PAINWeek Journal, Vol 3, Q4

MAKING MEDICATIONS WORK FOR DEPRESSIONP.20 VIRTUAL REALITY: DOES IT HAVE A ROLE IN PAIN MANAGEMENT?P.26 PASTRAMI OR PRESCRIPTIONS: THE DELI CAN WAIT…WE NEED MORE AND BETTER PAIN PRACTITIONERS NOW!P.34 THE BULLET-

PROOF PRESCRIBERP.40

vol. 3 q 4 2015

TIME TO DUAL

Limitations of Use• Because of the risks of addiction, abuse, and

misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain

• NUCYNTA® ER is not indicated as an as-needed (prn) analgesic

Not an actual patient.

NUCYNTA® ER is the first and only FDA-approved long-acting opioid designed to control both nociceptive pain and the neuropathic pain associated with diabetic peripheral neuropathy (DPN).

NUCYNTA® ER is an opioid agonist indicated for the management of:

• pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate

Please see additional Important Safety Information and Brief Summary, including BOXED WARNING, on the following pages.

TWO SOURCESOF PAIN

ONE SOURCE OF RELIEF

PRESCRIBE NUCYNTA® ER FOR ONE SOURCE OF RELIEF • Proven efficacy in chronic low back pain and DPN1,2

- Based on efficacy demonstrated in a prospective, randomized, double-blind, active- and placebo-controlled, multicenter phase 3 chronic low back pain study (N=981) showing significant change in mean pain intensity from baseline in Week 15 (Week 12 of the maintenance phase) vs placebo1

- Based on efficacy demonstrated in a double-blind, parallel-group, enriched-enrollment randomized phase 3 DPN study (N=977) showing significant change in mean pain intensity over the last week of the 12-week, double-blind, maintenance phase vs placebo2

• 5 dosage strengths: 50 mg, 100 mg, 150 mg, 200 mg, and 250 mg3* Individualize dosing based on patient’s prior analgesic treatment experience and risk

factors for addiction, abuse, and misuse; titrate as needed to provide adequate analgesia and minimize adverse reactions

• Administer NUCYNTA® ER ~q12h3

*Please see full Prescribing Information for DOSAGE AND ADMINISTRATION.† Some restrictions and limitations apply. See full terms and conditions available at NUCYNTA.com. Available to commercially insured and cash-paying patients only. Patients covered by Medicare, Medicaid, or any other state- or federally funded benefit program are excluded. Patients must be 18 years of age or older. This promotion cannot be combined with any other programs, offers, or discounts. Depomed reserves the right to rescind, revoke, or amend this offer without further notice.

‡ Source: MMIT 2.0, May 2015.

References: 1. Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase Ill study. Expert Opin Pharmocother. 2010;11(11):1787-1804. 2. Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011;27(1):151-162. 3. NUCYNTA® ER [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2014.

COVERED FOR

94%OF COMMERCIALLY

INSURED PATIENTS.‡

PREFERRED FOR UNITEDHEALTH

GROUP AND SILVERSCRIPT/

CVS CAREMARK PART D PLANS‡

CONTRAINDICATIONS: Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; and

INTERACTION WITH ALCOHOLSee full prescribing information for complete boxed warning.

• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1)

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2)

• Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2)

• Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)

• Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4)

VISIT NUCYNTA.COM FOR MORE INFORMATION AND TO DOWNLOAD A NUCYNTA® ER SAVINGS CARD†

• $0 co-pay for first prescription of NUCYNTA® ER with a $25 co-pay on each additional prescription if eligible†

Nuc_PainWeekJourn.indd 1 9/29/15 9:08 AM

NUCYNTA® ER (tapentadol) IMPORTANT SAFETY INFORMATION (continued)

WARNINGS AND PRECAUTIONS: Addiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, an opioid agonist and a Schedule II controlled substance that can be abused in a manner similar to other opioid agonists, legal or illicit. There is a greater risk for overdose and death due to the larger amount of tapentadol present in NUCYNTA® ER. Assess risk for opioid abuse or addiction prior to prescribing NUCYNTA® ER. Addiction can occur in patients appropriately prescribed NUCYNTA® ER at recommended doses; in those who obtain the drug illicitly; and if the drug is misused or abused. Therefore, routinely monitor for signs of misuse, abuse, and addiction. Patients at increased risk (e.g., patients with a personal or family history of substance abuse or mental illness) may be prescribed NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use along with intensive monitoring for signs of addiction, abuse, and misuse.

Life-threatening Respiratory Depression: Can occur at any time during the use of NUCYNTA® ER even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. To reduce the risk of respiratory depression, proper dosing and titration are essential. Overestimating the dose when converting patients from another opioid product can result in fatal overdose with the first dose. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate, which may be life-threatening and require management according to protocols developed by neonatology experts. Neonatal opioid withdrawal syndrome presents as poor feeding, irritability, hyperactivity and abnormal sleep pattern, high-pitched cry, tremor, rigidity, seizures, vomiting, diarrhea, and failure to gain weight.

Interactions With Central Nervous System Depressants: Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, tranquilizers, general anesthetics, neuroleptics, other opioids). When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the duration of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.

Use in Elderly, Cachectic, or Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharmacokinetics or altered clearance. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients in the lower range of recommended doses. Closely monitor these patients, particularly when initiating and titrating NUCYNTA® ER and when given concomitantly with other drugs that depress respiration.

Use in Patients With Chronic Pulmonary Disease: Patients with significant chronic obstructive pulmonary disease or cor pulmonale and patients having a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, should be monitored for respiratory depression particularly when initiating therapy and titrating with NUCYNTA® ER. Consider the use of alternative nonopioid analgesics in these patients.

Hypotensive Effect: May cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor for signs of hypotension during dose initiation or titration. Avoid use in patients with circulatory shock; may cause vasodilation that can further reduce cardiac output and blood pressure.

Use in Patients With Head Injury or Increased Intracranial Pressure: Monitor patients who may be susceptible to the intracranial effects of CO

2

retention (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy. NUCYNTA® ER may reduce respiratory drive, and the resultant CO

2

retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.

Seizures: May aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures. Monitor patients with a history of seizure disorders for worsened seizure control during therapy.

Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been reported with the concurrent use of NUCYNTA® ER and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system, and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g.,

tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination), and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal. If concomitant treatment with SSRIs, SNRIs, TCAs, or triptans is clinically warranted, careful observation of the patient is advised, particularly when initiating or titrating the dose.

Use in Patients With Gastrointestinal (GI) Conditions: Contraindicated in patients with Gl obstruction including paralytic ileus; may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.

Avoidance of Withdrawal: Withdrawal symptoms (e.g., anxiety, sweating, insomnia, restlessness, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection) may occur:

• After abrupt discontinuation or a significant dose reduction of NUCYNTA® ER in physically dependent patients. When discontinuing NUCYNTA® ER, gradually taper the dose.

• If mixed agonist/antagonist (e.g., butorphanol, nalbuphine, pentazocine) and partial agonist (e.g., buprenorphine) analgesics are used in patients who have received or are receiving NUCYNTA® ER. Avoid use with mixed agonists/antagonists and partial agonists.

• If opioid antagonists (e.g., naloxone, nalmefene) are administered in physically dependent patients. Administration of the antagonist should be begun with care and by titration with smaller than usual doses of the antagonist.

Driving and Operating Heavy Machinery: May impair the mental or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® ER and know how they will react to the medication.

Hepatic Impairment: Avoid use in patients with severe hepatic impairment (Child-Pugh Score 10 to 15). In patients with moderate hepatic impairment (Child-Pugh Score 7-9), initiate treatment with NUCYNTA® ER 50 mg no more than once every 24 hours, with a maximum dose of 100 mg per day. Monitor for respiratory and CNS depression when initiating and titrating NUCYNTA® ER.

Renal Impairment: Use in patients with severe renal impairment (CL

CR <30 mL/min) is not recommended

due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

DRUG INTERACTIONS

Alcohol: See BOXED WARNING.

Muscle Relaxants: Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected. Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression.

Anticholinergics: Use with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.

USE IN SPECIFIC POPULATIONS

Pregnancy/Nursing Mothers: Pregnancy Category C. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms. Observe newborns for symptoms of neonatal opioid withdrawal syndrome. Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped.

Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter-acting analgesics or other analgesic techniques are more appropriate.

Use in Elderly, Renal Impairment, and Hepatic Impairment: See WARNINGS AND PRECAUTIONS.

DRUG ABUSE AND DEPENDENCE: See BOXED WARNING

OVERDOSAGE: Institute supportive measures to manage respiratory depression, circulatory shock, and pulmonary edema as required. The opioid antagonists, naloxone or nalmefene, are specific antidotes to respiratory depression.

ADVERSE REACTIONS: In clinical studies, the most common (≥10%) adverse reactions were nausea, constipation, vomiting, dizziness, somnolence, and headache.

Select Postmarketing Adverse Reactions: Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. Advise patients how to recognize such reactions and when to seek medical attention. Panic attack has also been reported.

© July 2015, Depomed, Inc. All rights reserved. APL-NUCX-0029 Rev.2

Please see Brief Summary, including BOXED WARNING, on the following pages.


BRIEF SUMMARY OF FULL PRESCRIBING INFORMATIONThis does not include all the information needed to use NUCYNTA® ER safely and effectively. See full Prescribing Information for NUCYNTA® ER.INDICATIONS AND USAGE NUCYNTA® ER is indicated for the management of: • pain severe enough to require daily, around-the-clock, long-term opioid treatment and for

which alternative treatment options are inadequate• neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults severe enough

to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.

Limitations of Usage• Because of the risks of addiction, abuse, and misuse with opioids, even at recommended

doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve NUCYNTA® ER for use in patients for whom alternative treatment options (e.g., nonopioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain.

• NUCYNTA® ER is not indicated as an as-needed (prn) analgesic.

WARNING: ADDICTION, ABUSE, AND MISUSE; LIFE-THREATENING RESPIRATORY DEPRESSION; ACCIDENTAL INGESTION; NEONATAL OPIOID WITHDRAWAL SYNDROME; AND INTERACTION WITH ALCOHOLSee full prescribing information for complete boxed warning.• NUCYNTA® ER exposes users to risks of addiction, abuse, and misuse, which can lead to

overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions. (5.1)

• Serious, life-threatening, or fatal respiratory depression may occur. Monitor closely, especially upon initiation or following a dose increase. Instruct patients to swallow NUCYNTA® ER tablets whole to avoid exposure to a potentially fatal dose of tapentadol. (5.2)

• Accidental ingestion of NUCYNTA® ER, especially in children, can result in fatal overdose of tapentadol. (5.2)

• Prolonged use of NUCYNTA® ER during pregnancy can result in neonatal opioid with-drawal syndrome, which may be life-threatening if not recognized and treated. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available. (5.3)

• Instruct patients not to consume alcohol or any products containing alcohol while taking NUCYNTA® ER because co-ingestion can result in fatal plasma tapentadol levels. (5.4)

CONTRAINDICATIONS Significant respiratory depression; acute or severe bronchial asthma or hypercarbia in an unmon-itored setting or in the absence of resuscitative equipment; known or suspected paralytic ileus; hypersensitivity (e.g., anaphylaxis, angioedema) to tapentadol or to any other ingredients of the product; concurrent use of monoamine oxidase inhibitors (MAOIs) or use within the last 14 days. WARNINGS AND PRECAUTIONSAddiction, Abuse, and Misuse: NUCYNTA® ER contains tapentadol, a Schedule II controlled sub-stance. As an opioid, NUCYNTA® ER exposes users to the risks of addiction, abuse, and misuse. As modified-release products such as NUCYNTA® ER deliver the opioid over an extended period of time, there is a greater risk for overdose and death due to the larger amount of tapentadol present.Although the risk of addiction in any individual is unknown, it can occur in patients appropriately prescribed NUCYNTA® ER and in those who obtain the drug illicitly. Addiction can occur at recom-mended doses and if the drug is misused or abused.Assess each patient’s risk for opioid addiction, abuse, or misuse prior to prescribing NUCYNTA® ER, and monitor all patients receiving NUCYNTA® ER for the development of these behaviors or conditions. Risks are increased in patients with a personal or family history of substance abuse (including drug or alcohol addiction or abuse) or mental illness (e.g., major depression). The potential for these risks should not, however, prevent the prescribing of NUCYNTA® ER for the proper management of pain in any given patient. Patients at increased risk may be prescribed modified-release opioid formulations such as NUCYNTA® ER, but use in such patients necessitates intensive counseling about the risks and proper use of NUCYNTA® ER along with intensive monitoring for signs of addiction, abuse, and misuse.Abuse or misuse of NUCYNTA® ER by crushing, chewing, snorting, or injecting the dissolved product will result in the uncontrolled delivery of tapentadol and can result in overdose and death.Opioid agonists such as NUCYNTA® ER are sought by drug abusers and people with addiction dis-orders and are subject to criminal diversion. Consider these risks when prescribing or dispensing NUCYNTA® ER. Strategies to reduce these risks include prescribing the drug in the smallest ap-propriate quantity and advising the patient on the proper disposal of unused drug. Contact local state professional licensing board or state controlled substances authority for information on how to prevent and detect abuse or diversion of this product.Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depres-sion has been reported with the use of modified release opioids, even when used as recommended. Respiratory depression from opioid use, if not immediately recognized and treated, may lead to respiratory arrest and death. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status. Car-bon dioxide (CO

2) retention from opioid-induced respiratory depression can exacerbate the sedating effects of opioids.While serious, life-threatening, or fatal respiratory depression can occur at any time during the use of NUCYNTA® ER, the risk is greatest during the initiation of therapy or following a dose increase.Closely monitor patients for respiratory depression when initiating therapy with NUCYNTA® ER and following dose increases. To reduce the risk of respiratory depression, proper dosing and titration of NUCYNTA® ER are essential. Overestimating the NUCYNTA® ER dose when converting patients from another opioid product can result in fatal overdose with the first dose.Accidental ingestion of even one dose of NUCYNTA® ER, especially by children, can result in respiratory depression and death due to an overdose of tapentadol.

Neonatal Opioid Withdrawal Syndrome: Prolonged use of NUCYNTA® ER during pregnancy can result in withdrawal signs in the neonate. Neonatal opioid withdrawal syndrome, unlike opioid with-drawal syndrome in adults, may be life threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.Neonatal opioid withdrawal syndrome presents as irritability, hyperactivity and abnormal sleep pat-tern, high pitched cry, tremor, vomiting, diarrhea and failure to gain weight. The onset, duration, and severity of neonatal opioid withdrawal syndrome vary based on the specific opioid used, duration of use, timing and amount of last maternal use, and rate of elimination of the drug by the newborn.Interactions with Central Nervous System Depressants: Patients must not consume alcoholic beverages or prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy. The co-ingestion of alcohol with NUCYNTA® ER may result in increased plasma tapentadol levels and a potentially fatal overdose of tapentadol.Hypotension, profound sedation, coma, respiratory depression, and death may result if NUCYNTA® ER is used concomitantly with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, other opioids).When considering the use of NUCYNTA® ER in a patient taking a CNS depressant, assess the dura-tion of use of the CNS depressant and the patient’s response, including the degree of tolerance that has developed to CNS depression. Additionally, evaluate the patient’s use of alcohol or illicit drugs that cause CNS depression. If the decision to begin NUCYNTA® ER is made, start with NUCYNTA® ER 50 mg every 12 hours, monitor patients for signs of sedation and respiratory depression, and consider using a lower dose of the concomitant CNS depressant.Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients as they may have altered pharma-cokinetics or altered clearance compared to younger, healthier patients. Therefore, closely monitor such patients, particularly when initiating and titrating NUCYNTA® ER and when NUCYNTA® ER is given concomitantly with other drugs that depress respiration.Use in Patients with Chronic Pulmonary Disease: Monitor for respiratory depression those patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients hav-ing a substantially decreased respiratory reserve, hypoxia, hypercarbia, or pre-existing respiratory depression, particularly when initiating therapy and titrating with NUCYNTA® ER, as in these patients, even usual therapeutic doses of NUCYNTA® ER may decrease respiratory drive to the point of apnea. Consider the use of alternative non-opioid analgesics in these patients if possible.Hypotensive Effect: NUCYNTA® ER may cause severe hypotension. There is an increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressantdrugs (e.g., phenothiazines or general anesthetics). Monitor these patients for signs of hypotension after initiating or titrating the dose of NUCYNTA® ER. In patients with circulatory shock, NUCYNTA® ER may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of NUCYNTA® ER in patients with circulatory shock.Use in Patients with Head Injury or Increased Intracranial Pressure: Monitor pa-tients taking NUCYNTA® ER who may be susceptible to the intracranial effects of CO2 reten-tion (e.g., those with evidence of increased intracranial pressure or brain tumors) for signs of sedation and respiratory depression, particularly when initiating therapy with NUCYNTA® ER. NUCYNTA® ER may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may also obscure the clinical course in a patient with a head injury.Avoid the use of NUCYNTA® ER in patients with impaired consciousness or coma.Seizures: NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. The active ingredient tapentadol in NUCYNTA® ER may aggravate convulsions in patients with convulsive disorders, and may in-duce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during NUCYNTA® ER therapy.Serotonin Syndrome: Cases of life-threatening serotonin syndrome have been report-ed with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepineph-rine Reuptake Inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (e.g. mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) and can be fatal.Use in Patients with Gastrointestinal Conditions: NUCYNTA® ER is contraindicated in patients with GI obstruction, including paralytic ileus. The tapentadol in NUCYNTA® ER may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis, for worsening symptoms.Avoidance of Withdrawal: Avoid the use of mixed agonist/antagonist (i.e., pentazocine, nalbu-phine, and butorphanol) or partial agonist (buprenorphine) analgesics in patients who have received or are receiving a course of therapy with a full opioid agonist analgesic, including NUCYNTA® ER. In these patients, mixed agonists/antagonists and partial agonist analgesics may reduce the analgesic effect and/or may precipitate withdrawal symptoms.When discontinuing NUCYNTA® ER, gradually taper the dose.Driving and Operating Heavy Machinery: NUCYNTA® ER may impair the mental or physical abili-ties needed to perform potentially hazardous activities such as driving a car or operating machinery. Warn patients not to drive or operate dangerous machinery unless they are tolerant to the effects of NUCYNTA® ER and know how they will react to the medication.Hepatic Impairment: A study with an immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Avoid use of NUCYNTA® ER in patients with severe hepatic impairment. Reduce the dose of NUCYNTA® ER in patients with moderate hepatic impairment. Closely monitor patients with moderate hepatic impairment for respiratory and central nervous system depression when initiating and titrating NUCYNTA® ER.Renal Impairment: Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in the labeling:• Addiction, Abuse, and Misuse [see Warnings and Precautions (5.1)]• Life-Threatening Respiratory Depression [see Warnings and Precautions (5.2)]• Neonatal Opioid Withdrawal Syndrome [see Warnings and Precautions (5.3)]• Interaction with Other CNS Depressants [see Warnings and Precautions (5.4)]• Hypotensive Effects [see Warnings and Precautions (5.7)]• Gastrointestinal Effects [see Warnings and Precautions (5.11)]• Seizures [see Warnings and Precautions (5.9)]• Serotonin Syndrome [see Warnings and Precautions (5.10)]Clinical Trial Experience Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Chronic Pain due to Low Back Pain or OsteoarthritisThe most common adverse reactions (reported by ≥10 % in any NUCYNTA® ER dose group) were: nausea, constipation, dizziness, headache, and somnolence.The most common reasons for discontinuation due to adverse reactions in eight Phase 2/3 pooled studies reported by ≥1% in any NUCYNTA® ER dose group for NUCYNTA® ER- and placebo-treated patients were nausea (4 % vs. 1%), dizziness (3% vs. <1%), vomiting (3% vs. <1%), somnolence (2% vs. <1%), constipation (1% vs. <1%), headache (1% vs. <1%), and fatigue (1% vs. <1%), respectively.Commonly-Observed Adverse Reactions in Clinical Studies with NUCYNTA® ER in Patients with Neuropathic Pain Associated with Diabetic Peripheral NeuropathyThe most commonly reported ADRs (incidence ≥ 10% in NUCYNTA® ER-treated subjects) were: nausea, constipation, vomiting, dizziness, somnolence, and headache.Postmarketing Experience: The following adverse reactions, not above, have been identified during post approval use of tapentadol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.Psychiatric disorders: hallucination, suicidal ideation, panic attack. Anaphylaxis, angioedema, and anaphylactic shock have been reported very rarely with ingredients contained in NUCYNTA® ER. The psychiatric disorders end with panic attack. Advise patients how to recognize such reactions and when to seek medical attention.DRUG INTERACTIONSAlcohol: Concomitant use of alcohol with NUCYNTA® ER can result in an increase of tapentadol plasma levels and potentially fatal overdose of tapentadol. Instruct patients not to consume alcoholic beverages or use prescription or non-prescription products containing alcohol while on NUCYNTA® ER therapy.Monoamine Oxidase Inhibitors: NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to po-tential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.CNS Depressants: The concomitant use of NUCYNTA® ER with other CNS depressants includ-ing sedatives, hypnotics, tranquilizers, general anesthetics, phenothiazines, other opioids, and alcohol can increase the risk of respiratory depression, profound sedation, coma and death. Monitor patients receiving CNS depressants and NUCYNTA® ER for signs of respiratory depression, sedation and hypotension.When combined therapy with any of the above medications is considered, the dose of one or both agents should be reduced.Serotonergic Drugs: There have been post-marketing reports of serotonin syndrome with the con-comitant use of tapentadol and serotonergic drugs (e.g., SSRIs and SNRIs). Caution is advised when NUCYNTA® ER is coadministered with other drugs that may affect serotonergic neurotransmitter systems such as SSRIs, SNRIs, MAOIs, and triptans. If concomitant treatment of NUCYNTA® ER with a drug affecting the serotonergic neurotransmitter system is clinically warranted, careful observa-tion of the patient is advised, particularly during treatment initiation and dose increases.Muscle Relaxants: Tapentadol may enhance the neuromuscular blocking action of skeletal muscle relaxants and produce an increased degree of respiratory depression. Monitor patients receiving muscle relaxants and NUCYNTA® ER for signs of respiratory depression that may be greater than otherwise expected.Mixed Agonist/Antagonist Opioid Analgesics: Mixed agonist/antagonist analgesics (i.e., pentaz-ocine, nalbuphine, and butorphanol) and partial agonists (e.g., buprenorphine) may reduce the anal-gesic effect of NUCYNTA® ER or precipitate withdrawal symptoms. Avoid the use of mixed agonist/antagonist analgesics in patients receiving NUCYNTA® ER.Anticholinergics: The use of NUCYNTA® ER with anticholinergic products may increase the risk of urinary retention and/or severe constipation, which may lead to paralytic ileus.USE IN SPECIFIC POPULATIONS Pregnancy Clinical ConsiderationsFetal/neonatal adverse reactionsProlonged use of opioid analgesics during pregnancy for medical or nonmedical purposes can result in physical dependence in the neonate and neonatal opioid withdrawal syndrome shortly after birth. Observe newborns for symptoms of neonatal opioid withdrawal syndrome, such as poor feeding, diarrhea, irritability, tremor, rigidity, and seizures, and manage accordingly.Teratogenic Effects - Pregnancy Category CThere are no adequate and well-controlled studies in pregnant women. NUCYNTA® ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Labor and Delivery: Opioids cross the placenta and may produce respiratory depression in neonates. NUCYNTA® ER is not for use in women during and immediately prior to labor, when shorter acting analgesics or other analgesic techniques are more appropriate. Opioid analgesics can pro-long labor through actions that temporarily reduce the strength, duration, and frequency of uterine contractions. However this effect is not consistent and may be offset by an increased rate of cervical dilatation, which tends to shorten labor.Nursing Mothers: There is insufficient/limited information on the excretion of tapentadol in hu-man or animal breast milk. Physicochemical and available pharmacodynamic/toxicological data on tapentadol point to excretion in breast milk and risk to the breastfeeding child cannot be excluded. Because of the potential for adverse reactions in nursing infants from NUCYNTA® ER, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Withdrawal symptoms can occur in breast-feeding infants when maternal administration of NUCYNTA® ER is stopped.Pediatric Use: The safety and efficacy of NUCYNTA® ER in pediatric patients less than 18 years of age have not been established.Geriatric Use: Of the total number of patients in Phase 2/3 double-blind, multiple-dose clinical studies of NUCYNTA® ER, 28% (1023/3613) were 65 years and over, while 7% (245/3613) were 75 years and over. No overall differences in effectiveness or tolerability were observed between these patients and younger patients.In general, recommended dosing for elderly patients with normal renal and hepatic function is the same as for younger adult patients with normal renal and hepatic function. Because elderly patients are more likely to have decreased renal and hepatic function, consideration should be given to starting elderly patients with the lower range of recommended doses.Renal Impairment: The safety and effectiveness of NUCYNTA® ER have not been established in patients with severe renal impairment (CLCR <30 mL/min). Use of NUCYNTA® ER in patients with severe renal impairment is not recommended due to accumulation of a metabolite formed by glucuronidation of tapentadol. The clinical relevance of the elevated metabolite is not known.Hepatic Impairment: Administration of tapentadol resulted in higher exposures and serum levels of tapentadol in subjects with impaired hepatic function compared to subjects with normal hepatic function. The dose of NUCYNTA® ER should be reduced in patients with moderate hepatic impair-ment (Child-Pugh Score 7 to 9).Use of NUCYNTA® ER is not recommended in severe hepatic impairment (Child-Pugh Score 10 to 15).DRUG ABUSE AND DEPENDENCEControlled Substance: NUCYNTA® ER contains tapentadol, a Schedule II controlled substance with a high potential for abuse similar to fentanyl, methadone, morphine, oxycodone, and oxymor-phone. NUCYNTA® ER can be abused and is subject to misuse, addiction, and criminal diversion. The high drug content in the extended release formulation adds to the risk of adverse outcomes from abuse and misuse.

Abuse: All patients treated with opioids require careful monitoring for signs of abuse and addic-tion, because use of opioid analgesic products carries the risk of addiction even under appropriate medical use.

Drug abuse is the intentional non-therapeutic use of an over-the-counter or prescription drug, even once, for its rewarding psychological or physiological effects. Drug abuse includes, but is not limited to the following examples: the use of a prescription or over-the-counter drug to get “high,” or the use of steroids for performance enhancement and muscle build up.Drug addiction is a cluster of behavioral, cognitive, and physiological phenomena that develop after repeated substance use and include: a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal.“Drug-seeking” behavior is very common to addicts and drug abusers. Drug-seeking tactics include emergency calls or visits near the end of office hours, refusal to under-go appropriate examination, testing or referral, repeated claims of loss of prescriptions, tampering with prescriptions and reluctance to provide prior medical records or contact information for other treating physician(s). “Doctor shopping” (visiting multiple prescribers) to obtain additional prescriptions is common among drug abusers, and people suffering from untreated addiction. Preoccupation with achieving pain relief can be appropriate behavior in a patient with poor pain control.Abuse and addiction are separate and distinct from physical dependence and tolerance. Physicians should be aware that addiction may not be accompanied by concurrent tolerance and symptoms of physical dependence in all addicts. In addition, abuse of opioids can occur in the absence of true addiction.NUCYNTA® ER, like other opioids, can be diverted for non-medical use into illicit channels of distribution. Careful record-keeping of prescribing information, including quantity, frequency, and renewal requests, as required by law, is strongly advised. Proper assessment of the patient, proper prescribing practices, periodic re-evaluation of therapy, and proper dispensing and storage are appropriate measures that help to limit abuse of opioid drugs.Dependence: Both tolerance and physical dependence can develop during chronic opioid therapy. Tolerance is the need for increasing doses of opioids to maintain a defined effect such as analgesia (in the absence of disease progression or other external factors). Tolerance may occur to both the desired and undesired effects of drugs, and may develop at different rates for different effects.Physical dependence results in withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. Withdrawal also may be precipitated through the administration of drugs with opioid antagonist activity, e.g., naloxone, nalmefene, mixed agonist/antagonist analgesics (pen-tazocine, butorphanol, nalbuphine), or partial agonists (buprenorphine). Physical dependence may not occur to a clinically significant degree until after several days to weeks of continued opioid usage.NUCYNTA® ER should not be abruptly discontinued. If NUCYNTA® ER is abruptly discontinued in a physically-dependent patient, an abstinence syndrome may occur. Some or all of the following can characterize this syndrome: restlessness, lacrimation, rhinorrhea, yawning, perspiration, chills, pilo-erection, myalgia, mydriasis, irritability, anxiety, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhea, increased blood pressure, respiratory rate, or heart rate.Infants born to mothers physically dependent on opioids will also be physically dependent and may exhibit respiratory difficulties and withdrawal symptoms.OVERDOSAGEClinical Presentation: Acute overdosage with opioids can be manifested by respiratory depres-sion, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes pulmonary edema, bradycardia, hypotension and death. Marked mydriasis rather than miosis may be seen due to severe hypoxia in overdose situations.Treatment of Overdose: In case of overdose, priorities are the re-establishment of a patent and protected airway and institution of assisted or controlled ventilation if needed. Employ other supportive measures (including oxygen, vasopressors) in the management of circulatory shock and pulmonary edema as indicated. Cardiac arrest or arrhythmias will require advanced life support techniques.

Rx Only© 2015 Depomed, Inc., Newark, CA 94560 USANUCYNTA® ER is a registered trademark of Depomed, Inc. All rights reserved.APL-NUCX-0041 Rev.2


8 | PWJ | www.painweek.org Q4 | 2015

EXECUTIVE EDITOR KEVIN L. ZACHAROFF MD, FACPE, FACIP, FAAP

PUBLISHER PAINWeek, 6 Erie Street, Montclair, NJ 07042

ART DIRECTOR DARRYL FOSSA

EDITORIAL DIRECTOR DEBRA WEINER

EDITOR HOLLY CASTER

Charles E. Argoff MD, CPE Professor of Neurology

Albany Medical College Department of Neurology

Director Comprehensive Pain Center

Albany Medical Center Department of Neurology

Albany, NY

Paul Arnstein RN, PhD, ACNS-BC, FNP-C, FAAN Clinical Nurse Specialist for Pain Relief

Massachusetts General Hospital Boston, MA

Said R. Beydoun MD, FAAN Professor of Neurology

Director of the Neuromuscular Program Keck Medical Center of

University of Southern California Los Angeles, CA

Jennifer Bolen JD Founder

Legal Side of Pain Knoxville, TN

Paul J. Christo MD, MBA Associate Professor

Johns Hopkins University School of Medicine Department of Anesthesiology and

Critical Care Medicine Baltimore, MD

Michael R. Clark MD, MPH, MBA Vice Chair, Clinical Affairs

Johns Hopkins University School of Medicine Department of Psychiatry and Behavioral Sciences

Director, Pain Treatment Programs Johns Hopkins Medical Institutions

Department of Psychiatry and Behavioral Sciences Baltimore, MD

Geralyn Datz PhD Affiliate

University of Southern Mississippi Department of Psychology

Clinical Director Southern Behavioral Medicine Associates

Hattiesburg, MS

Peter A. Foreman DDS, DAAPM Consultant

Rotorua Hospital and Private Practice Rotorua, New Zealand

Gary W. Jay MD, FAAPM Chief Officer

AdviseClinical Raleigh, NC

Mary Lynn McPherson PharmD, BCPS, CPE, FASPE Professor and Vice Chair

University of Maryland School of Pharmacy Department of Pharmacy Practice and Science

Hospice Consultant Pharmacist Baltimore, MD

Srinivas Nalamachu MD Clinical Assistant Professor

Kansas University Medical Center Department of Rehabilitation Medicine

Kansas City, KS President and Medical Director

International Clinical Research Institute Overland Park, KS

Bruce D. Nicholson MD Clinical Associate Professor Department of Anesthesia

Penn State College of Medicine Hershey Medical Center

Hershey, PA Director of Pain Specialists

Lehigh Valley Health Network Department of Anesthesiology

Allentown, PA

Marco Pappagallo MD Director of Medical Intelligence

Grünenthal USA Bedminster, NJ

Director Pain Management & Medical Mentoring

New Medical Home for Chronic Pain New York, NY

Steven D. Passik PhD Director of Clinical Addiction Research and Education

Millennium Laboratories San Diego, CA

John F. Peppin DO, FACP Director

The Center for Bioethics Pain Management and Medicine

University City, MO Medical Director

The Infinity Center-Frankfort LLC, Frankfort, KY

Joseph V. Pergolizzi MD Adjunct Assistant Professor

Johns Hopkins University School of Medicine Department of Medicine

Baltimore, MD Senior Partner

Naples Anesthesia and Pain Medicine Naples, FL

Robert W. Rothrock PA-C, MPA University of Pennsylvania

Department of Anesthesiology and Critical Care Pain Medicine Division

Philadelphia, PA

Michael E. Schatman PhD, CPE, DASPE Executive Director

Foundation for Ethics in Pain Care Bellevue, WA

Sanford M. Silverman MD, PA CEO and Medical Director

Comprehensive Pain Medicine Pompano Beach, FL

Thomas B. Strouse MD Medical Director

Stewart and Lynda Resnick Neuropsychiatric Hospital at UCLA

Los Angeles, CA

EDITORIAL BOARD

Copyright © 2015, PAINWeek.

The opinions stated in the enclosed printed materials are those of the authors and do not necessarily represent the opinions of PAINWeek or its publication staff. PAINWeek does not give guarantees or any other representation that the printed material contained herein is valid, reliable, or accurate. PAINWeek does not assume any responsibility for injury arising from any use or misuse of the printed materials contained herein. The printed materials contained herein are assumed to be from

reliable sources, and there is no implication that they represent the only, or best, methodologies or procedures for the pain condition discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and drug dosage information contained herein, and to make modifications as new information arises.

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The national conference on pain for frontline practitioners.

IndIcatIonsRELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

Important safety InformatIon RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other

conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal.

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nursing mothers, a decision should be made to discontinue nursing or

discontinue the drug, taking into account the importance of the drug to the mother. In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

Please see Brief Summary of full Prescribing Information for RELISTOR on the adjacent page.references 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the

treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562.

2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc.

Product under license from

Manufactured for: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024

RELISTOR is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. All other product/brand names are trademarks of their respective owners. ©2015 Valeant Pharmaceuticals North America LLC. All rights reserved. Printed in USA. REL-US-0152 v.1 www.salix.com

Get things moving with reliable and rapid relief.RELISTOR helps provide chronic non-cancer pain patients relief from opioid-induced constipation—without compromising analgesia.1,2

• 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients (n=150) had at least 3 Spontaneous Bowel Movements (SBMs) per week (P<0.001)1,2

• One-third of patients taking RELISTOR (n=150) experienced an SBM within 4 hours of their first dose (P<0.001)1

029757_salrep_dogad_pw_jrnl_fa.indd 1 10/12/15 9:42 AM


CONTENTS /PWJ/Q4/201514 | EXECUTIVE EDITOR’S LETTERby kevin l. Zacharoff

FEATURES

20 | PHARMACOTHERAPYMAKING MEDICATIONS WORK FOR DEPRESSIONby mark Sullivan

26 | TECHNOLOGYVIRTUAL REALITY:does it have a role in pain management? by theresa Mallick-Searle

34 | PAINWEEK 2015 KEYNOTE ADDRESSPASTRAMI OR PRESCRIPTIONS?the deli can wait…we need more and better pain practitioners now!by charles e. Argoff

40 | MEDICAL/LEGALTHE BULLETPROOF PRESCRIBERby marc Gonzalez

SHORT CUTS

48 | ONE-MINUTE CLINICIANwith ted Jones , cynthia Knorr-Mulder , natalie Strand , tanya Uritsky

49 | PAIN BY NUMBERS

51 | CLINICAL PEARLSby doug Gourlay

52 | PUNDIT PROFILEwith mel Pohl

IndIcatIonsRELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain.

RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient. Use of RELISTOR beyond four months has not been studied.

Important safety InformatIon RELISTOR® (methylnaltrexone bromide) Subcutaneous Injection is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at increased risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

Cases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other

conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.If severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their physician.

Symptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia and should be monitored for adequacy of analgesia and symptoms of opioid withdrawal.

Avoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.

RELISTOR may precipitate opioid withdrawal in a fetus and should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In nursing mothers, a decision should be made to discontinue nursing or

discontinue the drug, taking into account the importance of the drug to the mother. In the clinical study in adult patients with opioid-induced constipation and chronic non-cancer pain, the most common adverse reactions (≥ 1%) were abdominal pain, nausea, diarrhea, hyperhidrosis, hot flush, tremor, and chills.In clinical studies in adult patients with opioid-induced constipation and advanced illness, the most common adverse reactions (≥ 5%) were abdominal pain, flatulence, nausea, dizziness, and diarrhea.

Please see Brief Summary of full Prescribing Information for RELISTOR on the adjacent page.references 1. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for the

treatment of opioid-induced constipation in patients with chronic nonmalignant pain: a randomized controlled study. J Pain. 2011;12(5):554-562.

2. RELISTOR® (methylnaltrexone bromide) Prescribing Information, Salix Pharmaceuticals, Inc.

Product under license from

Manufactured for: Salix Pharmaceuticals, a division of Valeant Pharmaceuticals North America LLC 8510 Colonnade Center Drive, Raleigh, NC 27615 For additional information, call: 1-866-669-SLXP (7597) To report adverse events, call: 1-800-508-0024

RELISTOR is a trademark of Valeant Pharmaceuticals International, Inc. or its affiliates. All other product/brand names are trademarks of their respective owners. ©2015 Valeant Pharmaceuticals North America LLC. All rights reserved. Printed in USA. REL-US-0152 v.1 www.salix.com

Get things moving with reliable and rapid relief.RELISTOR helps provide chronic non-cancer pain patients relief from opioid-induced constipation—without compromising analgesia.1,2

• 6 out of 10 RELISTOR® (methylnaltrexone bromide) patients (n=150) had at least 3 Spontaneous Bowel Movements (SBMs) per week (P<0.001)1,2

• One-third of patients taking RELISTOR (n=150) experienced an SBM within 4 hours of their first dose (P<0.001)1


The following is a brief summary only; see full Prescribing Information for complete product information.

INDICATIONS AND USAGEOpioid-Induced Constipation in Adult Patients with Chronic Non-Cancer Pain RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with chronic non-cancer pain. Opioid-Induced Constipation in Adult Patients with Advanced Illness RELISTOR is indicated for the treatment of opioid-induced constipation in adult patients with advanced illness who are receiving palliative care, when response to laxative therapy has not been sufficient.

Limitation of use: Use of RELISTOR beyond four months has not been studied in the advanced illness population.

CONTRAINDICATIONSRELISTOR is contraindicated in patients with known or suspected gastrointestinal obstruction and patients at risk of recurrent obstruction, due to the potential for gastrointestinal perforation.

WARNINGS AND PRECAUTIONSGastrointestinal PerforationCases of gastrointestinal perforation have been reported in adult patients with opioid-induced constipation and advanced illness with conditions that may be associated with localized or diffuse reduction of structural integrity in the wall of the gastrointestinal tract (e.g., peptic ulcer disease, Ogilvie’s syndrome, diverticular disease, infiltrative gastrointestinal tract malignancies or peritoneal metastases). Take into account the overall risk-benefit profile when using RELISTOR in patients with these conditions or other conditions which might result in impaired integrity of the gastrointestinal tract wall (e.g., Crohn’s disease). Monitor for the development of severe, persistent, or worsening abdominal pain; discontinue RELISTOR in patients who develop this symptom.Severe or Persistent DiarrheaIf severe or persistent diarrhea occurs during treatment, advise patients to discontinue therapy with RELISTOR and consult their healthcare provider.Opioid WithdrawalSymptoms consistent with opioid withdrawal, including hyperhidrosis, chills, diarrhea, abdominal pain, anxiety, and yawning have occurred in patients treated with RELISTOR. Patients having disruptions to the blood-brain barrier may be at increased risk for opioid withdrawal and/or reduced analgesia. Take into account the overall risk-benefit profile when using RELISTOR in such patients. Monitor for adequacy of analgesia and symptoms of opioid withdrawal in such patients.

ADVERSE REACTIONSClinical Trial ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.Opioid-Induced Constipation in Adult Patients with Chronic Non-Cancer PainThe safety of RELISTOR was evaluated in a double-blind, placebo-controlled trial in adult patients with opioid-induced constipation and chronic non-cancer pain receiving opioid analgesia. This study (Study 1) included a 4-week, double-blind, placebo controlled period in which adult patients were randomized to receive RELISTOR 12 mg once daily (150 patients) or placebo (162 patients). After 4 weeks of double-blind treatment, patients began an 8-week open-label treatment period during which RELISTOR 12 mg was administered less frequently than the recommended dosage regimen of 12 mg once daily. Adverse reactions in adult patients with opioid-induced constipation and chronic non-cancer pain receiving RELISTOR are shown in the following table. The adverse reactions in the table below may reflect symptoms of opioid withdrawal.

Adverse Reactions* in 4-Week Double-Blind, Placebo-Controlled Period of Clinical Study of RELISTOR in Adult Patients with Opioid-Induced Constipation and Chronic

Non-Cancer Pain

Adverse Reaction

RELISTOR12 mg once daily

n = 150

Placebon = 162

Abdominal Pain 21% 6%

Nausea 9% 6%

Diarrhea 6% 4%

Hyperhidrosis 6% 1%

Hot Flush 3% 2%

Tremor 1% < 1%

Chills 1% 0%* Adverse reactions occurring in ≥ 1 % of patients receiving RELISTOR 12 mg once daily and at an incidence greater than placebo.

During the 4-week double-blind period, in patients with opioid-induced constipation and chronic non-cancer pain that received RELISTOR 12 mg every other day, there was a higher incidence of adverse reactions, including nausea (12%), diarrhea (12%), vomiting (7%), tremor (3%), feeling of body temperature

change (3%), piloerection (3%), and chills (2%) as compared to daily RELISTOR dosing. Use of RELISTOR 12 mg every other day is not recommended in patients with OIC and chronic non-cancer pain. The rates of discontinuation due to adverse reactions during the double-blind period (Study 1) were higher in the RELISTOR once daily (7%) than the placebo group (3%). Abdominal pain was the most common adverse reaction resulting in discontinuation from the double-blind period in the RELISTOR once daily group (2%).The safety of RELISTOR was also evaluated in a 48-week, open-label, uncontrolled trial in 1034 adult patients with opioid-induced constipation and chronic non-cancer pain (Study 2). Patients were allowed to administer RELISTOR 12 mg less frequently than the recommended dosage regimen of 12 mg once daily, and took a median of 6 doses per week. A total of 624 patients (60%) completed at least 24 weeks of treatment and 477 (46%) completed the 48-week study. The adverse reactions seen in this study were similar to those observed during the 4-week double-blind period of Study 1. Additionally, in Study 2, investigators reported 4 myocardial infarctions (1 fatal), 1 stroke (fatal), 1 fatal cardiac arrest and 1 sudden death. It is not possible to establish a relationship between these events and RELISTOR.Opioid-Induced Constipation in Adult Patients with Advanced IllnessThe safety of RELISTOR was evaluated in two, double-blind, placebo-controlled trials in adult patients with opioid-induced constipation and advanced illness receiving palliative care: Study 3 included a single dose, double blind, placebo-controlled period, whereas Study 4 included a 14-day multiple dose, double-blind, placebo-controlled period.The most common (≥5%) adverse reactions in adult patients with opioid-induced constipation and advanced illness receiving RELISTOR are shown in the following table.

Adverse Reactions from all Doses in Double-Blind, Placebo-Controlled Clinical Studies of RELISTOR in Adult Patients with Opioid-Induced Constipation and Advanced Illness*

Adverse Reaction

RELISTORn = 165

Placebon = 123

Abdominal Pain 29% 10%

Flatulence 13% 6%

Nausea 12% 5%

Dizziness 7% 2%

Diarrhea 6% 2%

* Adverse reactions occurring in ≥ 5 % of patients receiving all doses of RELISTOR (0.075, 0.15, and 0.30 mg/kg/dose) and at an incidence greater than placebo.

The rates of discontinuation due to adverse events during the double-blind placebo controlled clinical trials (Study 3 and Study 4) were comparable between RELISTOR (1%) and placebo (2%).Postmarketing ExperienceThe following adverse reactions have been identified during post-approval use of RELISTOR. Because they are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.GastrointestinalPerforation, cramping, vomitingGeneral Disorders and Administrative Site DisordersDiaphoresis, flushing, malaise, pain. Cases of opioid withdrawal have been reported.

DRUG INTERACTIONSOther Opioid AntagonistsAvoid concomitant use of RELISTOR with other opioid antagonists because of the potential for additive effects of opioid receptor antagonism and increased risk of opioid withdrawal.Drugs Metabolized by Cytochrome P450 IsozymesIn healthy subjects, a subcutaneous dose of 0.30 mg/kg of methylnaltrexone did not significantly affect the metabolism of dextromethorphan, a CYP2D6 substrate.

USE IN SPECIFIC POPULATIONSPregnancyPregnancy Category C There are no adequate and well-controlled studies with RELISTOR in pregnant women. The use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the immature fetal blood brain barrier. In animal reproduction studies, no effects on embryo-fetal development were observed with the administration of intravenous methylnaltrexone during organogenesis in rats and rabbits at doses up to 20 times and 26 times, respectively, the maximum recommended human dose (MRHD) of 0.2 mg/kg/day. RELISTOR should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing MothersIt is not known whether RELISTOR is present in human milk. However, methylnaltrexone bromide is present in rat milk. Because of the potential for serious adverse reactions, including opioid withdrawal, in nursing infants, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.Pediatric UseSafety and effectiveness of RELISTOR have not been established in pediatric patients.In juvenile rats administered intravenous methylnaltrexone bromide for 13 weeks, adverse clinical signs such as convulsions,

tremors and labored breathing were observed, and the juvenile rats were found to be more sensitive to the adverse effects of methylnaltrexone bromide when compared to adult animals. Juvenile dogs administered intravenous methylnaltrexone bromide for 13 weeks had a toxicity profile similar to adult dogs. Geriatric UseIn the double-blind studies, a total of 118 (14%) patients aged 65-74 years (79 methylnaltrexone bromide, 39 placebo) and a total of 108 (13%) patients aged 75 years or older (64 methylnaltrexone bromide, 44 placebo) were enrolled. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Based on pharmacokinetic data, and safety and efficacy data from controlled clinical trials, no dose adjustment based on age is recommended.Renal ImpairmentNo dose adjustment is required in patients with mild or moderate renal impairment. Dose reduction by one-half is recommended in patients with severe renal impairment (creatinine clearance less than 30 mL/min as estimated by Cockcroft-Gault). Hepatic ImpairmentNo dose adjustment is required for patients with mild or moderate hepatic impairment.

OVERDOSAGEA study of healthy volunteers noted orthostatic hypotension associated with a dose of 0.64 mg/kg administered as an intravenous bolus. Monitor for signs or symptoms of orthostatic hypotension and initiate treatment as appropriate.If a patient on opioid therapy receives an overdose of RELISTOR, the patient should be monitored closely for potential evidence of opioid withdrawal symptoms such as chills, rhinorrhea, diaphoresis or reversal of central analgesic effect. Base treatment on the degree of opioid withdrawal symptoms, including changes in blood pressure and heart rate, and on the need for analgesia.

PATIENT COUNSELING INFORMATIONAdvise patients to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).AdministrationAdvise all patients to:

• Inject RELISTOR subcutaneously in the upper arm, abdomen or thigh. Do not inject at the same spot each time (rotate injection sites).

• Safely dispose of needles by following the sharps disposal recommendations described in the RELISTOR Instructions for Use.

• Be within close proximity to toilet facilities once RELISTOR is administered.

• Discontinue RELISTOR if treatment with the opioid pain medication is also discontinued.

Advise chronic non-cancer pain patients receiving RELISTOR for opioid-induced constipation to:

• Discontinue all maintenance laxative therapy prior to initiation of RELISTOR. Laxative(s) can be used as needed if there is a suboptimal response to RELISTOR after three days.

• Inject one dose every day.• Inform their healthcare provider if their opioid regimen is

changed, to avoid adverse reactions, such as diarrhea.Advise patients with advanced illness receiving RELISTOR for opioid-induced constipation to:

• Inject one dose every other day, as needed, but no more frequently than one dose in a 24-hour period.

Gastrointestinal PerforationAdvise patients to discontinue RELISTOR and to promptly seek medical attention if they develop unusually severe, persistent, or worsening abdominal pain.Severe or Persistent DiarrheaAdvise patients to discontinue RELISTOR if they experience severe or persistent diarrhea.Opioid WithdrawalAdvise patients that symptoms consistent with opioid withdrawal may occur while taking RELISTOR, including sweating, chills, diarrhea, abdominal pain, anxiety, and yawning.PregnancyAdvise females of reproductive potential, who become pregnant or are planning to become pregnant that the use of RELISTOR during pregnancy may precipitate opioid withdrawal in a fetus due to the undeveloped blood brain barrier.NursingAdvise females who are nursing against breastfeeding during treatment with RELISTOR due to the potential for opioid withdrawal in nursing infants.You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.To report adverse events, a product complaint, or for additional information, call: 1-800-508-0024.Manufactured for: Under License from:

Salix Pharmaceuticals, Inc. Raleigh, NC 27615

Progenics Pharmaceuticals, Inc.Tarrytown, NY 10591

REL-RALAB56-102014


Live conference 6.0 Ce/CMe credits

*2 day meeting = 12.0 AMA Category 1 Credits™.This activity is provided by Global Education Group. 7.o AMA Category 1 Credits™.This program was planned in accordance with AANP CE Standards and Policies and AANP Commercial Support Standard.

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MASHANTUCKeT CTPHOeNiX AZ*

LOS ANGeLeS CAiNDiANAPOLiS IN*

BiRMiNGHAM ALDeNVeR CO*

NASHViLLe TN*

FT. LAUDeRDALe FL

RALeiGH-DURHAMNC*

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different place with a functional capacity that’s significantly better than their norm. Mallick-Searle outlines both the history of VR and its promise as a valuable component of a truly multidisciplinary pain treatment plan.

Next is a recap of Dr. Charles Argoff’s keynote from the PAINWeek conference. It’s titled Pastrami or Prescriptions? The Deli Can Wait… In it, he gives us perspective about his career in pain management and his personal desires, and their intersection resulting in his dedication to caring for patients with pain. Most prominent to me is the discussion of the importance of education in helping to solve some of the biggest challenges we face in pain management. Not just education of healthcare providers, but also patients with pain. Dr. Argoff reinforces an argument that I have made many times—that it’s likely not possible to provide patients with appropriate pain care in the face of the lack of education about it in the course of training. His comments are heart-felt, inspiring, and worthy of reading and translating into some kind of action; see what resonates most with you.

In discussing the bulletproof prescriber, Dr. Marc Gonzalez gives us a reason to pause, think about, and prepare for the possibility of being the subject of an investigation—something we may hear discussed, but not often formally addressed. While I’m not sure that there is anything one can do in a real-life, clinical practice to guarantee being truly “bulletproof,” I am a firm believer in being prepared, doing things proactively, and getting professional assistance when things do happen. I can assure you that there are a number of good practical steps in this article which can help you stay on the rails and navigate situations like this to the best degree possible.

Lastly is this issue’s Pundit Profile, an inspiring and insightful look into the personal side of Dr. Mel Pohl. I’m sure there’s something in it that will resonate with you. Personally gratifying to me was hearing a colleague say that their goals are to be good at what they do, to be compassionate about how they do it, and to teach people along the way. Kudos to Dr. Pohl! In my opinion, better words have not been spoken.

So as we bring this year to a close, Happy Holidays and Happy New Year. I hope you enjoy this issue, and see you next year!

—KEVIN L. ZACHAROFF

Kevin L. Zacharoff, MD, FACIP, FACPE, FAAP, is Pain Educator and Consultant and Faculty, Clinical Instructor at SUNY Stony Brook School of Medicine, Department of Preventive Medicine, in Stony Brook, New York.

.

KEVIN L.ZACHAROFF

MD, FACPE, FACIP, FAAP

elcome to the December issue of PWJ. Amazingly, the annual PAINWeek conference is in the rearview mirror. It outpaced previ-ous years in attendance, variety of sessions, and, most of all, interest in learning more about pain and its management. 2015 has been a very tumultuous year, with continued intense discussions about many important topics. Most notable were the debates about everything from best practices to measuring outcome to the familiar topic of the use of opioid therapy in the management of chronic noncancer pain. 2016 promises to be no different. PWJ has been, and will continue to be, there with you, providing a unique and clinically pertinent perspective.

Our first article highlights the often intimate relationship between chronic pain and depression; likely no secret to any of us. Dr. Mark Sullivan delivers a clinically rational and detailed summary about depression, its comorbidity with chronic pain, and how the treatment of coincident depression could be an extremely important component of a successful pain treatment plan. Dr. Sullivan provides so much valuable information—about treatment approaches when patients have pain and comorbid depression—that I highly recommend you keep this article easily accessible to refer to time and again. I guar-antee it will come in handy.

Distraction therapy has long had a place in the treatment of many chronic conditions, including chronic pain. Theresa Mallick-Searle provides the reader with a modern-day/futuristic form of nonphar-macological treatment: distraction therapy utilizing virtual real-ity. When you think about it, it makes so much sense to give the chronic pain patient a technological way to feel as if they are in a

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■ Theresa Mallick-Searle MS, RN-BC, ANP-BC P.26Theresa Mallick-Searle is an Adult Nurse Practitioner specializing in acute and chronic pain management at Stanford Health Care in the Department of Pain Medicine, Palo Alto, California. As part of her commitment to bringing awareness to the impact of unmanaged pain, she lectures nationally on topics surrounding both acute and chronic pain.

■ Marc Gonzalez PharmD P.40Marc Gonzalez is President, Pharmaceutical Diversion Consultants, and NADDI National Associate Training and Education Coordinator. He is also a DoD Consultant and Executive Board Member of Safe Call Now (SCN).

■ Mark D. Sullivan MD, PhD P.20 Mark Sullivan is a Professor of Psychiatry and Behavioral Sciences, and an Adjunct Professor of Anesthesiology and Pain Medicine, Bioethics and Humanities at the University of Washington in Seattle.

■ Charles E. Argoff MD, CPE P.38Charles Argoff is Professor of Neurology, Albany Medical College.and Director, Comprehensive Pain Center, Albany Medical Center, Department of Neurology in New York. Dr. Argoff specializes in pain management and chronic headaches, predominately treating patients with chronic and neuropathic pain. Dr. Argoff’s goal is to offer patients a better quality of life through proper diagnosis and effective treatment.

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By M

ark D

. Sul

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hD

“We can’t make it all go away. But we can make your life better.”


Weight loss or gain, without trying

Insomnia or hypersomnia

Psychomotor agitation or retardation

Fatigue or loss of energy

Worthlessness or guilt

Trouble concentrating or deciding

Thoughts of death or suicide

abstract: In the United States, major depression affects 10% to 100% of patients in pain clinics. Antidepres-sants do not remove all pain or depression, or create happiness, but they can remove the burden of despair and restore interest in favorite activities and relationships. Most people, whether in pain or not, experience depression to var-ious degrees, including feeling down, sad, or disinterested. Major depressive disorder, however, is a more severe and enduring experi-ence. It is defined by the DSM as either depressed mood or loss of pleasure for a period of 2 weeks nearly every day AND includes 4 of the following symptoms:

PHARMACOTHeRAPY

www.painweek.org | PWJ | 23Q4 | 2015

CO-OCCURReNCeSIn a WHO study of persistent pain in primary care, 5438 patients at 15 sites in 14 countries were assessed by inter-view and questionnaires.3 Of those primary care patients, 22% had persistent pain lasting over 6 months, were more likely to have anxiety or depressive disorder, experienced significant limitations in their activities, and have unfa-vorable health perceptions. Pain and distress relationships were more consistent across cultures than pain and disabil-ity relationships. The study concluded that persistent pain was consistently associated with psychological illness across the 15 centers in 14 countries involved in the study.

In a follow-up study of some of these same patients, 3197 were assessed at baseline and 12 months.4 Half of those with persistent pain at baseline still had pain at 12 months, which could be predicted by number of pain sites at base-line. Almost 9% had new-onset persistent pain, predicted by psychiatric disorder, perceived poor health, and occupa-tional role disability. Persistent pain at baseline predicted the onset of a psychological disorder with the same strength that a baseline psychological disorder predicted the onset of persistent pain. The study concluded that there is a strong, symmetrical relationship between persistent pain and psy-chological disorder, with impairment of daily activities a central component of that relationship.

CHRONiC PAiN ReDUCeS ReSPONSe TO DePReSSiON TReATMeNTPosthoc analysis of data from multiple randomized trials has shown that chronic pain makes depression harder to treat. In the ARTIST efficacy trial (n=573) that tested response to SSRIs, the risk for poor treatment response increased in those with mild pain or=1.5 (25%), with mod-erate pain or=2.0 (30%), and especially in those with severe pain or=4.1 (14%).5 Resistance to depression treatment for patients with chronic pain has also been documented in randomized trials of collaborative care for depression such as the IMPACT effectiveness trial (n=1801). In that trial, 49% of patients with no/low pain interference achieved a depression response, while only 37% of those with high pain interference achieved a depression response.6

DePReSSiON ReDUCeS ReSPONSe TO PAiN TReATMeNTAs is obvious to anyone observing injured patients in the Emergency Department or postoperative patients in the recovery room, distress accompanying acute pain is reduced with opioid treatment. But this is not true for distress associ-ated with chronic pain. In fact, negative affect (depression) is associated with reduced response to acute opioid treatment of discogenic back pain.7 Among patients receiving chronic

“The study concluded that there is a strong, symmetrical relationship between persistent

pain and psychological disorder, with impairment of daily activities a central

component of that relationship.”

Major depression in the United States affects 2% to 4% of the general public, 5% to 9% of ambulatory medical patients, 15% to 20% of medical inpatients, and, as stated above, from 10% to 100% of people in pain clinics.1,2 This variability in prevalence rates at pain clinics is likely due to the different referral patterns to these clinics rather than any unique asso-ciation of one kind of chronic pain with depression.


opioid therapy, depression was the strongest predictor of ambivalence about opioids.8 Ambivalent patients desired to cut down their opioid use, despite reporting that it was help-ful for pain. This suggests that the depressed patients were not having a positive overall experience with opioid therapy. Indeed, a number of recent studies have suggested that long-term opioid therapy induces depression in patients.9,10

ANTiDePReSSANT eFFeCTiVeNeSSMost studies of antidepressants use single medications compared to placebo. While these trials can demonstrate the efficacy of antidepressant agents, they don’t mimic the decisions faced by clinicians in practice very well. These cli-nicians are tasked with finding some way to help the patient in their office feel better. This often takes multiple trials of medications, often in combinations. The Sequenced Treat-ment Alternatives to Relieve Depression—or STAR*D trial—was designed to help address these decisions.11 It was the largest (n=2876) open-label, pragmatic trial of treatment of major depressive disorder in primary and specialty care. In 4 treatment levels of STAR*D, patients were randomized to various single antidepressants, combinations, or augmen-tation strategies. Patients who did not respond at one level were randomized to treatments at the next level.

Treatment Strategies Tested in STAR*D Trial

● Level 1: flexible doses of citalopram for 14 weeks

● Level 2: one of 7 strategies

▸ Add bupropion SR▸ Add buspirone▸ Add cognitive therapy (CT)▸ Switch to bupropion▸ Switch to sertraline▸ Switch to venlafaxine XR▸ Switch to CT

● Level 3: one of 4 strategies

▸ Add lithium▸ Add T3 (triiodothyronine)▸ Switch to mirtazapine▸ Switch to nortriptyline

● Level 4:

▸ Switch to tranylcypromine▸ Switch to venlafaxine XR plus mirtazapine

ReSULTS FROM THe STAR*D TRiALThe STAR*D trial demonstrated that only a minority of

depressed patients achieved remission during first-line treatment with antidepressant monotherapy. This is con-sistent with the oft reported need in clinical practice to use multiple strategies to achieve depression remission. In addition, no specific treatment modality was statistically superior within any treatment step. Each switching, aug-mentation, or combination strategy helped 15% to 25% of patients, but not most patients. Patients who did achieve depression remission (phq-9 score <5) were less likely to relapse during one year of naturalistic follow-up, compared with patients achieving response but not remission.

SeLLiNG ANTiDePReSSANTS TO PATieNTS WiTH CHRONiC PAiNIt is important not to oversell antidepressants to patients with chronic pain. They are imperfect medications with side effects. For patients ambivalent about antidepressants (eg, with a record of not tolerating multiple antidepressants), practitioners should become less rather than more assertive. Offer your patient options. Encourage your patient to “put their nickel down” by choosing a treatment among a set of reasonable alternatives. If they are invested in the choice of treatment, they are less likely to reject the treatment. Patients with a history of psychological trauma, especially those with posttraumatic stress disorder, may have adverse reactions to antidepressants. These patients may need to be seen by an expert psychiatrist.

ANTiDePReSSANT CHOiCeAntidepressants with norepinephrine reuptake inhibition (TCAs, SNRIs) are generally better analgesics. They are clearly preferred for neuropathic pain and probably pre-ferred for musculoskeletal pain. Antidepressants with 5ht2 blockade are associated with more rapid improvement of sleep and anxiety. These include TCAs, trazodone, nefazo-done, and mirtazapine, and are better tolerated especially by patients with PTSD or panic.

CHRONiC PAiN, DePReSSiON, AND OPiOiDSWhen talking to patients with pain about starting antide-pressant therapy, it is useful to accept the patient’s argu-ment that pain caused the depression. But do not accept the conclusion that treatment of pain (usually with opioids) will make the depression go away. Opioids have a transient anxiety-reducing and mood-elevating effect, but do not show sustained antidepressant effectiveness. In 7 prospec-tive cohort studies, opioid treatment of injured workers decreased return to work in a dose-dependent fashion.12

Emphasize to your patient that depression treatment will help her/his other pain treatments work better. But what hap-pens when a patient says “Antidepressants made me worse”? This does happen. Explore this with the patient before

PHARMACOTHERAPY


dismissing or accepting this statement at face value. It can mean: “I felt the clinician was ignoring my pain, or ignoring me, and writing a prescription to get me out the door.” It can mean: “The antidepressant made me more anxious, more angry, more depressed.” This is often true in patients with a history of psychological trauma, as discussed above.

DePReSSiON-PAiN COMPLiCATiONSDepression with chronic pain is often complicated by sub-stance abuse (alcohol, tobacco, opioids, benzodiazepines), anxiety disorders (PTSD, panic), and sometimes personality disorders (borderline). These require adjustments or addi-tions to depression treatment. Patients with depression and chronic pain often have many types of trauma (psychologi-cal, physical) over an extended period of time (childhood to present). This trauma needs to be recognized and addressed before depression treatment can succeed.

ReCOVeRY FROM ACUTe VS CHRONiC iLLNeSSRecovery from acute illness means returning to your former health, life, and identity: You are the same person after recovery from pneumonia that you were before you got ill. Recovery from chronic illness is not returning to yourself, but reinventing yourself. Chronically depressed patients need to be warned that seeking a nondepressed identity will feel odd. Specifically, the new social initiatives necessary will feel risky, “Like I’m just going to get rejected again.” Major depression can arise as acute illness, but depression with chronic pain is often chronic itself. Since depression is so awful, we must ask: what sustains it chronically? The surprising answer is that depression protects against disap-pointment. If you are already on the ground, you can’t fall down. Any effort to change entrenched avoidance behav-iors will feel to the patient like he/she is “asking for trou-ble.” Reducing chronic pain intensity is usually the wrong goal for chronic pain treatment. It is important to focus on the resumption of life, rather than cessation of pain. Tell patients, “We can’t make it all go away. But we can make your life better.” Remember that partial victories are still victories.

CONCLUSiONIt can be quite challenging to treat depression in someone with chronic pain. These are certainly people who “have

a good reason to be depressed,” as they often tell us. But depression and pain feed off of each other. Reducing depres-sion can often be one of the best ways to lessen the burden of chronic pain.

References

1. Bair MJ, Robinson RL, Katon W, et al. Depression and pain comorbid-ity: a literature review. Arch Intern Med. 2003;163(20):2433–2445.

2. Gureje O, Von Korff M, Kola L, et al. The relation between multiple pains and mental disorders: results from the World Mental Health Surveys. Pain. 2008;135(1–2):82–91.

3. Gureje O, Von Korff M, Simon GE, et al. Persistent pain and well-being: a World Health Organization study in primary care. JAMA. 1998;280:147–151.

4. Gureje O, Simon GE, Von Korff. A cross-national study of the course of persistent pain in primary care. Pain. 2001;92:195–200.

5. Bair MJ, Robinson RL, Eckert GJ, et al. Impact of pain on depression treatment response in primary care. Psychosom Med. 2004;66(1):17–22.

6. Thielke SM, Fan MY, Sullivan M, et al. Pain limits the effectiveness of collaborative care for depression. Am J Geriatr Psychiatry. 2007;15(8):699–707.

7. Wasan AD, Davar G, Jamison R. The association between negative affect and opioid analgesia in patients with discogenic low back pain. Pain. 2005;117(3):450–461.

8. Howe CQ, Sullivan MD, Saunders KW, et al. Depression and ambivalence toward chronic opioid therapy for chronic noncancer pain. Clin J Pain. 2012;28:561–566.

9. Scherrer JF, Svrakic DM, Freedland KE, et al. Prescription opioid analgesics increase the risk of depression. J Gen Intern Med. 2014;29(3):491–499.

10. Scherrer JF, Salas J, Lustman PJ, et al; Residency Research Network of Texas (RRNeT) Investigators. Change in opioid dose and change in depression in a longitudinal primary care patient cohort. Pain. 2015;156(2):348–355.

11. Sinyor M, Schaffer A, Levitt A. The sequenced treatment alter-natives to relieve depression (STAR*D) trial: a review. Can J Psychiatry. 2010;55(3):126–35.

12. Sullivan MD, Howe CQ. Opioid therapy for chronic pain in the United States: promises and perils. Pain. 2013;154 suppl 1:S94-S100.

“…there is a strong, symmetrical relationship between persistent pain and psychological

disorder, with impairment of daily activities a central component of that relationship.”

By Th

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-BC

, AN

P-BC

TeCHNOLOGY

abstract: Pain is the most common cause of suffering and disability, affecting mil-lions of people around the globe. The direct and indirect costs of unmanaged pain are tremendous, both to the individ-ual and to society.1 Nonpharmacological intervention is a critical component to pain management protocols. Recent de-velopments have made the use of virtual reality technology a feasible, available, and unique option in the management of pain, incorporating themes of relax-ation, hypnosis, and distraction. This ar-ticle focuses on the past, present, and future of virtual reality and explores its role in pain management.

Does It Have a Role in Pain Management?

By Th

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alli

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earl

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S, RN

-BC

, AN

P-BC


iNTRODUCTiONWhat is virtual reality (VR)? In its most basic definition, VR is the creation of an artificial environment or reality, using computer hardware and software. Virtual reality therapy (VRT) uses specially programmed computers, visual immersion devices, and artificially created envi-ronments to give the individual a simulated experience.2 VRT will often require the patient to wear special gloves, earphones, and goggles in order to be further immersed in the experience. Other currently used therapies that incorporate the use of VR technology include virtual reality exposure therapy (VRET) and computerized cognitive behavior therapy (CCBT),3 both of which have proven to be very effective in treating patients with anxiety disorders and phobias.3-5 VRT is now one of the primary treatments for PTSD.6

TECHNOLOGY


became mainstream with the availability of the personal computer and has dominated our popular culture ever since. From the early science fiction writings of Aldous Huxley in his novel Brave New World, to the blending of reality in the popular Matrix films, to the ability of having Michael Jackson, Elvis, and Freddie Mercury perform a

“live concert” on stage together, we have assimilated VR into our current reality. VR is commonly used in education and training, through programs such as the virtual classroom,9 flight simulation for pilots,10 and VR combat simulation.11 In health care, VR is used for skill development and train-ing with programs such as surgery simulation and robotic surgery,12 in medicine through programs such as virtual diagnosis,13 and preventative medicine (nutrition counsel-ing, smoking cessation),14 and in psychology treating PTSD, autism, addiction.6,15

PAiN MANAGeMeNTOne of the best ways to alleviate pain is to introduce a dis-traction. Because virtual reality therapy immerses users in a 3-dimensional computer-generated world, it is uniquely suited to distracting patients from their pain.

Hunter Hoffman, PhD, a VR researcher from the University of Washington (UW) Human Interface Technology Labora-tory in Seattle, Washington, and David Patterson, PhD, Head of the Division of Psychology at UW Department of Rehabili-tation Medicine, also in Seattle, co-originated a new technique of using VR for pain control. Where the previous prevailing theory was that the use of VR simply altered the way patients interpret incoming pain signals, we now have fMRI evidence that it may directly have an effect on brain neuroplasticity.16-19 The utility of being able to physically change pain in the central nervous system may introduce greater utility of VR in chronic, persistent pain. VR is currently being used in the management of acute pain such as burn pain20-27 and painful dental procedures,28,29 has been shown effective in relieving pain in healthy volunteers exposed to experimental painful stimuli,30-32 and more recently is being investigated in chronic or persistent pain such as fibromyalgia,33-35 phantom limb pain,36-38 and other chronic pain.39-44

In the late 1990s, Hoffman and Patterson’s research focused on burn pain in the acute setting. Joined by a multidisciplinary team from UW School Of Medicine and the Harborview Burn Center, the group opened an imaginary world to patients suffering from uncontrolled pain.45 One example—and the

HiGHLiGHTS iN VR HiSTORY7,8

1950s: Morton Heilig, called the Father of Virtual Reality, developed Sensorama, a simulator that provided the illusion of reality using a 3-D motion picture with smell, stereo sound, seat vibrations, and wind to create an illusion

1961: Philco Corporation constructed Headsight, the first single cathode-ray tube element attached to a helmet with a magnetic tracking system that determined head direction; it was used for remotely viewing dangerous situations

1965: The Ultimate Display was created by Ivan Sutherland: it had a stereoscopic display; the head mounted device had a mechanical tracking system; later Sutherland experimented with an ultrasonic tracker

1980s: Jaron Lanier, founder of VPL Research, coins the term “virtual reality”

1988: NASA developed the Virtual Environment Workstation (VIEW) called BOOM— Binocular Omni-Orientation Monitor

1990s onward: Refinement of software (Virtual Reality Modeling Language), improvements in device wearability, such as the Oculus Rift head-mounted display, Microsoft Kinect body tracker


program credited as the first to use VR technology hypno-sis45—is “Snow World,” which is used to treat burn pain. Introduced and currently used at Virtual Reality Pain Reduc-tion Lab (HITLab) at UW Seattle and Harborview Burn Center, Snow World was the first immersive virtual world designed for reducing pain. The premise behind this comput-er-generated world is simple: patients listen to Paul Simon’s Graceland as they pelt virtual snowmen with snowballs, all while cruising around a winter wonderland. Burn patients undergoing wound care report that their pain drops dramati-cally when they engage in virtual reality programs. Functional MRI shows that virtual reality actually reduces the amount of pain-related activity in the brain.46 (To view VR brain scans, go to

FUTUReVR technologies are rapidly evolving. One of the most prom-ising areas for future study is developing and evaluating tailored VR environments that are optimally effective in pain control and individualized for a given patient. The integration of VR with other behavioral interventions such as cognitive behavior therapy and hypnosis will be explored. In the future, greater evidence may show that VR plays a role in effecting brain neuronal plasticity and modulation.

Companies such as Oracle, Sun Microsystems, and Micro-soft will lead the way in developing user friendly technology and systems to individualize the patient’s experience. The future of virtual reality in health care requires the ultimate collaboration of researchers at academic medical centers, such as University of Washington, along with neuroscien-tists and computer scientist worldwide.

ON THe HORiZON:

● Engage the body with more realistic devices, movement in the virtual environment, interaction, and control of objects, with rapid feedback—more important than photo realism.

● Collaborative virtual environments featuring virtual worlds, multiparticipant capabilities, able to communicate via text, audio, and video, and embodied through avatars.

● Researchers at UW Seattle are actively experimenting with augmented reality in a new generation of contact lenses built with very small circuits and LEDs that promises bionic eyesight.47

● The connection between brain-computer interface technology, videogames, and VR technologies offers a promising research area. Researchers have developed impressive prototypes in laboratories over the past few years that let people navigate virtual worlds or manipulate remote virtual objects using only their cerebral activity.48

CONCLUSiONSThe use of VR technology as an innovative, personalized, and interactive approach to pain management is on the verge of reality. It is important for the pain practitioner and researcher to keep abreast of this rapidly developing technology to keep at the forefront of new ways to impact their patient’s lives. Over 10 years ago, Norcross, Hedges,

“One of the best ways to alleviate pain is to introduce a distraction. Because virtual reality therapy immerses users in a 3-dimensional computer-generated world, it is uniquely suited to distracting patients from their pain.”

TECHNOLOGY


and Prochaska conducted a Delphi poll on psychotherapy trends expected in the ensuing decade.49 A panel of 62 psy-chotherapy experts ranked the use of virtual reality tech-nology 3rd among 38 therapeutic interventions expected to increase the most by 2010. Now there is solid evidence from controlled research that VR distraction is effective for reducing experimental pain, as well as the pain associated with burn injury care.

If Moore’s law50 is correct and the number of transistors in a dense integrated circuit continues to double approximately every 2 years, we should have a computer powerful enough to run immersive VR programs in our own homes by the year 2037. Meanwhile, the next 10 years will hopefully see the proliferation of methodologically sound and statisti-cally well-powered controlled studies of the effectiveness of immersive VR distraction for reducing the discomfort associated with a variety of invasive medical procedures, as well as chronic pain conditions.

For a system review of virtual reality studies, including methodology, type of pain, and VR application, go to painweek.org or http://www.painweek.org/journal/vol-3-q4-documents/.

References

1. Institute Of Medicine. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Available at: iprcc.nih.gov/docs/032712_mtg_presentations/IOM_Pain_Report_508comp.pdf.

2. Virtual reality. Wikipedia. Available at: en.m.wikipedia.org/wiki/Virtual_reality.

3. Virtual reality therapy. Wikipedia. Available at: en.m.wikipedia.org/wiki/Virtual_reality_therapy.

4. Hoffman HG. Virtual reality therapy. Sci Am. 2004;291(2):258–265.

5. Rothbaum BO, Hodges AL, Kooper K. Virtual reality exposure therapy. J Psychother Pract Res. 2002;9:51–54.

6. Institute of Medicine. Committee on the Assessment of Ongoing Effects in the Treatment of Posttraumatic Stress Disorder. Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Initial Assessment. Available at: www.aamc.org/download/298324/data/iomptsdstudy.pdf.

7. Virtual reality. Available at: www.vrs.org.uk/virtual-reality/history.html.

8. Blastr. A comprehensive timeline of virtual-reality up to Ron Moore’s Virtuality. Available at: www.blastr.com/2009/06/a_comprehensive_ timeline.php.

9. Rizzo AA, Bowerly T, Buckwalter G, et al. A virtual reality scenario for all seasons: the virtual classroom. CNS Spectr. 2006;11(1):35–44.

10. Airforce-Technology.com. Virtual reality media–military aircraft simu-lators and training systems. Available at: www.airforce-technology.com/contractors/training/virtual-reality-media/.

11. Haar R. Virtual reality in the military: present and future. Paper presented at 3rd Twente Student Conference on IT, Enschede June, 2005. Available at: citeseerx.ist.psu.edu/viewdoc/download?doi=10.1.1.76.3048&rep=rep1&type=pdf.

12. Fried MP, Satava R, Weghorst S, et al. The use of surgical simulators to reduce errors. Adv Patient Saf. 2005;4:165–177.

13. UHN. Virtual interactive case system. Available at: pie.med.utoronto.ca/PIE/PIE_whatWeDo_VPatient.html.

14. The potential for virtual reality to improve health care. Available at: http://www.vrphobia.eu/files/download/74.

15. ScienceRoll. The use of virtual reality in addiction medicine. Available at: scienceroll.com/2009/01/05/the-use-of-virtual-reality-in- addiction-medicine/.

16. Valet M, Sprenger T, Boecker H, et al. Distraction modulates connec-tivity of the cingulo-frontal cortex and the midbrain during pain – an fMRI analysis. Pain. 2004;109(3):399–408.

“VR is currently being used in the management of…burn pain…dental procedures…has been shown effective in relieving pain in healthy volunteers exposed to experimental painful stimuli…[and] is being investigated in…fibromyalgia, phantom limb pain, and other chronic pain.”


17. Hoffman HG, Richards TL, Coda B, et al. Modulation of thermal pain-related brain activity with virtual reality: evidence from fMRI. Neuroreport. 2004;7:1245–1248.

18. Hoffman HG, Richards TL, Van Oostrom T, et al. The analgesic effects of opioids and immersive virtual reality distraction: evidence from subjective and functional brain imaging assessments. Anesth Analg. 2007;105:1776–1783.

19. Cheung KL. Neuroplasticity and virtual reality. In Weiss PL, Keshner T, Levin EA, et al, eds. Virtual Reality for Physical and Motor Rehabilitation, Virtual Reality Technologies for Health and Clinical Applications. New York, NY: Springer Science+Business Media; 2014:5–24.

20. Hoffman HG, Doctor JN, Patterson DR, et al. Virtual reality as an adjunctive pain control during burn wound care in adolescent patients. Pain. 2000;85:305–309.

21. Mott J, Bucolo S, Cuttle L, et al. The efficacy of an augmented virtual reality system to alleviate pain in children undergoing burns dressing changes: A randomized controlled trial. Burns. 2008;34:803–808.

22. Brown NJ, Kimble RM, Rodger S, et al. Play and heal: randomized controlled trial of Ditto intervention efficacy on improving re-epithelialization in pediatric burns. Burns. 2014;40(2):204–213.

23. Hoffman HG, Chambers GT, Meyer WJ, et al. Virtual reality as an adjunctive non-pharmacological analgesic for acute burn pain during medical procedures. Ann Behav Med. 2011;41(2):183–191.

24. Kipping B, Rodger S, Miller K, et al. Virtual reality for acute pain reduction in adolescents undergoing burn wound care: A prospective randomized controlled trial. Burns. 2012;38:650–657.

25. Konstantatos AH, Angliss M, Costello V, et al. Predicting the effec-tiveness of virtual reality relaxation on pain and anxiety when added to PCA morphine in patients having burns dressings changes. Burns. 2009;35:491–499.

26. Morris LD, Louw QA, Grimmer-Somers K. The effectiveness of virtual reality on reducing pain and anxiety in burn injury patients: a systematic review. Clin J Pain. 2009;25:815–826.

27. Hua Y, Qiu R, Yao WY, et al. The effect of virtual reality distraction on pain relief during dressing changes in children with chronic wounds on lower limbs. Pain Manag Nurs. 2015 May 9. [Epub ahead of print]

28. Furman E, Jasinevicius TR, Biassed NF, et al. Virtual reality distraction for pain control during periodontal scaling and root planing procedures. J Am Dent Assoc. 2009;140(12):1508–1516.

29. Hoffman HG, Garcia-Palacios A, Patterson DR, et al. The effectiveness of virtual reality for dental pain control: a case study. Cyberpsychol Behav. 2001;4(4):527–535.

30. Gutierrez-Maldonado J, Gutierrez-Martinez O, Loreto-Quijada D, et al. The use of virtual reality for coping with pain with healthy participants. Psicothema. 2012;24(4)516–522.

31. De Tommaso M, Ricci K, Laneve L, et al. Virtual visual effect of hospital waiting room on pain modulation in healthy subjects and patients with chronic migraine. Pain Res Treat. 2013;2013:515730. [Epub ahead of print]

32. Patterson DR, Hoffman HG, Palacios AG, et al. Analgesic effects of posthypnotic suggestions and virtual reality distraction on thermal pain. J Abnorm Psychol. 2006;115(4):834–841.

33. Botella C, Garcia-Palacios A, Vizcaino Y, et al. Virtual reality in the treatment of fibromyalgia: a pilot study. Cyberpsychol Behav Soc Netw. 2013;16:215–223.

34. Garcia-Palacios A, Herrero R, Vizcaino Y, et al. Integrating virtual reality with activity management for the treatment of fibromyalgia: acceptability and preliminary efficacy. Clin J Pain. 2015;31(6):564–572.

35. Morris LD, Grimmer-Somers KA, Spottiswoode B, et al. Virtual reality

exposure therapy as treatment for pain catastrophizing in fibromyalgia patients: Proof of concept study (Study Protocol). BMC Musculoskelet Disord. 2011;12(1):85–92.

36. Cole J, Crowle S, Austwick G, et al. Exploratory findings with virtual reality for phantom limb pain; from stump motion to agency and analgesia. Disabil Rehabil. 2009;31:846–854.

37. Perry BN, Mercier C, Pettifer SR, et al. Virtual reality therapies for phantom limb pain. Eur J Pain. 2014;18(7):897–899.

38. Murray CD, Patchick E, Pettifer S, et al. Investigating the efficacy of a virtual mirror box in treating phantom limb pain in a sample of chronic sufferers. Proc. 6 Intl Conf. Disability, Virtual Reality & Assoc. Tech; Esbjerg, Denmark. 2006.

39. Sato K, Fukumori S, Matsusaki T, et al. Nonimmersive virtual reality mirror visual feedback therapy and its application for the treatment of complex regional pain syndrome: an open-label pilot study. Pain Med. 2010;11:622–629.

40. Gromala D, Shaw C, Song M. Chronic pain and the modulation of self in immersive virtual reality. Papers from the AAAI Fall Symposium (FS-09–01). Washington, DC: Association for the Advancement of Artificial Intelligence (AAAI), 2009;121–124.

41. Gromala D, Song M, Yim J, et al. Immersive VR: a non-pharmaco-logical analgesic for chronic pain. In: Proceedings of the 2011 Annual Conference Extended Abstracts on Human Factors in Computing Systems. New York: Association for Computing Machinery; 2011:1171–1176.

42. Keefe J, Huling DA, Coggins MJ, et al. Virtual reality for persistent pain: a new direction for behavioral pain management. Pain. 2012;153:2163–2166.

43. Wiederhold BK, Gao K, Sulea C, et al. Virtual reality as a distrac-tion technique in chronic pain patients. Cyberpsychol Behav Soc Netw. 2014;17(6):346–352.

44. Shiri S, Feintuch U, Weiss N, et al. A virtual reality system combined with biofeedback for treating pediatric chronic headache—a pilot study. Pain Med. 2013;14:621–627.

45. Virtual Reality Pain Reduction Lab (HITLab). University of Washington Seattle & U.W. Harborview Burn Center. Available at: www.hitl.washing-ton.edu/projects/vrpain.

46. Hoffman HG, Richards TL, Bills AR, et al. Using FMRI to study the neural correlates of virtual reality analgesia. CNS Spectr. 2006;11(1):45–51.

47. Augmented reality in a contact lens: A new generation of contact lenses built with very small circuits and LEDs promises bionic eye-sight. Available at: http://spectrum.ieee.org//biomedical//bionics//augmented-reality-in-a-contact-lens.

48. Brain-computer interfaces, virtual reality, and videogames. Available at: people.rennes.inria.fr/Anatole.Lecuyer/Lecuyer_computer_draft.pdf.

49. Norcross JC, Hedges M, Prochaska JO. The face of 2010: A Delphi poll on the future of psychotherapy. Prof Psychol Res Pr. 2002;33:316–322.

50. Wikipedia. Moore’s law. Available at: en.m.wikipedia.org/wiki/Moore%27s_law.

TECHNOLOGY

June 24 – July 1, 2016

Venice, ItalyZadar, Croatia

Kotor, MontenegroCivitavecchia (Rome), Italy

Livorno (Florence/Pisa), ItalyFlorence, Italy

Toulon (Provence), FranceBarcelona, Spain

Earn up to 12 Category 1 CE/CME Hours!(includes ANCC and ACPE Contact Hours)

For more information visit www.painweek.org/sea

Celebrity Constellation

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Some of you may want to know how this keynote address got its title. I am truly grateful for this opportunity to share my thoughts. I probably should give you all a little background: there I was having a lovely dinner in June, with Debra Weiner* and other PAINWeek at Sea colleagues, and out of nowhere, Debra asked me if I wasn’t doing this, what would I be doing? I then had the good fortune, or made the mistake depending upon how you look at it, of spilling my guts and telling her that I had a nearly lifelong dream of running my own delicatessen. Born in Brooklyn, New York, I grew up having tremendous respect and awe for good corned beef, pastrami, knishes, and other delicacies that you can only get in a good New York deli. I wanted to open mine, however, in Vermont. I also love Brooklyn bagels and during my honeymoon almost 30 years ago, as my wife and I drove through Basel, Switzerland, I turned to her and wondered out loud what the Basel bagel response would be if we opened a bagel store there.Debra then reminded me as we continued to discuss my deli interests the implications of my no longer being involved in pain management, clinically or academically, and that is when it hit me. I think I said something like, “The deli is going to have to wait. These are vital times for pain management. To paraphrase Dickens, these are the best of times and these are the worst of times. I need to stay in this for my own well-being, I need to know what’s going on. I can’t leave.” So what exactly did I mean by that? I’d like to share with you the key reasons why “The deli will have to wait.”

*Debra Weiner is the Director of Program Development for PAINWeek, PAINWeekEnd, and PAINWeek at Sea conferences.


ReASON #1: The current state of pain management in generalPain is the number one reason why a person seeks health care. The number one reason. The recent Institute of Medicine report and the even more recent release of the National Pain Strategy together outline in great detail the staggering numbers of people in the United States that experience chronic pain (100 million) as well as a plan to address how we can optimally treat people currently and improve upon such in the future. The draft National Pain Strategy was released on April 2, 2015, for a 45 day public comment period that closed on May 20, 2015. This document includes objectives and plans related to key areas of pain and pain care, including professional education and training, public education and communication, service delivery and reimbursement, prevention and care, disparities, and population research. We truly have only just begun to address pain management in a systematic and coordinated fashion. There are new scientific discoveries reported nearly daily and treatments both medical and nonmedical newly available or in development: now is not the time to leave.

ReASON #2: The public perception of painDespite these huge numbers of patients in need of care, there is still a lifetime of work to be done in educating the public, the media, healthcare professional training programs, and payors that chronic pain is real and should be taken seriously.

The media has had a tragic field day focusing nearly solely on negative aspects of pain management without reporting sufficiently on the very positive and exciting progress being made in our field. I was recently interviewed by a reporter at the NY Times. The interview was supposed to be focused on many aspects of pain management. Instead, it turned out that the reporter was only interested in one thing and one thing only: opioid misuse and abuse, as if “pain management” was a synonym for opioid use. In other words, this was what

defined pain management. More to follow though about this concept in just a moment. Well, I am a reasonable person in general. I figured that this same reporter would be interested in steps being taken by the federal, state, and local governments as well as the pharmaceutical industry and law enforcement agencies to address opioid related abuse and misuse issues. I invited her to report upon these efforts and to assist in such reporting to attend a public hearing at the FDA that addressed such efforts. I am sure you would not be surprised to learn that not only did she not report on the positive steps being taken to limit harm in one area of pain management, she also did not attend this hearing. Pain is often IGNORED, MISCONSTRUED, and further steps should be taken to EDUCATE and ENGAGE the PUBLIC.

ReASON #3: There are just not enough qualified pain management providersWe need to address the gap in the US among the number of people in pain who are in need of further evaluation and treatment, the number of pain specialists, and the number of primary care providers who are also involved in the care of the person in pain. The IOM report suggests that there are 100 million adults in the US who experience chronic pain, yet there are only 3000 to 4000 pain specialists in the US. At the same time there are over 400,000 primary care providers (internists, family practice, pediatricians, OB-GYN, geriatricians). The results of a recent survey (done by mail) of 3000 primary care providers, pain specialists, chiropractors, and acupuncturists suggested that 52% of chronic pain patients are primarily treated by a PCP, 2% by a pain specialist, 40% by a chiropractor, and 7% by an acupuncturist. The results of this survey also suggested that certain medical therapies such as long-acting opioids, anticonvulsants, or antidepressants for pain reduction were prescribed much more frequently—almost double the frequency—by pain specialists compared to PCPs. Both PCPs and pain specialists reported prescribing opioids less often due to concerns regarding regulatory oversight (this survey was completed before the rescheduling of hydrocodone). Also

…THeRe iS STiLL A LiFeTiMe OF WORK TO Be DONe iN eDUCATiNG THe PUBLiC, THe MeDiA, HeALTHCARe PROFeSSiONAL TRAiNiNG PROGRAMS, AND PAYORS THAT CHRONiC PAiN iS ReAL AND SHOULD Be TAKeN SeRiOUSLY.”

PW15 KEYNOTE ADDRESS


of interest in this survey was that many PCPs did not feel comfortable in their ability to manage musculoskeletal pain and neuropathic pain BUT were also not likely to favor mandatory pain education for all PCPs. What was not analyzed was the effect on patient care that these practices resulted in. Our system needs to be designed so that the needs of people experiencing chronic pain are matched to and addressed by the appropriate practitioner. This also means addressing the mismatch that may occur if a person experiencing chronic pain winds up in the office of a provider who may not offer the treatment that would be considered optimal for that person’s needs. Pain management is a medical specialty that spans multiple conditions as well as multiple treatment approaches. Having the skill set and wisdom to offer the person in pain what is best for that person is key to success. We would not expect a single provider to be able to provide every type of cardiac care to a person with a cardiovascular disorder. Why would we expect anything different in pain management?

ReASON #4: Optimal pain management is not molecule based or procedure based but most often requires a multidisciplinary effortPeople in pain benefit most when their pain is assessed and addressed in a multidisciplinary, integrated fashion. This approach must be embraced by those providing undergraduate or graduate level healthcare provider education, those paying for health care, those reporting about health care as well as those receiving heath care. How can we rest, how can I open the deli, while signs are being placed outside healthcare providers’ offices stating that chronic pain patients are not welcome there? Or as I learned from my nephew, who is in his last year of an orthopedic residency at a major medical school in the northeast, that he has had no training in pain management and that his attendings feel that unless a person is going to be operated on, that person is not worth seeing, and that all people in pain are drug seeking at some level. Chronic pain does not exist in a VACUUM and the broader medical community needs to become ENGAGED.

ReASON #5: Lifelong educationI hope we would agree that medical education is not only important, but how we are educated and what we are educated about has lasting influences throughout our professional careers. If your professional education does not include sufficient training in pain management, how can you effectively manage the pain of the people who have entrusted their lives to you, including assuming that you have the ability to evaluate and treat their acute and chronic pain complaints?

Currently, far less than 50% of the over 170 accredited US medical schools or osteopathic schools require students to complete a pain management course as part of undergraduate medical education. Furthermore, for those of you who have completed any residency training, how much pain management training have you formally received? How can we possibly be prepared to optimally evaluate our patients who are experiencing acute and chronic pain unless we do receive such training. Given the sheer numbers of people who experience pain, such training needs to be mandatory and UNIFORM at multiple levels and across all healthcare providers. Progress is being made but not quickly enough, certainly not at a rate that will sufficiently help the millions of people who we treat with chronic pain. One consequence of this is the demonization of the person in pain. We as human beings simply often do not react well to situations in which we feel ill prepared. With so many healthcare providers ill prepared to appropriately and comprehensively assess and treat people with chronic pain, the person in pain becomes the problem to those providers—a seemingly unconscionable outcome, but one that happens multiple times daily! What about the providers who are being attacked seemingly merely because they see people in pain? We need more EDUCATION on pain management.

ReASON #6: Where will you be treated if YOU need pain management?

“IF YOUR PROFeSSiONAL eDUCATiON DOeS NOT iNCLUDe SUFFiCieNT TRAiNiNG iN PAiN MANAGeMeNT, HOW CAN YOU eFFeCTiVeLY MANAGe THe PAiN OF THe PeOPLe WHO HAVe eNTRUSTeD THeiR LiVeS TO YOU?”


At Albany Medical Center, we received the following referral letter from a PCP practicing just south of Albany:

“DR has been under my care for many years and has been on many regimens for management of her chronic postcervical fusion pain including opioids and adjuncts. Currently my colleagues and I are in the process of dis-continuing prescribing opioids in patients under 65. The lack of consensus in the profession about the efficacy of opioids in chronic noncancer patients makes it difficult to justify use of opioids in primary care practice. Having said that, I think DR has done better on opioids than without them.” Like the development of a perfect storm, as nonpain management providers “refuse to treat” pain, as pain spec-ialists agree to treat patients only with certain but not all possibly effective and relevant therapies, too many people in pain are lost and have no one to care for them. What would I do if I couldn’t find someone to treat MY pain?

ReASON #7: Are your patients satisfied? The new approach to measuring patient satisfactionCMS* is now using NEW measures of patient satisfaction that may significantly impact pain management. Historically, there have been many approaches to measuring patient satisfaction as I am sure we are all aware. Now, per new CMS measures, when patients are surveyed about their satisfaction with their care and other measures, they are asked to rate these on a zero to 10 scale. The number reported by CMS is the percent of respondents who answer 9 or 10. This has to be 80% or above to pass. The mean score has no meaning and any score less than 9 is UNFAVORABLE, zero counting as much as 8. This principle applies to many measures used by CMS for addressing patient satisfaction. All responses less than 9 ARE EQUALLY BAD. Patients do not know this and, per CMS guidelines, providers are not allowed to coach patients regarding the scoring system NOR provide them with a practice questionnaire. This “scheme” may have profound implications as reimbursement is tied to these and similar measures and it is mathematically impossible for every provider and every hospital or other relevant facility to win.

ReASON #8: The need to teach evidence based medicine as it was defined!How many of you believe in evidence based medicine? What exactly is evidence based medicine, and what isn’t it?

In 1996 in the BMJ David Sackett and several international colleagues wrote an editorial outlining what EBM is and what it is not, defining evidence based medicine as “integrating individual clinical expertise and the best external evidence.” It was described as “the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. The practice of evidence based medicine means integrating individual clinical expertise with the best available external clinical evidence from systematic research. By individual clinical expertise we mean the proficiency and judgment that individual clinicians acquire through clinical experience and clinical practice.” That is certainly not the way in which so called evidence based guidelines are used. Many clinical guidelines used in clinical care are themselves derived NOT from patient care experiences in any way but solely as a literature review analyzed with levels of evidence and recommendations made from such. Such reviews and therefore the guidance that would come from such, leaves out most of the patients I take care of—perhaps yours too—since many of the people I take care of, let’s say experiencing spinal stenosis or postherpetic neuralgia, also experience other medical comorbidities that would have disqualified them from the particular studies that guidelines for their care are coming from. Am I the only one who sees the lack of logic here? In addition, sometimes published guidelines conveniently don’t tell the truth, leaving out data—can you believe that? In 2014, the American Academy of Neurology published a position paper regarding chronic opioid therapy for chronic noncancer pain. First, this position paper was authored by one person only. Second, contrary to the statement made in this position paper that, “there is no substantial evidence for maintenance of pain relief over longer periods of time” there are actually multiple published studies demonstrating the long-term benefit of opioid analgesics. How did this happen? It would appear that

“IT iS TiMe FOR US TO LOOK AT THe eLePHANT iN THe ROOM AND TAKe A STAND AGAiNST CORPORATiONS DeLeGATiNG HOW We SHOULD TReAT OUR PATieNTS.”

*CMS=Centers for Medicare and Medicaid Services

PW15 KEYNOTE ADDRESS


this supposed evidence based guideline did not follow EBM principles!

ReASON #9: Does anyone besides me see that an inherent conflict of interest MUST be addressed?There is an inherent conflict of interest when the virtues of a company are on level playing field with what is best for the patient. Within the past year, we received notice from one of the largest US healthcare insurers stating that use of onabotulinum toxin A for chronic migraine is considered experimental (it has been FDA approved since October 2010 for this condition) and that per this company’s written policy regarding such, patients had to first fail to respond adequately to 60 days of treatment with 3 separate prophylactic medications, with several listed by that company that are not currently FDA approved for the treatment of migraine. Yes, they rejected our request as experimental! Here is how we responded: “Botox is the only FDA approved treatment for chronic migraine. There is no requirement in the prescribing information for Botox for chronic migraine for a person with the diagnosis of chronic migraine to first fail multiple trials of oral medications BEFORE being treated with or before being considered an appropriate candidate for Botox for chronic migraine. Furthermore, there is no specific requirement from the FDA for Botox to be used for chronic migraine only AFTER the person with chronic migraine has failed multiple trials of oral medications. The steps and medications that are suggested in your onabotulinum toxin A policy (2014) as being required to be taken including demonstrated treatment failure of 3 oral medications (for 60 days each) prior to your coverage of onabotulinum toxin A for chronic migraine ARE NOT FDA approved for chronic migraine nor are they required per the prescribing information for Botox for chronic migraine. Ironically, it is your policy that is recommending OFF LABEL, experimental uses of those oral medications for chronic migraine as they are not FDA approved for chronic migraine.” This is just one example in a sea of instances.

Many of the largest health insurance companies are in fact publically traded companies. For publically traded companies, the law requires corporate directors and managers to pursue long-term, sustainable shareholder wealth maximization in preference to the interests of other stakeholders or society at large. The leading statement of the law’s view on corporate social responsibility goes back to Dodge v. Ford Motor Co., a 1919 decision that held that “a business corporation is organized and carried on primarily for the profit of the stockholders.” That case, in which Henry Ford was challenged by shareholders when he tried to reduce car prices at their expense, also established that “it is not within the lawful powers of a

board of directors to shape and conduct the affairs of a corporation for the primary purpose of benefiting others.” This remains the law today. A 2010 decision, eBay Domestic Holdings Inc. v. Newmark, held that corporate directors are bound by “fiduciary duties and standards” which include “acting to promote the value of the corporation for the benefit of its stockholders.” How then can such companies’ actions be considered as in the best interest of the person who we are trying to treat? It is time for us to look at the elephant in the room and take a stand against corporations delegating how we should treat our patients.

ReASON #10: Remembering why we chose to become healthcare providersAs Sir William Osler, the father of modern medicine, said:

“It is much more important to know what sort of a patient has a disease than what sort of a disease a patient has.” He also said, “The good physician treats the disease; the great physician treats the patient who has the disease.”

I don’t think I am alone in considering other options and activities at some point in my life after a challenging and rewarding career in pain management; I hope that you will all continue to be active in pain management embracing the multidisciplinary opportunities that we have in pain management to be great healthcare providers treating the PERSON who is experiencing the pain. We are here at PAINWeek, the largest pain conference held in the United States, to listen to and learn from a faculty with varied backgrounds regarding a wide range of pain management topics, to speak and interact with each other, to debate and argue with each other, to learn from each other all in the name of improving the care that we can offer to the PEOPLE who we take care of. There is so much more that we can do to accomplish better care—more at all levels—

THe DeLi WiLL JUST HAVe TO WAiT.

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abstract: Can any practice become completely bulletproof? This article covers the whys and hows of an investigation into prescriber mis-conduct and then suggests how a prescriber can become bulletproof should they become involved in such an investigation.

MeDiCAL / LEGAL


There are various ways that a case may merit sanc-tions as outlined below as the investigator may recommend that the case be referred to the state prosecutors as an administrative action against the prescriber’s license. This could result in disciplinary action against one’s license and would never entail any type of imprisonment. The burden here is “clear and convincing evidence beyond a reasonable certainty” meaning the evidence is just below what an inves-tigator would need to file a criminal action. If they were to file a criminal action with the district attorney or the US attorney that is when the burden increases dramatically to

“beyond a reasonable doubt.”

Civil Suits

There is one more avenue that has been utilized by inves-tigators and that is in the civil arena. An investigator can submit their case to the civil section of the US Attorney’s Office for consideration of a civil suit against the prescriber. When a prescriber signs on the dotted line to obtain their DEA registration they also acknowledge to abide by the Code of Federal Regulations relating to the appropriate prescribing of control substances. If they do not follow those rules and regulations then they can be sanctioned in

There are stages of an investigation against a prescriber’s practice. Causes for investigations come in from complaints from the public, other law enforce-ment agencies (such as local law enforcement), a state regulatory agency, or anonymous tips. Depending on who is doing the investigation—whether it be a federal or local law enforcement agency or a state regulatory agency—it is more likely going to be handled by the state regulatory agency that licenses the prescriber. A central complaint unit triages cases and will provide an investi-gational packet containing background materials, collected by various intelli-gence gathering ancillary personnel, on the prescriber about whom a complaint was filed. These can include but are not limited to civil indexing, articles of incorporation, information from local medical societies, and board certifica-tion affirmations for the investigator to review. If there is a complainant, the investigator(s) will do a detailed interview of that complainant. In drug pre-scribing cases, the investigator(s) typically look at whether the prescribing is appropriate as it relates to legitimate medical purpose. They have an approved list of experts who’ll determine what the community standard is for legitimate medical purpose based on all the facts that they have gathered. Does this mean that a practitioner in the area of pain management is required to have expert standing in the community? No, it just means that a prescriber has to be an ordinary, reasonable prescriber within the community in relation to practicing pain management.


the civil arena for a monetary settlement. The burden here is “a preponderance of evidence” or basically 51% of a jury siding with the plaintiff.

The investigators will generally continue to do interviews and gather evidence, which may involve obtaining a copy of a recent prescription monitoring program data sheet that illustrates the prescribing of the prescriber in question. During the course of the investigation the investigators would be looking at requisite knowledge that show potential intent to divert pharmaceutical drugs to an illegal market, which is better known as pharmaceutical diversion. Some of these factors include but are not limited to: the lack of a good faith examination, issuing an inordinate number of the prescriptions per day, directing patients to fill prescrip-tions at multiple pharmacies or to travel long distances to have those prescriptions filled, having the patient decide what drugs they would like prescribed to them (patient pre-scribing), prescribing a cocktail of 4 different drugs at the same strength to every patient in the practice, or charging a surcharge for controlled substance prescriptions. There are various methods in which the investigator can deter-mine many of these requisite intent issues. For example, for determining whether there was an inordinate amount of prescriptions written, investigators would typically take the amount of prescriptions that were written in one par-ticular day and determine how much time was taken with each patient in an 8 hour day. Just as a rough example, let’s say 400 prescriptions were generated from one prescriber in an 8 hour day. That equates to 50 prescriptions an hour. That may seem somewhat extreme but there was one inves-tigation that determined a prescription was generated every 7 seconds; clearly an extreme departure from the standard in the community.

The Prescriber

Usually the final interview is that of the subject prescriber. An investigator often shows up at the office right in the middle of a busy day for the prescriber. If the prescriber decides to talk to the investigator, the investigator will frequently start with background, experience, education, board certification, and then ask very poignant questions relating to each particular patient’s prescribing. They ask whether alternative methods had been used in addition to the prescribing of medications. Investigators ask what meth-ods have been used to proactively prevent the diversion of any drugs that are prescribed; these may include, but are not limited to urine screens, pill counts, pain diaries, and prescription monitoring reports.

At this point I highly recommend that a prescriber first ask the investigator whether they themselves are the subject of the investigation. If they are the subject of the investigation they should tell the investigator that they want to coop-erate fully, however, they are very busy seeing patients at this time. Tell the investigator that they want to make an appointment. It is important not to go any further in the questioning. All of you have watched cop shows and know the phrase, “You have the right to remain silent!” As soon as questioning becomes poignant, that is your cue to reiterate that you are busy seeing patients and want to cooperate, but that it is too difficult to remember all your patients in the middle of a busy day. Make an appointment. Prior to that appointment, the prescriber should seek counsel with an expert in administrative proceedings. Not just any attorney can deal with prescribing issues. We have tremendous due process in the United States and it is incumbent upon all

informed consent.”

“Many cases broughtto investigation

involve a lack of


prescribers to utilize that legal protection. Your counsel can usually obtain a copy or summary of the complaint prior to the appointment.

Case Review

Once all the interviews and evidence gathering is complete the investigator will typically have the case reviewed by a consultant prescriber that will generate a memorandum evaluating the prescribing practices in relation to what would be the standard in the community. If there is a sig-nificant amount of aberrant prescribing, the consultant pre-scriber would make a recommendation that an expert may be necessary to evaluate and comment on the prescribing practices. If the information does not merit any further review by an expert and appears to be within the normal limits of a community standard then the case could possibly be closed at that time. If the case does move forward then it is delivered to an expert in the community who will review the prescriber’s practices in relation to a typical pain man-agement practice.

The expert can then make a determination that there is no deviation, a simple deviation, or an extreme (departure) deviation from the standard of care. The only way that the case would move forward to meaningful prosecution is if there was an extreme departure from the standard of care—basically an act or failure to act that shocks. Writing one prescription every 7 seconds would definitely shock and be considered an extreme departure from the standard of care.

At this point the investigator usually has the case evaluated with expert opinion by their supervisor and a decision is made whether to file the case administratively, criminally, or civilly.

Being Bulletproof

Let’s discuss ways to become more bulletproof. Seeking counsel that has expertise in administrative proceedings is paramount if you do have an investigation against you. Another must is having the patient sign a pain agreement. This pain agreement is even more importantly an informed consent document. It is your duty to warn the patient about all issues regarding treatment, including warning them about operating machinery while on any medication, includ-ing over-the-counter medication. Many cases brought to investigation involve a lack of informed consent. The more that can be put into a pain agreement in regards to warnings

the better. Let patients know that they will be discharged if 1) they test positive for street drugs without a reason-able explanation, 2) they don’t test positive for prescribed drugs, 3) they are caught selling any of the medications that are prescribed to them, and 4) they are seeing another prescriber and obtaining the same medications prescribed by you. Always have your legal counsel review your agree-ments to assure you have covered all potential liabilities. Each patient should sign a medical release every year so that if an anonymous call comes in saying they are receiving the same medications from Dr. X, the prescriber will be able to contact Dr. X with that release and discuss the case with them without the issue of privilege under HIPAA.

Bulletproof: Practice/Pain Committees

The next suggestion for attaining bulletproof status is the formation of a practice (or pain) committee that meets quar-terly. This committee can be comprised of prescribers in the community who will bring the charts of their more difficult patients for discussion generically in an effort to formulate a treatment plan that best suits each particular patient. In this way the prescriber is utilizing let’s say 5 other prescribers on the practice committee in determining what the community standard is for treating their particular patient. Then if at a later date regulatory comes knocking on a prescriber’s door, saying an expert has reviewed their prescribing habits for this particular patient and feel it may be inappropriate, the prescriber can say that this patient’s treatment plan has been evaluated by 5 other prescribers in the community and this is the best course of treatment that they could formulate for this patient. The investigator may have one expert while you have 5. Make sure you follow the treatment plan formulated by the committee.

If you have a patient with a history of substance abuse, con-sider having that patient evaluated by a psychologist with an expertise in addiction. The psychologist can recommend a course of treatment and safeguards for you to follow. Make sure you follow their recommendations.

Many general practitioners are deathly afraid to prescribe controlled substances to their patients. As soon as a patient requires a standing order of even a small amount of opi-oids, a general practitioner refers the patient to a pain management specialist. However, some of these patients are very well controlled with a nominal dose of opioid per day and never require any further titration. These patients could stay in the GP’s practice and give the pain specialist some breathing room to handle the more difficult cases. By overburdening the pain specialist, more regulatory scrutiny is placed on their practice. Prescribers need to share the burden and help each other out.


Remember! “You have the right to remain silent!”

Although this is not a complete compellation of recommendations to keep regulatory from knocking at your door, it does contain some of my more salient points for protecting your practice.

Conclusion

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The Ingredients of Better Treatment Planning: Risk AssessmentTed Jones, PhD, CPE

Medical recordkeeping has the potential to be reduced to checkboxes: I’ve done this, I’ve done that, I’m good with the people who will review my records, so I’m done. But integrating the information in a mean-ingful fashion is the next level. In addition to the pain complaint, do a risk assessment and know what those risk assessment tools are. Practitioners then need to know what impact that risk assess-ment level should have on their treatment planning. Risk assessment information guides monitoring level—how often are you going to have the patient come back, how often are you going to do a drug screen, how often are you going to do a pill count, how often are you going to check the pharmacy monitoring program of your state. For example, Medicare has now asked that clinicians do drug screening based on risk. You can’t just drug-screen somebody every session. You need to titrate it to risk. With someone who’s high risk, you might want to drug screen every time. If somebody’s low risk, not so much. Risk also affects the types of medicines that you would choose for a patient. In general, with higher risk patients, the thinking is that you would select more long-acting, less abusable medications, lower dose quantities in terms of units. Risk might suggest going to a patch vs an oral formulation that’s more abusable. So it’s going to affect the types of medicines that you prescribe and also the amount that you’re going to prescribe.

Distinguishing Dependence From AddictionCynthia Knorr-Mulder, MSN, BCNP, NP-C

Dependence and addiction are often confused—not only by patients, but also by healthcare providers. The postoperative patient who is afraid of addiction should be educated that opioids are okay for them because they’ve had surgery. But we practitioners also need to further investigate to see if that patient has any history of addiction that should cause us to be cautious in what we’re prescribing. Patients on medication for pain can become dependent on it and exhibit symptoms of withdrawal if they stop taking it. This does not mean that they’re addicted. Patients have a fear of becoming addicted and becoming a junkie, so clearly patient education is the most important thing you can do to help take care of their pain and help them stay compliant with their treatment. A lot of patients see opioid treatment as a stigma. They see and hear stories on the news. The nurse practitioner can really help to educate these patients. Ask them to bring in a family member so you can let them know as well that the medication is okay for this short time while the patient is having pain. There are also misconceptions on our side. Healthcare providers can be equally guilty of stigma. Just because the patient is on oxycodone does not make them an addict. Yet clinicians should be alert for red flags of real addiction and consider those to be an indication of the need for further assessment.

1 |

2 |

Peripheral Neuropathies: Presentation, Diagnosis, and Treatment

Natalie Strand, MD

When a clinician sees a patient with painful peripheral neuropathies, there are several things to note on history or exam. The patient may complain of a pins and needles sensation or of a numbness sensation like a thin stock-

ing is on a hand or a limb. Often, painful peripheral neuropathies are in a glove and stocking distribution. That’s a giveaway. There may be some motor signs, fasciculations, atrophy, changes in nail or hair growth patterns, things of that nature, and of course, filament test-ing, testing to light touch. Perhaps the patient experiences allodynia, hyperpathia, hyperalgesia, or other things that suggest a peripheral neuropathy. Because there are so many types of peripheral neuropa-thies, the diagnostic procedures that one chooses really are going to be dependent on the entire picture. In general, nerve conduction studies, EMGs, and sometimes QST (Quantitative Sensory Testing) can be very helpful in evaluating peripheral neuropathies. Peripheral neuropathies can be very difficult to treat. Often, first line treatments involve cor-recting an underlying cause, if there is one. Sometimes the cause can be reversible. If a patient who is diabetic has poor glycemic control, improving that can also improve the painful neuropathy. There are antiseizure medications; some of the antidepressants are very helpful. Topical compounded creams can be helpful as well. TENS units or implantable spinal cord stimulators or peripheral nerve stimulators can also be useful. In some peripheral neuropathies, even surgical correction such as a decompressive surgery can be helpful as well.

Methadone, Ketamine, and Lidocaine: Advanced Therapies for “Difficult” PainTanya Uritsky, PharmD, BCPS

We tend to reserve methadone for the more refractory pain patients. It’s an agent that has a lot of pharmacokinetic variability and so requires skill to use. There are not that many providers who can manage it well and not everybody is educated in using it, and special-ist referral is warranted if the clinician is unsure. It really can be very effective in patients who have high opiate requirements, in patients who have neuropathic pain, and just about any patient who has pain and other agents have been tried. Ketamine targets the NMDA receptor. Pharmacologically the data supports its use around postoperative pain, neuropathic pain, and opiate induced hyperalgesia because of that NMDA receptor which is a central mechanism behind all of those differ-ent states. The adverse effects of ketamine aren’t as significant because the doses are very low. But again it may be best left to people who have a little more experience. Finally, lidocaine may be best left to the anesthesiologists, the folks who have more experience with it, because at higher doses the adverse effects, including cardiac adverse effects, can be severe. Pharmacologically it’s used mostly for neuropathic pain, and here the infusions are much lower than the doses that are required when used for cardiac reasons. But if you’re not monitoring carefully and you’re accustomed to using this agent, then you may end up in an area that’s not safe.

3 |

4 |

SHORT CUTS


The CDC reported a

increase in heroin use in the US over the past

The agency says that

of Americans who are addicted to heroin are also addicted to prescription opioids4

10years

63%

45%

SHORT CUTS

1. http://bit.ly/1X9bAJh 2. http://bit.ly/1PK6tLc 3. http://bit.ly/1SW2vgm 4. http://bit.ly/1OnYqAy 5. http://bit.ly/1LvJhsv 6. http://bit.ly/1SW2Vn5

1 in 7 WOMEN

MILLION

Estimates are that

Americans suffer from bladder pain and up to

are affected by chronic pelvic pain2

30

According to an opioid study, 1 in 45 men amplified their prescribed dosage to more than

of morphine or equivalent, compared to 1 in 70 women. The escalation increased the

risk of death by a factor of

24 XThe study examined health records of over

250,000 Canadian patients aged 15 to 64: more than 1 in 10 were prescribed

opioids for the first time and became chronic users. Deaths from long-term opioid use was 1 in 350 men and 1 in 850 women3

200mg

Women aged <45 who experience migraine

with aura are also at increased risk of stroke.

were recorded during the study period1

with an average age of 68 were tracked for an average of 11 years.

Of those, 187 had migraine without aura and 75 had

migraine with aura. A total of

migraines sufferers

strokes, heart attacks, and death

1292

294

64%

Delirium occurs in up to

and is associated with a 2 to 3 times increase

in the later development of dementia5

of

hospitalized older patients

4.575%

66%

43%

27%

30%

Dementia, including Alzheimer’s, afflicts more than

with the number expected to triple in the next 25 years.

More than

of older adults with dementia live in private homes.

Of patients with dementia,

reported pain and

had pain severe enough to limit activities.

of respondents without dementia were similarly affected.

Among those reporting pain,

rarely or never took any relieving medications6

million Americans,


SHORT CUTS

It takes 30 seconds to say “Yes”

but 30 minutes to say “No”

when writing prescriptions. Use your time wisely!

Until you are certain that a particular medication is effective and appropriate for a given patient,

consider writing for smaller amounts (“interval dispensing”). All prescriptions, especially for

controlled substances, need to be carefully thought through.

If a patient attempts to pressure you into writing a prescription,

identify this as aberrant behavior. Go with your gut!

By Doug Gourlay MD, MSc, FRCPC, FASAM


with

MelPohlMD

Mel Pohl, MD, is Clinical Assistant Professor, University of Nevada School of Medicine, and Medical Director, Las Vegas Recovery Center in Nevada. He is author of The Pain Antidote.

SHORT CUTS


What inspired you to become a healthcare provider?

My Dad always “nagged” me to become a doctor, since I was a little boy. I resisted because I had a fear of blood. My older brother went to medical school and when I visited him, I went to his gross anatomy lab and, despite the foul smell of formaldehyde, when I witnessed the dissection of an arm, I was hooked. I got serious about studying and applied to medical school a few years later and never looked back.

Why did you focus on addiction and pain management?

My first job out of residency was working for a family doctor, and I was responsible for covering calls at an addiction treatment center. I loved the work immediately—such an array of diagnoses and a chance to really impact human suffering. About 10 years ago, I realized that opioid dependence and chronic pain coexisted in the majority of my patients, and I proceeded to start studying chronic pain and developing protocols to treat these patients.

Who were your mentors?

Dr. Barry Rosen was one of the first doctors I met who was treating pain and drug addiction. He was a most gentle soul. Dr. Jodi Trafton is a brilliant neuroscientist whose lectures intrigued and drew me deeper into the science. Two Buddhist teachers who had a great impact on my conception of mind-fulness were Jon Kabat-Zinn and Pema Chodron.

If you weren’t a healthcare provider, what would you be?

A standup comedian. I love to entertain while I’m teaching, engaging the audience. Leave them laughing.

What is your most marked characteristic?

My insight. I’m not sure where it comes from, but I have the ability to connect with patients. I am

able to listen compassionately and help people to see their own hard truths.

What do you consider your greatest achievement?

It is the establishment of the Las Vegas Recovery Center Pain Recovery Program. We have created a program where patients can safely detoxify from habit-forming medications. It’s a supportive environ-ment where they can find a new path towards a fulfilling life.

What is your favorite language?

French, because my dad spoke it like a native. I learned to enjoy its melody and expressiveness.

If you had to choose one book, one film, and one piece of music to take into space for an undetermined amount of time, what would they be?

Book: The Catcher in the Rye by JD Salinger or Man’s Search for Meaning by Viktor E. Frankl

Film: Pay It Forward

Music: Brahm’s 4th Symphony

What would you like your legacy to be?

I’d like people to remember me as a good doctor, teacher, and compassionate caregiver. I hope that people will continue to promote the lessons I’ve learned around spreading the message about opioid induced hyperalgesia and how life can be so much better by changing one’s attitude.

What is your motto?

All Pain Is Real!

“I love to entertain while I’m teaching, engaging the audience.

Leave them laughing”

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R E D E F I N I N G M E D I C I N E

GRALISE® (gabapentin) tablets

BRIEF SUMMARY: For full prescribing information, see package insert.

INDICATIONS AND USAGEGRALISE is indicated for the management of Postherpetic Neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

DOSAGE AND ADMINISTRATIONPostherpetic neuralgia• GRALISE should be titrated to an 1800 mg dose taken orally once daily with the evening meal. GRALISE tablets should be

swallowed whole. Do not split, crush, or chew the tablets.• If GRALISE dose is reduced, discontinued, or substituted with an alternative medication, this should be done gradually

over a minimum of one week or longer (at the discretion of the prescriber).• Renal impairment: Dose should be adjusted in patients with reduced renal function. GRALISE should not be used

in patients with CrCl less than 30 or in patients on hemodialysis.• In adults with postherpetic neuralgia, GRALISE therapy should be initiated and titrated as follows:

Table 1 GRALISE Recommended Titration Schedule

Day 1 Day 2 Days 3-6 Days 7-10 Days 11-14 Day 15

Daily dose 300 mg 600 mg 900 mg 1200 mg 1500 mg 1800 mg

CONTRAINDICATIONSGRALISE is contraindicated in patients with demonstrated hypersensitivity to the drug or its ingredients.

Table 2 GRALISE Dosage Based on Renal Function

Once-daily dosing

Creatinine clearance (mL/min) GRALISE dose (once daily with evening meal) ≥ 60 1800 mg 30-60 600 mg to 1800 mg < 30 GRALISE should not be administered Patients receiving hemodialysis GRALISE should not be administered

WARNINGS AND PRECAUTIONSGRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration. The safety and effectiveness of GRALISE in patients with epilepsy has not been studied. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including gabapentin, the active ingredient in GRALISE, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Table 3 Risk by Indication for Antiepileptic Drugs (including gabapentin, the active ingredient in Gralise) in the Pooled Analysis

Indication Epilepsy Psychiatric Other Total

Placebo patients with events per 1000 patients 1.0 5.7 1.0 2.4Drug patients with events per 1000 patients 3.4 8.5 1.8 4.3Relative risk: incidence of events in drug patients/incidence in placebo patients 3.5 1.5 1.9 1.8Risk difference: additional drug patients with events per 1000 patients 2.4 2.9 0.9 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing GRALISE must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which products containing active components that are AEDs (such as gabapentin, the active component in GRALISE) are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that GRALISE contains gabapentin which is also used to treat epilepsy and that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Withdrawal of Gabapentin Gabapentin should be withdrawn gradually. If GRALISE is discontinued, this should be done gradually over a minimum of 1 week or longer (at the discretion of the prescriber). Tumorigenic Potential In standard preclinical in vivo lifetime carcinogenicity studies, an unexpectedly high incidence of pancreatic acinar adenocarcinomas was identified in male, but not female, rats. The clinical significance of this finding is unknown. In clinical trials of gabapentin therapy in epilepsy comprising 2,085 patient-years of exposure in patients over 12 years of age, new tumors were reported in 10 patients, and preexisting tumors worsened in 11 patients, during or within 2 years after discontinuing the drug. However, no similar patient population untreated with gabapentin was available to provide background tumor incidence and recurrence information for comparison. Therefore, the effect of gabapentin therapy on the incidence of new tumors in humans or on the worsening or recurrence of previously diagnosed tumors is unknown. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking antiepileptic drugs, including GRALISE. Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. GRALISE should be discontinued if an alternative etiology for the signs or symptoms cannot be established. Laboratory Tests Clinical trial data do not indicate that routine monitoring of clinical laboratory procedures is necessary for the safe use of GRALISE. The value of monitoring gabapentin blood concentrations has not been established.

ADVERSE REACTIONSClinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. A total of 359 patients with neuropathic pain associated with postherpetic neuralgia have received GRALISE at doses up to 1800 mg daily during placebo-controlled clinical studies. In clinical trials in patients with postherpetic neuralgia, 9.7% of the 359 patients treated with GRALISE and 6.9% of 364 patients treated with placebo discontinued prematurely due to adverse reactions. In the GRALISE treatment group, the most common reason for discontinuation due to adverse reactions was dizziness. Of GRALISE-treated patients who experienced adverse reactions in clinical studies, the majority of those adverse reactions were either “mild” or “moderate”. Table 4 lists all adverse reactions, regardless of causality, occurring in at least 1% of patients with neuropathic pain associated with postherpetic neuralgia in the GRALISE group for which the incidence was greater than in the placebo group.

Table 4 Treatment-Emergent Adverse Reaction Incidence in Controlled Trials in Neuropathic Pain Associated with Postherpetic Neuralgia (Events in at Least 1% of all GRALISE-Treated Patients and More Frequent Than in the Placebo Group)

Body system—preferred term GRALISE N = 359, % Placebo N = 364, %

Ear and Labyrinth Disorders Vertigo 1.4 0.5 Gastrointestinal Disorders Diarrhea 3.3 2.7 Dry mouth 2.8 1.4 Constipation 1.4 0.3 Dyspepsia 1.4 0.8 General Disorders Peripheral edema 3.9 0.3 Pain 1.1 0.5

Infections and Infestations Nasopharyngitis 2.5 2.2 Urinary tract infection 1.7 0.5 Investigations Weight increased 1.9 0.5 Musculoskeletal and Connective Tissue Disorders Pain in extremity 1.9 0.5 Back pain 1.7 1.1 Nervous System Disorders Dizziness 10.9 2.2 Somnolence 4.5 2.7 Headache 4.2 4.1 Lethargy 1.1 0.3

In addition to the adverse reactions reported in Table 4 above, the following adverse reactions with an uncertain relationship to GRALISE were reported during the clinical development for the treatment of postherpetic neuralgia. Events in more than 1% of patients but equally or more frequently in the GRALISE-treated patients than in the placebo group included blood pressure increase, confusional state, gastroenteritis viral, herpes zoster, hypertension, joint swelling, memory impairment, nausea, pneumonia, pyrexia, rash, seasonal allergy, and upper respiratory infection. Postmarketing and Other Experience with other Formulations of Gabapentin In addition to the adverse experiences reported during clinical testing of gabapentin, the following adverse experiences have been reported in patients receiving other formulations of marketed gabapentin. These adverse experiences have not been listed above and data are insufficient to support an estimate of their incidence or to establish causation. The listing is alphabetized: angioedema, blood glucose fluctuation, breast hypertrophy, erythema multiforme, elevated liver function tests, fever, hyponatremia, jaundice, movement disorder, Stevens-Johnson syndrome. Adverse events following the abrupt discontinuation of gabapentin immediate release have also been reported. The most frequently reported events were anxiety, insomnia, nausea, pain and sweating.

DRUG INTERACTIONSCoadministration of gabapentin immediate release (125 mg and 500 mg) and hydrocodone (10 mg) reduced hydrocodone Cmax

by 3% and 21%, respectively, and AUC by 4% and 22%, respectively. The mechanism of this interaction is unknown. Gabapentin AUC values were increased by 14%; the magnitude of this interaction at other doses is not known. When a single dose (60 mg) of controlled-release morphine capsule was administered 2 hours prior to a single dose (600 mg) of gabapentin immediate release in 12 volunteers, mean gabapentin AUC values increased by 44% compared to gabapentin immediate release administered without morphine. The pharmacokinetics of morphine were not affected by administration of gabapentin immediate release 2 hours after morphine. The magnitude of this interaction at other doses is not known. An antacid containing aluminum hydroxide and magnesium hydroxide reduced the bioavailability of gabapentin immediate release by about approximately 20%, but by only 5% when gabapentin was taken 2 hours after antacids. It is recommended that GRALISE be taken at least 2 hours following antacid administration. There are no pharmacokinetic interactions between gabapentin and the following antiepileptic drugs: phenytoin, carbamazepine, valproic acid, phenobarbital, and naproxen. Cimetidine 300 mg decreased the apparent oral clearance of gabapentin by 14% and creatinine clearance by 10%. The effect of gabapentin immediate release on cimetidine was not evaluated. This decrease is not expected to be clinically significant. Gabapentin immediate release (400 mg three times daily) had no effect on the pharmacokinetics of norethindrone (2.5 mg) or ethinyl estradiol (50 mcg) administered as a single tablet, except that the Cmax

of norethindrone was increased by 13%. This interaction is not considered to be clinically significant. Gabapentin immediate release pharmacokinetic parameters were comparable with and without probenecid, indicating that gabapentin does not undergo renal tubular secretion by the pathway that is blocked by probenecid.

USE IN SPECIFIC POPULATIONSPregnancy Pregnancy Category C: Gabapentin has been shown to be fetotoxic in rodents, causing delayed ossification of several bones in the skull, vertebrae, forelimbs, and hindlimbs. There are no adequate and well-controlled studies in pregnant women. This drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the effects of in utero exposure to GRALISE, physicians are advised to recommend that pregnant patients taking GRALISE enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/. Nursing Mothers Gabapentin is secreted into human milk following oral administration. A nursed infant could be exposed to a maximum dose of approximately 1 mg/kg/day of gabapentin. Because the effect on the nursing infant is unknown, GRALISE should be used in women who are nursing only if the benefits clearly outweigh the risks. Pediatric Use The safety and effectiveness of GRALISE in the management of postherpetic neuralgia in patients less than 18 years of age has not been studied. Geriatric Use The total number of patients treated with GRALISE in controlled clinical trials in patients with postherpetic neuralgia was 359, of which 63% were 65 years of age or older. The types and incidence of adverse events were similar across age groups except for peripheral edema, which tended to increase in incidence with age. GRALISE is known to be substantially excreted by the kidney. Reductions in GRALISE dose should be made in patients with age-related compromised renal function. [see Dosage and Administration]. Hepatic Impairment Because gabapentin is not metabolized, studies have not been conducted in patients with hepatic impairment. Renal Impairment GRALISE is known to be substantially excreted by the kidney. Dosage adjustment is necessary in patients with impaired renal function. GRALISE should not be administered in patients with CrCL between 15 and 30 or in patients undergoing hemodialysis [see Dosage and Administration].

DRUG ABUSE AND DEPENDENCEThe abuse and dependence potential of GRALISE has not been evaluated in human studies.

OVERDOSAGEA lethal dose of gabapentin was not identified in mice and rats receiving single oral doses as high as 8000 mg/kg. Signs of acute toxicity in animals included ataxia, labored breathing, ptosis, sedation, hypoactivity, or excitation. Acute oral overdoses of gabapentin immediate release in humans up to 49 grams have been reported. In these cases, double vision, slurred speech, drowsiness, lethargy and diarrhea were observed. All patients recovered with supportive care. Gabapentin can be removed by hemodialysis. Although hemodialysis has not been performed in the few overdose cases reported, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

CLINICAL PHARMACOLOGYPharmacokinetics Absorption and Bioavailability Gabapentin is absorbed from the proximal small bowel by a saturable L-amino transport system. Gabapentin bioavailability is not dose proportional; as the dose is increased, bioavailability decreases. When GRALISE (1800 mg once daily) and gabapentin immediate release (600 mg three times a day) were administered with high fat meals (50% of calories from fat), GRALISE has a higher Cmax

and lower AUC at steady state compared to gabapentin immediate release. Time to reach maximum plasma concentration (T

max) for GRALISE is 8 hours, which is about 4-6 hours longer compared to gabapentin immediate release.

NONCLINICAL TOXICOLOGYCarcinogenesis, Mutagenesis, Impairment of Fertility Gabapentin was given in the diet to mice at 200, 600, and 2000 mg/kg/day and to rats at 250, 1000, and 2000 mg/kg/day for 2 years. A statistically significant increase in the incidence of pancreatic acinar cell adenoma and carcinomas was found in male rats receiving the high dose; the no-effect dose for the occurrence of carcinomas was 1000 mg/kg/day. Peak plasma concentrations of gabapentin in rats receiving the high dose of 2000 mg/kg/day were more than 10 times higher than plasma concentrations in humans receiving 1800 mg per day and in rats receiving 1000 mg/kg/day peak plasma concentrations were more than 6.5 times higher than in humans receiving 1800 mg/day. The pancreatic acinar cell carcinomas did not affect survival, did not metastasize and were not locally invasive. The relevance of this finding to carcinogenic risk in humans is unclear. Studies designed to investigate the mechanism of gabapentin-induced pancreatic carcinogenesis in rats indicate that gabapentin stimulates DNA synthesis in rat pancreatic acinar cells in vitro and, thus, may be acting as a tumor promoter by enhancing mitogenic activity. It is not known whether gabapentin has the ability to increase cell proliferation in other cell types or in other species, including humans. Gabapentin did not demonstrate mutagenic or genotoxic potential in 3 in vitro and 4 in vivo assays. No adverse effects on fertility or reproduction were observed in rats at doses up to 2000 mg/kg (approximately 11 times the maximum recommended human dose on an mg/m2 basis).

© December 2012, Depomed, Inc. All rights reserved. GRA-410-P.1

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Indication and Usage GRALISE is indicated for the management of postherpetic neuralgia (PHN). GRALISE is not interchangeable with other gabapentin products because of differing pharmacokinetic profiles that affect the frequency of administration.

Important Safety Information Antiepileptic drugs, including gabapentin, the active ingredient of GRALISE, increase the risk of suicidal thoughts or behavior. Increased seizure frequency may occur in patients with seizure disorders if GRALISE is rapidly discontinued. Withdraw GRALISE gradually over a minimum of 1 week. The most common adverse reaction to GRALISE (≥5% and twice placebo) is dizziness.

Please see adjacent page for Brief Summary of Prescribing Information. Full Prescribing Information and Medication Guide are available at GRALISE.com.

FOR NIGHT & DAY

References: 1. Argoff CE, Chen C, Cowles VE. Clinical development of a once-daily gastroretentive formulation of gabapentin for treatment of postherpetic neuralgia: an overview. Expert Opin Drug Deliv. 2012;9:1147-1160. 2. Data on file, 2013. Depomed Inc. 3. Gupta A, Li S. Safety and efficacy of once-daily gastroretentive gabapentin in patients with postherpetic neuralgia aged 75 years and over. Drugs Aging. 2013;30:999-1008. 4. GRALISE [prescribing information]. Newark, CA: Depomed Inc.; December 2012.

© April 2015, Depomed Inc. All rights reserved. APL-GRA-0173

GRALISE THE NIGHT RELEASE THE DAY

When your PHN patients face challenges by Night and DayGRALISE is indicated for the management of postherpetic neuralgia (PHN).

&

• Side effects that are transient1

• Dizziness (10.9%) and somnolence (4.5%) were the most common side effects, and declined during the 2-week titration period to reach sustained low levels thereafter

• In clinical trials, 9.7% of GRALISE patients discontinued prematurely due to adverse reactions versus 6.9% for placebo4

• Dosage adjustment of GRALISE is necessary in patients with impaired renal function. GRALISE should not be administered in patients with creatinine clearance <30 mL/min or in patients undergoing hemodialysis. Reductions in GRALISE dose should be made in patients with age-related compromised renal function.

Once-daily GRALISE delivers 24-hour pain control, Night and Day1

Elderly patients experienced consistent results by Night and Day - even those over 753

• At night, when pain is at its worst1

• GRALISE is taken with the evening meal

NIGHTTIME DAYTIME EVENINGMEAL

TAKE WITH

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PAINWeek Journal, Vol 3, Q4

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Transcript of PAINWeek Journal, Vol 3, Q4