administration (DEA) for more information about drug disposal, National Prescription Drug Take-Back Day events, and local DEA-authorized collectors.

Naloxone AdministrationNaloxone can be used to save lives during overdose, and its presence increases safety for the patient and others who live in or visit the home.13 Take-home naloxone is recommended with the

presence of opioid overdose risk factors, such as history of overdose, history of SUD, clinical depression, opioid dosages ≥50 MME/day, or concurrent benzodiazepine use13 or with evidence of increased risk by other measures to include behaviors, family history, UDT or PDMP data, and questionnaire scores. Approved naloxone products have 3 delivery formulations. One is an injectable delivery system that requires professional training to administer. Two easily administered products are an auto-injection device that provides verbal instructions to the user once activated and a nasal spray that requires no assembly. The recommended dose is 0.4 mg for intramuscular or intranasal use with a second dose available if the first is ineffective or wears off before emergency help arrives. Patients given an automatic injection device or nasal spray should keep the item available at all times.31 Family members can also be prescribed naloxone for use with a patient. Naloxone administration can cause withdrawal symptoms, and people who have been administered naloxone should have follow-up medical care. Laws vary by state regarding immunity for physicians or laypeople administering naloxone and can be checked here: http://www.pdaps.org/datasets/laws-regulating-administration-of-naloxone-1501695139.

Signs of an opioid overdose include:59,73

• Small, constricted “pinpoint pupils” • Falling asleep or loss of consciousness • Slow, shallow breathing • Choking or gurgling sounds • Limp body • Pale, blue, or cold skin • Snoring heavily and cannot be awakened • Periods of ataxic (irregular) or other sleep-

disordered breathing • Trouble breathing • Dizziness, confusion or heart palpitations

Patients and their caregivers and other family members should be counseled to do the following if an opioid overdose is suspected:73

• Call 911 immediately • Administer naloxone if available • Try to keep the person awake and breathing• Lay the person on his or her side to prevent

choking• Stay with him or her until emergency workers

arrive

Examples of informed consent and agreement documents are available online from the New Hampshire Medical Society at https://www.nhms.org/content/examples-opioid-informed-consent-agreement. These may be combined into one document and adapted to the HCPs needs and preferences.

The FDA Patient Counseling Guide (Table 9) and product-specific Medication Guide should be given to patients, who, along with their caregivers, should be encouraged to read these materials. Prescribers may download a medication guide for patients at http://www.accessdata.fda.gov/scripts/cder/daf/ and the FDA Patient Counseling Guide at https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_Analgesic_2018_09_18_Patient_Counseling_Guide.pdf

Reporting adverse eventsAll suspected adverse events and reactions with opioids may be reported directly to the FDA’s MedWatch Reporting System by calling 1-800-FDA-1088 (1-800-332-1088); by going online at https://www.accessdata.fda.gov/scripts/medwatch/medwatch-online.htm; or by mail using the Form FDA 3500 available at http://www.fda.gov/downloads/AboutFDA/Repor tsManualsForms/Forms/UCM163919.pdf. Ongoing Management of Patients on Opioid Analgesics Patients on LTOT should be monitored regarding potential misuse and abuse as well as for therapeutic goals of pain relief and function. The CDC has issued a guideline stating that patients on opioid therapy should be reevaluated within 1-4 weeks of initiation or dosage change and every 3 months thereafter to ensure benefits outweigh risks.13 Other guidance has recommended using risk stratification to set clinic visit frequency and other monitoring measures as determined by patient risk category (low, moderate, or high risk) during initial screening and clinical follow-up.11 The clinical principle is that patients with more comorbidities or higher abuse risk require more stringent monitoring measures and more frequent follow-up than patients with less risk for harm.

HCPs should evaluate and document effects of LTOT on include analgesia, daily activities, adverse effects, aberrant drug-related behaviors, cognition, function, and quality of life. Tools available to assist with frequent reassessment and documentation include the Pain Assessment and Documentation Tool (PADT)74 and the COMM.42 Keep in mind patients may misuse opioids for various reasons that include misunderstanding of medical instructions, unauthorized self-medication of pain, mood, or sleep problems, wish to avoid withdrawal symptoms, desire for psychoactive reward such as euphoria, compulsive use due to OUD, and illegal diversion for financial gain.75

Ongoing periodic monitoring should incorporate checks of the PDMP and UDT.76 Pill counts may be conducted periodically for high-risk patients. The recommended frequency for periodic review of

13

PDMP data ranges from every prescription to every 3 months.13 A consensus-based recommendation for UDT frequency is to test every patient at least 1 time annually and higher-risk patients from 2 to 3 times annually.76 It is best to present UDT, PDMP data, and other monitoring measures to patients as a routine, consensual part of medical care using nonjudgmental language.

Results of a UDT are used to identify the presence of prescribed medications and the use of unauthorized prescription and illegal drugs. The UDT may also help guide clinical decisions, serving as alert to potential drug-drug interactions. The first step is generally immunoassay testing that can be done at the point of care (POC) and help quickly establish whether a new patient has recently ingested illegal drugs or other opioid and prescription drugs.76 The immunoassay detects certain drug classes but typically cannot isolate specific opioids.

If results of a POC test are inconsistent with medical direction, the next step is a quantitative evaluation, usually via gas chromatography/mass spectrometry (GC/MS) technology or liquid chromatography dual mass spectrometry (LC/MS/MS). These tests are more specific than immunoassay and can detect actual drugs and their metabolites. Some laboratories offer definitive testing via LC-MS/MS that may be given as the initial test; however, most guidelines still suggest immunoassay ahead of confirmatory testing due to cost concerns.76

Healthcare providers should exercise caution in interpreting UDT results, recognizing limitations and taking care not to stigmatize patients but to base interpretation on objective results.1

Limitations of UDT include:76

• Cross-reactivity with other drugs or substances• Potential for false positives (e.g., poppy seeds

positive for opiates)• Potential for false negatives• Variable drug metabolism• Laboratory error

Unexpected results, such as the absence of prescribed medications that could indicate diversion, should be discussed with the patient and documented in the record along with plans to address the results.

In the presence of ongoing or severe ADRBs, HCPs should consider that patient suffering may be linked to OUD or other SUD or psychiatric disorders. HCPs should be prepared to offer MAT or refer patients for treatment; discharging a patient solely due to an OUD is not considered acceptable. Criteria of an OUD may be reviewed in Table 2.

Signs and symptoms seen in a clinical scenario include:37

• Taking opioids compulsively and long term for no legitimate medical purpose

• If pain is present, taking opioids in excess of prescription

• Obtaining opioids from unauthorized sources• Falsifying or exaggerating medical problems to

receive opioids• Significant tolerance and physical dependence

(also occurs in non-SUD patients)• Conditioned responses of craving that persist

after cessation

Other circumstances that may accompany OUD include:37

• History of drug-related crimes• History of legal problems• Marital problems, including divorce• Unemployment and irregular employment

When an active SUD or a recent SUD history is present, HCPs should strongly consider referral to SUD specialists and pain specialists regarding pain management and/or tapering opioids and managing pain with nonopioid therapies.13

Before moving on to the next section, please spend the allotted time on Exercise 3.

Luke, 23, presents near clinic closing time and requests 2 prescriptions for ongoing left knee pain, an ER and IR oxycodone formulation. He had 2 surgeries more than 1 year ago. Physical exam shows surgical scars, no swelling, and limited range of motion on flexion. He says he is allergic to NSAIDs and codeine makes him vomit. He has participated in physical therapy but says it made his knee worse. He describes his pain as stabbing and near constant VAS 9/10. He resists UDT screening, claiming it invades his privacy. Initial urine immunoassay is positive for THC and cocaine. A check of the PDMP reveals he has obtained 28 prescriptions for opioids (IR oxycodone/ACET, ER oxycodone) from 4 different providers and 5 pharmacies. Luke, 23, presents near clinic closing time and requests 2 prescriptions for ongoing left knee pain, an ER and IR oxycodone formulation. He had 2 surgeries more than 1 year ago. Physical exam shows surgical scars, no swelling, and limited range of motion on flexion. He says he is allergic to NSAIDs and codeine makes him vomit. He has participated in physical therapy but says it made his knee worse. He describes his pain as stabbing and near constant VAS 9/10. He resists UDT screening, claiming it invades his privacy. Initial urine immunoassay is positive for THC and cocaine. A check of the PDMP reveals he has obtained 28 prescriptions for opioids (IR oxycodone/ACET, ER oxycodone) from 4 different providers and 5 pharmacies.

EXERCISE 3How do you handle prescribing for this patient?

A. Write ER opioid prescription to last through weekend, refer back to earlier provider

B. Write 30-day ER and IR opioid prescription, order diagnostic tests on injury

C. Do not write opioid prescription today; send UDT for further laboratory testing; refer for addiction specialist evaluation

The best choice would be C.

Instructions: Take 5 minutes to read the case below and answer the question as it relates to the case presented.

Notes:

14

Discontinuing OpioidsReasons to discontinue opioid therapy may include failure to achieve sufficient analgesia, intolerable side effects, resolution of pain, development of OUD, or repeated or egregious ADRBs.

Serious nonadherence to the treatment plan and written agreement or other unsafe ADRBs include:11

• Repeatedly increasing dose without HCP knowledge

• Sharing medications• Unapproved opioid use • Use of illicit drugs• Obtaining opioids from unauthorized sources• Prescription forgery• Multiple episodes of losing prescriptions• Polysubstance abuse

Before initiating opioid therapy, HCPs should have an exit strategy in place to humanely taper opioids and treat pain or refer for treatment with alternatives to opioid therapy. In an outpatient setting, taper should be done to avoid opioid withdrawal in physically dependent patients. Approaches range from a slow 10% dose reduction per week to a more rapid 25% to 50% reduction every few days (until 5-10 mg is reached at which time the opioid can be stopped).11 It may be medically risky to abruptly discontinue opioids in a physically dependent patient. Taper may be accomplished in a rehabilitation setting if the patient is unable to reduce opioid dose.

Patients with no evidence of aberrant behavior who have a history of LTOT may be continued on treatment if an adequate clinical indication is present, although such long-term treatment is not preferred.

Consider the expert-consensus guidelines below:12,59

• Evaluate comorbidities, the patient’s psychological condition, and other relevant factors before beginning the taper

• Educate the patient and family about the taper protocol

• When safety allows, consider a 5% to 20% reduction every 4 weeks. Individualize this schedule based on patient needs and symptoms. Some patients may tolerate a faster taper, while others may need to slower the dose adjustments to monthly rather than weekly

• Managing opioid abstinence syndrome if symptoms (e.g., nausea, diarrhea, muscle pain, myoclonus) occur, using nonopioid analgesics and adjuvant agents: clonidine 0.2 mg po bid or tizanidine 2 mg po tid

• HCPs can consider weekly or bimonthly follow-up during opioid taper

• Referral for counseling or other support during the taper if there are significant behavioral issues

• For complicated withdrawal symptoms, refer the patient to a pain specialist or chemical dependency center

Referral should include, as indicated, treatment of OUD, which may include MAT, or management of psychiatric illnesses.31

Diversion of opioids or other controlled substances is a contraindication for continuing opioid therapy.12

If evidence emerges that patients are at imminent risk of danger from overdose death or addiction, opioids should be discontinued and patients treated for withdrawal if necessary; exceptions include patients with unstable angina, who might be harmed, and pregnant patients, particularly during the third trimester, who might be pushed into labor by sudden discontinuance. These patients should be tapered in a gradual manner with close follow-up

Documenting in the Patient Record It is essential to diligently document in the patient record all treatment decisions, patient counseling sessions, and risk management measures when treating patients with opioids (Table 5). Good documentation facilitates clinical decisions and ensures timely attention to medical issues.

It is also necessary for compliance with federal and state regulations that govern the prescribing of controlled substances and to practice in concert with best practices outlined by medical boards and specialty guidelines for pain treatment. When federal and state law conflict, the more restrictive law applies. The Prescription Drug Abuse Policy System (PDAPS), funded by the National Institute on Drug Abuse, tracks key state laws related to prescription drug abuse here: http://www.pdaps.org/.

Table 5. Items to Document in the Patient Record11,71

Informed consent

Opioid treatment agreement(s)

Medical history

Results of physical exam, diagnostic, and imaging tests

Pain intensity and level of functioning

Results of risk assessment, screening tools

Rationale for opioid therapy and previous treatments

Description of all treatments provided (date, type, dose, quantity)

Prescription of naloxone provided and rationale

All prescription orders for opioids and other controlled substances

Instructions to patient, including addressing nonadherence and ongoing discussions of risks vs. benefits

Assessments of progress toward achieving therapeutic goals

Notes on consultations with specialists

Presence of adverse events

Adherence to prescribed therapies, including results of UDT and PDMP checks

Notes on continuing, revising, or terminating treatment

Authorization for release of information to other treatment providers• UDT = urine drug testing• PDMP = prescription drug-monitoring programs

15

Each practitioner must keep current with applicable state regulations, which are evolving rapidly and contain restrictions and directives such as:77

• Expanded PDMPs and new requirements for their use

• Required pain management or prescribing education

• Required written pain treatment agreements• Requirements for a physical exam prior to

prescribing• Requirements for a bona fide patient-physician

relationship• Presentation of patient identification to a

pharmacist prior to receiving opioids• Medicaid plans requiring single prescriber and

single pharmacy for certain high-risk patients

HCPs should be aware that it is permissible under the Health Insurance Portability and Accountability Act of 1996 to share health information with a patient’s family or other loved ones in an emergency, when a patient is incapacitated or unconscious, or where a serious and imminent threat to a patient’s health or safety exists.82 Such a circumstance would include a current overdose or evidence of continued dangerous use of opioids following discharge after an opioid overdose.

A Primer on Addiction MedicineAddiction, while not a DSM-5 diagnosis, is still a commonly used term that generally refers to severe OUD.78 As a primary, chronic, neurobiologic disease whose development and manifestations are influenced by genetic, psychosocial, and environmental factors, a severe OUD is characterized by impaired control over drug use, compulsive use, continued use despite harm, and craving.1 Understanding the fundamentals of addiction medicine can help HCPs identify and manage patients with severe OUD without the use of stigmatizing language but with the recognition of severe OUD as a disease state.

All reinforcing drugs exert effects as a result of dopamine stimulation in the mesolimbic system of the brain.79 When a drug stimulates the brain’s mu opioid receptors, cells in the ventral tegmental area release dopamine into the nucleus accumbens, causing pleasurable feelings.79 The PK and lipophilicity of the drug and its route of administration influence the speed and amount of dopamine released and thus the degree of reward experienced by the user. Intravenous and inhalational use speeds onset more than oral ingestion. However, ER/LA opioids can be altered by the user to produce a rapid onset of action by crushing, chewing, or dissolving in liquids, for example.58

As the stimulation of the brain’s reward system leads to repeated ingestion, other areas of the brain create conditioned associations or lasting memories that associate reward with environmental cues of drug use. Normally, feedback from the prefrontal cortex helps most individuals to overcome drives to obtain pleasure through unsafe actions.79 However, this feedback becomes compromised in individuals who become addicted to drugs. As the person develops tolerance and dependence (susceptibility to withdrawal symptoms), more drug is necessary to obtain the same reward. The locus coeruleus area of the brain plays an important role in the production or suppression of withdrawal symptoms. When an OUD is present, the compulsion to use opioids repeatedly goes beyond the reward drive. This further use promotes long-lasting changes in the brain that disallow the individual to experience pleasure and that underlie the compulsive drug use despite adverse consequences that characterizes OUD.79

Opioids and Concurrent CannabisRelief from pain is the most common condition patients cite for the medical use of cannabis.80 The scientific literature on the therapeutic use of cannabis is growing, and public sentiment is shifting to accommodate the potential for benefit in pain therapy and other areas.80 Medical cannabis laws are associated with reductions in opioid analgesic overdose mortality on a population level, but cause and effect is not proven.81 However, synthesis of the data has been incomplete to guide clinical choices, and the short- and long-term health and safety effects have remained elusive. There are some data suggesting those who take medical marijuana are similar demographically to those who use marijuana recreationally.82

In 2016, a committee appointed by the Health and Medicine Division of the National Academies of Sciences, Engineering, and Medicine comprehensively reviewed evidence of harms and benefits with the goal of recommending research directions and identifying areas of therapeutic benefit.80

The committee reported that there is:

• Conclusive or substantial evidence that cannabis is effective for the treatment of chronic pain in adults

• Moderate evidence that cannabinoids (primarily nabiximols) are effective for improving short-term sleep outcomes in individuals with sleep disturbance associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, and multiple sclerosis

• Limited evidence that cannabinoids (nabiximols, dronabinol, and nabilone) are ineffective for reducing depressive symptoms in individuals with chronic pain

In adults with chronic pain, those treated with cannabis or cannabinoids were more likely to experience a clinically significant reduction in pain symptoms.80 A number of patients with pain appear to be replacing opioids with cannabis; however, it is important to note that the FDA has not approved cannabis for the treatment of chronic pain.80 In addition, little is known about the efficacy, dose, routes of administration, or side effects of available cannabis products.

A systematic review and meta-analysis of double-blind randomized controlled trials comparing cannabis preparations to placebo in patients with chronic pain found that cannabis reduced pain intensity compared to placebo, with an overall effect size of -0.61 (-0.84 to -0.37).83 The identified harms included euphoria, dysphoria, disturbances in perception and motor function, altered cognitive function, and gastrointestinal side effects. The studies have several limitations that include short follow-up periods, small sample sizes, and inconsistent and incomplete reporting methods.

Some patients who are taking opioids for pain are also using cannabis concurrently. A prospective cohort study of patients with musculoskeletal pain who are also on a stable dose of opioids was conducted to compare those who endorsed past-month cannabis for pain to those who denied any cannabis or illicit drug use.84 Of 17% who endorsed past-month cannabis use for pain, 31% had a current medical marijuana card, and 66% reported that marijuana was helpful for reducing pain. Those who used cannabis for pain had higher rates of nicotine use, risk for prescription opioid misuse, and hazardous opioid use. No difference between groups were found in opioid dose, pain intensity, pain interference, or depression severity.

Because some patients who are taking opioids will elect to use cannabis, HCPs should be aware of certain clinical recommendations:85

• Keep current with relevant federal, state, and institutional policies and laws

• Establish goals of care for cannabis use • Screen for signs of misuse, cannabis use

disorder (CUD), and diversion• Counsel patients on harms and risks on

the basis of symptoms, condition, and comorbidities

• Advise on routes of administration using current evidence base

• Continually monitor similarly to opioids (informed consent, written agreement, regular follow-up, functional status, considering periodic urine testing, symptom severity, and use of other medications or substances)

• Monitor for other harms, including car accidents and falls

• Advise on discontinuation or referral to CUD treatment if pain relief and function goals are not being met without harm

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The most common route of administration is smoking, despite risks of pulmonary effects. Some evidence suggests vaporization may be safer in this regard, although other research notes similar exposure as smoking to carbon monoxide and other respiratory toxins.85 Other delivery options including edibles and extracts. Patients may develop CUD and be unable to stop use on their own even though it is interfering with their health and function. Signs of CUD include:84

• Using a larger quantity or over a longer duration than intended

• Unsuccessful attempts to limit or quit • Significant amounts of time spent obtaining

cannabis • Cravings • School or occupational impairment • Social or interpersonal impairment • Reduction of social, occupational, or

recreational activities • Recurrent use in physically harmful situations • Continued use despite recurrent physical or

psychological harms • Tolerance • Withdrawal

Although not specific to pain therapy, useful measures to screen for CUD include:

• Single question: How often in the past year did you use marijuana (never, less than monthly, monthly, weekly, daily or almost daily)84

• The 8-item Cannabis Use Disorders Identification Test-Revised (CUDIT-R)86

• Comprehensive Marijuana Motives Measure87

Use of Short-Acting OpioidsThe FDA has sent letters to 74 manufacturers of IR opioids notifying them that they must make REMS-compliant training available to prescribing clinicians.89 Once finalized, the action is expected to cover 277 IR opioid analgesics.

The most recent VA/DoD practice guideline recommends against initiating opioid therapy with ER/LA agents and describes additional areas of dosage and clinical considerations for short-acting opioids (i.e.., IR opioids) shown in Table 6.12 No strong evidence supports the choice of one opioid agent over another for LTOT.12 Wisconsin guidelines discourage use of oxycodone as a first-line choice and suggest that its prescription be reserved for patients who cannot tolerate other opioids and who are not at increased risk for misusing opioids. These guidelines are not intended to define a standard of care and should not be construed as one. Neither should they be interpreted as prescribing and exclusive course

of management. These guidelines are designed to provide information and assist decision making.12

In these guidelines are tables for short-acting opioids that have been incorporated into Exercise 4 (Pg. 17). PLEASE SPEND THE ALLOTED TIME COMPLETING THIS EXERCISE.

General Drug Information for the Class of ER/LA OpioidsThe class of ER/LA opioids has some commonalities that limit their usage:58,88

• Not for use as needed• Not for mild pain or pain that is not expected

to persist for an extended duration• Not for use to treat acute pain• Not for use in opioid-naïve patients: tolerance

is critical to safe use (see individual product PI for criteria for strengths, daily doses, special populations, and product-specific safety concerns)

Exercise 5 (Pg. 22) covers general and specific information for ER/LA Opioid Analgesics, including Table 7 and Table 8. PLEASE SPEND THE ALLOTTED TIME COMPLETING THIS EXERCISE.

For detailed information, prescribers can refer to prescribing information available online via DailyMed at www.dailymed.nlm.nih.gov or Drugs@FDA at www.fda.gov/drugsatfda.

SummaryPrescription opioid abuse and overdose is a national crisis, and HCPs who treat pain are called upon to play a role in prevention. Risk mitigation and best practice strategies include understanding how to assess patients for treatment and how to initiate, modify, and discontinue doses of SA and ER/LA opioids. Familiarity with monitoring practices that include periodic UDT and check of PDMP data is also necessary. Patients should also receive instruction on proper storage and disposal of opioid analgesics and (when indicated) how to administer naloxone to reverse opioid-related overdose. The goal is to ensure that opioids are used in the clinical context of a comprehensive pain treatment plan that benefits patients without contributing to opioid-related harm in the patient or society.

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3. Name the maximum daily dose of acetaminophen in healthy patients and in patients with alcoholism or hepatic impairment.

1. Name 3 drugs that act as CYP-2D6 inhibitors and describe their effects on opioid metabolism.

2. Name a contraindication for the use of oxymorphone.

4. Describe seizure concerns with use of tramadol.

5. Describe the initial dose of an oxycodone-combination product for an opioid-naïve patient.

EXERCISE 4

USE OF SHORT-ACTING, ORALLY-ADMINISTERED OPIOIDS IN ADULTS

Instructions: Spend 20-25 minutes completing the following

1. Conduct a detailed review of Table 6, which includes Drug Information for Short Acting, Orally Administered Opioids, in Adults.

2. Complete the learning questions below related to Short Acting, Orally Administered Opioids, in Adults only after completing step 1.

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Table 6. Use of Short-Acting, Orally-Administered Opioids in Adults12

Short-Acting Opioids1 Initial Oral Dosage (in opioid-naïve)

Additional Dosage Information

Analgesic Onset (min) Peak

(min) Duration (hr)

Dosing In Special Populations

Other Considerations

Codeine (alone or in combination with APAP or ASA) • Codeine available

as 15, 30 and 60 mg tablets

• Combination products vary in codeine content from 15 to 60 mg/dose unit

• 15 to 30mg every 4 to 6 hr

• Initial dose based upon codeine component, maximum dose based upon non- opioid component

• Maximum APAP dose: 4000 mg/d (2000 mg/d in chronic alcoholics or in hepatic impairment)

• Analgesic ceiling effect occurs with codeine at doses>60 mg/dose

• Codeine alone is a weak analgesic; more effective alternatives are available (including codeine in combination with APAP or ASA)

15 to 30 30 to 60 4 to 6

• Elderly or debilitated: Use with caution

• Hepatic dysfunction: Conversion to active metabolite (morphine) may be reduced in patients with cirrhosis; avoid use in patients with liver disease

• Renal dysfunction: Use lower dosage or an alternative analgesic

• Codeine may be less effective in patients with decreased CYP- 2D6 activity (due to poor CYP- 2D6 metabolism or CYP-2D6 inhibiting drugs2) because of decreased conversion to the active metabolite, morphine

• CYP-2D6 ultra-rapid metabolizers3 can have extensive conversion to morphine with increase in opioid-mediated effects

Hydrocodone (in combination with APAP, ASA, or IBU)• Combination

products vary in hydrocodone content (2.5 to 10 mg per dosage unit)

• 5 to10mg every 6 hr (hydrocodone component)

• Initial dose based upon hydrocodone component

• Maximum dose based upon non-opioid component

• Maximum dose: • 60 mg/d (4000

mg/d APAP; 2000 mg/d APAP in chronic alcoholics or hepatic impairment) for hydrocodone + APAP combination OR

• 37.5 to 50 mg/d (1000 mg/d IBU) for hydrocodone + IBU combination

10 to 20 60 to 100 4 to 8

• Elderly or debilitated: Use with caution; start with reduced dose (2.5-5 mg) of hydrocodone component

• Hepatic dysfunction: Use with caution

• Conversion to the active metabolite, hydromorphone, may be decreased in patients with decreased CYP-2D6 activity (due to poor CYP-2D6 metabolism or CYP-2D6 inhibiting drugs2)

• CYP-2D6 ultra-rapid metabolizers3 can have extensive conversion to hydromorphone with potential increase in opioid-mediated effects

Hydromorphone Available as oral liquid 1 mg/ml, and 2, 4, and 8 mg tablets

• 2mg every 4to 6 hr • May give an initial dose

of 4 to 8 mg for severe pain

There is no optimal or maximum dose of hydromorphone; patients on LOT are likely to become tolerant4 and require doses higher than the usual dosage range to maintain the desired effect

15 to 30 30 to 60 3 to 4

• Elderly or debilitated: Use with caution, start at 25% to 50% of usual dose at low end of dosing range

• Hepatic / Renal dysfunction: Reduce initial dose for moderate impairment, more with severe impairment

19

Table 6. Use of Short-Acting, Orally-Administered Opioids in Adults12 (Continued)Short-Acting

Opioids1

Initial Oral Dosage (in opioid-naïve)

Additional Dosage Information

Analgesic Onset (min) Peak

(min) Duration (hr)

Dosing In Special Populations

Other Considerations

Morphine • Available as

oral solution (10 or 20 mg/5 ml, or 100 mg/5 ml for opioid- tolerant patients only) or as 15 or 30 mg tablets

10 to 30mg every 4 hr There is no optimal or maximum dose of morphine; patients on LOT are likely to become tolerant4 and require doses higher than the usual dosage range to maintain the desired effect

30 603 to 5

• Elderly or debilitated: Give with extreme caution; use lower dose

• Hepatic dysfunction: Use carefully in patients with cirrhosis and consider reducing dose or extending dosing interval by 1.5 to 2 times; half-life may be doubled (3 to 4 hr) and bioavailability is increased

• Renal dysfunction: Reduce dose or, if severe renal impairment exists, avoid use (see Other Considerations)

• M6G, an active metabolite, may accumulate in renal impairment

• M3G, a metabolite without analgesic activity, may accumulate in renal impairment; this metabolite has been implicated in morphine-induced neurotoxicity, hyperalgesia, and allodynia

Oxycodone (alone or in combination with APAP or ASA)• Single-agent

oxycodone available as oral solution 5 mg/5 ml, 20 mg/1 ml, and oral tablet 5, 10, 15, 20, and 30 mg

• Combination products vary in oxycodone content, 2.5 to 10 mg per dose unit

• 5 to15mg every 4 to 6 hr

• Initial dose based upon oxycodone component

• Maximum dose based upon non-opioid component

• For combination products, maximum dose is limited by APAP or ASA content (4000 mg/d for both; 2000 mg/d APAP in chronic alcoholics or patients with hepatic impairment)

• There is no optimal or maximum dose of oxycodone; patients on LOT are likely to become tolerant4 and require doses higher than the usual dosage range to maintain the desired effect

10 to 15 30 to 60 3 to 6

• Elderly or debilitated: reduce dosage

• Hepatic / Renal: Use with caution; consider reducing dose and increasing frequency of dosing

• Conversion to the active metabolite, oxymorphone, may be decreased in patients with decreased CYP-2D6 activity (due to poor CYP-2D6 metabolism or CYP-2D6 inhibiting drugs2)

20

Table 6. Use of Short-Acting, Orally-Administered Opioids in Adults12 (Continued)Short-Acting

Opioids1

Initial Oral Dosage (in opioid-naïve)

Additional Dosage Information

Analgesic Onset (min) Peak (min)

Duration (hr)

Dosing In Special Populations

Other Considerations

Oxymorphone• Available as

5 or 10 mg tablets

5mg every 4 to 6 hr • There is no optimal or maximum dose of oxymorphone; patients on LOT are likely to become tolerant4 and require doses higher than the usual dosage range to maintain the desired effect

30 to 45 N/A4

• Elderly or debilitated: Use with caution and start at low end of dosing range; levels are increased 40% in patients ≥65 years

• Hepatic dysfunction:• Mild hepatic

impairment: Use cautiously, start at low end of dosing range

• Moderate and severe hepatic impairment: Contraindicated

• Renal dysfunction: Bioavailability is increased 57-65% in moderate and severe impairment; start at lower doses and adjust slowly

• Food has been shown to increase peak levels of oxymorphone immediate-release by 38%; must be taken on an empty stomach at least 1 hr before or 2 hr after a meal

• Must NOT be taken concomitantly with alcohol; alcohol (240 ml of 4% to 40% ethanol) can cause highly variable effects on peak drug levels, ranging from a decrease of 50% to an increase of 270% (demonstrated with ER oxymorphone)

Tapentadol• Available

as 50, 75, or 100 mg tablets

50 mg every 4 to 6 hr • Subsequent dose is 50, 75, or 100 mg every 4 to 6 hr, adjusted to analgesia and tolerability

• Second dose may be given 1 hr after the first dose if necessary

• Max recommended dose: 700 mg on first day, 600 mg on subsequent days

• Use tapentadol only under careful medical supervision at lowest effective dose

• Patients on LOT are likely to become tolerant4 and require doses higher than the usual dosage range to maintain the desired effect

N/A (rapid) 604 to 6

• Elderly: Consider starting at the lowest recommended dose

• Hepatic dysfunction:• Mild hepatic

impairment: No dosage adjustment

• Moderate hepatic impairment: Start at 50 mg and give subsequent doses at least 8 hr apart (max. 3 doses in 24 hr)

• Severe hepatic impairment: Use is not recommended

• Renal dysfunction: No dosage adjustment for mild or moderate renal impairment; not recommended in severe renal impairment

• Respiratory dysfunction: Use with caution because of respiratory depressant effects; consider non–mu opioid agonist analgesics

• Must NOT be taken concomitantly with alcohol which can increase serum tapentadol concentration

• If used in combination with other CNS depressants, consider dose reduction of one or both agents

• Use with or within 14 days of MAOIs is contraindicated

21

Table 6. Use of Short-Acting, Orally-Administered Opioids in Adults12 (Continued)Short-Acting

Opioids1

Initial Oral Dosage (in opioid-naïve)

Additional Dosage Information

Analgesic Onset (min) Peak (min)

Duration (hr)

Dosing In Special Populations

Other Considerations

Tramadol (alone or in combination with APAP)• Tramadol

available as 50 mg tablet, or in tablet combination with APAP (325 mg APAP, 37.5 mg tramadol)

25 mg every morning • May increase by 25 mg per day every 3 days to 100 mg tramadol/d (25 mg every 6 hr)

• Subsequent increments of 50 mg/d may then be made every 3 days to 200 mg/d (50 mg every 6 hr)

• After titration, may give 50 to 100 mg every 4 to 6 hr

• Maximum daily dose of tramadol: 400 mg/d

• Combination product: maximum 4000 mg/d APAP; 2000 mg/d APAP in chronic alcoholics or in hepatic impairment

<60~120 to 240 6

• Elderly or debilitated: In elderly patients >75 years: give <300 mg/d in divided dose; use with caution in patients

• Hepatic dysfunction: Decrease dosage to 50 mg once every 12 hr in patients with cirrhosis

• Renal dysfunction:• CrCl >30 ml/

min: No change in dose or frequency required

• CrCl <30 ml/min: Increase dosing interval to 12 hr and decrease maximum daily dose to 200 mg

• Dialysis patients: Can receive their regular dose on the day of dialysis (<7% of a dose is removed by hemodialysis)

• Slower initiation and titration improves tolerability

• Inhibits reuptake of serotonin and norepinephrine; concomitant use with MAOIs or SSRIs may increase risk of seizures, serotonin syndrome

• Dose carefully or use another agent in patients on serotonergic agents

• Seizures reported within the recommended dosage range; increased risk above recommended dosage range and in patient with seizure disorder, history of seizures, in conditions with increased risk of seizures, or with other drugs that increase seizure risk; observe maximum dose limits

• Serious anaphylactoid reactions reported, often following first dose; patients with a history of anaphylactoid reaction to codeine and other opioids may be at increased risk

Source: VA/DoD practice guideline for Management of Opioid Therapy (OT) for Chronic Pain ( February 2017) https://www.healthquality.va.gov/guidelines/Pain/cot/VADoDOTCPG022717.pdf. Last accessed June,2018.

1 Check local formulary for available formulations.2 CYP-2D6 Inhibiting Drugs: Antiarrhythmics (amiodarone, propafenone, quinidine [strong inhibitor]); analgesics (methadone [weak inhibitor], propoxyphene);antihistamines (diphenhydramine, chlorpheniramine [in vitro], brompheniramine [in vitro], triprolidine [in vitro]); histamine2 receptor antagonists (cimetidine); neuroleptics (chlorpromazine, haloperidol, methotrimeprazine, perphenazine, thioridazine); protease inhibitors (ritonavir), quinine compounds (hydroxychloroquine, quinacrine, quinine); selective serotonin reuptake inhibitors (fluoxetine, fluvoxamine, paroxetine, sertraline), miscellaneous compounds (clomipramine, ketoconazole, ticlopidine)3 CYP-2D6 ultra-rapid metabolizers include 1% of Asian and Hispanic, 1-10% of Caucasians, 3% of African-Americans, and 16-28% of N. African and Arabic populations.4Opioid tolerance is assumed in patients already taking fentanyl 25 mcg/hr OR daily doses of the following oral agents for ≥ 1 week: ≥ 60 mg oral morphine, 30 mg oxycodone, 8 mg hydromorphone, 25 mg of oxymorphone or equianalgesic dose of another opioid.

APAP = acetaminophenASA = acetylsalicylic acidCNS = central nervous systemCrCl = creatinine clearanced = day(s)ER = extended-releasehr = hour(s)IBU = ibuprofenLTOT = long-term opioid therapyM3G = morphine-3-glucuronideM6G = morphine-6-glucuronideMAOIs = monoamine oxidase inhibitorsmg = milligram(s)min = minute(s)mL = milliliter(s)SSRIs = selective serotonin reuptake inhibitors

22

EXERCISE 5

COMMON & SPECIFIC DRUG INFORMATION FOR ER/LA OPIOID ANALGESIC PRODUCTS

Instructions: Spend 20-25 minutes completing the following

1. Read and review Table 7, which includes information regarding general characteristics, toxicities and drug interaction for Extended-Release and Long-Acting Opioid Analgesics.

2. Conduct a detailed review of Table 8, which includes information regarding Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics.

3. Complete the learning questions below only after completing steps 1 and 2.

2. Name three classes of drugs that should be avoided by patients who have been prescribed an ER/LA opioid analgesic. Describe the underlying reasoning for avoiding concurrent use of the drugs.

1. Are ER/LA opioids recommended for treating acute pain? Why or Why Not?

4. Describe disposal methods for used or unused fentanyl transdermal patches.

3. Name 3 safety measures to take during the application of the buprenorphine transdermal system.

23

Table 7. Drug Information Common to the class of ER/LA Opioid Analgesic Products

A. ER/LA opioid analgesic products are scheduled under the Controlled Substances Act and can be misused and abused.

B. Respiratory depression is the most important serious adverse effect of opioids as it can be immediately life-threatening.

C. Constipation is the most common long-term side effect and should be anticipated.

D. Drug-drug interaction profiles vary among the products. Knowledge of particular opioid-drug interactions, and the underlying

pharmacokinetic and pharmacodynamic mechanisms, allows for the safer administration of opioid analgesics.

i. Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants, including alcohol, may

result in profound sedation, respiratory depression, coma, and death. Reserve concomitant prescribing for use in patients for

whom alternative treatment options are inadequate; limit dosages and durations to the minimum required; and follow patients

for signs and symptoms of respiratory depression and sedation.

ii. Some ER opioid formulations may rapidly release opioid (dose dump) when exposed to alcohol. Some drug levels may increase

without dose dumping when exposed to alcohol. See individual product labeling.

iii. MAOI interactions with opioids may manifest as serotonin syndrome or opioid toxicity(e.g., respiratory depression, coma).

Certain ER/LA opioids are contraindicated with MAOIs (tapentadol, morphine). See individual product labeling.

iv. Opioids can reduce the efficacy of diuretics by inducing the release of antidiuretic hormone (ADH).

v. Some opioids (methadone, buprenorphine) can prolong the QTc interval.

vi. Concomitant drugs that act as inhibitors or inducers of various cytochrome P450 enzymes can result in higher or lower than

expected blood levels of some opioids.

vii. See Table 8 for product-specific information.

E. Tolerance to sedating and respiratory-depressant effects of opioids is critical to the safe use of ER/LA opioid analgesics.

i. For ER products, patients must meet the criteria for opioid tolerance before using:

a. certain products,

b. certain strengths,

c. certain daily doses, and

d. in specific indicated patient populations (e.g., pediatric patients).

ii. See the (Table 8) for product-specific information.

F. ER/LA opioid analgesic tablets must be swallowed whole. ER/LA opioid analgesic capsules should be swallowed intact or when

necessary, the pellets from some capsules can be sprinkled on applesauce and swallowed without chewing.

G. For transdermal products, external heat, fever, and exertion can increase absorption of the opioid, leading to fatal overdose.

Transdermal products with metal foil backings are not safe for use in MRIs.

H. For buccal film products, the film should not be applied if it is cut, damaged, or changed in any way. Use the entire film.

I. Follow the instructions for conversion in the Dosage and Administration section (2.1) in the Prescribing Information of each product

when converting patients from one opioid to another.

Prescribers should be knowledgeable about general characteristics, toxicities, and drug interactions for ER/LA opioid analgesic products.

2427

Arymo ER Morphine SulfateExtended-Release Tablets, 15 mg, 30 mg, 60 mg

Dosing Interval Every 8 or 12 hours

Key Instructions • Initial dose in opioid-naïve and opioid non-tolerant patients is15mg every8 or 12 hours

• Dosage adjustment may be done every 1 to 2 days.• Take one tablet at a time, with enough water to ensure complete swal-

lowing immediately after placing in the mouth.

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) can increase the exposure of morphine byabout two-fold and increase risk of respiratory depression

Use in Opioid-Tolerant Patients A single dose of ARYMO ER greater than 60 mg, or total daily dose greater than 120 mg, is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns • Do not attempt to chew, crush, or dissolve. Swallow whole.• Use with caution in patients who have difficulty in swallowing or have

underlying GI disorders that may predispose them to obstruction, suchas a small gastrointestinal lumen.

Avinza Morphine Sulfate ERCapsules, 30 mg, 45 mg, 60 mg, 75 mg, 90 mg, and 120 mg

Dosing Interval Once a day

Key Instructions • Initial dose in opioid non-tolerant patients is 30 mg.• Titrate in increments of not greater than 30 mg using a minimum of 3

to 4 day intervals.• Swallow capsule whole (do not chew, crush, or \dissolve).• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing; use immediately.• Maximum daily dose:1600 mg due to risk of serious renal toxicity by

excipient, fumaric acid.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in therapid release and absorption of a potentially fatal dose of morphine.

• P-gp inhibitors(e.g. quinidine) may increase the absorption/exposure ofmorphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients 90 mg and 120 mg capsules are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Belbuca Buprenorphine Buccal Film, 75 mcg, 150 mcg, 300 mcg, 450 mcg, 600 mcg, 750 mcg, and 900 mcg

Dosing Interval Every 12 hours (or once every 24 hours for initiation in opioid naïve patients and patients taking less than 30 mg oral morphine sulfate equivalents)

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics) Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

2528

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions ◊ Opioid-naïve patients or patients taking less than 30 mg oral morphinesulfate equivalents: Initiate treatment with a 75 mcg buccal film, oncedaily, or if tolerated, every 12 hours.

• Titrate to 150 mcg every 12 hours no earlier than 4 days after initiation.• Individual titration to a dose that provides adequate analgesia and

minimizes adverse reactions should proceed in increments of 150 mcgevery 12 hours, no more frequently than every 4 days.

◊ When converting from another opioid, first taper the current opioid tono more than 30 mg oral morphine sulfate equivalents per day prior toinitiating Belbuca.

• If prior daily dose before taper was 30 mg to 89 mg oral morphinesulfate equivalents, initiate with 150 mcg dose every 12 hours.

• If prior daily dose before taper was 90 mg to 160 mg oral morphinesulfate equivalents, initiate with 300 mcg dose every 12 hours.

• Titration of the dose should proceed in increments of 150 mcg every12 hours, no more frequently than every 4 days.

◊ Maximum dose: 900 mcg every 12 hours due to the potential for QTcprolongation

◊ Severe Hepatic Impairment: Reduce the starting and incremental doseby half that of patients with normal liver function.

◊ Oral Mucositis: Reduce the starting and incremental dose by half that ofpatients without mucositis

◊ Do not use if the package seal is broken or the film is cut, damaged, orchanged in any way

Specific Drug Interactions • CYP3A4 inhibitors may increase buprenorphine levels.• CYP3A4 inducers may decrease buprenorphine levels.• Benzodiazepines may increase respiratory depression.• Class IA and III anti arrhythmics, other potentially arrhythmogenic

agents, may increase risk for QTc prolongation and torsade de pointes.

Use in Opioid-Tolerant Patients Belbuca 600 mcg, 750 mcg, and 900 mcg are for use following titration from lower doses of Belbuca.

Product-Specific Safety Concerns • QTc prolongation and torsade de pointes• Hepatotoxicit

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Butrans BuprenorphineTransdermal System, 5 mcg/hr, 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, 20 mcg/hr

Dosing Interval One transdermal system every 7 days

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

2629

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions • Initial dose in opioid non-tolerant patients when converting from lessthan 30 mg morphine equivalents, and in mild to moderate hepaticimpairment - 5 mcg/hr dose.

• When converting from 30 mg to 80 mg morphine equivalents - firsttaper to 30 mg morphine equivalent, then initiate with 10 mcg/hr dose.

• Titrate in 5 mcg/hour or 10 mcg/hour increments by using no morethan two patches of the 5 mcg/hour or 10 mcg/hour system(s) with aminimum of 72 hours between dose adjustments. The total dose fromall patches should not exceed 20 mcg/hour

• Maximum dose: 20 mcg/hr due to risk of QTc prolongation.• Application• Apply only to sites indicated in the Full Prescribing Information.• Apply to intact/non-irritated skin.• Skin may be prepped by clipping hair, washing site with water only• Rotate site of application a minimum of 3 weeks before reapplying to

the same site.• Do not cut.• Avoid exposure to heat.• Dispose of used/unused patches by folding the adhesive side together

and flushing down the toilet.

Specific Drug Interactions • CYP3A4 Inhibitors may increase buprenorphine levels.• CYP3A4 Inducers may decrease buprenorphine levels.• Benzodiazepines may increase respiratory depression.• Class IA and III anti arrhythmics, other potentially arrhythmogenic

agents, may increase risk for QTc prolongation and torsade de pointe.

Use in Opioid-Tolerant Patients Butrans 7.5 mcg/hr, 10 mcg/hr, 15 mcg/hr, and 20 mcg/hr transdermal systems are for use in opioid- tolerant patients only.

Drug-Specific Safety Concerns • QTc prolongation and torsade de pointe• Hepatotoxicity• Application site skin reactions

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Dolophine Methadone Hydrochloride Tablets, 5 mg and 10 mg

Dosing Interval Every 8 to 12 hours

Key Instructions • Initial dose in opioid non-tolerant patients: 2.5 to10 mg• Conversion of opioid-tolerant patients using equianalgesic tables can

result in overdose and death. Use low doses according to the table inthe full prescribing information.

• Titrate slowly, with dose increases no more frequent than every 3 to 5days. Because of high variability in methadone metabolism, somepatients may require substantially longer periods between doseincreases (up to 12 days).

• High inter-patient variability in absorption, metabolism, and relativeanalgesic potency.

• Opioid detoxification or maintenance treatment shall only be providedin a federally certified opioid (addiction) treatment program (Code ofFederal Regulations, Title 42, Sec 8).

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

2730

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Specific Drug Interactions ◊ Pharmacokinetic drug-drug interactions with methadone are complex.• CYP450 inducers may decrease methadone levels.• CYP450 inhibitors may increase methadone levels.• Anti-retroviral agents have mixed effects on methadone levels.◊ Potentially arrhythmogenic agents may increase risk for QTc

prolonga-tion and torsade de pointe.◊ Benzodiazepines may increase respiratory depression.

Use in Opioid-Tolerant Patients Refer to full prescribing information.

Product-Specific Safety Concerns • QTc prolongation and torsade de pointe.• Peak respiratory depression occurs later and persists longer than

analgesic effect.• Clearance may increase during pregnancy.• False positive urine drug screens possible.

Relative Potency To Oral Morphine Varies depending on patient’s prior opioid experience.

Duragesic FentanylTransdermal System, 12, 25, 37.5*, 50, 62.5*, 75, 87.5*, and 100 mcg/hr (*These strengths are available only in generic form)

Dosing Interval Every 72 hours (3 days)

Key Instructions ◊ Use product specific information for dose conversion from prior opioid◊ Use 50% of the dose in mild or moderate hepaticorrenal impairment,

avoid use in severe hepatic or renal impairment◊ Application• Apply to intact/non-irritated/non-irradiated skin on a flat surface.• Skin may be prepped by clipping hair, washing site with water only• Rotate site of application.• Titrate using a minimum of 72 hour intervals between dose

adjustments.• Do not cut.◊ Avoid exposure to heat.◊ Avoid accidental contact when holding or caring for children.◊ Dispose of used/unused patches by folding the adhesive side together

and flushing down the toilet.Specific contraindications:• Patients who are not opioid-tolerant.• Management of acute or intermittent pain, or in patients who require

opioid analgesia for a short period of time.• Management of post-operative pain, including use after out-patient or

day surgery.• Management of mild pain.

Specific Drug Interactions • CYP3A4 inhibitors may increase fentanyl exposure.• CYP3A4 inducers may decrease fentanyl exposure.• Discontinuation of a concomitantly used cytochrome P450 3A4 inducer

may result in an increase in fentanyl plasma concentration.

Use in Opioid-Tolerant Patients All doses of Duragesic are indicated for use in opioid-tolerant patients only.

Product-Specific Safety Concerns • Accidental exposure due to secondary exposure to unwashed/unclothedapplication site.

• Increased drug exposure with increased core body temperature or fever.• Bradycardia• Application site skin reactions

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

2831

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid

Embeda Morphine Sulfate ER-NaltrexoneCapsules, 20 mg/0.8 mg, 30 mg/1.2 mg, 50 mg/2 mg, 60 mg/2.4 mg, 80 mg/3.2 mg, 100 mg/4 mg

Dosing Interval Once a day or every 12 hours

Key Instructions • Initial dose as first opioid: 20mg/0.8mg.• Titrate using a minimum of 1 to 2 day intervals.• Swallow capsules whole(do not chew, crush, or dissolve)• Crushing or chewing will release morphine, possibly resulting in fatal

overdose, and naltrexone, possibly resulting in withdrawal symptoms.• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing, use immediately.

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in therapid release and absorption of a potentially fatal dose of morphine.

• P-gp inhibitors (e.g.quinidine) may increase the absorption/exposure ofmorphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients Embeda 100 mg/4 mg capsule is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Exalgo Hydromorphone HydrochlorideExtended-Release Tablets, 8 mg, 12 mg, 16 mg or 32 mg

Dosing Interval Once a day

Key Instructions • Use the conversion ratios in the individual product information.• Start patients with moderate hepatic impairment on 25% dose that

would be prescribed for a patient with normal hepatic function.• Start patients with moderate renal impairment on 50%, and patients

with severe renal impairment on 25% of the dose that would beprescribed for a patient with normal renal function.

• Titrate in increments of 4 to 8 mg using a minimum of3 to 4 day intervals

• Swallow tablets whole (do not chew, crush, or dissolve).• Do not use in patients with sulfite allergy—contains sodium

metabisulfite.

Specific Drug Interactions None

Use in Opioid-Tolerant Patients All doses of Exalgo are indicated for opioid-tolerant patients only.

Drug-Specific Adverse Reactions Allergic manifestations to sulfite component.

Relative Potency To Oral Morphine Approximately 5:1 oral morphine to hydromorphone oral dose ratio, use conversion recommendations in the individual product information.

Hysingla ER Hydrocodone bitartrateExtended-Release Tablets, 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, and 120 mg

Dosing Interval Every 24 hours (once-daily)

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

2932

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions • Opioid-naïve patients: initiate treatment with 20 mg orally once daily.During titration, adjust the dose in increments of 10 mg to 20 mg every3 to 5 days until adequate analgesia is achieved.

• Swallow tablets whole (do not chew, crush, or dissolve).• Consider use of an alternative analgesic in patients who have difficulty

swallowing or have underlying gastrointestinal disorders that maypredispose them to obstruction.

• Take one tablet at a time, with enough water to ensure complete swal-lowing immediately after placing in the mouth.

• Use 1/2 of the initial dose and monitor closely for adverse events, suchas respiratory depression and sedation, when administering Hysingla ERto patients with severe hepatic impairment or patients with moderate tosevere renal impairment.

Specific Drug Interactions • CYP3A4 inhibitors may increase hydrocodone exposure.• CYP3A4 inducers may decrease hydrocodone exposure.• Concomitant use of Hysingla ER with strong laxatives (e.g., Lactulose)

that rapidly increase GI motility may decrease hydrocodone absorption and result in decreased hydrocodone plasma levels.

• The use of MAO inhibitors or tricyclic antidepressants with Hysingla ER may increase the effect of either the antidepressant or Hysingla ER.

Use in Opioid-Tolerant Patients A single dose of Hysingla ER greater than or equal to 80 mg is only for use in opioid tolerant patients.

Product-Specific Safety Concerns • Use with caution in patients with difficulty swallowing the tablet orunderlying gastrointestinal disorders that may predispose patients toobstruction.

• Esophageal obstruction, dysphagia, and choking have been reportedwith Hysingla ER.

• In nursing mothers, discontinue nursing or discontinue drug.• QTc prolongation has been observed with Hysingla ER following daily

doses of 160 mg. Avoid use in patients with congenital long QTcsyndrome. This observation should be considered in making clinicaldecisions regarding patient monitoring when prescribing Hysingla ERin patients with congestive heart failure, bradyarrhythmias, electrolyteabnormalities, or who are taking medications that are known to prolongthe QTc interval. In patients who develop QTc prolongation, considerreducing the dose.

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid

Kadian Morphine SulfateExtended-Release Capsules, 10 mg, 20mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 100 mg, 130 mg, 150 mg, and 200 mg

Dosing Interval Once a day or every 12 hours

Key Instructions • Product information recommends not using as first opioid.• Titrate using a minimum of 2-day intervals.• Swallow capsules whole (do not chew, crush, or dissolve).• May open capsule and sprinkle pellets on applesauce for patients who

can reliably swallow without chewing, use immediately.

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

3033

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in therapid release and absorption of a potentially fatal dose of morphine.

• P-gp inhibitors(e.g. quinidine) may increase the absorption/exposure ofmorphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients Kadian 100 mg, 130 mg, 150 mg, and 200 mg capsules are for use in opioid- tolerant-patients only

Product-Specific Safety Concerns None

MorphaBond Morphine SulfateExtended-release Tablets, 15 mg, 30 mg, 60 mg, 100 mg

Dosing Interval Every 8 hours or every 12 hours

Key Instructions For opioid-naïve and opioid non-tolerant patients, initiate treatment with 15mg tablets orally every 12 hours. Swallow tablets whole (do not cut, break, chew, crush, or dissolve).

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) may increase the absorption/exposure ofmorphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients MorphaBond ER 100 mg tablets, as single dose greater than 60mg, or a totaldaily dose greater than 120mg, are only for use in patients in whom toleranceto an opioid of comparable potency has been established.

Product-Specific Safety Concerns None

MS Contin Morphine SulfateExtended-release Tablets, 15 mg, 30 mg, 60 mg, 100 mg, and 200 mg

Dosing Interval Every 8 hours or every 12 hours

Key Instructions • Product information recommends not using as first opioid.• Titrate using a minimum of 1 to 2-day intervals.• Swallow tablets whole (do not chew, crush, or dissolve).

Specific Drug Interactions P-gp inhibitors (e.g. quinidine) may increase the absorption/exposure ofmorphine sulfate by about two-fold.

Use in Opioid-Tolerant Patients MS Contin 100 mg and 200 mg tablet strengths are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Nucynta ER TapentadolExtended-Release Tablets, 50 mg, 100mg, 150 mg, 200 mg, and 250 mg

Dosing Interval Every 12 hours

Key Instructions • Use 50 mg every 12 hours as initial dose in opioid nontolerant patients.

• Titrate by 50 mg increments using a minimum of 3-day intervals.• Maximum total daily dose is 500 mg.• Swallow tablets whole (do not chew, crush, or dissolve).• Take one tablet at a time and with enough water to ensure complete

swallowing immediately after placing in the mouth.• Dose once daily in moderate hepatic impairment with100 mg per day

maximum.• Avoid use in severe hepatic and renal impairment.

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

3134

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result inthe rapid release and absorption of a potentially fatal dose oftapentadol.

• Contraindicated in patients taking MAOIs.

Use in Opioid-Tolerant Patients No product-specific considerations.

Product-Specific Safety Concerns • Risk of serotonin syndrome• Angioedema

Relative Potency To Oral Morphine Equipotency to oral morphine has not been established.

Opana ER Oxymorphone HydrochlorideER Tablets, 5 mg, 7.5 mg, 10 mg, 15 mg, 20 mg, 30 mg, and 40 mg

Dosing Interval Every 12h dosing, some may benefit from asymmetric (different dose given in AM than in PM) dosing.

Key Instructions • Use 5 mg every 12 hours as initial dose in opioid non-tolerant patients and patients with mild hepatic impairment and renal impairment (creati-nine clearance < 50 mL/min) and patients over 65 years of age.

• Swallow tablets whole (do not chew, crush, or dissolve).• Take one tablet at a time, with enough water to ensure complete

swallowing immediately after placing in the mouth.• Titrate in increments of 5 to 10 mg using a minimum of 3 to 7-day

intervals.• Contraindicated in moderate and severe hepatic impairment.

Specific Drug Interactions Alcoholic beverages or medications containing alcohol may result in the absorption of a potentially fatal dose of oxymorphone.

Use in Opioid-Tolerant Patients No product specific considerations.

Product-Specific Safety Concerns Use with caution in patients who have difficulty in swallowing or have under-lying GI disorders that may predispose them to obstruction, such as a small gastrointestinal lumen.

Relative Potency To Oral Morphine Approximately 3:1 oral morphine to oxymorphone oral dose ratio

OxyContin Oxycodone HydrochlorideExtended-release Tablets, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg

Dosing Interval Every 12 hours

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

3235

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions ◊ For Adults:• Initial dose in opioid-naïve and opioid non-tolerant patients is 10 mg

every 12 hours.• If needed, adult dosage may be adjusted in 1 to 2 day intervals.• When a dose increase is clinically indicated, the total daily oxycodone

dose usually can be increased by 25% to 50% of the current dose.◊ For Pediatric patients (11 years and older): Use only in opioid-tol-

erant patients (see below, Use in Opioid-Tolerant Patients for dosinginformation).

◊ For all patients:• Hepatic impairment: start with one third to one half the usual dosage• Renal impairment (creatinine clearance <60 mL/min): start with one

half the usual dosage.• Consider use of other analgesics in patients who have difficulty swallow-

ing or have underlying GI disorders that may predispose them obstrucu-tion. Swallow tablets whole (do not chew, crush, or dissolve).

• Take one tablet at a time, with enough water to ensure completeswallowing immediately after placing in the mouth.

Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure.• CYP3A4 inducers may decrease oxycodone exposure.

Use in Opioid-Tolerant Patients ◊ For Adults:• Single dose greater than 40 mg or total daily dose greater than 80 mg

are for use in adult patients in whom tolerance to an opioid of compara-ble potency has been established.

◊ For Pediatric patients (11 years and older):• For use only in opioid-tolerant pediatric patients already receiving and• tolerating opioids for at least 5 consecutive days with a minimum of 20

mg per day of oxycodone or its equivalent for at least two days immedi-ately preceding dosing with OxyContin.

• If needed, pediatric dosage may be adjusted in 1 to 2 day intervals.• When a dose increase is clinically indicated, the total daily oxycodone

dose usually can be increased by 25% of the current total daily dose.

Product-Specific Safety Concerns • Choking, gagging, regurgitation, tablets stuck in the throat, difficultyswallowing the tablet.

• Contraindicated in patients with gastrointestinal obstruction.

Relative Potency To Oral Morphine Approximately 2:1 oral morphine to oxycodone oral dose ratio.

Targiniq ER Oxycodone Hydrochloride / Naloxone HydrochlorideExtended-release tablets, 10 mg/5 mg, 20 mg/10 mg, and 40 mg/20 mg

Dosing Interval Every 12 hours

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

3336

TABLE 10: Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions • Opioid-naïve patients: initiate treatment with 10 mg/5 mg every 12hours.

• Titrate using a minimum of 1 to 2 day intervals.• Do not exceed 80 mg/40 mg total daily dose (40 mg/20 mg q12) of

Targiniq ER• May be taken with or without food.• Swallow tablets whole. Do not chew, crush, split, or dissolve, as this will

release oxycodone, possibly resulting in fatal overdose, and naloxone,possibly resulting in withdrawal symptoms.

• Hepatic impairment: contraindicated in moderate and severe hepaticimpairment. In patients with mild hepatic impairment, start with one thirdto one half the usual dosage.

• Renal impairment (creatinine clearance < 60 mL/min): start with onehalf the usual dosage.

Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure.• CYP3A4 inducers may decrease oxycodone exposure

Use in Opioid-Tolerant Patients Single dose greater than 40 mg/20 mg or total daily dose of 80 mg/40 mg are for use in opioid-tolerant patients only

Product-Specific Safety Concerns Contraindicated in patients with moderate to severe hepatic impairment.

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid.

Troxyca ER Oxycodone Hydrochloride/Naltrexone HydrochlorideExtended-Release Capsules, 10 mg/1.2 mg, 20 mg/2.4 mg, 30 mg/3.6 mg, 40 mg/4.8 mg, 60 mg/7.2 mg, 80 mg/9.6 mg

Dosing Interval Every 12 hours

Key Instructions • Opioid-naïve and opioid non-tolerant patients: 10 mg/1.2 mg, every 12hours

• Total daily dose may be adjusted by 20 mg/2.4 mg every 2 to 3 days asneeded

• Swallow capsule whole (do not chew, crush, or dissolve).• Crushing, chewing, or dissolving will release oxycodone, possibly result-

ing in fatal overdose, and naltrexone, possibly resulting in withdrawalsymptoms.

• For patients that have difficulty swallowing, Troxyca ER, can also betaken by sprinkling the capsule contents (pellets) on applesauce andswallowing immediately without chewing.

• Do not administer Troxyca ER pellets through a nasogastric or gastrictube

Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure.• CYP3A4 inducers may decrease oxycodone exposure.

Use in Opioid-Tolerant Patients Single doses of greater than 40 mg/4.8 mg, or a total daily dose greater than 80 mg/9.6 mg are only for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid.

Vantrela ER Hydrocodone BitartrateExtended-Release Tablets, 15 mg, 30 mg, 45 mg, 60 mg, and 90 mg

Dosing Interval Every 12 hours

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

34

Table 8. Specific Drug Information for Extended-Release and Long-Acting Opioid Analgesics(ER/LA opioid analgesics)

Key Instructions • Opioid naïve and opioid nontolerant patients: Initiate with 15 mg every 12 hours. Dose can be increased from the current dose to the next higher dose every 3 to 7 days as needed.

• Swallow tablets whole (do not chew, crush, or dissolve).• Mild or moderate hepatic and moderate to severe renal impairment: Initiate therapy with 1/2 of the recom-

mended initial dose in patients with either of these impairments. If a dose less than 15 mg is needed, use alternative analgesic options.

Specific Drug Interactions • CYP3A4 inhibitors may increase hydrocodone exposure.• CYP3A4 inducers may decrease hydrocodone exposure.

Use in Opioid-Tolerant Patients A 90 mg tablet, a single dose greater than 60 mg, or a total daily dose greater than 120 mg are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Relative Potency To Oral Morphine See individual product information for conversion recommendations from prior opioid.

Xtampza ER OxycodoneExtended-Release Capsules, 9 mg 13.5 mg, 18 mg, 27 mg, and 36 mg(strengths equivalent to 10mg, 15mg, 20mg, 30mg, and 40mg oxycodone hydrochloride, respectively)

Dosing Interval Every 12 hours

Key Instructions • Opioid naïve and opioid non-tolerant patients: Initiate with 9 mg every 12 hours.• Titrate using a minimum of 1 to 2 day intervals.• Take Xtampza ER capsules with the same amount of food in order to ensure consistent plasma levels are

achieved.• Maximum daily dose: 288 mg (8 x 36 mg capsules) because the safety of excipients has not been estab-

lished for higher doses• For patients that have difficulty swallowing, Xtampza ER can also be taken by sprinkling the capsule contents

on soft foods or into a cup and then administering directly into the mouth and swallowing immediately. Xtampza ER may also be administered through a gastrostomy or naso-gastric feeding tube.

• Hepatic impairment: Initiate therapy at 1/3 to 1/2 the usual dosage• Renal impairment: (creatinine clearance <60 mL/min): Follow a conservative approach to dose initiation

and adjust according to the clinical situation.

Specific Drug Interactions • CYP3A4 inhibitors may increase oxycodone exposure• CYP3A4 inducers may decrease oxycodone exposure

Use in Opioid-Tolerant Patients A single dose greater than 36 mg or a total daily dose greater than 72 mg is for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Relative Potency To Oral Morphine There are no established conversion ratios for conversion from other opioids to Xtampza ER defined by clinical trials

Zohydro ER Hydrocodone BitartrateExtended-Release Capsules, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, and 50 mg

Dosing Interval Every 12 hours

Key Instructions Initial dose in opioid non-tolerant patient is 10 mg.Titrate in increments of 10 mg using a minimum of 3 to 7day intervals.Swallow capsules whole (do not chew, crush, or dissolve).

Specific Drug Interactions • Alcoholic beverages or medications containing alcohol may result in the rapid release and absorption of a potentially fatal dose of hydrocodone.

• CYP3A4 inhibitors may increase hydrocodone exposure.• CYP3A4 inducers may decrease hydrocodone exposure.

Use in Opioid-Tolerant Patients Single dose greater than 40 mg or total daily dose greater than 80 mg are for use in opioid-tolerant patients only.

Product-Specific Safety Concerns None

Relative Potency To Oral Morphine Approximately 1.5:1 oral morpthine to hydrocodone oral dose ratio.Source: FDA Blueprint for Prescriber Education for Extended-Release and Long-Acting Opioid Analgesics. May, 2017.

https://www.fda.gov/downloads/Drugs/DrugSafety/InformationbyDrugClass/UCM515636.pdf. Last Accessed June, 2018.

Note: Prescribers should counsel patients on product specific information and ensure that patients are aware that selling or sharing any controlled substance with others is against the law

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What You Need to Know About Opioid Pain Medicines This guide is for you! Keep this guide and the Medication Guide that comes with your medicine so you can better understand what you need to know

about your opioid pain medicine. Go over this information with your healthcare provider. Then, ask your healthcare provider about anything that you do not understand.

Naloxone is never a substitute for emergency medical care. Always call 911 or go to the emergency room if you’ve used or given naloxone.

TABLE 9. PATIENT COUNSELING GUIDE

Source: FDA Opioid Analgesic REMS https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_Analgesic_2018_09_18_Patient_Counseling_Guide.pdf Last Accessed September, 2018

What are opioids? Opioids are strong prescription medicines that are used to manage severe pain.

What are the serious risks of using opioids? • Opioids have serious risks of addiction and overdose.• Too much opioid medicine in your body can cause your breathing to stop –

which could lead to death. This risk is greater for people taking other medicines that make you feel sleepy or people with sleep apnea.

• Addiction is when you crave drugs (like opioid pain medicines) because they make you feel good in some way. You keep taking the drug even though you know it is not a good idea and bad things are happening to you. Addiction is a brain disease that may require ongoing treatment.

You can get addicted to opioids even though you take them exactly as prescribed, especially if taken for a long time. If you think you might be addicted, talk to your healthcare provider right away. If you take an opioid medicine for more than a few days, your body becomes physically “dependent.” This is normal and it means your body has gotten used to the medicine. You must taper off the opioid medicine (slowly take less medicine) when you no longer need it to avoid withdrawal symptoms.

How can I take opioid pain medicine safely? • Tell your healthcare provider about all the medicines you are taking, including

vitamins, herbal supplements, and other over-the-counter medicines.• Read the Medication Guide that comes with your prescription.• Take your opioid medicine exactly as prescribed.• Do not cut, break, chew, crush, or dissolve your medicine. If you cannot swallow

your medicine whole, talk to your healthcare provider.• When your healthcare provider gives you the prescription, ask:

º How long should I take it? º What should I do if I need to taper off the opioid medicine (slowly take

less medicine)?• Call your healthcare provider if the opioid medicine is not controlling your pain.

Do not increase the dose on your own.• Do not share or give your opioid medicine to anyone else. Your healthcare

provider selected this opioid and the dose just for you. A dose that is okay for you could cause an overdose and death for someone else. Also, it is against the law.

• Store your opioid medicine in a safe place where it cannot be reached by children or stolen by family or visitors to your home. Many teenagers like to experiment with pain medicines. Use a lock- box to keep your opioid medicine safe. Keep track of the amount of medicine you have.

• Do not operate heavy machinery until you know how your opioid medicine affects you. Your opioid medicine can make you sleepy, dizzy, or lightheaded.

What other options are there to help with my pain? Opioids are not the only thing that can help you control your pain. Ask your healthcare provider if your pain might be helped with a non-opioid medication, physical therapy, exercise, rest, acupuncture, types of behavioral therapy, or patient self-help techniques.

What is naloxone? • Naloxone is a medicine that treats opioid overdose. It is sprayed inside your

nose or injected into your body.• Use naloxone if you have it and call 911 or go to the emergency room right

away if: º You or someone else has taken an opioid medicine and is having trouble

breathing, is short of breath, or is unusually sleepy º A child has accidentally taken the opioid medicine or you think they might

have• Giving naloxone to a person, even a child, who has not taken an opioid medicine

will not hurt them.

Where can I get naloxone? • There are some naloxone products that are designed for people to use in their

home.• Naloxone is available in pharmacies. Ask your healthcare provider about

how you can get naloxone. In some states, you may not need a prescription.• When you get your naloxone from the pharmacy, read the Patient Information

on how to use naloxone and ask the pharmacist if anything is unclear.• Tell your family about your naloxone and keep it in a place where you or your

family can get to it in an emergency.

What things should I know about the specific opioid medicine that I am taking? Your healthcare provider has prescribed ________________________for you.

Read the Medication Guide for this medicine, which is information provided by your pharmacy. Remember this other important information about your opioid medicine:

Dosing instructions: _________________________________________

Any specific interactions with your medicines: _______________________

________________________________________________________

What if I have more questions? • Read the Medication Guide that comes with your opioid medicine prescription

for more specific information about your medicine.• Talk to your healthcare provider or pharmacist and ask them any questions

you may have.• Visit: www.fda.gov/opioids for more information about opioid medicines.

Risk Factors for Opioid Abuse: • You have:

º a history of addiction º a family history of addiction

• You take medicines to treat mental health problems• You are under the age of 65 (although anyone can abuse opioid medicines)

When you no longer need your opioid medicine, dispose of it as quickly as possible. The Food and Drug Administration recommends that most opioid medicines be promptly flushed down the toilet when no longer needed, unless a drug take-back option is immediately available. A list of the opioid medicines that can be flushed down the toilet is found here: https://www.fda.gov/drugdisposal

What should I avoid taking while I am taking opioids? Unless prescribed by your healthcare provider, you should avoid taking alcohol or any of the following medicines with an opioid because it may cause you to stop breathing, which can lead to death:• Alcohol: Do not drink any kind of alcohol while you are taking opioid medicines.• Benzodiazepines (like Valium or Xanax)• Muscle relaxants (like Soma or Flexeril)• Sleep medicines (like Ambien or Lunesta)• Other prescription opioid medicines

36

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Scope and purpose of the guideline: To help providers make informed decisions about acute and chronic pain treatment -pain lasting longer than three months or past the time of normal tissue healing. The guideline is not intended for patients who are in active cancer treatment, palliative care, or end-of-life care. Although not specifically designed for pediatric pain, many of the principals upon which they are based could be applied there, as well.

Opioids pose a potential risk to all patients. The guideline encourages providers to implement best practices for responsible prescribing which includes prescribing the lowest effective dose for the shortest possible duration for post-operative care and acutely-injured patients.

Identify and treat the cause of the pain, use non-opioid therapiesUse non-pharmacologic therapies (such as yoga, exercise, cognitive behavioral therapy and complementary/alternative medical therapies) and non-opioid pharmacologic therapies (such as acetaminophen and anti-inflammatories) for acute and chronic pain. Don’t use opioids routinely for chronic pain. When opioids are used, combine them with non-pharmacologic or non-opioid pharmacologic therapy, as appropriate, to provide greater benefits.

Start low and go slowWhen opioids are used, prescribe the lowest possible effective dosage and start with immediate- release opioids instead of extended-release/long-acting opioids. Only provide the quantity needed for the expected duration of pain.

Close follow-upRegularly monitor patients to make sure opioids are improving pain and function without causing harm. If benefits do not outweigh harms, optimize other therapies and work with patients to taper or discontinue opioids, if needed.

What’s included in the guideline?The guideline addresses patient-centered clinical practices including conducting thorough assessments, considering all possible treatments, treating the cause of the pain, closely monitoring risks, and safely discontinuing opioids. The three main focus areas in the guideline include:

1. Determining when to initiate or continue opioids-Selection of non-pharmacologic therapy, non-opioid pharmacologic therapy, opioid therapy -Establishment of treatment goals-Discussion of risks and benefits of therapy with patients

2. Opioid selection, dosage, duration, follow-up and discontinuation-Selection of immediate-release or extended-release and long-acting opioids -Dosage considerations-Duration of treatment-Considerations for follow-up and discontinuation of opioid therapy3. Assessing risk and addressing harms of opioid use-Evaluation of risk factors for opioid-related harms and ways to mitigate/reduce patient risk -Review of prescription drug monitoring program (PDMP) data-Use of urine drug testing-Considerations for co-prescribing benzodiazepines-Arrangement of treatment for opioid use disorder

Prescription Opioid Guideline1. Pain is a subjective experience and at present, physicians lack options to objectively quantify pain severity other than by patient reported measures including pain intensity. While accepting the patient’s report of pain, the clinician must simultaneously decide if the magnitude of the pain complaint is commensurate with causative factors and if these have been adequately evaluated and addressed with non-opioid therapy.

2. It is best practice for a practitioner to consider guidelines within their specialty when prescribing opioids.

3. In treating acute pain, if opioids are at all indicated, the lowest dose and fewest number of opioid pills needed should be prescribed. In most cases, less than 3 days’ worth are necessary, and rarely more than 5 days’ worth. Left-over pills in medicine cabinets are often the source for illicit opioid abuse in teens and young adults. When prescribing opioids, physicians should consider writing two separate prescriptions for smaller amounts of opioids with specific refill dates, rather than a single large prescription. Most patients do not fill the second prescription, thus limiting opioid excess in a patient’s home and potential misuse.

4. A practitioner’s first priority in treating a patient in pain is to identify the cause of the pain and, if possible, to treat it. While keeping the patient comfortable during this treatment is important, it is critical to address to the extent possible the underlying condition as the primary objective of care.

a. Patients unwilling to obtain definitive treatment for the condition causing their pain should be considered questionable candidates for opioids. If opioids are prescribed to such patients, documentation of clear clinical rationale should exist.

b. Opioids should not be prescribed unless there is a medical condition present which would reasonably be expected to cause pain severe enough to require an opioid. For conditions where this is questionable, use of other treatments instead of opioids should be strongly considered.

c. Consultation should be considered if diagnosis of and/or treatment for the condition causing the pain is outside of the scope of the prescribing practitioner.

5. Opioids should not necessarily be the first choice in treating acute or chronic pain.

a. Acute pain: Evidence for opioids is weak. Other treatments such as acetaminophen, anti- inflammatories, and non-pharmacologic treatments should be attempted prior to initiating opioid therapy. Although opioids could be simultaneously prescribed if it is apparent from the patient’s condition that he/she will need opioids in addition to these. Don’t use opioids routinely for chronic pain. When opioids are used, combine them with non-pharmacologic or non-opioid pharmacologic therapy, as appropriate, to provide greater benefits.

b. Acute pain lasting beyond the expected duration: A complication of the acute pain issue (surgical complication, nonunion of fracture, etc.) should be ruled out. If complications are ruled out, a transition to non-opioid therapy (tricyclic antidepressant, serotonin/norepinephrine re-uptake inhibitor, anticonvulsant, etc.) should be attempted.

c. Chronic pain: Evidence for opioids is poor. Other treatments such as acetaminophen, anti- inflammatories, and non-pharmacologic treatments (such as yoga, exercise, cognitive behavioral therapy and complementary/alternative medical therapies) should be utilized. Multiple meta-analyses demonstrate that the benefits of opioids are slight, while annualized mortality rates dramatically increased. There are few if any treatments in medicine with this poor a risk/benefit ratio, and there should be adequate clinical indication to indicate why chronic opioid therapy was chosen in a given patient. Note: There is no high-quality evidence to support opioid therapy longer than 6 months in duration. Despite this fact, it is considered acceptable although not preferable to continue patients on treatment who have been on chronic opioid therapy prior to this Guideline’s release and who have shown no evidence of aberrant behavior.

d. Patients unwilling to accept non-pharmacological and/or nonnarcotic treatments (or those providing questionably credible justifications for not using them) should not be considered candidates for opioid therapy.

6. Patients should not receive opioid prescriptions from multiple physicians. There should be a dedicated provider such as a primary care or pain specialist to provide all opioids used in treating any patient’s chronic pain, with existing pain contracts being honored. Physicians should avoid prescribing controlled substances for patients who have run out of previously prescribed medication or have had previous prescriptions lost or stolen.

7. Physicians should avoid using intravenous or intramuscular opioid injections for patients with exacerbations of chronic non-cancer pain in the emergency department or urgent care setting.

8. Physicians are encouraged to review the patient’s history of controlled substance prescriptions using the Wisconsin Prescription Drug Monitoring Program (PDMP) data to determine whether the patient is receiving opioid dosages or dangerous combinations that put him or her at high risk for overdose. As of April 2017, Wisconsin state law requires prescribers to review the PDMP before prescribing any controlled substance for greater than a three-day supply.

9. Pain from acute trauma or chronic degenerative diseases can oftentimes be managed without opioids prior to surgery. Surgical patients using opioids preoperatively have higher complications rates, require more narcotics postoperatively, and have lower satisfaction rates with poorer outcomes following surgery.

10. Prescribing of opioids is strongly discouraged in patients taking benzodiazepines or other respiratory depressants. Benzodiazepines triple the already high increases in respiratory depression and annual mortality rates from opioids. If they are used concurrently, clear clinical rationale must exist.

11. The use of oxycodone is discouraged. There is no evidence to support that oxycodone is more effective than other oral opioids, while there are multiple studies indicating that oxycodone is more abused and has qualities that would promote addiction to a greater degree than other opioids. As a result, oxycodone should not be considered first-line and should be used only in patients who cannot tolerate other opioids and who have been evaluated for and found not to demonstrate increased risk of abuse.

APPENDIX A. Wisconsin Medical Examining Board Opioid Prescribing Guidelines - January 16, 2019https://dsps.wi.gov/Documents/BoardCouncils/MED/20190116MEBGuidelinesv9.pdf

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12. Patients presenting for chronic pain treatment should have a thorough evaluation, which may include the following:

a. Medical history and physical examination targeted to the pain condition.b. Nature and intensity of the pain.c. Current and past treatments, with response to each treatment.d. Underlying or co-existing diseases or conditions, including those which could complicate treatment (i.e., renal disease, sleep apnea, chronic obstructive pulmonary disease (COPD), etc.).e. Effect of pain on physical and psychological functioning.f. Personal and family history of substance abuse.g. History of psychiatric disorders associated with opioid abuse (bipolar, attention deficit disorders (ADD/ADHD), sociopathic, borderline, untreated/severe depression).h. Medical indication(s) for use of opioids.

13. Initiation of opioids for chronic pain should be considered on a trial basis. Prior to starting opioids, objective symptomatic and functional goals should be established with the patient. If after a reasonable trial these goals are not met, then opioids should be weaned or discontinued.

14. Practitioners should always consider the risk-benefit ratio when deciding whether to start or continue opioids. Risks and benefits should be discussed with patients prior to initiating chronic opioid therapy and continue to be reassessed during that therapy. If evidence of increased risk develops, weaning or discontinuation of opioids should be considered. If evidence emerges that indicates that the opioids put a patient at the risk of imminent danger (overdose, addiction, etc.), or that they are being diverted, opioids should be discontinued, and the patient should be treated for withdrawal, if needed.

a. Exceptions to this include patients with unstable angina and pregnant patients, especially in the 3rd trimester (withdrawal could precipitate pre-term labor).b. Components of ongoing assessment of risk include:

i. Review of the Prescription Drug Monitoring Program (PDMP) information.ii. Periodic urine drug testing (including chromatography) – at least yearly in low risk cases, more frequently with evidence of increased risk.iii. Violations of the opioid agreement.iv. Periodic pill counts may also be considered for high risk patients.

15. All patients on chronic opioid therapy should have informed consent consisting of:

a. Specifically detailing significant possible adverse effects of opioids, including (but not limited to) addiction, overdose, and death. It is also recommended practitioners discuss with patients the effect opioid use may have on the ability to safely operate machinery or a vehicle in any mode of transportation.b. Treatment agreement, documenting the behaviors required of the patient by the prescribing practitioner to ensure that they are remaining safe from these adverse effects.

16. Initial dose titration for both acute and chronic pain should be with short-acting opioids. For chronic therapy, it would be appropriate once an effective dose is established to consider long- acting agents for a majority of the daily dose.

17. Opioids should be prescribed in the lowest effective dose. This includes prescribing the lowest effective dose for the shortest possible duration for post-operative care and acutely-injured patients. If daily doses for chronic pain reach 50 morphine milligram equivalents (MMEs), additional precautions should be implemented (see #14.b. above). Given that there is no evidence base to support efficacy of doses over 90 MMEs, with dramatically increased risks, dosing above this level is strongly discouraged, and appropriate documentation to support such dosing should be present on the chart.

18. The use of methadone is not encouraged unless the practitioner has extensive training or experience in its use. Individual responses to methadone vary widely; a given dose may have no effect on one patient while causing overdose in another. Metabolism also varies widely and is highly sensitive to multiple drug interactions, which can cause accumulation in the body and overdose. For a given analgesic effect, the respiratory depressant effect is much stronger compared to other opioids. Finally, methadone can have a potent effect on prolonging the QTc, predisposing susceptible patients to potentially fatal arrhythmias.

19. Prescribing of opioids is strongly discouraged for patients abusing illicit drugs. These patients are at extremely high risk for abuse, overdose, and death. If opioids are prescribed to such patients, a clear and compelling justification should be present.

20. During initial opioid titration, practitioners should re-evaluate patients every 1-4 weeks. During chronic therapy, patients should be seen at least every 3 months, more frequently if they demonstrate higher risk.

21. Practitioners should consider prescribing naloxone for home use in case of overdose for patients at higher risk, including:

a. History of overdose (a relative contraindication to chronic opioid therapy).b. Opioid doses over 50 MMEs/day.c. Clinical depression.d. Evidence of increased risk by other measures (behaviors, family history, PDMP, UDS, risk questionnaires, etc.).

The recommended dose is 0.4 mg for IM or intranasal use, with a second dose available if the first is ineffective or wears off before EMS arrives. Family members can be prescribed naloxone for use with the patient.

22. All practitioners are expected to provide care for potential complications of the treatments they provide, including opioid use disorder. As a result, if a patient receiving opioids develops behaviors indicative of opioid use disorder, the practitioner, when possible, should assist the patient in obtaining addiction treatment, either by providing it directly (buprenorphine, naltrexone, etc. plus behavioral therapy) or referring them to an appropriate treatment center or provider willing to accept the patient. Discharging a patient from the provider’s practice solely due to an opioid use disorder is not considered acceptable.

23. Discontinuing Opioid Therapya. If lack of efficacy of opioid therapy is determined, safe discontinuation of opioidtherapy should be performed.b. If evidence of increased risk develops, safe discontinuation of opioid therapy should be considered.c. If evidence emerges that indicates that the opioids

put a patient at the risk of imminent danger (overdose, addiction, etc.), or that they are being diverted, opioids should be immediately discontinued, and the patient should be treated for withdrawal, if needed.

Exceptions to abrupt opioid discontinuation include patients with unstable angina and pregnant patients. These patients should be weaned from the opioid medications in a gradual manner with close follow-up.

24. Current HIPAA Guidance for the Sharing of Protected Health Information with a Patient’s Family Members and Loved Ones Irrespective of Patient Wishes.

Interpretive guidance from the US Department of Health and Human Services Office of Civil Rights, indicates that HIPAA regulations allow health professionals to share health information with a patient’s loved ones in emergency or dangerous situations such as opioid overdose. HIPAA allows health care professionals to disclose some health information without a patient’s permission under certain circumstances, including: in cases where the patient is incapacitated or unconscious, or where a serious and imminent threat to a patient’s health or safety exists. For example, a doctor whose patient has overdosed on opioids is presumed to have complied with HIPAA if the doctor informs family, friends, or caregivers of the opioid abuse after determining, based on the facts and circumstances, that the patient poses a serious and imminent threat to his or her health through continued opioid abuse upon discharge. Resources

CDC Guideline for Prescribing Opioids for Chronic Pain--United States 2016. Dowell D1, Haegerich TM1, Chou R1., JAMA. 2016 Apr 19;315(15):1624-45. doi:10.1001/jama.2016.1464.

Chronic Opioid Clinical Management Guidelines for Wisconsin Worker’s Compensation Patient Care. https://dwd.wisconsin.gov/wc/medical/pdf/CHRONIC%20OPIOID%20CLINICAL%20 MANAGEMENT%20GUIDELINES%20.pdf

Within-subject comparison of the psychopharmacological profiles of oral oxycodone and oral morphine in non-drug-abusing volunteers. Zacny, James, & Lichtor, Stephanie.

Psychpharmacology (2008) 196:105-116

Subjective, Psychomotor, and Physiological Effects Profile of Hydrocodone/Acetaminophen and Oxycodone/Acetaminophen Combination Products. Zachny, James, & Gutierrez, Sandra. Pain Medicine (2008) Vol 9, No 4: 433-443

Positive and Negative Subjective Effects of Extended-Release Oxymorphone versus Controlled- Release Oxycodone in Recreational Opioid Users. Schoedel, Kerri et. al. Journal of Opioid Management 7:3 May/June 2011. 179-192

Tapentadol Abuse Potential: A Postmarketing Evaluation Using a Sample of Individuals Evaluated for Substance Abuse Treatment. Stephen F. Butler, PhD et. al., Pain Medicine 2015; 16: 119–130

Methadone Safety: A Clinical Practice Guideline from the American Pain Society and College on Problems of Drug Dependence, in collaboration with the Heart Rhythm Society. Chou R1, et. al., J Pain. 2014 Apr;15(4):321-37

Emerging Issues in the Use of Methadone. SAMHSA Substance Abuse Treatment Advisory, Spring 2009, Volume 8, Issue 1, available at http://store.samhsa.gov/shin/content//SMA09- 4368/SMA09-4368.pdf

Opioid Use, Misuse, and Abuse in Orthopedic Practice. American Academy of Orthopedic Surgeons, Information Statement 1045, October, 2015, available at https://www.aaos.org/uploaded Files/PreProduction/About/Opinion_Statements/advistmt/1045%20Opioid%20Use,%20Misuse,%2 0and%20Abuse%20in%20Practice.pdf

Wisconsin Medical Society Opioid Prescribing Principles. https://www.wisconsin medicalsociety.org/advocacy/boards-councils/society-initiatives/opioid-task-force/opioid- prescribing-principles/

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1. When evaluating patients for treatment with extended-release/long-acting (ER/LA) opioid analgesics, which is an important risk to consider? A. Respiratory depression, particularly in elderly patientsB. History of autoimmune disease C. Co-ingestion with nonsteroidal anti-inflammatory drugsD. Numeric pain scale rating >5

2. Which of the following is true of methadone?A. The peak of respiratory depression can persist longer

than the analgesic effectsB. Fewer drug-drug interactions are observed than with

other opioidsC. Equianalgesic tables may be used without modification

to convert to another opioidD. Only patients with opioid-use disorder and co-occurring

pain should receive methadone

3. Nonpharmacologic therapies for pain treatment:A. Are most effective when combined with opioid therapyB. Are usually covered by insuranceC. Are encouraged as part of a comprehensive pain

treatment planD. Are less effective than nonopioid pharmacologic

therapies

4. For which of the following pain conditions are ER/LA opioids indicated?A. Acute or postoperative pain that does not resolve after

1 weekB. As needed for severe headache or migraine pain C. Severe chronic pain as a first-line therapyD. For pain severe enough to require daily, around-

the-clock, long-term analgesia for which alternative treatment options are inadequate

5. According to assessment tools, which of the following factors heighten risk for opioid-use disorder?A. Comorbid psychiatric conditions such as post-traumatic

stress disorderB. A diagnosis of fibromyalgia C. Sleep apneaD. A family history of mental illness

6. Name one method by which patients should be encouraged to dispose of unused opioids:A. Throwing away after separating from the prescription

bottleB. Crushing pills and placing in a trash receptacleC. Participating in a community drug take-back eventD. Hiding in a safe, locked location within the home

7. Name one way patients should be monitored for adherence to medical direction during long-term opioid therapy:A. Periodically check prescription drug monitoring

programs B. Perform laboratory testing of triglycerides C. Document that physical dependence has not developedD. Periodically warn that medical marijuana use is

prohibited during long-term opioid therapy

8. Which of the following is true of potential drug-drug interactions with opioids?A. Monoamine oxidase inhibitors are preferred

antidepressants in combination with opioidsB. Central-nervous system depressants can potentiate

the respiratory depression effects of opioidsC. Initiation of a CYP 3A4 inhibitor can result in lower

blood levels of opioidsD. Pharmacokinetic, but not pharmacodynamic, effects

contribute to the onset and duration of opioid analgesia

9. In which of the following clinical scenarios may a patient be discontinued from opioids without taper and management of withdrawal symptoms?A. Evidence of illegal diversion includes patient selling

prescriptions to othersB. Patient achieves inadequate analgesia despite titrationC. Patient engages in repeated escalation of opioid doses

without medical authorizationD. Patient experiences intolerable side effects

PRESCRIBER EDUCATION FOR OPIOID ANALGESICS

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10. Which of the following is one indication for take-home naloxone with opioid prescription?A. Family history of alcohol use disorder B. History of opioid overdoseC. Opioid dosages ≥20 MME/dayD. Co-prescription of a tricyclic antidepressant

11. Increased monitoring of patient response is essential during opioid dose initiation, upward titration, rotation, and addition of other central-nervous system depressants because:A. Constipation is more common during these timesB. Pain control is often inadequateC. Risk for respiratory depression is heightened D. Substance-use disorder is an expected outcome

12. Urine drug testing as a monitoring measure can tell the clinician which of the following:A. The types and dosages of opioids ingested by the patientB. Whether the patient has an opioid-use disorderC. Whether prescribed medications are present at the point

of testingD. Whether the patient has been “doctor shopping”

13. Which of the following factors increases a patient’s risk of opioid misuse?A. Severe migraine painB. History of illicit drug useC. Family history of domestic violenceD. Work as a manual laborer

14. Recommended frequency to check the prescription drug-monitoring database is:A. Once at baselineB. At baseline and every 6 months thereafterC. At baseline followed by every prescription to every 3

monthsD. Only when aberrant drug-related behaviors are observed

clinically

15. Which of the following influences the amount of dopamine released and the degree of reward experienced by an opioid user?A. Prior recreational drug useB. Combination with monoamine oxidase inhibitorsC. The route of drug administrationD. The presence of multiple medical comorbidities

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Read the course materials

Complete the self-assessment questions at the end. A score of 70% is required.

Return your customer information/answer sheet, evaluation, and payment to InforMed by mail, phone, fax or complete online at course website under NETPASS.

Completion of this course will better enable the course participant to:1. Explain the purpose and role of the Controlled Substances Act (CSA) as it relates to clinical practice.2. Explain the similarities and differences between the 5 DEA schedules for controlled substances.3. Know what pieces of information must be included on all prescriptions for controlled substances.4. Describe at least 4 signs that a controlled substance may be inappropriately prescribed.5. Describe the key steps recommended for the responsible prescribing of controlled substances.6. Describe pharmacological treatment options for treating pain, anxiety disorder, insomnia, narcolepsy, obesity, and

attention-deficit hyperactivity disorder. 7. Describe at least 4 practices clinicians can use to minimize diversion of controlled substances. 8. Know the 6 approved pharmacotherapies for treating alcohol and opioid use disorders.

LEARNING OBJECTIVES

TARGET AUDIENCE

This course is designed for all physicians and health care providers involved in the treatment and monitoring of patients prescribed controlled substances.

COURSE OBJECTIVE

The purpose of this course is to educate health care providers about the requirements of the Controlled Substances Act and safe prescribing practices for both opioid and non-opioid controlled substances. In addition, some of the medical conditions for which controlled substances are most commonly prescribed will be reviewed, along with recommendations for responsible management of these conditions with specific controlled substances.

Release Date: 10/2018 Exp. Date: 09/2021

Enduring Material(Self Study)

4 AMA PRACategory 1 Credits™

EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTION

ACCREDITATION STATEMENT:InforMed is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

DESIGNATION STATEMENT:InforMed designates this enduring material for a maximum of 4 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

43

FACULTY

Stephen BraunMedical WriterBraun Medical Media

Beth DoveMedical WriterDove Medical Communications

Melissa B. Weimer, DO, MCR, FASAM Chief of Behavioral Health and Addiction Medicine Saint Peter’s Health Partners Clinical Assistant Professor of Medicine Oregon Health and Science University

ACTIVITY PLANNERJoseph J. McGurrin

DISCLOSURE OF INTEREST:In accordance with the ACCME Standards for Commercial Support of CME, InforMed implemented mechanisms, prior to the planning and implementation of this CME activity, to identify and resolve conflicts of interest for all individuals in a position to control content of this CME activity.

STAFF AND CONTENT REVIEWERS:InforMed staff, input committee and all content validation reviewers involved with this activity have reported no relevant financial relationships with commercial interests.

DISCLAIMER*2019. All rights reserved. These materials, except those in the public domain, may not be reproduced without permission from InforMed. This publication is designed to provide general information prepared by professionals in regard to the subject matter covered. It is provided with the understanding that InforMed, Inc is not engaged in rendering legal, medical or other professional services. Although prepared by professionals, this publication should not be utilized as a substitute for professional services in specific situations. If legal advice, medical advice or other expert assistance is required, the service of a professional should be sought. These materials are not meant to dictate medical decision making. They are generally accepted medical practices rather than absolutes. Providers still have flexibility to deal with exceptional cases; occasional deviation for appropriate medical reasons is to be expected and documented.

FACULTY/PLANNING COMMITTEE DISCLOSURE:The following faculty and/or planning committee members have indicated they have no relationship(s) with industry to disclose relative to the content of this CME activity:

• Melissa B. Weimer, DO, MCR, FASAM• Stephen Braun• Beth Dove• Joseph J. McGurrin

This course satisfies 4 AMA PRA Category 1 CreditsTM on controlled substances.

The Wisconsin Medical Examining Board requires all licensed physicians (MD/DO) to complete thirty (30) AMA PRA Category 1 CreditsTM or equivalent during each biennial

renewal cycle.

AMA PRA CATEGORY 1 CREDITSTM

SPECIAL DESIGNATION

4

44

Introduction

The use of controlled substances is a major public health issue in the United States. These are drugs regulated by the government for use as prescription medications under the care of a medical provider. Unfortunately, such drugs are not always taken by those to whom they were prescribed, they are not always taken as directed, and, even when used as directed, they can lead to serious adverse effects, including physical dependence, addiction, or death.Every year, millions of people use prescription medications for the first time, whether illicitly or prescribed. In 2016, the most recent data available at the time the writing of this monograph, there were:1

• 2.1 million new users of prescription opioid pain relievers

• 1.4 million new users of prescription tranquilizers (benzodiazepines, muscle relaxants)

• 294,000 new users of prescription sedatives (sleep-aides, e.g., zolpidem)

While most people who use prescription drugs do not develop unhealthy patterns of use, a significant fraction do, and a significant fraction of the drugs themselves become diverted, intentionally or not, and fall into the hands of people with existing patterns of misuse or addiction.2 In 2016, an estimated 3.3 million people were currently misusing opioid pain relievers, 2 million were misusing tranquilizers, 1.7 million were misusing stimulants, and 497,000 people were misusing sedative-hypnotics.3 In all, more than 6 million Americans are misusing prescription drugs (including opioids), which is more than the number of Americans using cocaine, heroin, hallucinogens, and inhalants, combined.4

Opioid analgesics are currently in the spotlight of both government and popular attention because of the extreme toll these drugs are taking in terms of addition, overdose, and association with subsequent use of heroin and other illicit drugs. But, as the numbers just cited illustrate, opioids are not the only problematic class of controlled substances being prescribed by health care professionals. Non-opioid controlled substances are a diverse group of agents that include anxiolytics (e.g., alprazolam, diazepam, and lorazepam) sedative-hypnotics (including zolpidem and eszopiclone), muscle relaxants (e.g., barbiturates such as carisoprodol), and stimulants (including amphetamine, methylphenidate, and appetite suppressants such as phentermine).

Physicians and other health care providers play important roles in the nationwide effort to stem the tide of inappropriate use of controlled substances.

Survey data show that over half of the nonmedical users of pain relievers, tranquilizers, stimulants, and sedatives obtained their prescription drugs “from a friend or relative for free.”5 In a follow-up question, three quarters or more of these respondents indicated that their friend or relative had obtained the drugs from one doctor.5

Health care providers can help reduce diversion of controlled substance by thoroughly understanding both the regulatory frameworks surrounding controlled substances as well as the most recent professional guidance for prescribing, monitoring, and managing controlled substances in clinical situations.

Unfortunately, many prescribers have had little or no education on substance use disorder issues, either in professional school or through recurrent training.6 Furthermore, many prescribers are not educated or trained in prescribing practices that minimize risk with commonly misused medications. Less than half of the states have statutes or regulations that require or recommend education for prescribers of prescription pain medication.7

This monograph addresses this common gap in professional knowledge and presents the latest evidence-based guidance and “best practices” for responsibly prescribing the most commonly misused controlled substances. It will review the substances themselves, provide context for the current legal framework governing controlled substances, and summarize the ways clinicians can help limit misuse or help patients who have developed unhealthy patterns of use with these drugs. (Note: cannabis is a controlled substance, can be legally prescribed for a range of medical indications in a number of states, and, like any drug, can also lead to unhealthy patterns of use or behavior. This monograph, however, does not cover cannabis because the legal, medical, and cultural dimensions of this drug are in such dynamic flux at the time of this writing.)

Definitions

Because the problematic side of controlled substances involves misuse, physical dependence, and addiction, it is important to be clear about what these, and related terms, mean. The American Society of Addiction Medicine (ASAM), the American Academy of Pain Medicine (AAPM), and the American Pain Society (APS) have recommended the following definitions:8

• Aberrant drug-related behavior. A behavior outside the boundaries of an agreed-upon treatment plan.

• Abuse. Any use of a drug, or the intentional self-administration of a medication, for a nonmedical purpose such as pleasure-seeking or altering one’s state of consciousness.

• Addiction. A chronic, neurobiological disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations, characterized by behaviors that include one or more of the following: craving, impaired control over drug use, compulsive use, and continued use despite harm.

• Diversion. The intentional transfer of a controlled substance from legitimate distribution and dispensing channels.

• Misuse. Use of a medication other than as directed or as indicated, whether willful or unintentional, and whether harm results or not.

• Physical Dependence. A state of physical adaptation (tolerance) that is manifested by a drug class-specific withdrawal syndrome that can be produced by abrupt cessation, rapid dose reduction, decreasing blood level of the drug, and/or administration of an antagonist. Physical dependence is not the same thing as addiction.

• Tolerance. A state of adaptation in which exposure to a drug induces changes that result in a diminution of one or more of the drug’s effects over time.

The Diagnostic and Statistical Manual 5th Edition (DSM 5) categorizes addictive disorders by the specific substance misused, e.g., alcohol use disorders, opioid use disorders, and others. The diagnostic criteria from the DSM 5 for substance use disorder are as follows: “A problematic pattern of substance use leading to clinically significant impairment or distress, as manifested by at least two of the following, occurring within a 12-month period”:9

1. More of the substance taken or they are taken over a longer period than planned

2. The patient has difficulty cutting down or controlling use

3. Large amounts of time are invested in attempting to obtain, use, or recover from, using

4. Craving5. Use causes a failure to fulfill roles at work,

school, or home6. Continued use despite having social or

interpersonal problems caused by use7. Social, occupational, or recreational activities

given up because of use8. Use even when physically hazardous9. Use despite physical or psychological problems

caused by substance use

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10. Tolerance, as defined by the need for an increased amount to achieve intoxication, or decreased effect with continued use of the same amount of a substance. (This criteria is exempted from consideration if a drug or substance is being taken under the guidance of a medical professional.)

11. Withdrawal symptoms upon cessation of use, or substances taken to avoid withdrawal. (This criteria is exempted from consideration if a drug or substance is being taken under the guidance of a medical professional.)

The severity of substance use disorders can be described by the number of criteria the patient meets. A patient with mild disorder meets 2-3 criteria, moderate disorder meets 4-5 criteria, and a patient with severe disorder meets 6 or more criteria.9

The Controlled Substances Act

The federal government’s first attempt at regulating medications was through the Harrison Act passed in 1914.10 The Harrison Act criminalized what, at that time, was considered to be the “recreational” use of opium, morphine, and cocaine. While these drugs could still be legally obtained, physicians, dentists and veterinary surgeons were now required to register, document, and pay taxes on any packages containing these drugs. Over the next few years, thousands of prescribers who did not comply with the law were arrested, convicted, and jailed.

In 1970, the United States government passed the Federal Comprehensive Drug Abuse Prevention and Control Act. Now known as the Controlled Substances Act (CSA), the law consists of three parts, including rehabilitation services for people with substance use disorder, the regulation and distribution of controlled substances, and regulation of the importation and export of controlled substances.11 The Drug Enforcement Administration (DEA) administers all parts of the CSA. The CSA is continually updated to add, remove, or transfer over 160 substances across schedules. This monograph reflects the most recent issue of Title 21 Code of Federal Regulations (CFR) Part 1300. It is limited to describing the controlled substances most frequently encountered by health care providers and is not a comprehensive list.12

Since many controlled drugs are important tools in the clinician’s pharmaceutical armamentarium, the CSA attempts to balance two competing needs: to maintain an adequate and uninterrupted supply of these controlled substances for legitimate purposes while simultaneously reducing their diversion and abuse.13

The CSA places all substances which were in some manner regulated under existing federal law into one of five schedules (with the exceptions of alcohol and tobacco). This placement is based on the substance’s perceived medical use, potential for abuse, safety, and dependence liability. The law also provides a mechanism for new substances to be added to or transferred between schedules or for substances to be removed from control.

In determining into which schedule a drug or other substance should be placed, or whether a substance should be decontrolled or rescheduled, certain factors are required to be considered, including:14

1. The drug’s actual or relative potential for abuse

2. Scientific evidence of the drug’s pharmacological effect, if known

3. Its history and current pattern of abuse 4. The scope, duration, and significance of abuse 5. What, if any, risk there is to public health 6. The drug’s psychic or physiological

dependence liability7. Whether the substance is an immediate

precursor of a substance already controlled

After considering the above listed factors, the DEA administrator may make specific findings concerning the drug or other substance. This will determine into which schedule (if any) the drug or other substance will be placed.

Schedules of Controlled Substances

Controlled substances under the CSA are classified into one or more of five schedules.

Schedule I Substances

Substances in this schedule are deemed to have a high potential for abuse, have been determined to have no currently-accepted medical use in the United States, and evidence for their safe use under medical supervision has not been accepted. Some examples of substances listed in schedule I are: heroin, lysergic acid diethylamide (LSD, i.e. “acid”), peyote, and 3,4-methylenedioxymethamphetamine (MDMA, i.e.“ecstasy”). (Note: government-approved scientific and clinical research is currently underway with some Schedule I drugs, such as LSD, exploring their utility to treat a variety of mental health disorders, including addiction, the results of which may alter their classification in the future.15)

Schedule II Substances

Substances in this schedule are considered to have a high potential for abuse which may lead to psychological or physical dependence, and yet the drug or substance also has one or more currently accepted medical use in the United States. Examples include many opioid pain medications, and stimulants such as amphetamine, methamphetamine, methylphenidate, and cocaine.

Schedule III Substances

Substances in this schedule have less potential for abuse than substances in schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence. These substances also have currently accepted medical uses in the United States. Examples include buprenorphine and products containing not more than 90 mg of codeine per dosage unit (i.e. Tylenol with codeine®). Examples of schedule III non-opioid drugs include benzphetamine, ketamine, and anabolic steroids such as oxandrolone.

Schedule IV Substances

Substances in this schedule are thought to have a low potential for abuse relative to substances in schedule III and have currently accepted medical uses in the United States. Examples include alprazolam, clonazepam, diazepam, lorazepam, phenobarbital, temazepam, and triazolam.

Schedule V Substances

Substances in this schedule have a low potential for abuse relative to substances listed in schedule IV. These are generally used for antitussive, antidiarrheal, and analgesic purposes. Examples include cough preparations containing not more than 200 mg of codeine per 100 milliliters or per 100 grams.

Did You Know?

Some drugs or substances appear in two or more schedules, depending on the specifics of their formulation. For example, raw cannabis is listed as Schedule I, although products containing one or more of the active ingredients in cannabis (i.e., tetrahydrocannabinol, or THC) are listed as Schedule III. Likewise, gamma-hydroxybutyric acid (GHB) as a street drug is Schedule I, although when formulated in a product for clinical use it is listed as Schedule III.

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Classes of Controlled Substances

The CSA regulates five classes of drugs:

• Opioids• Sedative-Hypnotics• Stimulants• Hallucinogens• Anabolic steroids

With the exception of anabolic steroids, controlled substances are abused to alter mood, thought, and feeling through their actions on the central nervous system (brain and spinal cord). Some of these drugs alleviate pain, anxiety, or depression. Some induce sleep and others energize. Though most controlled substances can be therapeutically useful, the “feel good” effects of these drugs may contribute to their potential for abuse.

The extent to which a substance can reliably produce intensely pleasurable feelings (euphoria) increases the likelihood of that substance being abused.14

Table 1 lists some of the controlled substances that are commonly encountered and/or prescribed in clinical settings. Note that some substances, such as many common products that emit fumes that can be inhaled to alter consciousness, are not scheduled because doing so would impede legitimate commerce.14 New substances are continually being either discovered or invented which have abuse potential and, thus, the list of controlled substances continues to grow.

Opioids

Opioids are used to treat moderate to severe pain that does not respond to non-opioids alone. They are often combined with non-opioids because this permits use of lower doses of the opioid (i.e., dose-sparing effect). Nearly all types of pain respond to opioids; however, nociceptive pain is generally more responsive to opioids than neuropathic pain, which may require higher doses of opioids.17 Opioids play a major role in the treatment of acute pain (e.g., trauma, postoperative pain), breakthrough pain, cancer pain, and some types of chronic non-cancer pain. Opioids may also help relieve certain types of neuropathic pain, such as the acute pain of herpes zoster.

Opioids as a class include many specific agents available in a wide range of formulations and routes of administration, including:

• Oral (e.g., tablets, capsules, solutions, lollipops)

• Transdermal• Transmucosal• Rectal• Intrathecal

Combination products join an opioid with a non-opioid analgesic, usually for use in patients with moderate pain. Using a combination product when dose escalation is required risks increasing adverse effects from the non-opioid co-analgesic, even if an increase of the opioid dose is appropriate. In such cases, using a pure opioid is preferable. Care, in particular, must be given to not exceed maximal daily doses of acetaminophen.

In their daily practice, clinicians who treat patients with opioid pain medications must balance pain relief with the risks associated with opioid analgesics. The term “pharmacovigilance” refers to the range of procedures and processes used to achieve this goal. These procedures need not be burdensome and are akin to similar risk/benefit calculations required in the prescription of a great many other therapeutic agents.18 What makes opioids of particular concern is the fact that they are highly sought-after by people who use drugs and criminal elements in society. In addition, opioids have a wide range of potential adverse effects that can expose a patient to serious morbidity and even mortality.

Table 1. Commonly-prescribed Controlled Substances16

Schedule Substance Common Name

II Hydrocodone Vicodin, Norco (with acetaminophen)

II Oxycodone Oxycontin, others

II Morphine Duramorph, Infumorph, Arymo ER, others

II Hydromorphone Exalgo, others

II Amphetamine Dexedrine, Adderall

II Lisdexamfetamine Vyvanse

II Methylphenidate Concerta, Ritalin, Methylin

II Phenobarbital Nembutal

III Buprenophine Suboxone, Buprenex, Butrans, others

III Codeine

III Anabolic steroids Anabolic steroids

III Chlorphentermine Pre-Sate, Lucofen, Apsedon, Desopimon

III Dronabinol Marinol

IV Tramadol Ultram, ConZip

IV Alprazolam Xanax

IV Barbital Veronal, Plexonal, Barbitone

IV Carisoprodol Soma

IV Chlordiazepoxide Librium, Libritabs, Limbitrol, SK-Lygen

IV Clonazepam Klonopin, Clonopin

IV Diazepam Valium, Diastat

IV Lorazepam Ativan

IV Midazolam Versed

IV Modafinil Provigil

IV Phentermine Ionamin, Fastin, Adipex-P, Zantryl

IV Phenobarbital Phenobarbital

IV Temazepam Restoril

IV Zaleplon Sonata

IV Zolpidem Ambien, Ivadal, Stilnoct, StilNox

IV Zopiclone Lunesta

V Pregabalin Lyrica

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Risk is increased among: older adults; those with impaired renal or hepatic function; individuals with obesity, cardiopulmonary disorders, sleep apnea, or mental illness; and in patients who combine opioids with other respiratory depressants such as alcohol, sedative-hypnotics, benzodiazepines, or barbiturates.

Extended-release/long-acting opioids

Little evidence exists that specific analgesic formulations or dosing schedules affect efficacy or addiction risk (aside from those specifically made to reduce abuse risk), so selection of agent should be based on the patient’s pain complaint, lifestyle, and preferences.19 Generally, if opioids are used at all, it is better to offer short-acting opioids PRN (Table 2). Extended-release (ER) or long-acting (LA) opioids (with duration of action typically between 4 and 72 hours) may be helpful for patients who have difficulty managing an “as needed” regimen, or who are physically dependent on opioid analgesics and require continued use to maintain their functioning.

Scheduled long-acting opioids have the advantage of producing a steady state, without the cycling effect of pain relief and withdrawal associated with short-acting opioids, which could, theoretically, lead to problematic behavior patterns.20 With LA/ER agents, however, patients may end up using more drug than is actually needed, and physiological adaptations to the steady state may ultimately decrease efficacy.21 Clinicians should warn patients that oral ER/LA opioids should not be broken, chewed, or crushed, and patches should not be cut or torn prior to use, since this may lead to rapid release of the opioid and could cause overdose or death.

Prescribers considering ER/LA opioid products should consider carefully the general characteristics, toxicities, and drug interactions for these agents. [For detailed information on current

ER/LA opioid analgesics, see the FDA Blueprint for Prescriber Education, available at: https://www.accessdata.fda.gov/drugsatfda_docs/rems/Opioid_analgesic_2018_09_18_FDA_Blueprint.pdf]. Knowledge of particular opioid-drug interactions, and the underlying pharmacokinetic and pharmacodynamic mechanisms, allows for safer administration of opioid analgesics. Methadone can be an effective opioid, for example, but it must be prescribed carefully and with full knowledge of its highly variable pharmacokinetics and pharmacodynamics.

Abuse-deterrent formulations

Concern about opioid misuse and abuse has spurred efforts to create abuse-deterrent opioid formulations. Two agents commonly available, which are co-formulated with an opioid antagonist are Targiniq ER (oxycodone and naloxone) and Embeda ER (morphine and naltrexone). The abuse-deterrent forms of long-acting oxycodone also contain a polymer that makes the pill difficult to crush, snort, or melt for injection. Transdermal opioid formulations were thought to be less vulnerable to misuse, but such formulations can be abused.22 Abuse-deterrent opioid formulations do not prevent users from simply consuming too much of a medication or using it without a prescription.

In 2016, the most commonly misused subtype of prescription pain relievers consisted of hydrocodone products (6.9 million abusers), which include Vicodin®, Lortab®, Norco®, Zohydro® ER, and generic hydrocodone.23

Side Effects

Binding of opioids to receptors in various body regions (e.g., CNS, GI tract) results in both therapeutic effects and side effects. Potential side effects of opioids as a class include respiratory depression, sedation, mental clouding or confusion,

nausea, vomiting, constipation, itching, and urinary retention. With the exception of constipation, these side effects tend to subside with time. Constipation is so common, in fact, that when patients use opioids and do not have constipation, clinicians should consider possible reasons ranging from rapid bowel transit time to drug diversion. Constipation requires proactive treatment, with stimulating laxatives prescribed at the time of initiating opioids, and frequent re-evaluation. With the exception of constipation, uncomfortable or unpleasant side effects may potentially be reduced by switching to another opioid or route of administration (such side effects may also be alleviated with adjunctive medications).

Use caution when prescribing opioids to patients with conditions that may be complicated by adverse effects from opioids, including chronic obstructive pulmonary disease (COPD), congestive heart failure, sleep apnea, current or past alcohol or substance use disorder, mental illness, advanced age, or patients with a history of renal or hepatic dysfunction.

All newly pregnant women should have a urine drug test administered by the appropriate women’s health provider. In addition, providers should discuss a birth control plan to prevent unintended pregnancy with every woman of child-bearing age who has reproductive capacity when opioids are initiated due to the high likelihood of neonatal abstinence syndrome in children whose mothers use opioids throughout their pregnancies. Finally, it is not recommended that chronic pain be treated with controlled substances through telemedicine.

All chronic opioid therapy should be handled by a single provider or practice and all prescriptions should be filled in a single pharmacy, unless the provider is informed and agrees that the patient can go to another pharmacy for a specific reason.

Table 2: Long Acting vs. Immediate Release OpioidsLong acting opioids Immediate release opioids

Buprenorphine patch (Butrans) Codeine (generics)

Fentanyl patch (Duragesic) Fentanyl – transmucosal (Abstral, Actiq, Fentora, Lazanda, Onsolis, Subsys)

Hydrocodone (Zohydro ER) Hydrocodone+acetaminophen (generics, Norco, Vicodin, Xodol)

Hydromorphone ER (generics, Exalgo) Hydromorphone (generics, Dilaudid)

Methadone (generics, Dolophine, Methadose) Levorphanol (generics)

Morphine ER (generics, Avinza, Kadian, MS Contin) Meperidine (generics, Demerol, Meperitab)

Oxycodone (Oxycontin) Morphine (generics)

Oxymorphone ER (generics, Opana ER) Oxycodone (generics, Roxicodone)

Tapentadol (Nucynta ER) Oxymorphone (generics, Opana)

Tramadol ER (generics, ConZip, Ultram ER) Tapentadol (Nucynta)

Tramadol (generics, Ultram)

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Sedative-Hypnotics

Sedative-hypnotics, lower arousal levels and reduce nervous system excitability via a range of pharmacological mechanisms, the most prominent of which are facilitation of gamma-aminobutyric acid (GABA) receptors, opioid receptors, or inhibition of glutamatergic or catecholaminergic activity.24 Although widely-prescribed for their anxiety-relieving, muscle-relaxing, and sleep-inducing properties, sedative-hypnotics are also widely abused for these properties as well as their abilities to induce euphoria. Because ethanol acts on many of the same neuronal receptor targets as many of the sedative-hypnotics, lethal synergistic effects may occur.

Barbiturates were the first class of synthetic sedative-hypnotics to be introduced and many specific types with varying durations of action are FDA-approved for indications such as the relief of anxiety, the promotion of sleep, or the treatment of epilepsy. Benzodiazepines were discovered in the 1950s and have largely eclipsed barbiturates for a range of indications including anxiety, insomnia, muscle spasms, alcohol withdrawal, and as premedication for certain medical or dental procedures.25 Although initially thought to be less prone to induce tolerance and dependence than barbiturates, benzodiazepines are now recognized to be just as liable to diversion and abuse.26 Benzodiazepines are categorized as either

short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are used for the treatment of anxiety, though they are not effective for long term treatment of anxiety.24

Flunitrazepam (Rohypnol®) is a benzodiazepine that has never been approved by the FDA in the United States, but which is available by prescription in other countries and also as illegal preparations.14 Because it can impair judgment and induce amnesia, particularly when combined with ethanol, flunitrazepam has been associated with sexual assault.14

Non-benzodiazepines are molecularly distinct from benzodiazepines, although they act on the same GABA receptor sites and produce similar sedative effects.27 Common non-benzodiazepines include zolpidem (Ambien®), Zaleplon (Sonata®) and Eszopiclone (Lunesta®).

Gamma-hydroxybutyric acid (GHB) and its chemical analogs are widely used, both as a prescription medicine (Xyrem®), and as industrial solvents or components in many commercial products. Sold as a liquid or as a powder that is dissolved in another liquid and swallowed, GHB induces euphoric and calming effects as well as amnesia.

Carisoprodol is a centrally-acting skeletal muscle relaxant whose primary active metabolite is meprobamate, a substance with well established abuse potential similar to that of benzodiazepines.28 A number of reports show that carisoprodol has been abused for its sedative and relaxant effects, to augment or alter the effects of other drugs, and by the intentional combination of carisoprodol and other non-controlled medications because of the relative ease (as compared to controlled substances) of obtaining prescriptions.

The diversion and abuse of carisoprodol and its adverse health effects appear to have dramatically increased in recent years.29 Clinicians have begun to see a withdrawal syndrome consisting of insomnia, vomiting, tremors, muscle twitching, anxiety, and ataxia in patients who abruptly cease intake of large doses of carisoprodol. Hallucinations and delusions may also occur. The withdrawal symptoms are very similar to those described for meprobamate withdrawal, suggesting that what may actually be occurring is withdrawal from meprobamate accumulated as a result of intake of excessive amounts of carisoprodol. However carisoprodol itself is capable of modulating GABA function, and this may contribute both to the drug’s abuse potential and to the occurrence of a withdrawal syndrome with abrupt cessation of intake.

Stimulants

Stimulants induce a range of effects on the body and mind by enhancing activity of the central and peripheral nervous systems. Common effects, which vary depending on the stimulant in question, may include: enhanced alertness, wakefulness, endurance, productivity, and motivation; increased sexual arousal, locomotion, heart rate, and blood pressure; and diminished appetite. Many stimulants temporarily improve mood or induce feelings of euphoria.

Stimulants exert their effects through a number of different pharmacological mechanisms, the most prominent of which are facilitation of norepinephrine and/or dopamine activity, adenosine receptor antagonism, and nicotinic acetylcholine receptor agonism.24 Not all stimulants are listed as controlled substances. Caffeine, theophylline, and nicotine are widely used and legally available. Amphetamines and methylphenidate are controlled substances but are also widely-prescribed to treat attention-deficit disorders, sleep disorders such as narcolepsy and shift-work disorders, and as adjuvant medications for depression, especially treatment-resistant depression.24 Cocaine has limited medical uses as a topical local anesthetic and for reducing bleeding of mucous membranes in the mouth, throat, and nasal cavities. Other stimulants such as crack cocaine have no approved medical uses.

Quick Sedative-Hypnotics Facts

Physical signs of depressant overdose:• Shallow respiration• Clammy skin• Dilated pupils• Weak and rapid pulse• Slurred speech• Loss of motor coordination• Blurred vision• Nausea• Vomiting• Low blood pressure

Drugs causing similar effects:• Alcohol (ethanol)• Antihistamines• Certain antipsychotics

Available forms:• Tablets• Capsules• Syrups• Injectable liquids

Quick Stimulant Facts

Physical signs of stimulant overdose:• Tremors• Headache• Flushed skin• Chest pain with palpitations• Excessive sweating• Vomiting• Abdominal cramps

Drugs causing similar effects:• Although often classified as a

hallucinogen, MDMA (ecstasy) is a stimulant and can induce responses similar to classic stimulants

Available forms:• Tablets• Capsules• Powder• “Rocks”• Injectable liquids

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The clandestine production of amphetamines in the past decade has increased dramatically, particularly the production of methamphetamine, which is a potent central nervous system stimulant and highly addictive.14 (Note that a single brand of methamphetamine, Desoxyn,® is approved by the FDA for the treatment of attention deficit disorders.)

So-called “bath salts” are synthetic stimulants, also known as synthetic cathinones, which is the active chemical found naturally in the khat plant.14 “Bath salts” are sold as powders, tablets, or capsules under various brand names. They are usually ingested by sniffing/snorting, though they can also be taken orally, smoked, or put into a solution for injection.

Tolerance to higher doses of stimulants can develop quickly, as can psychological dependence. Abrupt cessation of stimulants is typically followed by a “crash” of depression, anxiety, extreme fatigue, and drug craving. Accidental death may be caused by cardiovascular collapse, dehydration, or high fever (physical exertion increases the hazards of stimulant use because of the effects of stimulants on the body’s hypothalamic temperature-regulation mechanisms).

Gabapentinoids such as pregabalin (Lyrica®) as well as the original agent gabapentin (Neurontin®) are approved to treat a variety of conditions, including post-herpetic neuralgia, fibromyalgia, and neuropathic pain associated with diabetes, and some literature suggests that clinicians may be prescribing these drugs off-label as alternatives to opioids.30 Currently in Schedule V, in 2016, gabapentin was the 10th most commonly-prescribed medication in the United States: 64 million gabapentin prescriptions were dispensed, up from 39 million in 2012.30

Although data are limited, they suggest that gabapentinoid abuse and misuse may be growing, both when taken alone and in combination with opioids, benzodiazepines, or other central nervous system depressants. Drug users say gabapentin pills, known as “johnnies” or “gabbies,” which often sell for less than a dollar each, enhance the euphoric effects of heroin and when taken alone in high doses can produce a marijuana-like high.30

DEA Requirements for PrescribingControlled Substances

To be eligible for DEA registration and legally prescribe controlled substances, a health care provider must meet certain requirements. He or she “must be a physician, dentist, veterinarian, hospital, or other person licensed, registered, or otherwise permitted by the United States or the State in which he or she practices to dispense controlled substances in the course of professional practice.”31 As a result, a prescriber who does not have a professional license or whose professional license has been temporarily suspended cannot hold a DEA license or legally prescribe controlled substances. Similarly, prescribers must have a DEA license in the state where they are professionally licensed.

Providers must be aware of regulatory developments and legislation associated with the prescribing requirements for controlled substances.32 This section will review the appropriate documentation for writing prescriptions, DEA prescriber registration, renewal, and revocation of registration.

Rules for Documentation

All prescriptions for controlled substances must be either typed or written in ink or indelible pencil, though some states (e.g., New York) mandate that all prescriptions for controlled substances be sent via electronic prescription (i.e., e-prescribed).33 Although a designated individual may write the prescription, it must be manually signed by the responsible provider. All prescriptions must contain the following elements:

• Prescriber’s name, address, and DEA registration number

• Manual signature of prescriber• Patient’s name and address• Date of issue• Drug name• Drug strength• Dosage• Quantity prescribed• Number of refills (may be 0)• Directions for use

Schedule II controlled substance prescriptions must be written and signed by the prescriber. Under certain very strict circumstances, they can be e-prescribed, but the electronic medical record is required to have specific authentication steps. Schedule II medications cannot be refilled; they require a new prescription each time they are filled. In case of emergency, the prescriber may telephone the prescription for a schedule II controlled substance into the pharmacy, but the prescriber must follow up with a written prescription within seven days. Schedule III and IV controlled substance prescriptions may be written, called in or faxed to the pharmacy, and they have a maximum of five refills in six months. Prescriptions for schedule V controlled substances do not have a limit on refills.

Registration, Renewal, and Termination of DEA License

To prescribe controlled substances, practitioners must be registered with the DEA. There are three ways to obtain DEA Form 224 and apply for registration:4

• DEA Diversion Web Site: DEAdiversion.usdoj.gov

• DEA field office• Registration Call Center: 1-800-882-9539

Once obtained, the Certificate of Registration (DEA Form 223) must be kept at the registered location and be easily retrieved for official inspection. DEA registration should be renewed every three years using DEA Form 224a. The DEA will mail the renewal form to the address listed on the current registration 45 days before the expiration date. The renewal can be completed online at DEAdiversion.usdoj.gov, or the printed renewal form can be mailed to:

Drug Enforcement Administration Registration Unit Central Station P.O. Box 28083 Washington, D.C. 20038-8083

Prescribers are required to update the DEA if they change their business address or discontinue their business.

Revoking a DEA License

The DEA can deny, suspend, or revoke registration if the prescriber has committed any of the following:4

1. Falsified the DEA application2. Been convicted of a felony associated with a

controlled substance3. Lacks a state practitioner license or

registration

Tolerance v. Addiction

Tolerance is an unavoidable neurophysical adaptation of the brain to the presence of a drug. As a result, patients can be expected to need higher doses of medication to obtain the same effect. Tolerance also implies that a person will experience withdrawal symptoms if a drug is suddenly stopped.

Addiction is the compulsive seeking and use of a drug despite continuing harm and dysfunction. Continued use of a substance by someone who is addicted decreases their functioning; use of a substance by a non-addict typically improves functioning.

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4. Cannot participate in Medicaid or Medicare5. Acted in a way that is inconsistent with public

interest, including sustaining state licensing or professional disciplinary society sanctions or being convicted of a federal or state crime associated with controlled substances

Locum Tenens

Health care providers who are working in a locum tenens capacity must understand the laws surrounding their DEA registration. Physicians who function in a locum tenens capacity temporarily substitute for a permanently employed physician while he or she is on leave. Some locum tenens physicians may also provide temporary care in a short-staffed hospital or clinic. If these practitioners work within a single state, they must be licensed and registered within that state.34 If they register at one location in the state but practice at a different location, they are not required to re-register with the DEA. However, if they work throughout the U.S. and administer, dispense, or prescribe controlled substances in several states, they must obtain a separate DEA registration in each state where they work, use the hospital’s DEA license if the hospital agrees, or transfer their DEA registration from one state to another.

Appropriate and Inappropriate Prescribing Practices

The legal standard that a controlled substance may only be prescribed, administered, or dispensed for a legitimate medical purpose by a provider acting in the usual course of professional practice has been construed to mean that the prescription must be “in accordance with a standard of medical practice generally recognized and accepted in the United States.”4

Federal courts have long recognized that it is not possible to define the phrase “legitimate medical purpose in the usual course of professional practice” precisely enough to cover all of the varied situations providers may encounter in clinical practice.4 There are, however, recurring patterns that suggest inappropriate prescribing of controlled substances by a clinician:4

• An inordinately large quantity of controlled substances prescribed or large numbers of prescriptions issued compared to other providers in an area

• No physical examination given • Advising a patient to fill prescriptions at

different pharmacies • Issuing prescriptions knowing that the patient

was delivering the drugs to others • Issuing prescriptions in exchange for sex or

money

• Prescribing controlled drugs at intervals inconsistent with legitimate medical treatment

• The use of street slang rather than medical terminology for the drugs prescribed

• No logical relationship between the drugs prescribed and treatment of the condition allegedly existing

Each case must be evaluated on its own merits in view of the totality of circumstances particular to the provider and patient. Regulatory agencies, for example, are typically aware that what constitutes “an inordinately large quantity of controlled substances,” can vary greatly from patient to patient. A particular quantity of a powerful Schedule II opioid might be blatantly excessive for the treatment of mild temporary pain, and yet be insufficient to treat the unremitting pain of a cancer patient.4

Regulations Pertaining to Internet Access to Controlled Substances

In 2008, an amendment to the CSA was passed to add new regulatory requirements and criminal provisions designed to combat the proliferation of so-called “rogue Internet sites.”14 The Ryan Haight Act made it illegal to dispense controlled substances in all schedules via the Internet. An online pharmacy is defined as a person, entity, or Internet site, whether in the United States or abroad, that knowingly or intentionally delivers, distributes, dispenses, or offers to deliver, distribute, or dispense, a controlled substance by means of the Internet.

This law became effective April 13, 2009. As of that date, it is illegal under federal law to deliver, distribute, or dispense a controlled substance by means of the Internet unless the online pharmacy holds a modification of DEA registration authorizing it to operate as an online pharmacy.

Security Requirements Related to Controlled Substances

The CFR requires all registrants to provide effective controls and procedures to guard against theft and diversion of the controlled substances they store or handle. Factors used to determine the adequacy of these security controls include:4

1. The location of the premises and the relationship such location bears on security needs

2. The type of building and office construction3. The type and quantity of controlled substances

stored on the premises4. The type of storage medium (safe, vault, or

steel cabinet)

5. The control of public access to the facility6. The adequacy of registrant’s monitoring

system (alarms and detection systems)7. The availability of local police protection

Registered health care providers are required to store Schedule II through V controlled substances in a securely locked, substantially constructed cabinet. In order to maximize security related to controlled substances, DEA recommends that health care providers not employ any of the following persons if they will have potential access to controlled substances:

1. Any person who has been convicted of a felony offense related to controlled substances

2. Any person who has been denied a DEA registration

3. Any person who has had a DEA registration revoked

4. Any person who has surrendered a DEA registration for cause

Lastly, practitioners should notify the DEA field office in their area of the theft or significant loss of any controlled substances upon discovery.4

Disposal of Controlled Substances

A practitioner may dispose of out-of-date, damaged, or otherwise unusable or unwanted controlled substances, including samples, by transferring them to a registrant who is authorized to receive such materials.4 These registrants are referred to as “Reverse Distributors.” The practitioner should contact their local DEA field office for a list of authorized Reverse Distributors. Schedule I and II controlled substances should be transferred via the DEA Form 222, while Schedule III–V compounds may be transferred via invoice. The practitioner should maintain copies of the records documenting the transfer and disposal of controlled substances for a period of two years.4

Guidelines for Prescribing Controlled Substances

Patients have long turned to health care providers to relieve suffering or improve their health or general functioning. However, health care providers face challenges when they prescribe controlled substances to their patients to help achieve these ends. Providers find themselves balancing issues of safety, a complex array of therapeutic options, compliance with governmental regulation and a mandate to alleviate patient suffering.

Since the Controlled Substances Act was passed in 1970, more than 160 medications have been added, transferred, or removed from the lists of controlled substances.16 As part of their obligation

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to be responsible health care providers, prescribers must be aware of new legislation and regulatory requirements associated with practicing medicine.32 However, prescribers are not always aware of the latest additions, changes, and deletions made in the schedules of non-opioid controlled substances. Nevertheless, the Drug Enforcement Agency can punish prescribers who fail to comply with the latest updates by revoking their prescribing license, closing their businesses, implementing fines, or inflicting prison time. These negative outcomes may be prevented if prescribers educate themselves about which medications are on the controlled substances list and how to safely prescribe them to patients.

Health care providers who prescribe controlled substance to patients must understand all of the associated risks. For example, in one study examining the interaction between prescribing physicians and older patients on chronic anxiolytics, the prescribing physicians continued prescribing anxiolytic medications to their patients because they believed that elderly patients were at low risk of addiction.35 This practice is problematic, however, because even though the patients were at low risk of addiction they were also at increased risk of falls, motor vehicle collisions, and functional decline associated with the substances being prescribed.

Before a provider prescribes a controlled substance, he or she must understand all alternative treatments and be able to justify why the patient requires a controlled substance. Once a physician accurately diagnoses a disease, he or she cannot simply prescribe a controlled substance, but must remain updated on all of the latest management options including lifestyle changes, medical management, or surgical interventions. Moreover, health care providers are obligated to thoroughly document the patient history, physical examination and alternative treatments before prescribing a controlled substance.31

PLEASE SPEND THE ALLOTTED TIME ON EXERCISE 1.

Case Study Exercise 1

Instructions: Spend 5-10 minutes reviewing the case study below and considering the questions and commentary that follow.

Jenny Cook is a 42 year old woman who has recently relocated and become your patient. On her first visit to your clinic, she reports that her personal health has been quite good, except for an extra 100 pounds that she has been struggling to lose since she gained weight in college 20 years ago. She is sedentary and works at an office job, but she says she walks at the high school track for at least 30 minutes, 3 times a week. She reports, however, that she has been feeling a strange “fluttering” in her chest during those walks for the past 6 months. She doesn’t think it is anything serious, but decided to mention it anyway.

Question 1: What follow-up questions do you have about the patient’s chief complaint?

Commentary on Question 1: The patient’s chief complaint is the “fluttering” she has in her chest while exercising. Although she alludes to weight gain, it is important for you to investigate her possible arrhythmia first. As always, you must ask about the nature, timing, exacerbating and relieving factors associated with her “fluttering.” You should also ask her about any co-morbid conditions, past medical history, past surgical history, family history of heart disease or thyroid disease, and if she is taking any medications. When she tells you her medications, you must evaluate the side-effect profile of each medication.

Except for the extra weight, the patient denies any past medical or past surgical history. She does not have any allergies to medications, and she regularly takes a birth control pill, multivitamin, and phentermine. She requests re-fills on all of her medications. When you ask her how long she has been taking phentermine, she responds that she has been taking it on and off since it was initially prescribed for her by the health care provider at University Health Services. She had been taking the combination fenfluramine/phentermine (fen-phen), but stopped when that drug was taken off the market. However, a friend of hers, who is a nurse practitioner, began prescribing phentermine to Jenny again 5 years ago. Now that Jenny has moved to a different state, her friend told her that she could no longer prescribe phentermine because it is a controlled substance.

Question 2: Describe any concerns you have about the patient’s health history?

Commentary on Question 2: Although the patient denies any past medical problems, she has been taking phentermine for many years. Phentermine is a non-opioid stimulant controlled substance used for weight loss. It was previously approved as a combination medication with the drug fenfluramine to create fen-phen. Fen-phen was taken off the market when several studies showed that its side-effect profile included significant cardiac complications, with valvular regurgitation impacting over 20% of patients.36 Although the combination drug was taken off the market, patients who used to take the medication are still at risk for adverse events. You should be concerned that this patient did not undergo a cardiac evaluation after discontinuing fen-phen. In addition, phentermine is not meant to be used long-term, and patients who are currently taking this drug should be carefully monitored. This patient has been taking the drug chronically, and she was not monitored appropriately by a health care provider. (Case study continues later in this monograph.)

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Harm Reduction and Risk Mitigation

Providers should consider and implement risk mitigation strategies prior to prescribing controlled substances. Clinical decision making should remain patient-centered including focusing on patient safety. Risk mitigation strategies alone or in combination improve patient safety. The strategies and their frequency should be commensurate with risk factors and include:

• An informed consent conversation covering the risks and benefits of treatment with a controlled substance as well as alternative therapies

• Ongoing, random urine drug testing (including appropriate confirmatory testing), although providers should be aware that such testing can be expensive and is not always covered by a patient’s insurance

• Checking state prescription drug monitoring programs

• Monitoring for overdose potential and suicidality

• Providing overdose education• Prescribing naloxone rescue medication if

indicated

Evaluation and Risk Assessment

A Universal Precautions approach to prescribing controlled substances assumes that all patients are capable of prescription drug misuse and that procedures should be implemented to mitigate this risk. These procedures include making a clear diagnosis of the disorder being treated, assessing risk of drug misuse, obtaining informed consent regarding the abuse liability of controlled substances, and continually re-evaluating treatment effectiveness and patient adherence.37

Health care providers must perform and document a complete history and physical in accordance with the usual course of professional practice before legally prescribing any controlled substances. The documented history should include a description of the patient’s chief complaint, attempted treatments, and co-morbid conditions. The physical examination should be used to identify co-morbid conditions and should include a neurological assessment.

Essential questions about symptoms include:

• What are the symptoms? • When did the symptoms start? • Was there an inciting event? • How do symptoms impact daily life? • What did the patient do in response to the

symptoms?

• Has the patient been treated for this problem in the past?

• If so, were they prescribed a controlled substance?

• Who prescribed the controlled substance and at what doses?

Questions to consider when taking a history include:

• Does the patient have any other medical disorders? º Specifically for sedatives, any respiratory

disorders, frequent falls, or cognitive issues?

º Specifically for stimulants, any cardiovascular issues?

• Does the patient have a history of substance use disorders, including tobacco use? º Is there evidence in the chart of a

history of a substance use disorder that the patient may not be disclosing? Do they have a collateral contact, such as a spouse, to verify this? Is a urine drug screening needed to confirm?

• Has the patient ever had an opioid (or other substance) overdose?

• Does the patient have a history of psychiatric disorders? If so, is the disorder currently active? Is there any potential for suicide?

• Is the patient prescribed other central nervous system (CNS) depressants?

• Is there evidence of drug diversion in the past?

• Is there a family history of substance use disorders?

• Are there children in the household? • Can medications be secured?• Is there a history of trauma or abuse?

If the patient is currently taking a controlled substance, the provider should ask for the name and location of the previously treating physician and, if available, check a prescription monitoring program (PMP) to corroborate that information. The health care provider must learn if the patient has attempted other treatment modalities, including dietary modification, physical therapy, behavioral therapies, medical management with a non-controlled substance, or surgical intervention. The provider should also ask if the patient’s symptoms improved or deteriorated in response to prior interventions.

In order to safely manage the patient, the health care provider should find out if the patient is suffering from any co-morbid diseases or conditions, including a history of substance use disorders or harm related to substance use.

To safely treat patients with controlled substances, providers should be aware of risk factors for overdose and addiction. Addiction risk factors include a personal or family history of any substance use disorder (including current tobacco use), and psychiatric comorbidity.38 Chronic respiratory illness, acute psychiatric instability, uncontrolled suicidality, active substance use disorder, concomitant use of benzodiazepines or other known CNS depressants (including alcohol) and known diversion in the past are other relative contraindications to controlled substance prescribing.39

Providers should also perform a directed physical exam and review any additional diagnostic studies or labs the patients may have required in the past. Patients may need to undergo additional imaging or diagnostic testing. As above, a urine drug screen may be needed at baseline when there is a high suspicion of an active substance use disorder (alternatively, and less subjectively, all patients may be required to submit a baseline urine drug screen). On physical examination, the health care provider should be vigilant for signs of intoxication or withdrawal, track marks from injection drug use, bruising from needles, and physical exam findings that do not fit with the presenting complaint (for example, the patient is at an appropriate weight but seeking weight reduction).40

Once a rigorous clinical assessment has established a clear indication for the prescription, the clinician and patient must balance the potential benefit of the medication in treating the diagnosis with the risks inherent to the medication including addiction and overdose. Although most risk-management screening tools are designed for prescribing opioids, they can also be modified and applied to screen patients for risk of misuse of non-opioid controlled substances. The most common of these are the Opioid Risk Tool (ORT), the DIRE Score, and the Screener and Opioid Assessment for Patients with Pain (SOAPP). It should be noted that these tools assess risk and should not be used to determine whether or not opioids should be prescribed.

Several mental health assessment tools are available and may be prudent to use if there is suspicion of an underlying psychiatric disorder, which may enhance risk of misuse of controlled substances, if left untreated.

PLEASE SPEND THE ALLOTTED TIME ON EXERCISE 2.

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Case Study Exercise 2

Instructions: Spend 15-20 minutes reading the case study below, reviewing the mental health assessment tools, and considering the questions that follow.

Harold, a well-dressed 62-year-old African American man, uses a walker to slowly make his way down your clinic hallway. In the exam room, he says he has always been physically active, playing golf and enjoying long walks. He was diagnosed with metastatic prostate cancer 17 years ago, but the cancer has been held in check by a novel chemotherapeutic agent. Now, however, he has severe (8 out of 10) axial lumbar pain due to disc herniation at the L4 – L5 region. For the past four months he says he’s been unable to play golf or do any of his former activities, in addition to being tired from disrupted sleep. He describes breakthrough pain occurring despite the Tylenol #3 he was prescribed. “I just can’t go on like this,” he says. “You’ve got to help me out.”

Mental Health Assessment Tools1. Patient Health Questionnaire –2 (PHQ-2). This is a simple two-item screening tool. If it is positive on either item, the clinician should offer another

more detailed questionnaire to better assess the presence or absence of a depressive disorder. One link to this screening tool: cqaimh.org/pdf/tool_phq2.pdf

2. Patient Health Questionnaire–9 (PHQ-9). This nine-item tool screens for a depressive disorder, and often is used as a follow-up to the PHQ-2 if it is positive. It’s easy to score and use and available at: integration.samhsa.gov/images/res/PHQ%20-%20Questions.pdf

3. Zung Self-Rating Depression Scale (Zung). This is a 20-item written questionnaire available at: mentalhealthministries.net/resources/flyers/zung_scale/zung_scale.pdf

4. Hamilton Depression Rating Scale (Ham-D). This is 21-item screening questionnaire. Scores <7 are normal. http://img.medscape.com/pi/emed/ckb/psychiatry/79926-1889862-1859039-2124408.pdf

5. Generalized Anxiety Disorder 7-item Scale (GAD) available at: integration.samhsa.gov/clinical-practice/GAD708.19.08Cartwright.pdf6. Primary Care PTSD (PC-PTSD). This is a four-item screening test for post-traumatic stress disorder available at: integration.samhsa.gov/clinical-

practice/PC-PTSD.pdf

Question 1: Which of these tools might be appropriate to use with Harold?

Question 2: How might Harold’s mental health issues interact with the management of his pain?

Question 3: What other tools or techniques might be used to better characterize Harold’s overall mental and physical functioning? (E.g., taking a psychosocial history; using the DSM-5 to diagnose his mental status; or asking questions aimed at assessing his level of physical and social functioning.)

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Provider/Patient Agreements

Once the patient has been selected for management with any controlled substance, a robust treatment agreement should be used to build trust in the patient-physician relationship and to clarify expectations. Treatment agreements consist of informed consent language, descriptions of the treatment and what to expect, responsibilities of both parties, reasonable alternatives, benefits,

and risks. While data supporting the effectiveness of treatment agreements are lacking, they are considered a standard practice. Possible side effects, including addiction and overdose, need to be fully and clearly explained, both in writing and verbally.

Continual assessment of adherence and effectiveness of the treatment with a controlled substance is crucial. A functional assessment

of changes in daily activities, quality of life, and medication side effects is helpful in weighing the effectiveness of the prescribed medication. Medication adherence and other drug use can be assessed using regular urine drug screenings PMP queries, and pill counts.

PLEASE SPEND THE ALLOTTED TIME ON EXERCISE 3.

Case Study Exercise 3

Janet is an 82-year-old Caucasian woman. Her husband died of an ischemic stroke five years ago, and now her son Tim, who lives nearby, looks after her. Janet has had chronic left hip pain ever since a hip fracture repair two years ago developed a serious infection. She comes in to see you with Tim because she is having worsening pain.Although she has always been quick-witted and articulate, in recent years Janet has had memory problems, often pausing in mid-sentence as she searches for a name or word that’s “right on the tip of her tongue.” She views these memory lapses as completely normal, although Tim finds them worrisome. According to Janet, the pain medication she was prescribed (short-acting hydrocodone/acetaminophen) is not enough to quell the pain in her hip (she says both are now hurting). According to Tim, however, Janet often forgets how much medicine she has taken. Tim feels Janet is relying too heavily on the analgesics—he believes strongly that much of Western medicine is misguided, overly invasive, overly reliant on “pills for everything.” Janet dismisses Tim’s concerns and presses for a long-acting opioid she saw advertised on television.

Instructions: Spend 10-15 minutes reviewing the sample controlled substance patient agreement below, then answer the questions that follow related to the “Janet” scenario above:

SAMPLE PATIENT AGREEMENT: Controlled Substance Treatment

PATIENT NAME:

PRIMARY CARE PHYSICIAN/SITE:

I understand that this agreement between myself; and (insert name of medical office/group) is intended to clarify the manner in which chronic (long-term) controlled substances will be used to manage my chronic pain. Chronic controlled opioid therapy for patients who do not suffer from cancer pain is a controversial issue.I understand that there are side effects to this therapy; these include, but are not limited to, allergic reactions, depression, sedation, decreased mental ability, itching, difficulty in urinating, nausea and vomiting, loss of energy, decreased balance and falling, constipation, decreased sexual desire and function, potential for overdose and death. Care should be taken when operating machinery or driving a car while taking these medications, particularly if you feel impaired. When controlled substances are used long-term, some particular concerns include the development of physical dependence and addiction can occur. I understand these risks and have had my questions answered by my health care provider. I understand that my (insert name of medical group) health care provider will prescribe controlled substances only if the following rules are adhered to:• All controlled substance prescriptions must be obtained from your (insert name of medical group) primary care provider. If a new condition develops, such as trauma

or surgery, then the health care provider caring for that problem may prescribe opioids for the increase in pain that may be expected. I will notify my primary care provider within 48-hours of my receiving an opioid or any other controlled substance from any other licensed medical provider. For females only: If I become pregnant while taking this medicine, I will immediately inform my obstetrician and obtain counseling on risks to the baby.

• I will submit urine and/or blood on request for testing at any time without prior notification to detect the use of non-prescribed drugs and medications and confirm the use of prescribed ones. I will submit to pill counts without notice as per health care providers’ request. I will pay any portion of the costs associated with urine and blood testing that is not covered by my insurance.

• All requests for refills must be made by contacting my (insert name of medical group) primary care provider during business hours at least 3-workdays in advance of the anticipated need for the refill. All prescriptions must be filled at the same pharmacy, which is authorized to release a record of my medications to this office upon request. A copy of this agreement will be sent to my pharmacy.

• Pharmacy name/address/telephone: • The daily dose may not be changed without my (insert name of medical group) primary care provider’s consent. This includes either increasing or decreasing the

daily dose. • Prescription refills will not be given prior to the planned refill date determined by the dose and quantity prescribed. I will accept generic medications. • Accidental destruction, loss of medications or prescriptions will not be a reason to refill medications or rewrite prescriptions early. I will safeguard my controlled

substance medications from use by family members, children or other unauthorized persons. • You may be referred to an appropriate specialist to evaluate your physical condition. • You may be asked to have an evaluation by either a psychiatrist or psychologist to help manage your medication needs. • If your provider determines that you are not a good candidate to continue with the medication, you may be referred to a detoxification program or evaluation by a

pain management center. • These medications may be discontinued or adjusted at your provider’s discretion. I understand that it is my provider’s policy that all appointments must be kept or canceled at least 2-working days in advance. I understand that the original bottle of each prescribed controlled substance medication must be brought to every visit. I understand that I am responsible for meeting the terms of this agreement and that failure to do so will/may result in my discharge as a patient of (insert name of medical group). Grounds for dismissal from (insert name of medical group) include, but are not limited to: evidence of recreational drug use; drug diversion; altering scripts; obtaining controlled substance prescriptions from other providers without notifying this office; abusive language toward staff; development of progressive tolerance; use of alcohol or intoxicants; and engagement in criminal activities.

Patient’s Signature: Date:

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Patient Education About Controlled Substances

Responsible prescribing of controlled substances requires clinicians to fully educate patients about the many issues related to safe use, storage, and disposal of such substances. Not only will educating patients possibly improve their adherence to any medication regimen, it may prevent accidental overdose or inadvertent diversion to non-authorized users.

Controlled substances of all kinds require a higher level of care and responsibility on the part of patients due to their potential for misuse or abuse. Hence, education about safe use, storage, and disposal should be part of every provider-patient interaction involving these substances. This education may include verbal instructions delivered by a prescriber, nurse or other trained clinic staff person, written handouts, guidance through other media (such as DVDs or the Internet), or referral to other resources (such as a local clinic webpage or national resources). All patient-directed materials should be written at a 6th-7th grade reading level, or lower depending on patient literacy.

Patients should be instructed about the proper use and administration of any prescribed controlled substances, including special directions about timing

of doses, whether to administer the medication with food or without, and any foods or other medications to avoid while administering. Here are some other key ideas to convey to patients about proper use:

• Read the prescription container label each time to check dosage

• Never use medicines after the expiration date• Never share medicines with others• Do not take a medicine with alcohol or other

sedatives• Do not take a medicine to promote sleep

(unless it has been specifically prescribed for that use)

• Never break, chew, or crush medicines• Transdermal products may be affected by

external heat, fever, and exertion, which can increase absorption of a medication, leading to a potentially fatal overdose

• Transdermal products with metal foil backings are not safe for use in MRI scanners

Patients should be continually reminded that sharing, selling, or giving away controlled substances is against the law and poses significant hazards not just to the recipient of the medications, but to society at large.

Health care providers must also educate patients about the importance of proper storage of controlled substances. Even children or close relatives can be tempted to use medications they have not been prescribed, and these are often the way controlled substances become available to non-authorized uses. It is best if all controlled substances are stored in a locked cabinet or other secure storage unit. Storage areas should be cool, dry, and out of direct sunlight. Remind patients not to store medications in their car, to keep medications in the original containers, and to avoid storing medications in the refrigerator or freezer unless specifically directed to do so by a healthcare provider or pharmacist. Patients, family members, or care-givers should also monitor pill containers so they will know if any pills are missing.

Educating patients about proper disposal of unused controlled substances is also important. The U.S. Food and Drug Administration recommends a variety of disposal methods, depending on the specific drug being disposed.41 Some states, however, may have different or more stringent guidelines. California, for example, instructs consumers not to flush any medicines down the toilet or drain. If flushing medicines is not allowed in your state, instruct patients to follow the instructions of a pharmacist for disposal or to mix the medicines

Case Study Exercise 3 (Continued)

Question 1: Would this agreement be appropriate for use with Janet?

Question 2: Would this agreement need to be modified in any way because of the specifics of Janet’s case?

Question 3: Would it be prudent to include a family member in the discussion about treatment and to serve as a witness to the agreement?

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with an undesirable substance, such as used coffee grounds, put the mixture into a disposable container with a lid or a sealable bag, and place it in the trash. (Note: in 2014, the DEA loosened regulations to allow pharmacies, hospitals, clinics, and other authorized collectors to serve as drop-off sites for unused prescription drugs).

The DEA sponsors the National Take Back Initiative which coordinates periodic take-back programs at thousands of state and local law enforcement agencies across the country. More information about these programs can be found at: deadiversion.usdoj.gov/drug_disposal/takeback/.

Urine drug screening

Urine drug screening is noninvasive and widely available. Urine drug testing should be used to screen for the presence of prescribed and non-prescribed medications and illicit drugs. Urine drug testing does not definitively confirm whether prescription drug misuse has occurred and does not diagnose the presence of a substance use disorder, and, thus, should be used only as one tool to assess adherence or for the presence of a substance use disorder.

In the context of family practice settings, unobserved urine collection is usually an acceptable procedure for drug testing. Prescribers, however, should be aware of the many ways in which urine specimens can be adulterated. Specimens should be shaken to determine if soap products have been added, for example. The urine color should be noted on any documentation that accompanies the specimen for evaluation, since unusually colored urine could indicate adulteration. If possible, urine temperature and pH should be measured immediately after collection.42

One way to reduce the risk of urine test false positives or false negatives is to develop a relationship with a single laboratory, become familiar with its testing tools and threshold values, and use the same screening and confirmatory tests regularly to build familiarity with the range of normal results. Providers should only order the minimum necessary testing on a regular basis, however, as lab costs due to unnecessary testing can become quite expensive. For low risk patients, the number of tests needed per year may be as few as 2, or every 6 months. It is also generally not necessary to obtain quantitative results to confirm medication adherence.

Prescribers should be familiar with the metabolites associated with each opioid that may be detected in urine, since the appearance of a metabolite can be misleading. A patient prescribed codeine,

for example, may test positive for morphine because morphine is a metabolite of codeine. Similar misunderstandings may occur for patients prescribed hydrocodone who appear positive for hydromorphone or oxycodone and oxymorphone. If questions arise, it is important to reach out to the lab toxicologist for consultation. Additionally, it is not recommended that providers make decisions about patient care solely based on the result of one urine drug test. It is important to interpret the results with other clinical information.

Prescription Drug Monitoring Programs (PDMPs)

PDMPs are state-operated databases that collect information on dispensed medications. The first PDMP was established in 1939 in California, and by 1990 another eight state programs had been established.43 PDMPs periodically send reports to law enforcement, regulatory, or licensing agencies as part of efforts to control diversion of medication by prescribers, pharmacies, and organized criminals. Such diversion can occur through medication or prescription theft or illicit selling, prescription forgery or counterfeiting, nonmedical prescribing,

and other means, including diversion schemes associated with sleep clinics (sedative-hypnotics and barbiturates), weight clinics (stimulants), and pain clinics (opioid medications).43

The first PDMPs, which were paper-based, did not provide reports to healthcare providers for use during individual patient care; however, today’s electronic databases have a variety of features that make them practical for such care. Depending on the particular state law, the types of professionals who may register to access PDMP records include prescribers (e.g., primary care doctors, nurse practitioners, physician assistants), dispensers (e.g., pharmacists), medical examiners, practitioner licensure board members, third-party payers, public health and safety agency representatives, and law enforcement and drug court personnel.2 Most PDMPs permit providers to delegate access to a mid-level practitioner, such as a registered nurse or a pharmacy technician.2 In more than half of states, prescribers and pharmacists are required to register with their respective PDMP; in some of these states, registrants are also required to access the PDMP for a patient’s prescription history before prescribing or dispensing controlled substances.2

PDMPs Today

PDMP databases in most states are housed within a licensing or public health agency; in a few states, they are located within a law enforcement agency. Most states track prescriptions for Schedule II–V controlled medications, and some also track unscheduled medications with misuse potential (e.g., ephedrine, which can be used to make methamphetamine).

Most PDMPs update their data on a daily or weekly basis, enabling prescribers and dispensers to assess a patient’s recent patterns of use or misuse. Systems are evolving toward even more frequent updating; in 2012, Oklahoma became the first state to institute real-time reporting, with prescription data available within 5 minutes after medication is dispensed.44 Real-time reporting can offer some advantages; in particular, emergency department care providers can find near real-time prescription histories for patients presenting for acute care.

Some state PDMPs provide batch reporting; this is a utility that enables prescribers to obtain summary histories for a group of patients, such as those scheduled for upcoming appointments. The practitioner can review the summaries to determine whether a full report should be ordered for any particular patient.

Table 3: Metabolites of Common Opioid Pain Medications

Drug Metabolites

Morphine MorphineHydromorphoneCodeine

Codeine CodeineMorphineHydrocodone

Hydrocodone HydrocodoneHydromorphone6-Hydrocodol

Oxycodone OxycodoneOxymorphoneHydrocodone

Source: Webster LR, and Dove B. Avoiding Opioid Abuse While Managing Pain. Lifesource. 2007.

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Most state PDMPs are authorized to send unsolicited reports to providers, licensing boards, or law enforcement agencies when a prescriber’s or prescription recipient’s activity exceeds thresholds established by the PDMP.45 Unsolicited reports can alert healthcare providers to intervene with patients whose prescription-related behavior may suggest substance misuse, whereas unsolicited reports to investigative agencies or licensure boards can support investigations into potential drug diversion or problematic prescribing.

More than half of the states are building systems to allow for data sharing across systems, agencies, and states.7 Benefits of this system integration include the following: providers can obtain patient prescription history within the electronic health record system instead of logging into two separate systems; state Medicaid agencies can share information with federal health service providers (e.g., U.S. Department of Veterans Affairs, Indian Health Service); and adjacent states are able to share information to address illicit cross-border prescription filling or to provide for better coordination of the care that a patient is receiving in different states.

Collecting data

Pharmacies must submit required data to their state’s PDMP for each prescription they dispense for specified controlled substances. Pharmacies in the U.S. Department of Veterans Affairs and in the Indian Health Service are also authorized to submit data to PDMPs, and such pharmacies in many states do so.7 Depending on a state’s legislative requirements, the following entities/ individuals may also be required to submit prescription data when dispensing controlled substances: emergency departments, wholesale distributors, licensed hospital pharmacies, physicians, veterinarians, dentists, and medical and behavioral health service providers.

Information collected typically includes date dispensed, patient, prescriber, pharmacy, medication, and quantity. This information is submitted to databases in electronic form. The intervals at which pharmacies are required to submit data vary by state.

Typically, prescriptions for intravenous medications and those filled by hospice palliative care are not submitted to PDMPs. In addition, federal confidentiality rules exempt medications dispensed at opioid treatment programs (OTPs)—that is, when a medication for the treatment of a substance use disorder (e.g., methadone, buprenorphine) is dispensed at an OTP, patient-identifying information is not submitted to the PDMP. There are some exceptions specified in the federal regulations.

OTP-based prescribers may access PDMP information to help manage the care of their patients, and the Substance Abuse and Mental Health Services Administration (SAMHSA) encourages them to do so.1 It is especially important that OTP-based physicians and physicians who are qualified to prescribe buprenorphine for opioid use disorder (i.e., physicians who have received a waiver under the Drug Addiction Treatment Act of 2000) access the PDMP, because these physicians are the only practitioners who have full knowledge of their patients’ controlled medication histories.

Privacy and security

States work hard to ensure the privacy and security of health information to prevent identity theft and medical fraud. One such safeguard is that many PDMPs are prohibited from providing identifying information about individual patients or practitioners in reports to law enforcement agencies, except in specified situations such as in response to a subpoena or for an active case investigation. Such prohibitions are also intended to protect confidentiality and avoid potential targeting of providers engaged in legitimate prescribing and dispensing activities.

Using PDMP data

PDMP reports can be used by a healthcare practitioner with other support tools (e.g., documentation templates, patient data reports and summaries, computerized alerts and reminders) when screening a new patient or monitoring a current patient. The practitioner can review the patient’s prescription record from the PDMP to confirm or augment information provided by the patient’s own reports and the medical exam. Providers can promote patients’ acceptance of this tool by proactively informing them that PDMP data are routinely checked for all patients to enhance care and that confidentiality and privacy are protected by law and regulation.

For example, when treating for chronic pain, a practitioner can check the state PDMP for data on the patient’s history of prescriptions for controlled substances. This information can be used to determine whether the patient is already receiving opioid medications or other medications that, when combined with an opioid prescription, might put him or her at risk for overdose. The Centers for Disease Control and Prevention (CDC) advises: “Clinicians should review PDMP data when starting opioid therapy for chronic pain and periodically during opioid therapy for chronic pain, ranging from every prescription to every 3 months.”46

Whether updated in real time or at some other regular interval, a PDMP provides longitudinal information from which a healthcare practitioner can identify patterns of inappropriate prescription medication use or risky substance use behavior. PDMP data may suggest that a patient has an uneventful prescription history, giving confidence to the practitioner that the patient has a legitimate need for any scheduled prescription medications under consideration.

The data can also reveal whether the patient has been prescribed medication that may create a risk for interaction with a medication the practitioner is considering prescribing. For example, the data can suggest the total level of morphine equivalent to which a patient already has access and whether the patient has access to other medication(s) that may, in combination, put the patient at risk for overdose. Another potential use of the data is to determine whether a patient has failed to fill a prescription for medication previously prescribed by that practitioner; in such situations, the practitioner can initiate a conversation about why the patient is not taking the medication as indicated.

A practitioner can also use PDMP data to monitor patients with suspected or known substance use disorders by checking patient records for medically unwarranted concurrent use of prescription medication (e.g., high doses of several prescriptions, including long- and short-acting opioids as well as benzodiazepines) and use of multiple prescribers or pharmacies. Other indicators of potentially problematic prescription use that a practitioner can look for when reviewing PDMP data include early refills and dose escalation.

Behavior that suggests substance misuse, a substance use disorder, or diversion is known as aberrant drug-related behavior. PDMP data can alert a practitioner to aberrant behavior such as doctor shopping (obtaining overlapping prescriptions from different doctors for intended nonmedical use) or pharmacy shopping (visiting multiple pharmacies to fill prescriptions); these are called “multiple provider episodes.”

PDMP data are best used in conjunction with other sources of information, including clinical assessment, before making any determinations about aberrant behavior, because no validated and standardized criteria for the threshold of questionable activity have been established. A patient who has obtained prescriptions from multiple providers is not necessarily a “doctor shopper”; the patient could have legitimately received prescriptions from different specialists for diverse conditions (e.g., a terminal disease or disorder, chronic pain, postsurgical pain).

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There are also plausible reasons why a patient might fill prescriptions at multiple pharmacies (e.g., because different pharmacies may be closer to work or home, because a particular pharmacy offered a coupon). For these reasons, a proposed operational definition of shopping behavior for medications at high risk for misuse or diversion is having “overlapping prescriptions written by different prescribers and filled at three or more pharmacies.”7

When PDMP data, combined with other information, indicate that a patient may be engaging in aberrant behavior, the practitioner can use this information in the medical setting with the patient as a basis for an immediate conversation or intervention. To ensure that the patient does not misuse prescribed medication, the practitioner can monitor PDMP data in conjunction with urine drug testing and use of a treatment agreement (a contract between patient and practitioner on what each of them will do).

Before prescribing an opioid for pain, the practitioner can assess PDMP data to ensure that a patient is not obtaining, through other prescribers, medication with sedative effects (e.g., other opioids, benzodiazepines), which could heighten risk of overdose when used simultaneously with the opioid. PDMPs provide another valuable function in that providers can use them to periodically review their own prescribing record, to confirm that their Drug Enforcement Administration (DEA)-controlled substance number has not been used illegally by another person.

Not only prescribers but also pharmacists are enhancing patient care through their use of PDMPs. For example, pharmacists can identify interaction risks from multiple prescriptions. Pharmacists can also initiate conversations with patients whose prescription use patterns indicate possible substance misuse, and they can refer such patients for screening and counseling and link them with informational resources on substance use disorders and substance use disorder treatment. Alternatively, they can contact the patient’s prescriber, who may be best positioned to provide resources or referrals. Pharmacists can also use PDMP data to flag suspicious prescribing patterns that may indicate aberrant, illicit, or unsafe prescribing by medical professionals.

Evidence for Effectiveness

Provider surveys, case studies, state evaluations, and other reports offer growing evidence that individual state databases are reducing diversion while also improving individual clinical decision making and prescribing practices and lowering rates of admissions for substance use treatment.8

For example, after New York and Tennessee required prescribers to consult their state’s database before prescribing pain medications, the percentage of patients with multiple provider episodes (receiving prescriptions from five or more prescribers or filling prescriptions at five or more pharmacies in a 3-month period) dropped 75% and 36%, respectively.47

Evidence from states with mandates also suggests that PDMP use supports appropriate prescribing and dispensing. In the 1-year period beginning 2 months after Kentucky’s mandate on enrollment and use of its PDMP went into effect (in July 2012), overall dispensing of controlled substances in the state declined 8.5 percent. In approximately the same period, prescriptions for buprenorphine (a medication used in treatment of opioid use disorder) increased nearly 90 percent.47 According to the PDMP Center for Excellence, these two data points indicate that the PDMP mandate suppresses inappropriate prescribing but does not impinge on legitimate prescribing.47

PDMP use may also be a factor in reducing mortality associated with opioid use. A 2016 study of 34 states (32 with PDMPs) found that the rate of opioid-related deaths declined in states in the year after PDMP implementation. States whose PDMPs had more robust features (e.g., more frequently updated data) experienced greater reductions in deaths compared with states whose PDMPs did not have those features.48

Ohio’s experience indicates that PDMPs can be a significant tool in a broader program to encourage and enforce safe prescribing practices. In 2011, the state adopted rules that mandate prescriber and dispenser use of the PDMP under certain conditions. At the same time, the state instituted other measures designed to curb misuse of prescription drugs, including crackdowns on pill mills (physicians, clinics, or pharmacies that prescribe or dispense controlled medications inappropriately or for nonmedical reasons), licensing restrictions on pain management clinics to prevent over prescription of opioid pain medications, and the institution of a drug take-back program. In the first quarter of 2014 alone, the PDMP received requests for 2 million reports.48

A concern that has been raised about PDMPs is that they could suppress the availability of opioid medication for legitimate cases of pain. A 2016 study found that across 24 states implementing PDMPs, a sustained 30 percent reduction in the rate of prescribing Schedule II opioids occurred; however, there was no significant impact on the overall prescribing of pain medication (the study did not evaluate whether patients’ pain was effectively managed).49

One small study (N=179) of patients presenting with nonacute pain conditions in an emergency department found that in 41 percent of the cases, clinicians altered their prescribing plan after consulting the state’s PDMP; changes went in both directions, with the planned opioid prescribing reduced in 61 percent of the cases and increased in 39 percent.50

Other initial studies indicate that PDMPs do not have a suppressive effect, although they may affect the types of opioids that are prescribed.7 A 2009 study found that, between 1997 and 2003, compared with states without PDMPs, states with PDMPs had a smaller number of shipments per capita (from suppliers to distributors such as pharmacies) for oxycodone (a medication highly associated with drug diversion) and reduced admissions for the treatment of prescription opioid misuse. At the same time, overall opioid shipments increased, indicating no chilling effect on the prescribing of opioids overall. According to a study on Project Lazarus—a program in Wilkes County, NC, that combines PDMP surveillance data with public health education, prevention, and treatment efforts—overdose deaths in the county declined 69 percent from 2009 to 2011, even though the number of opioid prescriptions remained nearly level and was higher than the state average.

In a pilot study of the Indiana PDMP in 2012, physicians reported that the clinical care they provided was enhanced by use of PDMPs; depending on their patients’ clinical needs, physicians both reduced (by 58%) and increased (by 7%) the number of prescriptions written or number of pills dispensed.

Another concern is the perception that increased prescription monitoring through PDMPs may be a factor that causes people who are dependent on prescription opioids to switch to heroin use, contributing to heroin-related overdose deaths (the rate of heroin-related deaths almost tripled from 2010 through 2013). However, according to an analysis of 2002–2011 data from the National Survey on Drug Use and Health, of people who initiate nonmedical use of pain relievers, only 3.6% transition to heroin use within 5 years of initiation. According to the report Trends in Heroin Use in the United States: 2002 to 2013, “The concern that efforts to prevent the illegal use of prescription opioids are causing people to turn to heroin is not supported by the trend data. . . . Although research indicates that people who previously misused prescription pain relievers were more likely to initiate heroin use than people who had not misused prescription pain relievers, most people who misuse prescription pain relievers do not progress to heroin use.”51

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Furthermore, according to a 2016 review article, implementation of most policy decisions aimed at reducing rates of nonmedical use of opioid medications occurred after heroin use rates had begun trending upward.52 The authors point to heroin’s increased accessibility, reduced price, and high purity as factors that may have contributed to increases in the drug’s use. In addition, the review highlighted studies of Florida and Staten Island, NY, that found that policy-induced reductions in the rates of opioid prescribing were associated with reductions in overall opioid-related deaths (that is, deaths related to either heroin or opioid medication use). Based on the overall findings of the review, the authors recommended enhanced use of PDMPs as part of a comprehensive strategy.

Accessing PDMPs

A healthcare provider must enroll in a PDMP to become an authorized user before obtaining access to its data. Typically, the enrollment procedure involves certifying credentials, authenticating providers through proper identification, and establishing secure system access through passwords and/or biomarkers. These procedures are intended to restrict entry to users with legitimate purposes for accessing the data. Several states have developed streamlined registration systems that make enrollment easier, while still maintaining confidentiality and security.

PDMP use complements other measures that providers can take to prevent misuse and diversion of prescription medications and to help ensure the safety of patients using them. PDMPs are an increasingly valuable and easy-to-use resource for healthcare providers who prescribe and dispense controlled medication. Regulation and oversight of these databases ensure that the benefits for clinical care do not jeopardize patient privacy and security. Providers are encouraged to register to use their state’s PDMP and to routinely query the database in regard to their patients’ prescription histories. This practice can help curtail prescription medication misuse and diversion, reduce risk of substance use disorders, and prevent opioid overdoses and deaths

Condition-specific recommendations

General considerations

Drugs with the highest risk for addiction typically elicit rapid dopamine release in the midbrain. Therefore, potent high-dose immediate-onset medications have greater abuse liability than do their less-potent lower-dose extended-release counterparts.

It should be remembered that controlled substances are often the last therapeutic option that should be considered to manage a disease or condition, with behavioral, non-pharmacologic, and non-controlled medications tried prior to a trial of any controlled substances. Health care providers should be aware of all the available treatment options for each disease and be able to justify why they believe a controlled substance is the best therapeutic intervention. Providers should also understand the side-effects of each medication and how to monitor controlled substances for signs of misuse, addiction or abuse.

Anxiety

The CSA lists numerous anxiolytics as controlled substances. Scheduled drugs include the benzodiazepines, barbiturates, and so-called “z-drugs” such as zolpidem, zaleplon and eszopiclone. Benzodiazepines such as alprazolam, clonazepam, diazepam and lorazepam have largely replaced barbiturates for the short-term treatment of anxiety.53 Because many anxiolytics have sedating properties, these medications are also commonly used as sleep-inducing (hypnotic) agents.

Anxiety disorders share features of excessive fear and anticipation of future threat. Fear leads to autonomic arousal, a feeling of imminent danger, and an impulse to escape. Physical symptoms associated with anxiety include chest tightness, dyspnea, tachycardia, flushing, dry mouth, tremor, dizziness, blurry vision, nausea or vomiting, abdominal pain, diarrhea, and urinary urgency.54

Fear and anxiety can be non-pathologic, transient emotions. In contrast, pathologic anxiety disorders persist for longer than six months, exist when certain behaviors are no longer developmentally appropriate, or are out of proportion to the threatening event or object. They must also cause distress, significantly alter the patient’s routine, and diminish his or her functioning in everyday life. Examples of anxiety disorders include separation anxiety disorder, specific phobias, social anxiety disorder, panic disorder, agoraphobia, substance/medication-induced anxiety disorder, and generalized anxiety disorder (GAD). Obsessive compulsive disorders and trauma-related disorders are also common causes of anxiety symptoms, though DSM 5 has separated them from other anxiety disorders.

Although anxiety disorders are very common, little progress has been made in developing new anxiolytics over the past 50 years.55 Anxiolytics form a heterogeneous group of agents with a wide range of efficacy and some of these medications are controlled substances with a high potential

for morbidity and mortality. Barbiturates and benzodiazepines are commonly prescribed for patients suffering from anxiety. However, selective-serotonin uptake inhibitors (SSRIs) and behavioral interventions may be more effective, may have better long-term responses, and have a much smaller abuse potential.56

Barbiturates

Barbiturates were commonly used in the past as sedatives and hypnotics. However, they have serious safety problems and have been replaced by benzodiazepines outside the operating room. Barbiturates pose a risk of coma in high doses, induce tolerance, possess drug-interfering metabolites, create physical dependency, and incite severe withdrawal symptoms. Side-effects of these agents include drowsiness, decreased concentration, nausea, and dizziness. CNS, cardiovascular, and respiratory depression may cause overdose death.

Withdrawal from barbiturates can cause seizures, delirium, anxiety, weakness, restlessness, tremors, nausea, vomiting, cardiac arrest, and death. Barbiturates are still being used for surgical anesthesia and phenobarbital is used cautiously as an anticonvulsant. Carisoprodol is still prescribed as a muscle relaxant. It lacks effectiveness as a long term agent and should be used only for short periods, avoided in the elderly, and avoided in patients with substance use disorders. It is metabolized to meprobamate, which, though it was marketed as safer than barbiturates, has most of the pharmacological effects and dangers of barbiturates.

Benzodiazepines

Benzodiazepines have largely replaced barbiturates for short-term treatment of anxiety although they have a significant risk of morbidity and mortality, including addiction, injuries due to side-effects, potentially lethal interactions with other substances, and a risk of death from overdose. In 2010, 29% of overdose deaths in the United States involved benzodiazepines, though 77% of those deaths also involved opioid analgesics. When not used in combination with other drugs, benzodiazepines are implicated in only 3.7% of drug overdoses.57

In 2010, 2.2% of Americans misused tranquilizers, of which benzodiazepines were the major constituent. Nearly 10% of these individuals met criteria for a benzodiazepine use disorder.5 In a case-control study, risk factors for death from prescribed drug overdose included one or more sedative/hypnotic medication prescriptions, male sex, older age, increased number of prescriptions,

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higher dose of opioid analgesics, and a prescription for buprenorphine, fentanyl, hydromorphone, methadone, or oxycodone.58 Benzodiazepines produce behavioral disinhibition and amnesia and can enhance opioid-induced euphoria. Thus patients misusing both benzodiazepines and opioids may lose track of how much they have taken and be inclined to take more. Side-effects of long-term benzodiazepine use include tachycardia, hypertension, rebound anxiety, agitation, disorientation, hallucinations, and seizures.59

Before prescribing benzodiazepines, providers should obtain a current list of medications, and discuss and document the patient’s drug and alcohol history. Concomitant use of benzodiazepines and alcohol can increase the risk of overdose death and the provider may be held liable for unsafe prescribing practices if he or she has failed to document and address these risk factors.60 Benzodiazepines should only be prescribed with extreme caution to patients with past or current alcohol use disorder. In one pilot study, an audit of medical clinic records showed that 57% of the records did not contain any information about the patients’ alcohol use and the remaining records only provided limited information that was insufficient to safely prescribe benzodiazepines.60

Approximately one-third of patients who have long term use of benzodiazepines will experience withdrawal symptoms within two to 10 days of stopping use. Some patients will experience withdrawal symptoms on tapering benzodiazepines to a lower dose. Withdrawal symptoms include hyperarousal symptoms, such as insomnia, anxiety, photophobia, heightened sensitivity to sound, unsteadiness, and seizures.61 Patients in a nationwide study in Switzerland who abused benzodiazepines described self-medication for anxiety and insomnia as the primary motivation for misusing this controlled substance.62 Most patients began taking benzodiazepines after their provider prescribed the medication, and the prescribing provider usually detected the misuse.62

Benzodiazepines should be prescribed for short-term use only and very cautiously in older adults. Chronic daily use of benzodiazepines can lead to a profound physical dependence that is difficult to address. Adverse events associated with benzodiazepine use in older adults include motor vehicle collisions, falls, cognitive difficulties, delirium, sleep disturbances, drug-drug interactions, and impaired function.35 Studies of older patients who are taking benzodiazepines show that they come to rely on them for any anxiety symptoms, deny the presence of side-effects and are reluctant to taper or discontinue use even when they understand the risks of continued use.63 Health care providers

prescribe these medications because they view them as effective, rapidly acting, and eliciting strong patient satisfaction.64 Providers may minimize risks of these medications and may not view them as problematic in older patients because of the relatively low risk of addiction. As a result, they may not monitor these patients stringently or try to wean them off of long-term use of these drugs. These beliefs contradict practice guidelines and do not meet standard of care.

Insomnia

Insomnia is the most common sleep disorder and chronic insomnia is described as insomnia lasting longer than three months that is not better explained by use of substances, medications, or by another disorder.65 The routine evaluation of insomnia involves obtaining a thorough history and performing a physical examination. In obtaining a history, the health care provider should ask questions about medical and psychiatric co-morbidities including sleep apnea (the STOP-Bang questionnaire [stopbang.ca] is a good sleep apnea screening tool for primary care), substance use disorders, and stress. The provider may want to discuss the patient’s sleep habits with the patient’s partner or caregiver in case he or she has noticed any sleep abnormalities such as snoring, sleep apnea, sleepwalking, or unusual limb movements. Physical examination should include a neurological exam and an assessment for comorbidities. The provider should ask the patient about prescribed medications, caffeine intake, alcohol intake, and herbal supplements.

Initial treatment for chronic insomnia should involve cognitive behavioral therapy for insomnia (CBT-I), which is multimodal treatment involving education, stimulus control instructions, time-in-bed restriction, and relaxation training. 66 Some patients take over-the-counter antihistamines, opioids, or drink alcohol in an effort to treat insomnia. Providers should discourage patients from using opioids or alcohol as sleep agents. Antihistamines reduce sleep quality and produce residual daytime drowsiness, making them a poor choice for treating insomnia. Although benzodiazepines are commonly prescribed for their hypnotic properties, patients should not rely on benzodiazepines to treat chronic insomnia, and providers should preferentially prescribe non-benzodiazepine sleep agents, and then only for acute insomnia and for intermittent use for no more than 3-4 weeks.65 Although the margin of safety for both benzodiazepines and benzodiazepine receptor agonists (so-called Z-drugs) is relatively wide, adverse effects may include anterograde amnesia, complex sleep-related behaviors, falls, cognitive impairment, respiratory depression, and rebound insomnia.23

Pharmaceutical intervention for treating insomnia should be used when non-pharmaceutical treatments are ineffective, when insomnia significantly interferes with function, or when the underlying cause is addressed but insomnia persists.67 Health care providers should prescribe the lowest effective dose and for a short duration. The provider should avoid prescribing hypnotics for patients who have an underlying history of respiratory depression, myasthenia gravis, substance use disorder, or acute cerebrovascular accident.

Temazepam

Temazepam is a benzodiazepine used to treat patients with insomnia who wake up frequently during the night.68 Its peak sedative effect occurs 2-3 hours after it is taken, so patients must take this medication several hours before bedtime. It is a schedule IV controlled substance.

Z-Drugs

Like benzodiazepines, the Z-drugs (Zolpidem, Zaleplon, and Eszopiclone) enhance the effect of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter. Because they modulate a more specific GABA receptor subtype, the Z-drugs were thought to be less addictive and have less abuse potential than benzodiazepines. Evidence shows, however, that they elicit a similar behavioral profile including reinforcing effects, abuse potential, tolerance, physical dependence, and subjective effects.69 While Z-drug addiction is uncommon, the risk increases at higher doses and in patients with a history of substance use disorders.69 They can all cause withdrawal symptoms if abruptly discontinued after prolonged use. Side-effects are similar in all three and can include nightmares, agitation, hallucinations, dizziness, daytime drowsiness, headache and gastrointestinal problems.

Other agents

Doxepin is appropriate for sleep maintenance insomnia and may be useful for patients with contraindications to benzodiazepines or Z-drugs.70 Other agents that may be effective for chronic insomnia include suvorexant, remelteon, and low doses of the sedating antidepressants trazodone and mirtazapine.22

Narcolepsy

Narcolepsy is characterized by neural dysregulation of the sleep-wake cycle. As a result, individuals suddenly fall asleep in the middle of the day in “sleep attacks” and experience episodes of extreme daytime sleepiness.71 Males and females are equally affected, and narcolepsy is a life-long

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chronic condition that often begins between the ages of 7 and 25 years. Associated symptoms include vivid dreams, hallucinations, and total paralysis immediately before falling asleep or after waking. Some people with narcolepsy also have cataplexy, a loss of voluntary muscle tone that makes the sufferer limp and unable to move. These patients suffer from poor sleep in general and often enter REM sleep several minutes after falling asleep, in contrast to people with normal sleep cycles who enter REM sleep 80-100 minutes after falling asleep.

To diagnose narcolepsy, health care providers must take a careful sleep history to determine if shift-work, circadian rhythm abnormalities, or pre-existing sleep deprivation are present. The provider should note any symptoms consistent with cataplexy. Excessive daytime sleepiness and cataplexy are pathognomonic for this disease. Approximately half of patients have all four symptoms of hallucinations, sleep paralysis, cataplexy, and excessive daytime sleepiness.72 Preschool-age children may have different symptoms, including inattentiveness, emotional lability, and hyperactivity.73

Patients may be sent home with a sleep journal and asked to keep track of their sleep patterns for several weeks.71 A thorough physical examination must be performed to exclude any other underlying disease state that may cause similar symptoms, although cataplexy is rarely found outside of narcolepsy.

Treating narcolepsy is difficult because this disease is due to permanently low hypocretin levels.71 Although bench scientists are working on stem-cell therapies to replace hypocretin-producing cells, currently-approved treatments focus on alleviating symptoms. Patients with narcolepsy find this disease highly disruptive to their everyday function. They may fall asleep during work or school, in the middle of a conversation, or during a meal. More dangerously, they may fall asleep while driving or operating heavy machinery.

While they are awake, many patients describe persistent mental cloudiness, loss of concentration, fatigue, and extreme exhaustion. Therefore, health care providers prescribe treatments such as modafinil/armodafinil, amphetamines, SSRI’s, and TCA’s to improve wakefulness during the day. At night, patients with narcolepsy experience disrupted sleep, with hallucinations, paralysis, insomnia, and other sleep difficulties. Consequently, other treatments, including behavioral interventions, attempt to improve duration and quality of sleep. Sodium oxybate is the only medication approved in the United States to treat cataplexy.

First-line agents for patients with excessive daytime sleepiness are modafinil/armodafinil alone or in combination with sodium oxybate.74 Alternative treatments include amphetamines (including methylphenidate), SSRI’s, and TCA’s.

Modafinil/armodafinil

Modafinil and armodafinil (r-enantiomer) have replaced amphetamines to become the first-line stimulants for patients with narcolepsy.75 These medications reduce excessive daytime drowsiness and improve alertness with a better side-effect profile than amphetamines. They share a mechanism of action with amphetamines, namely blocking dopamine reuptake, though the observed effects are much milder.76 Modafinil is a schedule IV controlled substance. It has been shown to have similar mood elevating properties, though to a lower degree.76 Withdrawal symptoms include anhedonia, lethargy, anxiety and insomnia.

Sodium oxybate

Sodium oxybate (gamma hydroxybutyrate, GHB, Xyrem) is a sedative approved to decrease daytime sleepiness and cataplexy in the United States.75 It restores sleep continuity, decreases hallucinations, and reduces sleep paralysis. Sodium oxybate must be administered twice per night because of its short half-life, and dose titration can be challenging. Side-effects include nocturnal confusion, sleepwalking, dizziness, nausea and enuresis. Patients who are taking this medication should avoid alcohol and other sedating medications because overdose of sodium oxybate can lead to fatal respiratory depression. These safety concerns mean that the medication is tightly restricted and classified as a schedule III controlled substance, although in a recent analysis, rates of addiction are relatively low, <1%.77

Methylphenidate and amphetamine

Amphetamines block dopamine reuptake or increase dopamine synaptic release, which can improve alertness, decrease appetite, and reduce daytime drowsiness. Side-effects include neurological, cardiovascular, and gastrointestinal symptoms. Neurological symptoms range from insomnia, irritability, tremor, and dizziness to confusion, delirium, panic, and suicidal ideation. Cardiovascular side-effects can be serious, including cardiac arrhythmias, hypertension, angina, and circulatory collapse. Amphetamines should not be prescribed or administered to patients with cardiovascular disease or who are taking MAO-inhibitors. Lastly, patients taking amphetamines may experience anorexia, nausea/vomiting, abdominal pain or diarrhea. Chlorpromazine, an alpha-blocker, is the antidote for amphetamine overdose.

Though the percentage of past month users of prescription stimulants has remained stable, the Drug Abuse Warning Network data show that the number of emergency room visits related to nonmedical use of prescription stimulants has increased 189% since 2004.78 The misuse of stimulants is most common in adolescents and is often associated with the desire for cognitive enhancement and euphoria.14 Use patterns tend to coincide with examination periods and as a means to counter the effects of binge drinking and marijuana use.79 As with opioids, immediate-release formulations have more abuse liability, and long-acting and tamper-resistant formulations have been developed to discourage misuse. Stimulants should be prescribed with caution and closely monitored in patients with a history of substance use disorder.

Attention-Deficit/Hyperactivity Disorder (ADHD)

Attention-Deficit/Hyperactivity Disorder is one of the most commonly-diagnosed disorders of childhood. According to the CDC, 11% of children between the ages of 4 and 17 (6.4 million children) have been diagnosed with ADHD in the United States.80 Boys are twice as likely as girls to receive a diagnosis and the average age of diagnosis is 7 years old. Furthermore, the rate of diagnosis has been increasing 5% per year since 2003.

ADHD treatment involves both medical and behavioral interventions, with about half of preschoolers with ADHD taking a medication for this disease in 2011.80 Health care providers frequently prescribe amphetamines and methylphenidate, schedule II controlled substances, for the management of ADHD.

Neurobiological findings in children with ADHD include delayed brain maturation, inhibitory control defects, noradrenergic dysfunction, and dopaminergic dysfunction.81 However, the diagnosis of ADHD remains a clinical diagnosis. The American Academy of Pediatrics recommends that primary care providers consider evaluating pediatric patients between the ages of 4 and 18 who present with academic or behavioral problems and symptoms of inattention, hyperactivity, and impulsivity.82 Providers should use the criteria for a diagnosis of ADHD as described in the DSM 5. These criteria for diagnosing ADHD require a persistent pattern of inattention and/or hyperactivity-impulsivity. For a diagnosis of inattention, at least six out of nine symptoms must have been present for the past six months in children younger than 17 years. These symptoms must be developmentally inappropriate and disrupt school/work and social life.

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ADHD can have predominantly inattentive presentation, predominantly hyperactive/impulsive presentation, or combined presentation. Providers should document the severity of ADHD, ranging from mild to severe depending on the number of symptoms and impairment of social or occupational functioning. They should also make sure to assess the child and rule out other causes of symptoms or co-morbid conditions, such as deafness or cognitive delay.

Guidelines suggest that health care providers should take an interdisciplinary approach to treating ADHD. Educational interventions, behavioral approaches, and medication all may have roles in managing this disorder. For children ages 4-5 years, the health care provider should prescribe behavior therapy to be administered by the parent and/or teacher as first-line intervention. If the child continues to have moderate or severe functional disturbance or there is no improvement in behavior, the provider may prescribe methylphenidate. For older children, ages 6-11 years, the health care provider should prescribe teacher and/or parent administered behavioral intervention, FDA approved medication, or both. Evidence is strongest for prescribing stimulants, followed by, in descending order of efficacy for adolescents, atomoxetine, extended release guanfacine, and extended release clonidine. The values and preferences of the patient and family are critical factors in deciding whether or not to initiate medication.83

Behavioral interventions are preferred to medication as the initial intervention for preschool children with ADHD and are adjuncts to medication for school-aged children and adolescents.83

The choice of the initial medication depends upon a number of factors, including:83,84

• The duration of desired coverage (completion of homework or driving may require coverage into the evening)

• The ability of the child to swallow pills or capsules

• The time of day when the target symptoms occur

• The desire to avoid administration at school• Coexisting tic disorder • Coexisting emotional or behavioral condition • Potential adverse effects• History of substance use disorders in patient

or household member: avoid stimulants or use stimulants with less potential for abuse (slow-release, long acting)

• Preference of the child/adolescent and his/her parent/guardian

• Expense (in general, short acting stimulants are least expensive)

Methylphenidate and amphetamine

In one study evaluating the role of psychostimulants (such as methylphenidate, dexamphetamine, and modafinil) in managing co-morbid ADHD and non-ADHD disorders, these medications improved concentration, mood, and cognitive function while decreasing fatigue.85 Side-effects include anorexia, sleep difficulties, abdominal pain, and headaches. Some children have diminished height with long-term use.82 Psychiatric symptoms in younger children may include mood lability and dysphoria. Although rare, hallucinations and psychotic symptoms have been reported as a side-effect of stimulant use. Health care providers and parents are most concerned about reported cases of sudden cardiac death in previously healthy children who had been prescribed stimulants to treat ADHD. Providers must make sure to ask the child and parents about any specific cardiac symptoms or history of cardiovascular disease in the child. Furthermore, providers must obtain a thorough family history and ask about any cases of sudden death in the family, hypertrophic cardiomyopathy, Wolf-Parkinson-White syndrome, or long QT syndrome. Health care providers should avoid prescribing stimulants if they are concerned about increased risk of side-effects or potential for substance misuse or diversion.86

When prescribing stimulants, it is not only important to establish an accurate diagnosis of ADHD, but also to monitor symptoms and for evidence of misuse.83 Stimulant diversion and misuse can be minimized, to some extent, by prescribing long-acting stimulants with less potential for abuse, and by keeping track of prescription dates.87,88 Having open discussions with parents and patients about the risk of misuse and diversion is helpful, such that patients can be prepared if they are asked to sell their medications and so that parents are aware of the risks.87

The nonmedical use of prescription stimulants represents the second most-common form of illicit drug use in college, second only to marijuana use.89 A 2008 study showed that lifetime rates of diversion ranged from 16% to 29% of students with stimulant prescriptions who were asked to give, sell, or trade their medications.88 Risk factors for diversion in this study included white race, being a members of a fraternity or sorority, individuals with lower grade point averages, use of immediate-release compared to extended-release preparations. Reported reasons for use, misuse, and diversion of stimulants include to concentrate, improve alertness, “get high,” or to experiment.88

Evaluation for substance use disorders and binge drinking should also be undertaken when prescribing stimulants for ADHD. Although there is a higher risk of misuse and diversion of stimulants in

those with a history of substance use disorders, it should be noted that a critical risk factor for having ongoing substance use disorders in adulthood is the persistence of ADHD symptoms and adequate treatment of ADHD in childhood is associated with a lower risk of subsequent drug and alcohol use disorders.88

Atomoxetine

Atomoxitine is generally less effective than stimulants for ADHD symptoms.82 It is a non-stimulant norepinephrine reuptake inhibitor that can be used as second-line medical management of ADHD. Side-effects include gastrointestinal distress, somnolence, and anorexia. Rare side-effects include increase in suicidal ideation and drug-induced hepatitis. Atomoxitine may be more appropriate than stimulants for patients with a personal or family history of substance use disorders, or if there is concern for misuse or diversion due to its longer-acting effects.

ER Guanfacine

Extended release guanfacine is a non-stimulant adrenergic agonist.82 It is used to treat hypertension, anxiety, and ADHD. Side-effects include somnolence and dry mouth.

ER Clonidine

Like guanfacine, clonidine is an alpha-agonist that can be used to treat mild to moderate hypertension, as well as ADHD.68 Side-effects include mild sedation and dry mouth, but the patient may experience rebound hypertension if clonidine is abruptly withdrawn. Alpha-2-adrenergic agonists usually are used when children respond poorly to a trial of stimulants or atomoxetine, have unacceptable side effects, or have significant coexisting conditions

Obesity

Obesity is a complex chronic disease that is becoming increasingly common internationally and in the United States. The World Health Organization (WHO) reports that more than 1.9 billion people worldwide are obese or overweight, and the worldwide prevalence of obesity doubled between 1980 and 2014.90 In the United States, approximately 34.9% of adults, or 78.6 million people, have obesity.91 People who suffer from obesity have significant increases in morbidity and mortality.90

Weight loss can significantly improve obesity-associated morbidity and mortality. Patients with obesity or overweight are at risk for type 2 diabetes, weight loss of 2.5-5 kg over at least two years can

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decrease the risk of obesity-associated type 2 diabetes by 30-60%.92 Similarly, in overweight or obese adults with or without cardiovascular risk factors, lipid levels improve in a dose-response manner with weight loss.

In order to effectively treat obesity, health care providers should understand the appropriate behavioral and dietary changes patients must make in order to lose weight and maintain weight loss. They should also understand when it is appropriate to recommend medical management or surgical intervention, and the risks and benefits of those interventions.

Obesity can be very challenging to treat, in part because of physiological mechanisms that cause the human body to resist weight loss. Providers must learn the necessary skills for how to motivate patients while also respecting their autonomy. Effective management often involves interdisciplinary teamwork with nutritionists and other trained consultants.

Treatment for obesity includes dietary restriction, comprehensive lifestyle intervention, medical management, and surgical intervention. Here we focus just on medical management with controlled substances.

In 2011, 2.74 million patients were having their morbid obesity treated pharmacologically.93 Pharmaceutical interventions for weight reduction may suppress appetite, reduce absorption, or increase energy expenditure.94 Medications currently approved for pharmacological weight management include short-term use of phentermine, orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion, and liraglutide.95

Placebo-controlled trials show clinically meaningful weight loss ranging from 37–47% for lorcaserin, 35–73% for orlistat, and 67–70% for maximally dosed phentermine/topiramate-ER.93 Phentermine, an anorexic agent used to treat obesity, is classified as a schedule III controlled substance.

Phentermine

Phentermine is an anorexic agent. It reduces food intake by causing early satiety. It is an amphetamine-like drug that interferes with norepinephrine release. A similar drug, sibutramine was withdrawn from the market in 2010 because of its association with increased risk of cardiovascular events and stroke. Phentermine/topiramate was approved by the Food and Drug Administration (FDA) in 2012. It is well-tolerated with dose-dependent adverse events. Safety concerns include tachycardia, teratogenicity, metabolic acidosis, psychiatric disorders, and cognitive adverse events.3 It should not be used in patients with cardiovascular disease (hypertension or coronary heart disease) or in pregnant women because of an increased risk of orofacial clefts in infants exposed to the combination drug during the first trimester of pregnancy.

PLEASE SPEND THE ALLOTTED TIME ON EXERCISE 4.

Instructions: Spend 10-15 minutes reviewing the continuation case study below and considering the questions and commentary that follow.

Case Study Exercise 4

Jenny returns for a follow-up visit after completing a cardiovascular evaluation, which you ordered because of her heart-flutter symptoms and previous use of fen-phen. Even though her evaluation was negative for abnormalities, she has thought about the risks of phentermine and decided that she would like to consider alternative interventions for managing her obesity. In particular, she is concerned that her history of fen-phen use and a family history of heart disease might lead to cardiac problems in the future. You agree to not refill her prescription for phentermine.

Question 1: Describe alternative options Jenny may have for weight loss. (Options may include pharmaceutical and non-pharmaceutical alternatives.)

Commentary on Question 1: The patient’s non-pharmaceutical weight loss options include dietary changes, exercise, behavioral therapy, and surgical interventions. Dietary interventions for morbidly obese women may entail caloric reduction producing at least a 500 kcal/day deficit, resulting in a goal of 1,200-1,500 kcal consumed per day. Exercise goals include at least 150 minutes of aerobic activity per week, and behavioral therapy is meant to encourage adherence to dietary changes and physical activity.89

The patient should discuss whether or not she is a good candidate for surgical intervention with her bariatric surgeon in order to decide if any surgical interventions may help her with weight loss.

You refer Jenny to a comprehensive lifestyle intervention program at a local academic center. There, the patient begins taking orlistat, goes on an American Heart Association-approved diet, and starts walking and jogging for 30 minutes 6 times a week. She is carefully monitored by the medical team at her comprehensive lifestyle intervention program. Two months later, Jenny returns to your clinic. She has lost 10 lbs, and she is determined to continue on her program. However, she has been having difficulty sleeping for the past month, and was wondering if you could prescribe a medication she saw advertised on television to help her sleep.

Question 2: You note that the sleep agent the patient would like you to prescribe is a schedule IV controlled substance. How would you proceed with your insomnia evaluation?

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Pain Control

Pain remains the most common reason people seek health care.96 In fact, the incidence of chronic pain in the U.S. is estimated to be greater than that of diabetes, heart disease, and cancer combined.97,98 Inadequately treating pain can lead to a wide range of adverse consequences (in addition to causing needless suffering) including diminished quality of life, and a higher risk for anxiety or depression.99 Pain is also a major cause of work absenteeism, underemployment, and unemployment.96

Pain must be treated, but many types of pain treatments exist. Opioid analgesics may—or may not—be the right choice, particularly for those suffering from chronic non-cancer pain. Opioids do not address all of the physical and psychosocial dimensions of chronic pain, and they pose a wide range of potential adverse effects, including challenging side effects and the risk of abuse, addiction, and death.

Many pharmacologic and non-pharmacologic approaches to treating painful conditions are available to primary care physicians. These options should be employed by using the following general principles:

• Identify and treat the source of the pain, if possible, although treatment can begin before the source of the pain is determined

• Select the simplest approach to pain management. This generally means using non-pharmacologic approaches as much as possible and/or trying medications with the least severe potential side effects first, and at the lowest effective doses

• Establish a function-based management plan if treatment is expected to be long-term

In treating pain, clinicians can avail themselves of five basic modalities of pain-management:

1. Cognitive-behavioral approaches2. Rehabilitative approaches3. Complementary and alternative therapies4. Interventional approaches 5. Pharmacotherapy

These options can be used alone or in combinations to maximize pain control and functional gains. Only one of these options involves medications, and opioids are only one of many types of medications with potential analgesic utility. Which options are used in a given patient depends on the type of pain, the duration and severity of pain, patient preferences, co-occurring disease states or illnesses, patient life expectancy, cost, and the local availability of the treatment option. Because the focus of this monograph is on controlled substances, the rest of this section will review issues related specifically to the use of opioids for analgesia.

Prescribe with caution

The utility of opioid analgesics for treating chronic non-cancer pain is being increasingly questioned and a broad consensus is developing that these agents are not, in fact, suited for many patients with this type of pain. Clinical guidelines for the use of opioids in chronic non-cancer pain have shifted in recent years to focus on non-medication treatments. They have stressed the risks of opioids and strengthened procedures that prescribers should use to reduce the risk of addiction and misuse.100,18,101

Little evidence supports the assertion that long-term use of opioids provides clinically significant pain relief or improves quality of life or functioning for most chronic non-cancer related pain.102 The Agency for Healthcare Research and Quality (AHRQ), for example, recently found no studies that compare opioid therapy with either a placebo or a non-opioid treatment for long-term (>1 year) pain management.103 A Cochrane review of opioids for long-term treatment of non-cancer pain found that many patients discontinue long-term opioid therapy (especially oral opioids) due to adverse events or insufficient pain relief.102

A large—and growing—body of evidence, on the other hand, demonstrates that opioids pose

Case Study Exercise 4 (Continued)

Jenny returns to see you for a follow-up visit. She is excited to be losing weight and feeling healthier than she has ever felt in her adult life. However, she has recently been considering bariatric surgery and would like to discuss her options with you. After reviewing the risks and benefits of surgical intervention with her, you both agree to wait to see if she makes significant weight-loss progress through her current program. If she changes her mind, you plan to refer her to a bariatric surgeon affiliated with the local academic center. The patient also brings the results of her sleep journal and reports that her insomnia is getting worse, despite her adherence to sleep inducing behaviors and diligent use of melatonin. She is frustrated and exhausted.

Commentary on Question 3: Here are the recommended steps for ensuring best practices for prescribing a controlled substance:1. Document a thorough history and complete physical examination.2. Discuss the side-effects and addictive potential of the controlled substance with the patient.3. Check the prescription drug monitoring database to corroborate the patient’s controlled substance history.4. Document that you have discussed any history of substance use, concerns from the patient’s family members, and details about the patient’s

treatment plan in the chart. Advise the patient to not use concomitant alcohol.5. Establish guidelines and describe the duration of treatment.6. Carefully monitor the patient for any evidence of misuse during treatment.

Commentary on Question 2: First, obtain a thorough history, including a sleep history, and review the patient’s medical and psychiatric co-morbid conditions. The provider should ask the patient about prescribed medications, caffeine intake, alcohol intake, and herbal supplements. If anyone else knows about the patient’s sleep habits, ask that person if he or she has noticed any unusual patient sleep patterns, including snoring, sleep apnea, sleepwalking, or unusual limb movements. Next, perform a physical examination including a neurological assessment to identify any co-morbidities. Consider administering an Epworth Sleepiness Scale or the STOP-Bang test to assess for sleep apnea during the clinic visit. Finally, request that the patient keep a sleep log for 2 weeks to identify patterns of sleep disruption. She should follow up in 3 weeks with the results. In the meantime, review and encourage behavioral interventions to improve sleep, include exercise, relaxation therapy, and good sleep habits.65

Question 3: You decide to prescribe a schedule IV controlled substance for a short time to treat the patient’s insomnia. What 6 additional steps must you take to ensure you are following best practices for prescribing a controlled substance?

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many significant risks for adverse effects, abuse, addiction, and accidental overdose leading to death from respiratory depression.

Estimating the risk that patients face of becoming addicted to opioid analgesics is difficult because rigorous, long-term studies of these risks in patients without co-existing substance-use disorders have not been conducted.5 A few surveys conducted in community practice settings, however, estimate rates of prescription opioid abuse of between 4% to 26%.104,105,106,107 Risk rises with higher opioid doses and longer durations of opioid use.108

A 2011 study of a random sample of 705 patients prescribed long-term opioid therapy for non-cancer pain found a lifetime prevalence rate of DSM-5-defined opioid use disorder of 35%.109 The variability in such results probably reflects differences in opioid treatment duration, the short-term nature of most studies, and disparate study populations and measures used to assess abuse or addiction. Nonetheless, the levels of risk suggested by these studies are significant enough to warrant extreme caution in the prescription of any opioid for a chronic pain condition.

Caution is also required because a significant portion of patients can be expected not to use an opioid medication as prescribed. Fleming et al., conducted in-depth interviews with 801 patients prescribed long-term opioid therapy from a primary care provider and found the following:105

• 39% of patients increased their dose without direction from a health care provider

• 26% engaged in purposeful over-sedation• 20% drank alcohol concurrent with opioid use • 18% used opioids for purposes other than

pain relief• 12% hoarded their pain medications • 8% obtained extra opioids from other doctors

The risk of overdose with opioid analgesics is significant and, as with risk of abuse/dependence, rises with both dose and duration.110

In addition to the risks for misuse, addiction, and overdose, opioids can exert a wide range of uncomfortable or harmful adverse effects, the most common of which are neurologic (somnolence, dizziness), endocrine (hypogonadism), gastrointestinal (nausea, vomiting, and constipation), sexual (erectile dysfunction), and

cutaneous (pruritus). In randomized trials of opioids, 50%-80% of patients report an adverse side effect, and about 25% withdraw due to an adverse event.102,111,112

Although less common, there is also a dose-dependent increase in risk of fractures in opioid users compared to non-users, with risk highest in the period following initiation, particularly for short-acting opioids.113,114

An area of potential concern is the possibility that chronic opioid use may have immunosuppressive effects. Evidence from cell cultures and animal models is suggestive, and this is an area requiring further investigation.70 Dublin et al., in a population-based case-control study, found a significantly higher risk of pneumonia in immunocompetent older adults who were prescribed opioids.115 The risk was particularly high for adults taking long-acting opioids.115

Initiating Treatment With Opioids

Prior to an initial prescription of an opioid pain medication, clinicians should be certain that (1) all other potentially effective treatments that offer a more optimal benefit-to-risk profile have been considered or tried; (2) a complete evaluation has been performed and fully documented; (3) the patient’s level of opioid tolerance has been determined; and (4) informed consent and agreement to treat have been obtained.18 A patient having been prescribed opioids by a previous provider is not, in and of itself, a reason to continue opioids, and no provider is obligated to continue opioid therapy that was started by another provider. In addition, the use of an opioid, if necessary, should be just one component of a treatment plan that includes other modalities of pain management, such as physical therapy, exercise, the use of heat or cold, or any of a range of other techniques that can facilitate improved function and a decreased reliance on opioids.

At the outset, both the clinician and the patient should view a new opioid prescription as a short-term trial of therapy. The goal of the trial is to provide data to guide decisions on the continued appropriateness of opioid medications and on the specific dose and formulation of medication used. Such a trial might be as brief as a few days or as long as several months.

Opioid selection, initial dosing, and titration must be individualized to the patient’s health status, previous exposure to opioids, and treatment plan. A decision to continue opioid therapy after an appropriate trial should be based on careful review of the trial outcomes. Outcomes to consider include:

• Progress toward meeting therapeutic goals• Changes in functional status• Presence and nature of opioid-related

adverse effects• Changes in the underlying pain condition• Changes in medical or psychiatric comorbidities• Degree of opioid tolerance in the patient• Identification of altered or aberrant behaviors,

misuse, or diversion

Dose Titration

Patients who are opioid-naïve or have modest previous opioid exposure should be started at the lowest dose possible of a short-acting opioid and titrated slowly upward to decrease the risk of opioid-related adverse effects.18 If it is unclear whether a patient has recently been using opioids (either prescribed or non-prescribed), the clinician should assume that the patient is opioid-naïve (i.e., not tolerant) and proceed as just described.

Opioid tolerance should always be established before prescribing an ER/LA opioid. The selection of a starting dose and manner of titration are clinical decisions that must be made on a case-by-case basis because of the many variables involved. Some patients, such as frail older persons or those with comorbidities, may require an even more cautious therapy initiation. Short-acting opioids are usually safer for initial therapy since they have a shorter half-life and may be associated with a lower risk of overdose from drug accumulation.

Further studies are needed to confirm more consistent control of pain and improved adherence to prescribed therapy with use of ER/LA opioids. Although low-dose, short-acting opioids may offer the greatest safety for initiating opioid therapy, clinicians must recognize that short-acting opioids are not intrinsically safer than other formulations, and stress to their patients the importance of strict adherence to prescribed doses/administration.

PLEASE SPEND THE ALLOTTED TIME ON EXERCISE 5.

Calculating Morphine Milligram Equivalents (MMEs)Calculating a patient’s total daily dose of opioids is important to appropriately and effectively prescribe, manage, and taper opioid medications. This can be done with printed or online equianalgesic charts, which provide conversion factors and dose equivalents of all available opioid medications relative to a standard dose of morphine.

Care must be taken in using such charts because dose is not the only relevant variable. Clinicians must also consider the route of administration, cross tolerance, half-life, and the bioavailability of a drug. In addition, the patient’s existing level of opioid tolerance must be taken into account.

Printed equianalgesic charts are common, and online calculators are also freely available (a common one can be accessed at clincalc.com/Opioids). The CDC provides a helpful guide to opioid conversions available at: www.cdc.gov/drugoverdose/pdf/calculating_total_daily_dose-a.pdf

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Case Study Exercise 5

Based on what Mike has told you, you are concerned that he is at increased risk for opioid misuse, opioid overdose or addiction due to his young age, past significant alcohol use, current ongoing use of alcohol, and history of mental illness. You request a urine toxicology screen from the patient. He agrees and you excuse yourself from the room. When you check your state’s electronic prescription database, you see that he has had only one previous prescription for an opioid. The PDMP shows that this prescription was related to an ER visit for “trauma due to fall,” consistent with the patient’s history. The urine drug screen you request is negative for all substances.

When you return to speak to the patient, you tell him that you would like to treat his back pain like a chronic condition, starting with a non-opioid treatment plan, as this is first line treatment. For the next six weeks, you would like to start NSAIDs and a home exercise program.

Question 1: Do you think this patient a candidate for opioid analgesics?

Question 2: What other questions might you ask?

Now continue reading about this case study.

Instructions: spend 15-20 minutes reading the following case study, then answer the questions that follow.

Now consider the following questions:

Mike is a 30-year-old man who has come to your clinic seeking an opioid analgesic for back pain. You explain to Mike that your clinic has a policy of not prescribing controlled substances on the first visit, but that you would like to evaluate him. He initially seems annoyed and stands up to leave, but then he sits down and begins to answer your questions. He denies any past medical problems or surgical history. He did visit the ER once a few years ago for suicidal ideations, but says “I would never do that to my family” and he denies active suicidal ideation. He denies depressive symptoms. He has medication allergies to fentanyl and tramadol. When asked, he says they give him nausea but not anaphylaxis. He was given these medications in the hospital when he broke his arm a few years ago.

He reports that his back pain began when he fell off a roof two years ago. It has always been located on the right side of his back, and it is associated with electric type pain that shoots down his right leg. His back pain feels like muscle strain and the only treatment he had tried in the past was oxycodone. He is not sure if anything else might improve the pain, but he is hesitant to try physical therapy because of the pain. He reports that he is unable to walk to the grocery store or go to his construction job when his back pain is severe. He walks to the grocery store because his driver’s license was suspended after he was arrested for driving under the influence last year. He tells you that he continues to drink, but “not nearly as much.”

On physical examination, the patient is alert and oriented. He is not intoxicated or altered. His vital signs are all stable, heart rate is regular, lungs are clear to auscultation bilaterally, and his abdomen is soft and non-tender. His back is tender over the right side, but it is consistent with muscle pain. He has normal patellar reflexes and flexion. He has full range of motion and no neurological deficits. He does not have any tattoos, bruises, or track marks.

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Case Study Exercise 5 (Continued)

Question 3: What other non-pharmacologic treatment options might you consider for Mike?

After 12 weeks, Mike has adequately trialed a home exercise program, a formal physical therapy program, and non-opioid medications. He is resistant to trying psychological interventions, acupuncture, and chiropractic manipulations, but has had a few massages. Overall, he is feeling stronger, but his pain still interferes with his ability to work 3-4 days per month. He states that his mood is great, and he denies any alcohol use since his initial consultation.

His wife is in attendance and agrees that he has not had any alcohol. You decide, based on the fact that he has not improved with adequate trials of non-medication and non-opioid interventions to start a low dose opioid, intermittently for his chronic back pain. You give him #30 hydrocodone-ac-etaminophen, to take daily as needed, not more than one per day. You sign a treatment agreement with him and ask him to return in 30 days, at which time, you will re-evaluate the need for opioids. For 3 months he is very compliant. He continues a home exercise program and he is able to work. On the fourth month though, he calls 14 days into his prescription and asks for a refill, stating that he had to take more because his back pain worsened after lifting something heavy at work.

Question 4: What kind of functional goals can you set up for Mike that will be both motivating and helpful in guiding further treat-ment options?

Question 5: Does Mike’s request for an early refill constitute a violation of his agreement?

Question 7: Would referral to a pain medicine specialist be indicated at this point?

Question 6: Does Mike’s request suggest that treatment should be terminated, or that the situation requires further evaluation?

Now continue reading about this case study.

Consider the following questions:

Consider the following questions:

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Tapering protocols

Clinicians prescribing opioid therapy should continually reassess the risks and benefits of treatment, and when risks are determined to outweigh benefits or when patients voice a preference for reducing their risk, opioid therapy should be tapered to a reduced dose or tapered to discontinuation. A biopsychosocial assessment including evaluation of co-occurring medical and psychiatric conditions, opioid use disorder, as well as the patient’s social support system, will guide the opioid tapering process. Determination of the rate of opioid tapering takes into account many factors that include initial dose, formulations available, and risk factors that increase potential for harm.

A gradual taper pace of reducing opioid dosage by 5-20% every two to four weeks with the option to pause periodically allows time for neurobiological equilibration as well as the acquisition of new skills to manage pain and emotional distress. In some patients, a faster taper may be needed when risks are too high to consider a gradual taper; consider tapering the dose by 5-20% per day or every week in this patient population. Regardless of the initial speed of taper, the pace of taper should be reevaluated frequently and adjusted as needed to maximize safety and patient comfort as safety allows. When there is evidence of diversion or active severe opioid use disorder, opioids should be discontinued immediately and patient should be referred for treatment of opioid use disorder.

Follow-up should occur within a range of one week to one month after any opioid dosage change with the frequency and type of follow-up adjusted as needed throughout the course of the taper. Each follow-up interaction with the patient is an opportunity to provide education about self-management strategies and the risks associated with opioid therapy while optimizing whole person approaches to pain care and treatment of co-occurring medical and mental health conditions. The care team should take great efforts to ensure that the patient does not feel abandoned during the opioid tapering process by maintaining frequent contact and emphasizing that the care team will continue to pursue non-opioid pain care options during and after opioid tapering.

The risks and benefits of continuing opioid therapy should be evaluated along with the risks and benefits of tapering opioid therapy. It is important to maintain vigilance for symptoms of opioid use disorder and/or exacerbation of an underlying mental health condition that may manifest during an opioid taper. Clinicians should consider using an interdisciplinary, team-based approach that may include primary care, mental health, pain specialty/

rehabilitation, pharmacy, and/or physical therapy during the opioid tapering process, and in particular for patients with significant risk factors for adverse outcomes including very high prescribed opioid doses (> 90 mg MEDD), combined use of opioids and benzodiazepines, high risk patient behaviors, and the presence of psychiatric, medical, or substance use disorder comorbidities.

Monitoring for Overdose Potential and Suicidality

Substance use disorders are a prevalent and strong risk factor for suicide attempts and suicide. Individuals at acute risk for suicidal behavior who appear to be under the influence of alcohol or other drugs, either based on clinical presentation or objective data (e.g., breath or laboratory tests), should be maintained in a secure setting like a hospital or crisis unit until intoxication has resolved. Risk assessment needs to be repeated once the patient is sober in order to determine appropriate next steps. Risk management options include, but are not limited to, admitting the patient for inpatient hospital and psychiatric care, making a referral for detoxification, or scheduling outpatient follow-up in the near future when suicidal risk is reduced.

Intentional overdose is the most common method of attempted suicide. Therefore, the possibility that an overdose event was an intentional act of self-directed violence should always be considered. Obtaining additional information from family members, treatment providers, medical records, etc., can be invaluable in making the determination between intentional and unintentional overdose in equivocal cases.

The same factors that confer risk for suicidal behavior in non-substance abusers generally also confer risk among individuals with substance use disorders. For example, depression is a potent risk factor in both substance abusers and non-substance abusers. The presence of comorbidities (e.g., substance use disorder plus mood disorder) is the rule rather than the exception in high-risk clinical populations.

With effective treatment, illnesses and perpetuating factors can be alleviated, protective factors and coping strategies can be fortified, and the patient’s suicidality can resolve to a state of clinical recovery, where the acute risk has resolved and the risk of relapse has been minimized. Ongoing care may be warranted to provide early detection of recurrence.

Naloxone for overdose

Naloxone (trade name Narcan) is a high-affinity opioid antagonist used to reverse the effects of opioids. It can be administered via intramuscular, intravenous, or intranasal routes, with virtually no side effects and no effect in the absence of opioids. Counties and states that have implemented naloxone-based overdose prevention programs have significantly reduced the incidence of opioid overdose and opioid overdose-related mortality.116,117 The effects of naloxone typically last between 30 and 90 minutes, which means the naloxone may wear off before the effects of the opioid wear off, putting the person at risk of overdose again.118

The American Medical Association has endorsed the distribution of naloxone to anyone at risk for having or witnessing an opioid overdose,119 and, as of 2014, 25 states have amended or enacted laws that make it easier for health care providers to prescribe and dispense naloxone for use by patients and/or caregivers.120

When discussing naloxone with patients consider avoiding the single word “overdose,” which has negative connotations and may be off-putting.121 Instead, use language such as “accidental overdose,” “bad reaction,” or “opioid safety.” For example, one might say, “Naloxone is an antidote for opioids that can be sprayed in the nose or injected if there is a bad reaction and a person cannot be woken up.”

More information and many helpful resources about prescribing and using naloxone, including patient education materials, are available from: prescribetoprevent.org.

Treating pain in special populations

Opioids and pregnancy

Current guidelines suggest that clinicians should avoid prescribing opioids during pregnancy unless the potential benefits outweigh risks.122 Some data suggest an association between the use of long-term opioid therapy during pregnancy and adverse outcomes in newborns, including low birth weight and premature birth, though co-related maternal factors may play a role in these associations and causality is not certain.122 Exposure to these medications has also been associated with birth defects in some studies. Opioid withdrawal can be expected in up to half of newborns of opioid-dependent mothers (neonatal abstinence syndrome).122 If a mother is receiving long-term opioid therapy at or near the time of delivery, a professional experienced in the management of neonatal withdrawal should be available if neonatal abstinence syndrome occurs.

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Emergency room patients

Pain is a frequent complaint of emergency room (ER) patients, and ER providers are among the highest prescribers of opioids to patients ages 10-40.123 ER providers, however, face considerable challenges in determining a patient’s appropriateness for opioid therapy. A medical history is often lacking, and the provider seldom knows the patient personally. Time constraints, as well, can preclude the kinds of careful assessment and evaluation recommended for responsible opioid prescribing. Because of this, current guidelines from the American College of Emergency Physicians include the following recommendations:124

• ER/LA opioid medications should not be prescribed for acute pain

• PDMPs should be used where available to help identify patients at high risk for opioid abuse or diversion

• Opioids should be reserved for more severe pain or pain that doesn’t respond to other analgesics

• If opioids are indicated, the prescription should be for the lowest effective dose and for a limited duration (e.g., < 1 week).

Cancer pain

Pain is one of the most common—and most feared--symptoms of cancer. Pain is experienced by about 30% of patients newly-diagnosed with cancer, 30% - 50% of patients undergoing treatment, and 70% -90% of patients with advanced disease.98 Unrelieved pain adversely impacts motivation, mood, interactions with family and friends, and overall quality of life. Survival itself may be positively associated with adequate pain control.125 Opioid pain medications are the mainstay of cancer pain management and a trial of opioid therapy should be administered to all cancer patients with moderate or severe pain, regardless of the known or suspected pain mechanism.126

ER/LA opioid formulations may optimize analgesia and lessen the inconvenience associated with the use of short-acting opioids. Patient-controlled analgesia with subcutaneous administration using an ambulatory infusion device may provide optimal patient control and effective analgesia.127 The full range of adjuvant medications covered earlier should be considered for patients with cancer pain, with the caveat that such patients are often on already complicated pharmacological regimens, which raises the risk of adverse reactions associated with polypharmacy.

If cancer pain occurs in the context of a patient nearing the end of life, other treatment and care considerations may be appropriate. In these cases, patient integrated with a specialist in palliative care medicine may be advisable.

Pain at the end of life

Pain management at the end of life seeks to improve or maintain a patient’s overall quality of life. This focus is important because sometimes a patient may have priorities that compete with, or supersede, the relief of pain. For some patients mental alertness sufficient to allow lucid interactions with loved ones may be more important than physical comfort. Optimal pain management, in such cases, may mean lower doses of an analgesic and the experience, by the patient, of higher levels of pain.

Since dying patients may be unconscious or only partially conscious, assessing their level of pain can be difficult. Nonverbal signs or cues must sometimes be used to determine if the patient is experiencing pain and to what degree an analgesic approach is effective. In general, even ambiguous signs of discomfort should usually be treated, although caution must be exercised in interpreting such signs.128 Reports by family members or other people close to a patient should not be overlooked. In the Study to Understand Prognosis and Preference for Outcomes and Risks of Treatment (SUPPORT) , surrogates for patients who could not communicate verbally had a 73.5% accuracy rate in estimating presence or absence of the patient’s pain.129

Opioids are critical to providing effective analgesia at the end of life, and they are available in such a range of strengths, routes of administration, and duration of action that an effective pain regimen can be tailored to nearly each patient. No specific opioid is superior to another as first-line therapy. Rectal and transdermal routes of administration can be valuable at the end of life when the oral route is precluded because of reduced or absent consciousness, difficulty swallowing, or to reduce the chances of nausea and vomiting.130 When selecting an opioid, clinicians should also consider cost, since expensive agents can place undue burden on patients and families.

Fear of inducing severe or even fatal respiratory depression may lead to clinician under-prescribing and reluctance by patients to take an opioid medication.28 Despite this fear, studies have revealed no correlation between opioid dose, timing of opioid administration, and time of death in patients using opioids in the context of terminal illness.131 A consult with a specialist in palliative medicine in these situations may be advisable.

Older Adults

The prevalence of pain among community-dwelling older adults has been estimated between 25% and 50%.132 The prevalence of pain in nursing homes is even higher. Unfortunately, managing pain in older adults is challenging due to: underreporting of symptoms; presence of multiple medical conditions; polypharmacy; declines in liver and kidney function; problems with communication, mobility, and safety; and cognitive and functional decline in general.

Acetaminophen is considered the drug of choice for mild-to-moderate pain in older adults because it lacks the gastrointestinal, bleeding, renal toxicities, and cognitive side-effects that have been observed with NSAIDs in older adults (although acetaminophen may pose a risk of liver damage). Opioids must be used with particular caution, and clinicians should “Start low, go slow” with initial doses and subsequent titration. Clinicians should consult the American Geriatrics Society Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults for further information on the many medications that may not be recommended.31

Treating Substance Use Disorders, including Opioid Use Disorder

“Unfortunately, far too few people who suffer from opioid use disorder are offered an adequate chance for treatment that uses safe and effective medications,” FDA Commissioner Scott Gottlieb, M.D.133

Although primary care clinicians have not historically been directly involved in treating substance abuse disorders, they play a critical role in recognizing early signs of these disorders, referring patients to needed services, and supporting patients in the typically lengthy process of recovery from substance use or abuse. There are now many ways that they can assist with the treatment of opioid use disorder if they obtain a physician waiver to prescribe buprenorphine.

Substance use disorders are chronic brain diseases that impair one’s ability to control substance use. Repeated use of any controlled substance over time can lead to a use disorder, and long-term is by far the most powerful risk factor for developing this disorder. All persons using controlled substances are at risk for developing a use disorder, even those who take the substances as prescribed. An early sign of a developing use disorder is gradually becoming more preoccupied with substance use and spending more time seeking the drug, using it, or recovering from its effects.

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Persons with substance use disorder typically continue to use the drug even though they:

• Know the drug use is harmful• Often use more than they intended• Engage in risky behaviors such as driving

while intoxicated or combining alcohol with other drugs

• Have multiple unsuccessful attempts to cut down or control substance use

• Have strong craving or urges to use one or more substances in response to withdrawal symptoms, stress, negative emotions, or cues that the drug is available

The treatment system for substance use disorders is comprised of multiple service components, which may be available to various degrees in different regions. They include the following:

• Individual and group counseling in an outpatient setting

• Inpatient rehabilitation• Residential treatment• Intensive outpatient treatment• Partial hospital programs• Case or care management• Medication treatment• Recovery support services• 12-Step fellowship• Peer supports

A person accessing treatment may not need to access every one of these components, but each can play an important role. These systems are embedded in a broader community and the support provided by various parts of that community also play an important role in supporting the recovery of people with substance use disorders.

Counseling can be provided at the individual or group level. Individual counseling often focuses on reducing or stopping substance use, skill building, adherence to a recovery plan, and social, family, and professional/educational outcomes. Group counseling is often used in addition to individual counseling to provide social reinforcement for pursuit of recovery.

Counselors provide a variety of services to people in treatment for substance use disorders including assessment, treatment planning, and counseling.

These professionals provide a variety of therapies. Some common therapies include:

• Cognitive-behavioral therapy (CBT), which teaches individuals to recognize and stop negative patterns of thinking and behavior. For instance, CBT might help a person be aware

of the stressors, situations, and feelings that lead to substance use so that the person can avoid them or act differently when they occur.

• Contingency management provides incentives to reinforce positive behaviors, such as remaining abstinent from substance use.

• Motivational enhancement therapy helps people with substance use disorders to build motivation and commit to specific plans to engage in treatment and seek recovery. It is often used early in the process to engage people in treatment.

• 12-step facilitation therapy seeks to guide and support engagement in 12-step programs such as Alcoholics Anonymous or Narcotics Anonymous.

Some forms of counseling are tailored to specific populations. For instance, young people often need a different set of treatment services to guide them towards recovery. Treatments for youth often involve a family component. Two models for youth that are often used in combination and have been supported by grants from the Substance Abuse and Mental Health Services Administration are the Adolescent Community Reinforcement Approach (ACRA) and Assertive Continuing Care (ACC).134 ACRA uses defined procedures to build skills and support engagement in positive activities. ACC provides intensive follow up and home based services to prevent relapse and is delivered by a team of professionals.

Treatment provided through inpatient rehabilitation happens within specialty substance use disorder treatment facilities with a broader behavioral health focus, or by specialized units within hospitals. Longer-term residential treatment has lengths of stay that can be as long as six to twelve months and is relatively uncommon. These programs focus on helping individuals change their behaviors in a highly structured setting. Shorter term residential treatment is much more common, and typically has a focus on detoxification (also known as medically managed withdrawal) as well as providing initial intensive treatment, and preparation for a return to community-based and outpatient addiction treatment settings.

An alternative to inpatient or residential treatment is partial hospitalization or intensive outpatient treatment. These programs have people attend very intensive and regular treatment sessions multiple times a week early in their treatment for an initial period. After completing partial hospitalization or intensive outpatient treatment, individuals often “step down” into regular outpatient treatment which meets less frequently and for fewer hours per week to help sustain their recovery.

Using medication to treat substance use disorders is often referred to as Medication-Assisted Treatment (MAT). In this model, medication is used in combination with counseling and behavioral therapies. Medications can reduce the cravings and other symptoms associated with withdrawal from a substance by occupying receptors in the brain associated with using that drug (agonists or partial agonists), block the rewarding sensation that comes with using a substance (antagonists), or induce negative feelings when a substance is taken. MAT has been primarily used for the treatment of tobacco, alcohol, and opioid use disorders. (See Table 4 for a summary of medications used to treat alcohol and opioid use disorders [no medications are approved as of this writing to treat marijuana use disorders, stimulant use disorders, or other substance use disorders].)135

Focus on opioid use disorder

Opioid use disorder (OUD) is associated with premature death from opioid overdose and other medical complications such as AIDS, hepatitis C, and sepsis. On average, OUD carries a 40-60% 20-year mortality rate.136 Persons with OUD are at high-risk for premature death, not only from opioid overdose, but from other consequences. Thus, providing first-line treatment is important to save lives as well as to improve quality of life.

Strong evidence supports the use of medication-assisted therapy (MAT) (e.g., methadone, buprenorphine/naloxone, naltrexone) as first-line treatment for moderate-to-severe OUD.137 Patients and their treating clinicians may be concerned that treatments proven effective in different OUD populations may not be effective for patients with chronic pain, or may not be necessary for patients who have become addicted to prescription opioid analgesics. This concern may be unfounded and was addressed by Weiss and colleagues in the Prescription Opioid Abuse Treatment Study.138

In studies with patients who meet DSM 5 diagnostic criteria for opioid use disorder, buprenorphine maintenance therapy is more effective than a four-week taper with buprenorphine. MAT with moderate dose buprenorphine/naloxone and brief, structured counseling by the prescribing physician can be successful for about half of selected patients with prescription OUD, whereas withdrawal management alone, even with close weekly follow-up and counseling, is successful for less than 10% of patients.

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Table 4: Pharmacotherapies for treating alcohol and opioid use disorders135

Medication Use Dosage Form DEA Schedule* Application

Buprenorphine-Naloxone

Opioid use disorder Sublingual film**:118 2mg/0.5mg, 4mg/1 mg, 8mg/2mg, and 12mg/3mg Sublingual tablet: 1.4mg/0.36mg, 2mg/0.5mg, 2.9/0.71 mg, 5.7mg/1.4mg, 8mg/2mg, 8.6mg/2.1 mg, 11.4mg/2.9mg Buccal film: 2.1 mg/0.3mg, 4.2mg/0.7mg, 6.3mg/1mg

CIII Used for detoxification or maintenance of abstinence for individuals aged 16 or older. Physicians who wish to prescribe buprenorphine, must obtain a waiver from SAMHSA and be issued an additional registration number by the U.S. Drug Enforcement Administration (DEA).

Buprenorphine Hydrochloride

Opioid use disorder Sublingual tablet: 2mg, 4mg, 8mg, and 12mg

CIII This formulation is indicated for treatment of opioid dependence and is preferred for induction. However, it is considered the preferred formulation for pregnant patients, patients with hepatic impairment, and patients with sensitivity to naloxone. It is also used for initiating treatment in patients transferring from methadone, in preference to products containing naloxone, because of the risk of precipitating withdrawal in these patients.

Probuphine® implants: 80mgx4 implants for a total of 320mg

For those already stable on low to moderate dose buprenorphine. The administration of the implant dosage form requires specific training and must be surgically inserted and removed.

Methadone Opioid use disorder Tablet: 5mg, 10mg Tablet for suspension: 40mg Oral concentrate: 10mg/ml Oral solution: 5mg/5ml, 10mg/5ml Injection: 10mg/ml

CII Methadone used for the treatment of opioid addiction in detoxification or maintenance programs shall be dispensed only by Opioid Treatment Programs (OTPs) certified by SAMHSA and approved by the designated state authority. Under federal regulations it can be used in persons under age 18 at the discretion of an OTP physician.119

Naltrexone Opioid use disorder; alcohol use disorder

Tablets: 25mg, 50mg, and 100mg Extended-release injectable suspension: 380mg/vial

Not scheduled under the Controlled Substances Act

Provided by prescription; naltrexone blocks opioid receptors, reduces cravings, and diminishes the rewarding effects of alcohol and opioids. Extended-release injectable naltrexone is recommended to prevent relapse to opioids or alcohol. The prescriber need not be a physician, but must be licensed and authorized to prescribe by the state.

Acamprosate Alcohol use disorder Delayed-release tablet: 333mg

Not scheduled under the Controlled Substances Act

Provided by prescription; naltrexone blocks opioid receptors, reduces cravings, and diminishes the rewarding effects of alcohol and opioids. Extended-release injectable naltrexone is recommended to prevent relapse to opioids or alcohol. The prescriber need not be a physician, but must be licensed and authorized to prescribe by the state.

Disulfiram Alcohol use disorder Tablet: 250mg, 500mg

Not scheduled under the Controlled Substances Act

When taken in combination with alcohol, disulfiram causes se-vere physical reactions, including nausea, flushing, and heart palpitations. The knowledge that such a reaction is likely if alcohol is consumed acts as a deterrent to drinking.

Notes: *For more information about the DEA Schedule and classification of specific drugs, see Appendix D - Important Facts about Alcohol and Drugs. **This dosage form may be used via sublingual or buccal routes of administration; sublingual means placed under the tongue, buccal means applied to the buccal area (in the cheek). Source: Adapted from Lee et al., (2015).120

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Furthermore, the presence of chronic pain does not seem to interfere with the success of MAT.138,139 Given the high mortality associated with OUD and the safety and efficacy of MAT for OUD in multiple clinical trials and meta-analyses, MAT is recommended for those chronic pain patients who meet DSM-5 criteria for OUD. Those who do not respond to medication management alone through a primary care provider may benefit from a comprehensive assessment and more intensive treatment of OUD and any co-occurring conditions in SUD specialty care settings.

Methadone for OUD

Methadone is a synthetic opioid agonist that has long been used to treat the symptoms of withdrawal from heroin and other opioids. Much research supports the use of methadone as an effective treatment for opioid use disorder.135 It is also used in the treatment of patients with chronic, severe pain as a therapeutic alternative to morphine and other opioid analgesics. Any licensed physician can prescribe methadone for the treatment of pain, but methadone may only be dispensed for treatment of an opioid use disorder within licensed methadone treatment programs.135

Long-term methadone maintenance treatment for opioid use disorders has been shown to be more effective than short-term withdrawal management, and it has demonstrated improved outcomes for individuals (including pregnant women and their infants) with opioid use disorders.135 Studies have also indicated that methadone reduces deaths, HIV risk behaviors, and criminal behavior associated with opioid use.

Methadone treatment programs, also known as Opioid Treatment Programs (OTPs), must be certified by SAMHSA and registered by the U.S. Drug Enforcement Administration. OTPs are predominantly outpatient programs that provide pharmacotherapy in combination with behavioral therapies. OTPs incorporate principles of harm reduction and benefit both program participants and the community by reducing opioid use, mortality, crime associated with opioid use disorders, and infectious disease transmission.135

Individuals receiving medication for opioid use disorders in an OTP must initially take their doses daily under observation. Initiation of methadone treatment is done slowly and carefully. Federal law prohibits a dose greater than 40 mg for patients on their first day of treatment. Dose escalation is done slowly as patients stabilize on the medication. Therapeutic doses of methadone are typically 60-90 mg/day, though some patients may need doses much higher than this. After initiation, stabilization on methadone generally takes about 2 weeks.

Patients are monitored daily and given frequent urine drug tests throughout their treatment. Once patients have stabilized fully on the medication, are no longer using other opioids, and have stable living environments, they can become eligible for “take home” medication, meaning they self-administer methadone outside of the OTP. Take home approval is highly monitored and regulated. A patient receiving methadone from an OTP can only receive up to 28 days of take home medication and he/she must remain opioid abstinent at all times.135

Buprenophine for OUD

Buprenorphine is a partial opioid agonist. This means that, like opioids, it can produce effects such as euphoria and respiratory depression. With buprenorphine, however, these effects are weaker than those of full opioid agonists such as heroin and methadone.140 Buprenorphine’s opioid effects increase with each dose until, at relatively moderate doses, they level off and do not cause any additional opioid effect, even with further dose increases. This “ceiling effect” lowers the risk of misuse, dependency, tolerance, and side effects.

Approved for clinical use in October 2002 by the FDA, buprenorphine represents the latest advance in MAT.140 Medications such as buprenorphine, in combination with counseling and behavioral therapies, provide a whole-patient approach to the treatment of opioid use disorder. When taken as prescribed, buprenorphine is safe and effective.140 Buprenorphine as an opioid use disorder treatment is carefully regulated. Qualified physicians and advanced practice providers are required to acquire and maintain certifications to legally dispense or prescribe buprenorphine.

Unlike methadone treatment, which must be performed in a highly structured clinic, buprenorphine is the first medication to treat opioid use disorder that is permitted to be prescribed or dispensed in physician offices, significantly increasing treatment access. Under the Drug Addiction Treatment Act of 2000 (DATA 2000), qualified U.S. physicians can offer buprenorphine for opioid use disorder in various settings, including in an office, community hospital, health department, or correctional facility. Government-certified opioid treatment programs also are allowed to dispense buprenorphine

As with all medications used in MAT, buprenorphine is prescribed as part of a comprehensive treatment plan that includes counseling and participation in social support programs.

The FDA has approved the following buprenorphine products:140

• Bunavail (buprenorphine and naloxone) buccal film

• Suboxone (buprenorphine and naloxone) film• Zubsolv (buprenorphine and naloxone)

sublingual tablets• Buprenorphine-containing transmucosal

products for opioid use disorder

Buprenorphine’s side effects are similar to those of other opioids and can include:

• Nausea, vomiting, and constipation• Muscle aches and cramps• Cravings• Inability to sleep• Distress and irritability• Fever

Because of buprenorphine’s opioid effects, it can be misused, particularly by people who do not have an opioid use disorder. Naloxone is added to buprenorphine to decrease the likelihood of diversion and misuse. When these products are taken as sublingual tablets, buprenorphine’s opioid effects dominate and naloxone is inactive. If the sublingual tablets are crushed and injected intravenously, however, the naloxone effect dominates and can cause opioid withdrawal in people who are dependent on opioids.

Buprenorphine treatment typically happens in three phases:140

1. The Induction Phase is the medically monitored induction of buprenorphine treatment performed in a qualified medical provider’s office or certified opioid treatment program using approved buprenorphine products. The medication is administered when a person with a moderate to severe opioid use disorder has abstained from using opioids for 8 to 24 hours and is in the early stages of opioid withdrawal (identified by a Clinical Opioid Withdrawal Scale > to 10 . It is important to note that buprenorphine can precipitate acute withdrawal for patients who are not in the early stages of withdrawal and who have long-acting opioids like methadone in their bloodstream.

2. The Stabilization Phase begins after a patient has stabilized on buprenorphine, has discontinued or greatly reduced their use of the problem drug, no longer has opioid cravings, and experiences few, if any, side effects. The buprenorphine dose may need to be adjusted during this phase. Because of the long-acting nature of buprenorphine,

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once patients have been stabilized, they can sometimes switch to alternate-day dosing instead of dosing every day, though this is not common. In some cases patients may benefit from taking buprenorphine twice or three times a day, particularly patients with chronic pain.

3. The Maintenance Phase occurs when a patient is doing well on a steady dose of buprenorphine. The length of time of the maintenance phase is tailored to each patient and could be indefinite. Outcomes are best for patients who remain on buprenorphine maintenance treatment. Once an individual is stabilized, an alternative approach would be to go into a medically supervised withdrawal, which makes the transition from a physically dependent state smoother. People then can engage in further rehabilitation—with or without MAT—to prevent a possible relapse.

As with any other substance use disorder, treatment of opioid use disorder with buprenorphine is most effective in combination with counseling services, which can include different forms of behavioral therapy and self-help programs.

Preventing Diversion

The prescribing of opioids and other controlled substances brings with it the risk for diversion, which is the act of removing the medication from its intended and lawful use. To be lawful, the prescribing of controlled substances, including opioids, must occur for a legitimate medical purpose in the usual course of professional practice.141 The responsibility of the prescribing clinician includes reasonable measures to prevent abuse and diversion. Because diversion poses risks for patients, health care workers and other facility employees, and the public at large, it is important for prescribing clinicians to remain alert to signals and address them.

Under no circumstances may a clinician prescribe an opioid or other controlled substance with the knowledge that the medication will be diverted. Drug diversion is a crime with serious consequences that may occur in a variety of settings and at any point along the drug’s supply chain.142 Systemically, reducing diversion requires cooperation from multiple stakeholders, including government agencies, state legislators, pharmaceutical retailers, physicians and other clinicians, patients, pharmacists, and pharmaceutical companies.143

In hospital and acute care settings

Opioids are frequently left over from surgeries, trauma treatments, and other acute pain treatment clinical scenarios.144,145 From 33–75% of opioids prescribed after shoulder surgery remain unused,

and half of prescribed opioids remain unused after outpatient dental surgery.143 Many people save opioids in the event they may need them in the future, frequently storing the medications in unlocked locations in the home.143 These opioids and other controlled substances, which linger in medicine cabinets, can then become a significant source for diversion. The National Survey on Drug Use and Health reported that 60% of adults who misused opioids did not have a prescription, and 41% obtained their most recent misused opioids for free from friends or relatives.146

The CDC has proposed certain prescribing durations for episodes of surgical or other acute pain treatment to reduce the quantity of unused opioids. The CDC guideline states the following:147

• When opioids are used for acute pain, clinicians should prescribe the lowest effective dose of IR opioids and should prescribe no greater quantity than needed for the expected duration of pain severe enough to require opioids.

• Three days or less will often be sufficient; more than 7 days will rarely be needed.

Patients should be counseled never to share opioids with any other person and to store opioids in a locked area away from other family members and visitors.122 Leftover opioids, including transdermal fentanyl patches, should not be placed in the trash but should be taken to an authorized drug take-back facility or, if one is not available, flushed down the toilet or washed down the drain immediately.148 More information about drug disposal and national drug take-back events is available by calling 1-800-882-9539 or visiting the website (https://www.deadiversion.usdoj.gov/drug_disposal/index.html) of the Drug Enforcement Administration.

In clinicians’ offices

Opioids are the most diverted of controlled substances, and most diversion of opioids occurs in outpatient settings.142 Other drug classes with high diversion potential include hallucinogens, stimulants, anabolic steroids, and other CNS depressants.

Diversion by patients or persons posing as patients can take the form of visiting multiple providers to receive prescriptions, drug theft, prescription pad theft and forgery, and stealing prescription drugs. Any formulation may be misused or diverted: Extended-release (ER) opioids contain a higher dose per unit, which makes them attractive to manipulate and abuse; however, immediate-release (IR) opioids are more frequently prescribed and widely available and are generally preferred by nonmedical users.143

Clinical practices to minimize diversion include the following:149

• Caution when prescribing to patients who request combinations of drugs that may enhance effects, such as opioids with benzodiazepines

• Thorough documentation when prescribing or choosing not to prescribe opioids

• Keeping a DEA registrant or license number confidential unless disclosure is required

• Protecting access to prescription pads• Ensuring that prescriptions are written clearly

to minimize the potential for forgery• Moving to electronic prescribing so that paper

prescriptions are not required• Adhering to strict refill policies and educating

office staff• Using PDMPs to monitor new patients and on

refilling or adding new medications• Referring patients with extensive pain

management or prescription needs to specialists in relevant fields

• Collaborating with pharmacy benefit managers and managed care plans that seek to determine medical necessity of prescriptions

Generally speaking, risk mitigation measures to prevent nonmedical or other problematic opioid use by the patient are also helpful in determining whether a patient -- or a person posing as a patient -- is diverting controlled substances. These measures include opioid treatment agreements to lay out consequences of illegal behavior and initial, random, and ongoing checks of the state PDMP and UDT as appropriate. Diversion is one possible explanation if UDT results show the prescribed medications are not present. One should bear in mind, however, that the absence of the prescribed medication is not in itself proof of diversion (or hoarding for later use) but is one possible explanation that should be considered in context with other clinical signs. When diversion has occurred, immediate discharge from care is warranted.150

By facility health care workers

Unfortunately, the diversion of opioids by health care workers from their places of employment is not uncommon. A single provider may have multiple opportunities to divert drugs when procuring them from storage, preparing or administering them, and disposing of drug waste. Theft of patients’ medication is one form of health care worker diversion. Another is tampering or replacing the patient’s intended medication with another substance in order to use (i.e., inject) the patients’ medication for themselves. Tampering is particularly dangerous and includes the risk the patient may be exposed to infections.

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The risks are grave for patient trust and treatment and for clinic employee safety. Yet physicians and other clinicians rarely report their colleagues for suspected diversion or even impairment they directly observe.142 Reasons include fear of retribution, belief that the issue is being addressed by someone else, and fear that no action will come of the report.142

The best way for facilities to respond is to have clear policies and procedures in place to quickly identify diversion and intervene.142 Possibilities include urine drug screening and agreement to comply with diversion prevention policies prior to hiring in addition to ongoing random or “for cause” testing. Newly hired facility workers should receive education to prevent diversion, and that education should be ongoing. Mandatory reporting procedures and methods of surveillance, including checks of prescribing records and video surveillance, should be in place. It is important to check relevant laws in the state of practice as some states require that diversion of controlled substances be reported to federal authorities and result in loss of license to practice medicine.

Certain signs should alert supervisors to the possibility that diversion may be occurring, for example:151

• Removing controlled substances without a doctor’s order

• Removing controlled substances for patients “not assigned” to them

• Removing controlled substances for patients that have been discharged

• Removing controlled substances and not documenting them

• Pulling excessive quantities of as-needed medication compared to other health care workers assigned to the patient

• Exhibiting discrepancies in inventory on a regular basis

• Pulling out controlled substances in lower dosages in order to obtain more pills when the exact dosage is available

• Pulling out larger dosages of injectable medications to obtain more waste

• Continuing patient complaints of pain, despite documented administration of pain medications

• Falsifying records and failing to document waste

• Removing as-needed medications too frequently, for example pulling every 2 hours when the order is for every 4 hours

Staff members other than health care workers may also divert medications. Support staff employees who may be diverting controlled substances may be

spotted in areas where they are not unauthorized, may unnecessarily touch syringes, may stay late when their services are unnecessary, and may always volunteer to help or to dispose of waste.151 If health care workers or support staff are impaired, they may appear sleepy, exhibit personality changes, commit multiple errors or be unable to perform routine tasks, take excessive sick leave or extended breaks, and be the target of multiple patients complaints.151

To effectively combat diversion, cooperation is necessary across multiple teams and facility divisions. The Mayo Clinic has laid out the following set of recommended steps when diversion in the workplace is suspected or identified:142

• Secure whatever evidence is available• Initiate drug testing• Initiate a discussion with the employee’s

supervisor• Review of any records documenting handling

of controlled substances• Institute additional surveillance if necessary• Initiate recurring meetings of a drug diversion

response team to review findings• Quickly remove from patient care any employee

found to have diverted controlled substances• Quickly close the case of any employee

determined not to have diverted controlled substances

• Report findings to the Drug Enforcement Administration, the state pharmacy board, and local law enforcement

Conclusions

This monograph on best practices for prescribing controlled substances summarized the United States federal legislation governing the prescription of controlled substances and offered suggestions for how health care providers can comply with those regulations. The monograph provided a list of frequently encountered non-opioid controlled substances grouped by schedule. It reviewed the legal requirements for compliance in prescribing these substances, including how to perform critical components of the history and physical examination, assessing patients for substance use disorder risk, and documenting risk stratification. Before prescribing controlled substances, health care providers are obligated to document how they made the diagnosis and why a controlled substance is the best treatment for the patient. This monograph also reviewed some common conditions that may be treated with controlled substances.

The government frequently changes the requirements for compliance with controlled substances. Substances are added, removed, or

transferred between schedules in the controlled substance list. For example, the American Medical Association, the Institute of Medicine, and the American College of Physicians have petitioned the DEA to shift cannabis from Schedule I to Schedule II in light of the voluminous testimony that this substance does have valid medical uses and to facilitate research on more effective therapeutic uses of the relevant compounds contained in raw cannabis.152 (As noted above, this monograph does not cover cannabis because the legal, medical, and cultural dimensions of this drug are in such flux.)

In order to maintain compliance, responsible health care providers must be aware of changes in legislation and regulatory requirements associated with commonly prescribed substances. They must maintain current DEA licensure for the state in which they practice and ensure that the DEA has their most current mailing address. When prescribers fill out a prescription for a controlled substance, they must ensure that all parts of the prescription are filled out properly, and they should take schedules into account when sending prescriptions to the pharmacy or ordering re-fills. Lastly, health care providers should closely monitor patients who are taking controlled substances for signs of addiction, overdose, side-effects, and drug-drug interactions.

Clearly, the rise of substance use disorder and prescription drug abuse, and the wider use of controlled substances, is related to social, cultural, and economic forces that are larger and more powerful than any role that clinicians have in their day-to-day work with controlled substances.18 But at the same time, clinicians can take simple steps to insure that controlled substances are prescribed safely and effectively. By so doing, those prescribers help protect their patients, society at large and themselves should they encounter the scrutiny of regulators.

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82. American Academy of Pediatrics. ADHD: Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescent. 2015; http://pediatrics.aappublications.org/content/ear ly/2011/10/14/peds.2011-2654.full.pdf. Accessed June 27, 2015.

83. Subcommittee on Attention-Deficit/Hyperactivity D, Steering Committee on Quality I, Management, et al. ADHD: clinical practice guideline for the diagnosis, evaluation, and treatment of attention-deficit/hyperactivity disorder in children and adolescents. Pediatrics. 2011;128(5):1007-1022.

84. Pliszka S, Aacap Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.

85. Sinita E, Coghill D. The use of stimulant medications for non-core aspects of ADHD and in other disorders. Neuropharmacology. 2014;87:161-172.

86. Wilens TE, Morrison NR. The intersection of attention-deficit/hyperactivity disorder and substance abuse. Curr Opin Psychiatry. 2011;24(4):280-285.

87. Schonwald A. Update: attention deficit/hyperactivity disorder in the primary care office. Current opinion in pediatrics. 2005;17(2):265-274.

88. Wilens TE, Adler LA, Adams J, et al. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature. J Am Acad Child Adolesc Psychiatry. 2008;47(1):21-31.

89. Johnston LD, O’Malley PM, Bachman JG, Schulenberg JE. Monitoring the Future national survey results on drug use, 1975–2010: Volume I, Secondary school students. Ann Arbor: Institute for Social Research, The University of Michigan 2011.

90. World Health Organization. Obesity. 2015; http://www.who.int/mediacentre/factsheets/fs311/en/. Accessed June 23, 2015.

91. Ogden CL, Carroll MD, Kit BK, Flegal KM. Prevalence of childhood and adult obesity in the United States, 2011-2012. Jama. 2014;311(8):806-814.

92. National Heart Lung & Blood Institute. Obesity Evidence Review. 2015; https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/obesity-evidence-review.pdf. Accessed June 27, 2015.

93. Yanovski SZ, Yanovski JA. Long-term drug treatment for obesity: a systematic and clinical review. Jama. 2014;311(1):74-86.

94. American Family Physician. Medical Management of Obesity. 2015; http://www.aafp.org/afp/2000/0715/p419.html. Accessed June 27, 2015.

95. Fujioka K. Current and emerging medications for overweight or obesity in people with comorbidities. Diabetes Obes Metab. 2015;17(11):1021-1032.

96. Fox CD, Berger D, Fine P, et al. Pain assessment and treatment in the managed care environment: a position statement from the American Pain Society. Glenview, IL: American Pain Society;2000.

97. NCHS. Health, United States, 2006 with Chartbook on trends in the health of Americans. Hyattsville, MD: U.S. Department of Health and Human Services;2006.

98. American Cancer Society. Cancer Facts and Figures, 2012. Atlanta, GA: American Cancer Society;2012.

99. Becker N, Bondegaard Thomsen A, Olsen AK, Sjogren P, Bech P, Eriksen J. Pain epidemiology and health related quality of life in chronic non-malignant pain patients referred to a Danish multidisciplinary pain center. Pain. 1997;73(3):393-400.

100. California Medical Association. Prescribing Opioids: Care amid Controversy. Recommendations from the California Medical Association’s Council on Scientific Affairs. March, 2014.

101. Washington State Department of Labor & Industries. Guideline for prescribing opioids to treat pain in injured workers. Office of the Medical Director;2013.

102. Noble M, Treadwell JR, Tregear SJ, et al. Long-term opioid management for chronic noncancer pain. The Cochrane database of systematic reviews. (1):CD006605.

103. Agency for Healthcare Research and Quality. The effectiveness and risks of long-term opioid treatment of chronic pain. 2014.

104. Martell BA, O’Connor PG, Kerns RD, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Annals of internal medicine. 2007;146(2):116-127.

105. Fleming MF, Balousek SL, Klessig CL, Mundt MP, Brown DD. Substance use disorders in a primary care sample receiving daily opioid therapy. J Pain. 2007;8(7):573-582.

106. Banta-Green CJ, Merrill JO, Doyle SR, Boudreau DM, Calsyn DA. Opioid use behaviors, mental health and pain--development of a typology of chronic pain patients. Drug and alcohol dependence. 2009;104(1-2):34-42.

107. Fishbain DA, Cole B, Lewis J, Rosomoff HL, Rosomoff RS. What percentage of chronic nonmalignant pain patients exposed to chronic opioid analgesic therapy develop abuse/addiction and/or aberrant drug-related behaviors? A structured evidence-based review. Pain medicine. 2008;9(4):444-459.

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108. Edlund MJ, Martin BC, Russo JE, DeVries A, Braden JB, Sullivan MD. The role of opioid prescription in incident opioid abuse and dependence among individuals with chronic noncancer pain: the role of opioid prescription. The Clinical journal of pain. 2014;30(7):557-564.

109. Boscarino JA, Rukstalis MR, Hoffman SN, et al. Prevalence of prescription opioid-use disorder among chronic pain patients: comparison of the DSM-5 vs. DSM-4 diagnostic criteria. Journal of addictive diseases. 2011;30(3):185-194.

110. Dunn KM, Saunders KW, Rutter CM, et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Annals of internal medicine. 2010;152(2):85-92.

111. American Pain Society. Guideline for the use of chroni opioid therapy in chronic noncancer pain. 2009.

112. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther. 2005;7(5):R1046-1051.

113. Takkouche B, Montes-Martinez A, Gill SS, Etminan M. Psychotropic medications and the risk of fracture: a meta-analysis. Drug Saf. 2007;30(2):171-184.

114. Miller M, Sturmer T, Azrael D, Levin R, Solomon DH. Opioid analgesics and the risk of fractures in older adults with arthritis. J Am Geriatr Soc. 2011;59(3):430-438.

115. Dublin S, Walker RL, Jackson ML, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a population-based case-control study. J Am Geriatr Soc. 2011;59(10):1899-1907.

116. Walley AY, Xuan Z, Hackman HH, et al. Opioid overdose rates and implementation of overdose education and nasal naloxone distribution in Massachusetts: interrupted time series analysis. BMJ. 2013;346:f174.

117. Davidson PJ WE, Proudfoot J, Xu R, Wagner K. Naloxone distribution to drug users in California and opioid related overdose death rates. Unpublished manuscript; 2014.

118. Massachusetts Department of Public Health. Opioid overdose education and naloxone distribution, MDPH Naloxone pilot project core competencies.: Boston Public Health Commission; 2011.

119. American Medical Association. AMA adopts new policies at annual meeting: promoting prevention of fatal opioid overdose. June, 2012 2012.

120. Davis C. Legal interventions to reduce overdose mortality: naloxone access and overdose good samaritan laws. The Network for Public Health Law;2014.

121. San Francisco Department of Public Health. Naloxone for opioid safety: a provider’s guide to prescribing naloxone to patients who use opioids. 2015.

122. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130.

123. Volkow ND, McLellan TA, Cotto JH, Karithanom M, Weiss SR. Characteristics of opioid prescriptions in 2009. Jama. 2011;305(13):1299-1301.

124. Cantrill SV, Brown MD, Carlisle RJ, et al. Clinical policy: critical issues in the prescribing of opioids for adult patients in the emergency department. Annals of emergency medicine. 2012;60(4):499-525.

125. Cleeland CS, Gonin R, Hatfield AK, et al. Pain and its treatment in outpatients with metastatic cancer. N Engl J Med. 1994;330(9):592-596.

126. Cherny NI, Thaler HT, Friedlander-Klar H, et al. Opioid responsiveness of cancer pain syndromes caused by neuropathic or nociceptive mechanisms: a combined analysis of controlled, single-dose studies. Neurology. 1994;44(5):857-861.

127. Bader P, Echtle D, Fonteyne V, et al. Guidelines on pain management. 2010.

128. Forrow L, Smith HS. Pain management in end of life: palliative care. In: Warfield CA BZ, ed. Principles & Practice of Pain Medicine. 2nd ed. New York, NY: McGraw-Hill; 2004.

129. Desbiens NA, Mueller-Rizner N. How well do surrogates assess the pain of seriously ill patients? Critical care medicine. 2000;28(5):1347-1352.

130. Mercadante S. Intravenous morphine for management of cancer pain. The Lancet Oncology. 2010;11(5):484-489.

131. Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain Symptom Manage. 2001;21(4):282-289.

132. Ferrell BA. Pain management in elderly people. J Am Geriatr Soc. 1991;39(1):64-73.

133. U.S. Food and Drug Administration. FDA takes new steps to advance the development of innovative products for treating opiod use disorder. April 20, 2018; https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm605248.htm. Accessed June 24 2018.

134. Substance Abuse and Mental Health Services Administration. Treatments for Substance Use Disorders. 2018; https://www.samhsa.gov/treatment/substance-use-disorders. Accessed July 6 2018.

135. U.S. Department of Health and Human Services (HHS) OotSG. Facing Addiction in America: The Surgeon General’s Report on Alcohol, Drugs, and Health. Washington, DC November 2016.

136. Hser YI, Evans E, Grella C, Ling W, Anglin D. Long-term course of opioid addiction. Harv Rev Psychiatry. 2015;23(2):76-89.

137. Department of Veterans Affairs/DoD. Clinical Practice Guideline for the Management of Substance Use Disorders. http://www.healthquality.va.gov/guidelines/mh/sud/index.asp. Accessed June 24, 2018.

138. Weiss RD, Potter JS, Fiellin DA, et al. Adjunctive counseling during brief and extended buprenorphine-naloxone treatment for prescription opioid dependence: a 2-phase randomized controlled trial. Arch Gen Psychiatry. 2011;68(12):1238-1246.

139. Dennis BB, Bawor M, Naji L, et al. Impact of Chronic Pain on Treatment Prognosis for Patients with Opioid Use Disorder: A Systematic Review and Meta-analysis. Subst Abuse. 2015;9:59-80.

140. Substance Abuse and Mental Health Services Administration. Buprenophine. 2018; https://www.samhsa .gov /med i ca t i on -ass i s ted -treatment/treatment/buprenorphine. Accessed July 6 2018.

141. Code of Federal Regulations. Title 21 CFR §1306 Prescriptions §1306.04. https://w w w. d e a d i v e r s i o n . u s d o j . g o v / 2 1 c f r /cfr/1306/1306_04.htm. Accessed August 20 2018.

142. Berge KH, Dillon KR, Sikkink KM, Taylor TK, Lanier WL. Diversion of drugs within health care facilities, a multiple-victim crime: patterns of diversion, scope, consequences, detection, and prevention. Mayo Clin Proc. 2012;87(7):674-682.

143. Nalamachu SR, Shah B. Abuse of immediate-release opioids and current approaches to reduce misuse, abuse, and diversion. Postgrad Med. 2018:1-7.

144. Bicket MC, Long JJ, Pronovost PJ, Alexander GC, Wu CL. Prescription Opioid Analgesics Commonly Unused After Surgery: A Systematic Review. JAMA Surg. 2017;152(11):1066-1071.

145. Maughan BC, Hersh EV, Shofer FS, et al. Unused opioid analgesics and drug disposal following outpatient dental surgery: A randomized controlled trial. Drug and alcohol dependence. 2016;168:328-334.

146. Substance Abuse and Mental Health Services Administration. (2017). Key substance use and mental health indicators in the United States: Results from the 2016 National Survey on Drug Use and Health (HHS Publication No. SMA 17-5044, NSDUH Series H-52). Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/.

147. Dowell D, Haegerich TM, Chou R. CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016. MMWR Recomm Rep. 2016;65(1):1-49.

148. U.S. Food and Drug Administration. Disposal of Unused Medicines: What You Should Know. Updated January 11, 2018; https://www. f da .gov /D r ugs /Resou r cesFo rYou /Consumer s/Buy ingUsingMedic ineSafe ly/E n s u r i n g S a f e U s e o f M e d i c i n e /SafeDisposalofMedicines/ucm186187.htm. Accessed 3-19-18.

149. Centers for Medicare and Medicaid Services. Partners in Integrity: What is a Prescriber’s Role in Preventing the Diversion of Prescription Drugs? https://www.cms.gov/medicare...integrity.../prescriber-role-drugdiversion.pdf. Accessed 8-23-18.

150. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for Opioid Therapy for Chronic Pain. 2017.

151. Abramowitz LH, Bittinger AM. T. Diversion of Controlled Substance in Health Care Setting. Paper presented at: Physicians and Hospitals Law InstituteFebruary 5-7, 2014; Jacksonville, Florida.

152. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. 2012;87(2):172-186.

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EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT,AND HARM REDUCTION

16. In the United States, approximately how many non-medical users of pain relievers, tranquilizers, stimulants, and sedatives got their prescription drugs from a friend or relative for free? A. < 10%B. 25%C. 35%D. > 50%

17. What two competing needs must the CSA and regulators attempt to balance?A. The need to contain the spiraling costs of prescription

medications while also supporting the pharmaceutical industry’s need to support expensive research and development efforts

B. The need to maintain an adequate supply of controlled substances for legitimate purposes while simultaneously reducing their diversion and abuse

C. The need to regulate the pharmaceutical industry while also supporting law enforcement agencies

D. The need to punish those abusing prescription medications with the need to provide adequate social support for addicts

18. Which of the following factors might be used to determine into which schedule a drug or other substance should be placed?A. The history and current pattern of abuse of a drugB. Scientific evidence of the drug’s pharmacological effectC. The drug’s actual or relative potential for abuseD. All of the above

19. Into how many classes does the CSA assign drugs or other substances?A. 4B. 5C. 6D. 10

20. Which attribute of some drugs with legitimate therapeutic uses increases their likelihood of being abused?A. Whether the drug is compounded with another drug B. Whether the drug produces pleasurable feelingsC. Cost of the drug to patientsD. Whether the drug, as packaged and manufactured,

resembles other drugs with legitimate medical uses

21. Heroin, LSD, MDMA, and cannabis are currently listed in which CSA schedule?A. IB. IIC. IIID. IV

22. Drugs in which schedule are deemed to have a high potential for abuse or dependence but also have a currently accepted medical use in the US? A. IB. IIC. IIID. IV

23. The duration of action of ER/LA opioids is typically:A. 30 – 90 minB. 2- 4 hrsC. 4 – 24 hrsD. 4 – 72 hrs

24. Uncomfortable or unpleasant side effects (aside from constipation) may potentially be reduced by which two approaches?A. Switching to another opioid or taking the opioid with foodB. Switching to another opioid or changing the route of

administrationC. Adding a non-opioid analgesic or trying a complimentary

therapeutic techniqueD. Changing the route of administration or advising patients to

avoid alcohol consumption

25. What drug class has largely replaced barbiturates as treatment for anxiety and muscle spasms?A. AmphetaminesB. BenzodiazepinesC. Non-benzodiazepinesD. Serotonin-reuptake inhibitors

26. Any person who handles or intends to handle controlled substances must obtain what?A. A registration from their state Medical BoardB. A registration from the Drug Enforcement AdministrationC. A registration from the FDAD. A registration from the Department of Homeland Security

27. If a physician is filling in for another physician in another state as part of a locum tenens arrangement, the substitute physician can legally prescribe controlled substances as long as he or she is legitimately registered with the DEA in his or her home state. A. TrueB. False

28. In an emergency, a prescriber may phone or electronically submit a prescription for a Schedule II drug to a pharmacy but must follow up with a written prescription within 7 days.A. TrueB. False

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29. Which of the following items does not need to be contained in any prescription for a controlled substance? A. Proof of informed consentB. Patient’s name and addressC. Drug strengthD. Number of refills (if any)

30. Which of the following might suggest inappropriate prescribing of controlled substances by a clinician? A. Prescribing a drug for which no logical relationship exists

with the alleged condition of a patientB. Prescribing a substance without performing a physical

examinationC. Prescribing the substance at intervals inconsistent with

legitimate medical treatmentD. All of the above

31. The Ryan Haight Act made it illegal to:A. Dispense controlled substances in all schedules via the

Internet B. Dispense controlled substances in a state different from the

one in which a practitioner is registeredC. Dispense Schedule I substances to patients for any reasonD. Dispense controlled substances to minors

32. Which of the following is not a potential benefit of urine drug screening?A. May deter inappropriate useB. Provides objective evidence of abstinence from drugs of

abuseC. May demonstrate to regulatory authorities a clinician’s

dedication to monitoringD. Can differentiate between opioids that a patient may be

using

33. How frequently are the data in most prescription drug monitoring programs updated?A. HourlyB. Hourly or dailyC. Daily or weeklyD. Monthly

34. Drugs with the highest risk for subsequent addiction slowly elicit dopamine release in the midbrain.A. TrueB. False

35. Although initially thought to be less prone to induce tolerance and dependence than barbiturates, benzodiazepines are now recognized to be just as liable to diversion and abuse.A. TrueB. False

36. Little evidence supports the assertion that long-term use of opioids provides clinically significant pain relief or improves quality of life or functioning.A. TrueB. False

37. Roughly what percent of patients reported that they increased their dose of an opioid without talking to the prescribing physician in one study?A. 10%B. 20%C. 30%D. 40%

38. When opioid treatment is initiated, it should be viewed by both patient and clinician as:A. A commitment to long-term use of opioid therapyB. A commitment to gradual titration of the opioid to reach

optimal pain reliefC. A short-term trial of therapyD. An agreement to continue therapy until adequate pain relief

is achieved

39. Opioid tolerance must be demonstrated before prescribing any strength of:A. A short-acting opioidB. An ER/LA opioidC. A combination formulation of an opioidD. An abuse deterrent formulation of an opioid

40. What level of opioid dose is widely considered a red flag warranting more intense monitoring and/or referral to an interdisciplinary treatment team?A. > 75 mg MEDDB. > 80 mg MEDDC. > 90 mg MEDDD. >110 mg MEDD

41. What relatively new development may reduce the incidence of death from accidental overdose of an opioid medication?A. Mandatory CPR training for patients B. New restrictions on simultaneous prescribing of an opioid

and a central nervous system depressantC. Greater availability of 911 emergency response systemsD. Provision to patients of intranasal naloxone for home use

42. For patients at the end of life, optimal pain management may mean lower doses of an analgesic, and higher levels of pain, in order to allow the patient mental alertness sufficient for interactions with loved ones.A. TrueB. False

43. Medication-Assisted Treatment is primarily used for treating:A. Tobacco use disorderB. Opioid use disorderC. Alcohol use disorderD. All of the above

44. Which of the following is NOT a practice that clinicians can use to minimize diversion of controlled substances?A. Keeping DEA registrant or license number confidentialB. Implement mandatory urine drug testing for all patients

prescribed a controlled substanceC. Protecting access to prescription padsD. Using PDMPs on refilling or adding new controlled substance

prescription

45. Acamprosate is a medication that can be used in the treatment of:A. Marijuana use disorderB. Opioid use disorderC. Cocaine use disorderD. Alcohol use disorder

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VERIFIED CERTIFICATES AND LEARNER RECORDS1. Important: To ensure accurate record keeping and reporting, your personal information entered at the beginning of the assessment should match your license record.2. Why we collect this info: We use this information to uniquely identify each individual who successfully completes our activities and verify learner records for professional credentialing.

FIRST NAME:

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PHONE NUMBER:

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Mandatory CME on Opioid PrescribingWisconsin legislation and regulations require physicians licensed by the State of Wisconsin to

complete two (2) credit hours of continuing medical education on opioid prescribing. This includes all licensed physicians (MD/DO) with a current DEA registration.

Complete the customer information, self-assessment & activity evaluations on the next page.

Tear out the page. Mail the form in the self-addressed envelope.

Turn in information online or by following these easy steps:

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MEDICAL LICENSE NUMBER FORMATS:

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FIRST NAME:

EMAIL ADDRESS:

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LICENSE NUMBER: LICENSE EXPIRATION DATE:LICENSE STATE:

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EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTION (PG. 78-79)

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PRESCRIBER EDUCATION FOR OPIOID ANALGESICS (PG. 40-41)

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WI600CME

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ACTIVITY EVALUATION(S)

EVIDENCE-BASED GUIDANCE ON RESPONSIBLE PRESCRIBING, EFFECTIVE MANAGEMENT, AND HARM REDUCTION:DCBA

7. Describe the scope of current use and abuse of controlled substances in the U.S. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8. Interpret regulatory and legal framework for prescribing controlled substances. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

9. Explain best practices for prescribing controlled substances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10. Respond to addiction treatment & diversion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

11. Please identify a specific change, if any, you will make in your practice related to safe prescribing of controlled substances?

12. What do you see as a barrier to making these changes?

WI600CME

13. The program was balanced, objective & scientifically valid

14. Do you feel the program was scientifically sound & free of commercial bias or influence?

15. How can this program be improved?

16. Based on your educational needs, please provide us with suggestions for future program topics & formats.

PROGRAM EVALUATION:If no, please explain:NoYes

. . . . . . . . . . . . . . . . . . . . . . . . . . .

DCBA

1. Assess non-pharmacological, non-opioid and opioid analgesics therapies in comprehensive pain plan for patient . . . . . . . .

2. Distinguish the diagnostics criteria for substance abuse disorder, including opioids, to be utilized at all stages of

treatment and its impact on public health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3. Describe safety elements to address in the misuse and abuse of opioid analgesics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4. Initiate, manage and discontinue use of opioid analgesic therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5. Please identify a specific change, if any, you will make in your practice related to safe prescribing of opioid analgesics?

6. What do you see as a barrier to making these changes?

PRESCRIBER EDUCATION FOR OPIOID ANALGESICS:

83

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