Case Study - cmcgc.com · Case Study Past Medical History MD is a 52 y/o female with chronic pain...

Soothing the Savage Beast: Vignettes in Complicated Pain ManagementComplicated Pain Management

Case StudyPast Medical History

MD is a 52 y/o female with chronic pain from TMJ, fibromyalgia and ruptured L4-L5 disc. She is a former high school teacher. MD is currently on disability due to PTSD from a student assault she suffered that happened to her when she was teaching in another state 25 years ago. The events of this episode are sketchy at best. She states she tries to eat right and exercise, however her height is 5 ft. 2 in and her weight 230 lbs. Her BMI is 42.1. In her chart it states she has borderline personality, however

h k d b t thi h d f i l t t “Th l t it ! Iwhen asked about this she defensively states, “They always get it wrong! I don’t have borderline personality. In fact those psychiatrists were so bad they fired me, twice!!” When asked about sleep, she states she does snore and often wakes with a wet pillow case. She also states she has nightmares, and they center on her father. She states the oxycodone IR works better than the oxycodone (Oxycontin®) and she would like to stop the Oxycontin® and have all her oxycodone as the IR form and would also like to increase her total daily amount of IR oxycodone. In addition, patient states would like a refill on her carisoprodol (Soma®), as that is the only muscle relaxer that works for her and all her other doctors have given her this without any problems.

Case Study Continued

Her current medications include:• Oxycodone (Oxycontin®) 40mg tid• Oxycodone IR 15mg qid• Diazepam 10mg hs for sleep

She has failed:• Gabapentin: “gave me seizures”• Pregabalin (Lyrica®): “I try to watch my weight and don’t want to

gain weight”• Topiramate (Topamax®): “I couldn’t think”• Pregabalin (Lyrica®): “I had no energy to do my daily chores”• NSAIDs: “I have an ulcer and they upset my stomach”• All muscle relaxers except Soma: “They knocked me out”

Case Study Continued

Her current lab values are:• TSH: 13.00

• Free testosterone: < 0.01

• Total testosterone: < 0.01

Comorbidities Pain and Opioid TherapyComorbidities, Pain and Opioid Therapy

Mary Lynn McPherson, Pharm.D., BCPS, CPE

Professor

University of Maryland School of Pharmacy

[email protected]

Mary Lynn McPherson, Pharm.D., BCPS, CPE

Professor

University of Maryland School of Pharmacy

[email protected]

Nothing to Disclose

6

Mary Lynn McPherson has no relevant financial relationships to report

2012 Midyear Clinical Meeting

© 2012 American Society of Health-System Pharmacists of 15

Soothing the Savage Beast: Vignettes in Complicated Pain Management

Opioid Adverse Effects

Constipation Nausea/vomiting Anorexia Sweating Dysphoria/delirium

Tolerance Physical dependence Addiction Diversion/unintentional

deathy p Pruritus/urticaria Hormonal changes Bladder dysfunction Cardiac effects Opioid-induced

hyperalgesia

Sleep disturbances Psychomotor

impairment Clouded vision Respiratory depression

Opioid Adverse Effects

Constipation Nausea/vomiting Anorexia Sweating Dysphoria/delirium

Tolerance Physical dependence Addiction Diversion/unintentional

deathy p Pruritus/urticaria Hormonal changes Bladder dysfunction Cardiac effects Opioid-induced

hyperalgesia

Sleep disturbances Psychomotor

impairment Clouded vision Respiratory depression

What’s the big deal?

Prescription drug use AND abuse has increased significantly over the past decade.

(Opium) has kept, and does now keep down the pop lation the omen ha e fe er children thanpopulation: the women have fewer children than those of other countries…the feeble opium-smokers of Assam…are more effeminate than women.” Charles Alexander Bruce, 1839

Opioids and Hormonal Changes

100 million people in the US suffer from chronic pain

Opioids are increasingly used to manage pain

Opioids can suppress serum testosterone levels in animals and humans

H i• Heroin users

• High-dose methadone

• Intrathecal opioid therapy

• More recently seen with oral and transdermal opioid therapy

Unrecognized and undertreated

Hypotestosteronemia

Role of testosterone• More than a “sex hormone”

Intrauterine development → advanced age

Important contributor to the robust metabolic functioning f lti l b d tof multiple body systems• Stimulation of muscle mass increase and strength

• Linear growth and maturation of bone

• Mood and cognition centers in the brain

• Neuroactive steroids with a neuroprotective role

De Maddalena C et al. Pain Physician. 2012;15:ES111‐8. Brennan MJ et al. Opioid‐Induced Androgen Deficiency: Approaches to Diagnosis and Management; Supp PPM, 8/12




Opioid-Induced Modulation of Gonadal Function

Primarily by acting on opioid receptors in the hypothalamus• Decreased release or disruption of the normal plasticity of GnRh

secretion

• Results in reduction of the release of HS and FSH from pituitary p ygland and of testosterone or estradiol from the gonads

May have a direct effect on the pituitary gland and the testes

De Maddalena C et al. Pain Physician. 2012;15:ES111‐8. Brennan MJ et al. Opioid‐Induced Androgen Deficiency: Approaches to Diagnosis and Management; Supp PPM, 8/12

Specific Effects in Women

Decline in LH, FSH, E2, testosterone and progesterone• Affects menstruation

Long-term intrathecal opioid administration• 70% premenopausal women developed amenorrhea

• 30% developed irregularities in menstruation• 30% developed irregularities in menstruation

Chronic use of SR opioids in women• Profound inhibition of ovarian sex hormone and adrenal adrogen

produciton

• Important consequences on menstrual flow and reduced fertility

• Significantly increased opioid-associated depression, osteoporosis, hyperalgesia

De Maddalena C et al. Pain Physician. 2012;15:ES111‐8.

Management of Opioid-Induced Hypogonadism

Consider nonopioid pain management options• TENS, behavioral therapies, injections, radiofrequency, nerve

stimulation, nonopioid drugs

Consider opioid rotation

Consider strategies that allow opioid dose reduction• Concomitant nonopioid analgesics

• Nonpharmacologic modalities

Katz N, et al. Clin J Pain. 2009;25(2):170‐5.

• Nonpharmacologic modalities

Testosterone supplementation (men)• Consider consultation with an endocrinologist

• Choose formulation and dose• Transdermal gel

• Transdermal patch

• Intramuscular injection

• Monitor prostate-specific antigen and prostate examination in men

• Monitor clinical and laboratory results

Brennan MJ et al. Opioid‐Induced Androgen Deficiency: Approaches to Diagnosis and Management; Supp PPM, 8/12

Testosterone Replacement in Women

Diagnosis of androgen deficiency in women is difficult• Common tests for measuring circulating testosterone are not

precise or accurate for physiologically low female testosterone concentrations

Transdermal patch is the only formulation approved for women

Designed to deliver 300 mcg/d to achieve testosterone concentrations compatible with premenopausal levels• Steady-state serum concentrations achieved after application of

second patch

De Maddalena C et al. Pain Physician. 2012;15:ES111‐8.




Hypothyroidism-Induced Pain Can cause a variety of muscle or

joint-related symptoms General muscular weakness and

pain, including cramps, and stiffness M thi ( k l t l l ) Myopathies (skeletal muscle)

Carpal Tunnel Syndrome Tarsal Tunnel syndrome General joint pain, achiness,

stiffness, known as "arthropathy" Tendonitis in the arms and legs

Emedicine.medscape.com/article/313915

Hypothyroidism-Induced Pain

Hypothyroid myopathy typically manifests as:• Polymyositis-like myopathy

• Proximal muscle weakness

• Increased creatine kinase level

May manifest as muscle enlargement May manifest as muscle enlargement (pseudohypertrophy), AKA Hoffman syndrome

May be accompanied by rhabdomyolysis

Likely due to defective carbohydrate metabolism• Hypothyroidism causes slowed muscle contraction and

relaxation (AKA hypothyroid myopathy)

• May be associated with decrease in muscle carnitine


Hypothyroidism-Induced Pain

30-80% of patients with hypothyroidism may manifest neuromuscular symptoms

Weakness seen in 1/3 of patients with hypothyroidism

Carpel tunnel syndrome, a peripheral nerve dysfunction, i f d i 15 30% f ti t ith h th idiis found in 15-30% of patients with hypothyroidism

Management – thyroid replacement


Vitamin D and Chronic Pain

Inadequacies in Vitamin D have been linked to:• Chronic musculoskeletal pain

• Muscle weakness or fatigue

• Fibromyalgia syndrome

• Rheumatic disordersRheumatic disorders

• Osteoarthritis

• Hyperesthesia

• Migraine headaches

• Other chronic somatic complaints

• Mood disturbance of chronic fatigue syndrome

• Seasonal affective disorder

Pain Treatment Topics – Vitamin D for Chronic Pain – Briefing 2008

Vitamin D and Chronic Pain

Lack of circulating calcium due to inadequate vitamin D.

This stimulates parathyroid hormone secretion, and sets in motion a cascade of biochemical reactions that negatively affect bone metabolism.

Increased PTH leads to a softening of bone surfaces –osteomalacia – leads to pain


Vitamin D Supplementation

In patients with chronic, nonspecific musculoskeletal pain and fatigue syndromes• Vitamin D may be inadequate and concentrations of serum

25(OH)D may be insufficient or deficient.

All patients should take a multivitamin to assure at leastAll patients should take a multivitamin to assure at least minimal daily values of essential nutrients, including calcium and 400-800 IU of vitamin D.

Recommend a daily 2000 IU vitamin D3 supplement• May require extra calcium





Vitamin D Supplementation

Monitor patient compliance and results for up to 3 months.• Other therapies for pain already in progress are generally not

discontinued

If results are still lacking after 3 months or a persistentIf results are still lacking after 3 months, or a persistent 25(OH)D deficiency or osteomalacia is verified, consider a brief course of prescribed high-dose vitamin D3, with or without calcium.


The Effect of PTSDonon

Chronic Non Cancer PainErnest J. Dole, PharmD, PhC, FASHP, BCPS

Clinical PharmacistUniversity of New Mexico

Pain Consultation and Treatment Center

Ernest J. Dole, PharmD, PhC, FASHP, BCPSClinical Pharmacist

University of New MexicoPain Consultation and Treatment Center

Disclosure

Ernest J. Dole reports no relevant financial relationships.

Objectives

Describe the prevalence of co-morbidity of PTSD and chronic non-cancer pain (CNCP)

List the common symptoms of PTSD & CNCP and the impact that co-morbidity can have on symptoms of both conditionsconditions

Describe the different theoretical models used to describe the co-morbid condition of PTSD & CNCP

Describe the implications for assessment of therapy for patients with both PTSD & CNCP

Describe the implications for implementations of therapy for patients with PTSD & CNCP

Case Study Focus

MD is a 52 y/o female with chronic pain from TMJ, fibromyalgia and ruptured L4-L5 disc.

She is a former high school teacher.

MD is currently on disability due to PTSD from a student lt h ff d th t h d t h h hassault she suffered that happened to her when she

was teaching in another state 25 years ago.

What risk factors does MD have for the development of PTSD?

What questions could/should be asked that are not in the case?

Setting the Stage Definition of Post-Traumatic Stress Disorder (PTSD)

• an individual must have been exposed to a traumatic event

• have at least one re-experiencing, three avoidance, and two hyperarousal phenomena

• have had the symptoms for at least 1 month

• and the symptoms must cause clinically important distress or reduced day-to-day functioning.

• It is labeled as acute for the first 3 months and chronic if it lasts beyond 3 months

• People with sub-syndromal PTSD have all the criteria for PTSD except one of the re-experiencing, avoidance, or hyperarousalphenomena

Diagnostic and Statistical Manual-IV (DSM-IV)

Bisson J. Post-traumatic stress disorder. Clinical Evidence. 2010;2:1-29.




Setting the Stage

Wretched Statistics• Every 9 seconds in the US a woman is assaulted or beaten.• Domestic violence is the leading cause of injury to women—more than car

accidents, muggings, and rapes combined• One in every four women will experience domestic violence in her lifetime.• An estimated 1.3 million women are victims of physical assault by an intimate

partner each year.• Females who are 20-24 years of age are at the greatest risk of nonfatal intimate

partner violence.• Most cases of domestic violence are never reported to the police.

http://domesticviolencestatistics.org/domestic-violence-statistics/www.ncadv.org/files/DomesticViolenceFactSheet(National).pdf

Setting the Stage

A prime cause of PTSD is childhood sexual abuse.

About 16% of American women (about 40 million) are sexually abused (including rape, attempted rape, or other form of molestation) p p , )before they reach their 18th birthday

McCauley J, Kern DE, Kolodner K, Dill L etal. Clinical characteristics of women with a history of childhood abuse: Unhealed wounds. JAMA.1997; 277:1362-8.

Setting the Stage

Women are two times as likely to acquire PTSD after trauma compared to men.

Childhood abuse may be the most common cause of PTSD in American women, 10% of whom suffer from PTSD

Green BL. Psychological research in traumatic stress: an update. J Trauma Stress. 1994;7:341-62.

Breslau N Davis GC. Andreski P et al. Sex differences in posttraumatic stress disorder. Arch Gen Psychiatry.1997;54:1044-8.

Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the national comorbidity survey. Arch Gen Psychiatry.1995;52:1048-60.

Co-Morbidity of PTSD & CNCP

Prevalence of CNCP within trauma samples ranged from 20%–80%

Prevalence of PTSD within CNCP samples ranged from 10%–50%.

24%- 47% of fibromyalgia patients attribute the onset of their symptoms to a physical injury associated with antheir symptoms to a physical injury associated with an trauma such as MVA

In one study 57% of patients w/ fibromyalgia had clinically significant levels of PTSD sx

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406..Beck JG, Clapp JD. A Different Kind of Comorbidity: Understanding Posttraumatic Stress Disorder and Chronic Pain.Psychol Trauma. 2011;3:101–8..Cohen H, Neumann L, Haiman Y etal. Prevalence of Post-Traumatic Stress Disorder in Fibromyalgia Patients: Overlapping Syndromes or Post-Traumatic Fibromyalgia Syndrome? Seminars in Arthritis and Rheumatism. 2002;32:38-50.

Co-Morbidity of PTSD & CNCP

In a sample of PTSD patients reporting physical symptoms, CNCP was the most common physical complaint (45% back pain and 34% headaches)

PTSD & CNCP can share common symptoms of anxiety & depression, hyperarousal, fear & avoidance behavior, reduced activity levels

Evolving of PTSD & CNCP symptoms tend to develop in a parallelEvolving of PTSD & CNCP symptoms tend to develop in a parallel fashion

Studies suggest that the presence of both PTSD and chronic pain can increase the symptom severity of either condition

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406.Beck JG, Clapp JD. A Different Kind of Comorbidity: Understanding Posttraumatic Stress Disorder and Chronic Pain.Psychol Trauma. 2011;3:101–8.Cohen H, Neumann L, Haiman Y etal. Prevalence of Post-Traumatic Stress Disorder in Fibromyalgia Patients: Overlapping Syndromes or Post-Traumatic Fibromyalgia Syndrome? Seminars in Arthritis and Rheumatism. 2002;32:38-50

Theoretical Models

Mutual Maintenance Model• Attentional biases may be present in chronic pain and PTSD patients such that

they attend to threatening or painful stimuli.• Anxiety sensitivity (AS) may contribute toward a vulnerability to catastrophize.• Pain may be a reminder of the traumatic event, triggering an arousal response,

avoidance of the cause of pain, and any memories of the trauma.• In both disorders, avoidance may be adopted as a means to minimize pain and

disturbing thoughts.g g• Fatigue and lethargy associated with depression may contribute to both

disorders.• General anxiety may contribute to both disorders.• Cognitive demands from symptoms of pain and PTSD limit the use of adaptive

coping strategies.

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406.

Beck JG, Clapp JD. A Different Kind of Comorbidity: Understanding Posttraumatic Stress Disorder and Chronic Pain. Psychol Trauma. 2011;3:101–8.

Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psych. Rev2001:21:857- 77.




Theoretical Models

Shared Vulnerability Model• Anxiety sensitivity is a predisposing factor contributing to the

development of both PTSD and CNCP• AS enhances the perceived sense of alarm during a traumatic event,

this increases awareness of psychological threat and physical injury. The increased sensitivity is thought to exacerbate overall emotionality and increase the risk for development of PTSD.F PTSD th d f l d b th t i bi d ith• For PTSD, the degree of alarm caused by the stressor is combined with the alarm of physiological sensations to further exacerbate the emotional reaction, increasing the risk of developing PTSD.

• For chronic pain, anxiety sensitivity heightens fear and avoidance of activities that may induce pain, which further increase the chances that pain will be maintained over time.


Beck JG, Clapp JD. A Different Kind of Comorbidity: Understanding Posttraumatic Stress Disorder and Chronic Pain.Psychol Trauma. 2011;3:101-8.

Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psych Rev. 2001:21:857-77.

Theoretical Models

Triple Vulnerability• An integrated set of triple vulnerabilities needs to be present for developing

PTSD: a generalized biological vulnerability, a generalized psychological vulnerability based on early experiences of control over salient events, and a more specific psychological vulnerability in which one learns to focus anxiety on specific situations

• A true or false alarm develops during exposure to situations that symbolize or resemble an aspect of a traumatic event.

• To develop PTSD, there must be development of anxiety or the sense that these events, including individual emotional reactions to them, are preceding in an unpredictable and uncontrollable manner; so that when negative affect and a sense of uncontrollability develop, PTSD may emerge.

• this model also relates to the development of chronic pain; for development of a chronic pain condition, there must also be development of a belief that the pain is preceding in an unpredictable and uncontrollable manner.

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406.Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psych Rev.2001:21:857-77.

Theoretical Models

Fear Avoidance Model• Physiological symptoms (e.g., increased blood flow, heart rate, or muscle

tension) may directly increase pain sensations and reinforce fears and negative beliefs that activities will be painful.

• With confirmation of fears and negative beliefs , avoidance behavior increases

• Misinterpretations (e g catastrophizing) are thought be influenced by aMisinterpretations (e.g., catastrophizing) are thought be influenced by a patient’s response with fear to sensations that are anxiety- provoking (e.g., anxiety sensitivity, negative affect).

• With chronic pain, fear and avoidance generally refer to the avoidance of movements or activities, such as exercise or work, for fear of causing increased pain or injury.

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406.Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance?Clin Psych Rev.2001:21:857-77.

Traumatic

Event

Domestic; Physical; Sexual

Abuse

Dysfunctional Cognition

Depression; epression;

Anxiety

Avoidance;

Inactivity

Decreased

Sleep

Hyperarousal

Increased Pain

Catastrophizing/

fear‐avoidance

beliefs

PTSD

Cycle

Pain Cycle

Adapted Perpetual Avoidance Model. Adapted from Liedl A, Knaevelsrud C. Chronic pain and PTSD: the Perpetual voidance Model and its treatment implicationsTorture.2008:18:69‐76; Sharp TJ, Harvey AG. Chronic pain and posttraumatic stress disorder: mutual maintenance? Clin Psych Rev.2001:21:857‐77.

Implications for Therapy for Patients w/ Co-Morbid PTSD & CNCP

Assessment• CNCP

• McGill Pain Questionnaire• for a more comprehensive assessment, West Haven-Yale

Multidimensional Pain Inventory• PTSD• PTSD

• Posttraumatic Stress Disorder Checklist • Clinician Administered PTSD Scale Revised (for a diagnosis

of PTSD).


Implications for Therapy for Patients with Co-Morbid PTSD & CNCP

Assessment• Aberrant Behavior Use Risk (with opiates)

• Opioid Risk Tool• One question on sexual abuse• Of individuals with substance use disorders, 30%-60% meet the criteria for

comorbid PTSD• A study of 1007 young adults designed to look for a causal relationship between

PTSD and substance use disorders; PTSD was associated with a more than 4-fold increased risk of drug abuse and dependence.g p

• The risk for abuse or dependence was highest for prescribed psychoactive drugs. The results suggest that drug abuse or dependence in persons with PTSD might be caused by efforts to self-medicate.

National Institute on Drug Abuse

Chilcoat HD, Breslau N: Posttraumatic Stress Disorder and Drug Disorders. Archives of General Psychiatry, 1998; 55:913-917

Kerns RD. Trauma and chronic pain: transforming healthcare delivery to provide patient-centered and integrative care. Pain.2011;152:2196-7.

Phifer J, Skelton K, Weiss T etal. Pain symptomatology and pain medication use in civilian PTSD. Pain.2011;152:2233-40.

Andersen TE, Andersen PG, Vakkala MA, etal. The traumatised chronic pain patient—Prevalence of posttraumatic stress disorder - PTSD and pain sensitisation in two Scandinavian samples referred for pain rehabilitation.Scandanavin J Pain. 2012;3:39-43




Implications for Therapy in Patients with Co-Morbid PTSD & CNCP

Assessment• Co-morbidity of PTSD w/ CNCP has been associated w/ prior

opioid use when compared w/ patients w/ CNCP but no PTSD

• Advocate to screen for PTSD in all patients w/ PTSD and CNCP

National Institute on Drug Abuse

Chilcoat HD, Breslau N: Posttraumatic Stress Disorder and Drug Disorders. Archives of General Psychiatry, 1998; 55:913-917

Kerns RD. Trauma and chronic pain: transforming healthcare delivery to provide patient-centered and integrative care. Pain.2011;152:2196-7.

Phifer J, Skelton K, Weiss T etal. Pain symptomatology and pain medication use in civilian PTSD. Pain.2011;152:2233-40Andersen TE, Andersen PG, Vakkala MA, etal. The traumatised chronic pain patient—Prevalence of posttraumatic stress disorder - PTSD and pain sensitisation in two Scandinavian samples referred for pain rehabilitation. Scandanavin J Pain. 2012;3:39-43


Treatment• Eye Movement Desensitization & Reprocessing (EMDR)

• Per recent review judged to be “beneficial”• Basic Cognitive Behavioral Therapy (CBT)

• Per recent review judged to be “beneficial”• Hypnosis

• Percent review effectiveness is “unknown”• Group CBT

• Percent review effectiveness is “unknown”• Relaxation therapy

• Percent review effectiveness is “unknown

Otis JD, Keane TM, Kerns RD. An examination of the relationship between chronic pain and post-traumatic stress disorder. JRRD. 2003;40:397-406.Beck JG, Clapp JD. A Different Kind of Comorbidity: Understanding Posttraumatic Stress Disorder and Chronic Pain.Psychol Trauma. 2011;3:101–8Bisson J. Post-traumatic stress disorder. Clinical Evidence. 2010;2:1-29.

Implications for Therapy in Patients with Co-Morbid PTSD &CNCP

Pharmacotherapeutic Options

• TCA

• Few tolerate amitriptyline

• Per recent review effectiveness is “unknown”

• Use nortriptyline; desipramine

• Good for sleepGood for sleep

• Mirtazepine• 15-30mg hs

• Per recent review effectiveness is “unknown”


Implications for Therapy in Patients with Co-Morbid PTSD &CNCP

Pharmacotherapeutic Options• Dual Acting Agents

• Duloxetine (Cymbalta®)• Dose: 20 mg/day up to 120 mg/day• Caution/ADR: liver dysfunction; bleeding disorders

Mil i (S ll ®)• Milnacipran (Savella®)• 25 mg/day to 100 mg/day• 1st agent w/ more NE activity than serotonin

• Venlafaxine (Effexor®)• May need to get to 300 mg/day• 1:30 NE:serotonin• Per recent review, “unlikely to be beneficial”



Pharmacotherapeutic Options• Alpha Adrenergic Blocking Agents

• Prazocin• May help w/ nightmares during sleep• 1mg-5mg hs; may go as high as 13mg hs

• NMDA Receptor Antagonistsecepto tago sts• Memantine: 10 mg bid• Amantidine: 100mg bid• Dextromethorphan: 30mg bid

• Central Alpha-2 Adrenergic Agonists• Clonidine: 0.1mg bid• Guanfacine: 0.03mg-1.5mg q day• Tizanidine: 2mg-8mg q 8 hours


Implications for Therapy

Pharmacotherapeutic Options• Low Dose Naltrexone (LDN)

• 4.5mg 1 hour before sleep

• Safe and few ADRs; but must be willing to DC opiates

• May work on microglia cells, increase endorphin concentrations; increase endorphin receptor numbers




Impact of PTSD on CNCP

Conclusion• Both conditions co-occur in patients frequently; therefore screening

for PTSD in CNCP patients routinely may improve outcomes

• There are simultaneous trajectories of CNCP and PTSD; therefore simultaneous treatment PTSD in CNCP patients routinely may improve outcomesimprove outcomes

• CBT, EMDR therapy may help patients w/ both co-morbidities

• The ORT is only risk for aberrant assessment tool that asks about sexual abuse (PTSD)

• The use of SNRIs, with the possible exception of venlafaxine, central acting alpha-2 adrenergic agents, & alpha adrenergic blocking agents may be helpful for patients w/ both CNCP & PTSD

• LDN may hold promise in treatment of patients w/ both conditions

Sleep Apnea and Opioids

Chris Herndon, PharmD, FASHP

Associate Professor

Southern Illinois University Edwardsville

Chris Herndon, PharmD, FASHP

Associate Professor

Southern Illinois University Edwardsville

Disclosure

Chris Herndon reports no relevant financial relationships.

Objectives

Describe the pathophysiologic process and differences of central, obstructive, and mixed sleep apneas

Explain the process in which opioids effect respiratory drive

Di t t di ti i d i k f Discuss recent studies suggesting increased risk of opioid use in those with sleep apnea

Formulate a plan to incorporate screening tools into current health-systems practice

Back to the Case

MD is morbidly obese and snores

She is on opioids and a benzodiazepine

What questions do we need to ask that is not in the case?

What is MD at risk for?

Regulation of Ventilation

V NVagus Nerve

Thoracic Neural

Receptors




Regulation of Ventilation

PaCO2, PaO2, and pH stimulate ventilation• More sensitive to rise in PaCO2 than drop in PO2

Respiratory center (pons and medulla) responds to neural and chemical input• Upper airway patency• Thoracic musculature control

Thoracic neural receptors• Stretch fibers respond to lung volume• Irritant receptors respond to lung volume and noxious stimuli

Peripheral and central chemoreceptors• Peripheral: aortic and carotid bodies (primarily PaO2)• Central: ventral surface of medulla (primarily PaCO2 and pH)

Types of Sleep Apnea

Obstructive Sleep Apnea• Absent airflow with continued ventilatory effort

Central Sleep Apnea• Absent airflow AND absent ventilatory effort

• 5 subtypes one being opioid mediated and other depressants• 5 subtypes, one being opioid-mediated and other depressants

Mixed• Periods of absent ventilatory effort followed by obstructed airflow

with ventilatory effort

Hypopnea• Reduction in airflow not sufficient to meet diagnostic criteria for

apnea

Iber C, Ancoli‐Israel S, Chesson AL, et al. The AASM Manual for the Scoring of Sleep and Associated Events. American Academy of Sleep Medicine 2007. West Chester, IL.Aurora RN, et al. The treatment of central sleep apnea syndrome in adults: Practice parameters and evidence based review. Sleep 2012;35(1):17‐40.

Epidemiology of Obstructive Sleep Apnea (OSA)

26% of adults are estimated to be at risk for obstructive sleep apnea

African Americans effected more commonly than caucasians

P l i li l f 18 t 55 Prevalence increases linearly from age 18 to 55

Men > women

Flemons WW. NEJM 2002;347(7):498‐504.

Pathophysiology of OSA Upper airway obstruction

• Pharyngeal wall changes

• Nasal congestion

• Tonsillar hypertrophy

• Surrounding tissue changes due to obesity

• Direct trauma and inflammation (i e intubation)• Direct trauma and inflammation (i.e., intubation)

Neuronal contribution• Visceral fat mediated leptin resistance

• Upper airway preparation and patency

• Dilator muscle innervation

Medication effects on upper airway patency and drive

Hudgel DW, et al. J Appl Physiol 1990;69(2)443‐450.Schwab RJ, et al. Am J Respir Crit Care Med 1995;152:1673‐1689.

Clinical Features of OSA

More suggestive• Witnessed apneas by bed partner• Awakening with choking• Obesity• Large neck circumference• Daytime sleepiness• Snoring

Less suggestive• Morning headaches• Nocturnal restlessness• Non-restorative sleep• Hypertension

Diagnosis of OSA

Testing• Polysomnography• Portable monitoring

Events• Apnea – less than 20% of baseline for > 10 seconds / episode• Hypopnea – not apnea but reduced airflow for > 10 seconds / episodeyp p p p• Respiratory effort related arousals - awakening but not apnea or hypopnea• Hypoventilation – increase of PaCO2 10 mmHg > 25% of total sleep time

Indexes• Apnea Hypopnea Index (events / hour)• Respiratory Disturbance Index (events / hour)

Diagnosis• AHI or RDI > 15 AND asymptomatic• AHI or RDE > 5 AND symptomatic (disturbed sleep, snoring, fatigue)

Collop NA, et al. J Clin Sleep Med 2007;3(7):737‐747.




Is opioid induced sleep disordered breathing clinically relevant?

Webster LR, et al. An analysis of the root causes for opioid‐related deaths in the United States. Pain Medicine 2011;12:S26‐S35.

Opioid Effects on Sleep

Ataxic (Briot) Breathing• Inhibition of central chemoreceptors

• Typically associated with neurologic disease

• Irregular and variable respiratory rate and effort

Obstructive Sleep Apnea Obstructive Sleep Apnea• Increased accessory muscle rigidity

• Decreased airway patency via neuronal inhibition

Central Sleep Apnea• Blunted response to hypoxemic respiratory drive via peripheral

chemoreceptors

• Blunted compensatory response to airway resistance or loading

Yue HJ, et al. Opioid medication and sleep‐disordered breathing. Med Clin N Am 2010;94:435‐446.

Walker JM et al.

Retrospective cohort (n = 120)• 60 pts on chronic opioid therapy matched with 60 controls

Matched for age, sex, and BMI Exclusion criteria: age < 18, CHF, stroke, neurologic

disease, prior use of O2, lack of opioid dosing info, p 2, p g Results from polysomnography data

• AHI score greater in opioid vs. non-opioid group (43.5/h vs. 30.2/h; p < .001)

• CSA events greater in opioid vs. non-opioid group (12.8/h vs. 2.1/h; p<.001)

• Arterial oxygen saturation less in opioid vs. non-opioid group (-2.1%; p<.001)

• Dose response relationship in all events

Walker JM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3(5):455‐461.

Dose correlation Walker et al

Walker JM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3(5):455‐461.

Jungquist CR et al. Cross-section descriptive study of referrals to sleep clinic

meeting criteria for sleep-disordered breathing (AHI >5) Study arms include no pain (n=171), pain-no opioid (n=187),

and pain-opioid (n=61) Exclusion criteria: < 21 yrs, acute pain, methadone use for

addiction, surgical apnea correction, narcolepsy ResultsResults

• No difference in Central Apnea Index (CAI) between no-pain and pain-no opioids (p = .268)

• No difference in Obstructive Apnea Index (OAI)• Significant difference in CAI between pain-no opioids and pain-

opioids study arms (p < .001)• Significant correlation in pain intensity in OAI and CAI (p=.021 and

p=.009, respectively)• Dose correlation with CAI (p < .001), but not OAI

Jungquist CR, et al. Relationship between chronic pain and opioid use with respiratory disturbance during sleep. Pain Management Nursing 2012;13(2):70‐79.

Treatments

Continuous positive airway pressure (CPAP)• Usually reserved for OSA

• May worsen opioid-associated CSA

Bi-level positive airway pressure (BiPAP)

BiPAP ith b k t t l BiPAP with backup rate control• Superior to CPAP for opioid-associated sleep disordered

breathing

Adaptoservo Ventilation (ASV)• Variance of ventilatory support which adapts to breathing pattern

• Emerging data to suggest superiority over other modalities

Yue HJ, et al. Opioid medication and sleep disordered breathing. Med Clin N Am 2010;94:435‐446.




CSA treatment in chronic opioid use

Guilleminault C, et al. Obstructive sleep apnea and chronic opioid use. Lung 2010;188:459‐468..

STOP Bang Screening for Sleep Apnea

1. Do you snore loudly?

2. Do you often feel tired, fatigued, or sleepy during the daytime?

3. Has anyone observed you stop breathing during sleep?

4. Do you have or are you being treated for high blood pressure?

5. Body Mass Index > 35?y

6. Age over 50 yrs?

7. Neck circumference greater than 40cm (15.5 in)?

8. Male?

Silva GE, et al. Identification of patients with sleep disordered breathing: Comparing the four‐variable screening tool, STOP, STOP‐Bang, and Epworth Sleepiness Scales. J Clin Sleep Med 2011;7 (5):467‐472.

“Yes” to three or more of the eight questions indicates high risk for OSA

Conclusions

Opioid related sleep disorder breathing may present as both obstructive and central sleep apneas (CSA > OSA)

Treatment of OSA with CPAP may worsen underlying opioid associated CSA

S it f CSA i t d ith h i i id i Severity of CSA associated with chronic opioid use is dose related

Concurrent OSA and CSA results in significant hypoxemia

Sleep disordered breathing implicated in part of growing national problem of opioid overdose deaths

High-Dose Opioids for CNCP:Should the Sky be the Limit?Should the Sky be the Limit?

Michele L. Matthews, PharmD, CPEAssociate Professor of Pharmacy Practice

Massachusetts College of Pharmacy and Health Sciences – Boston

Clinical Pharmacy Specialist in Pain Management

Brigham and Women’s Hospital

Michele L. Matthews, PharmD, CPEAssociate Professor of Pharmacy Practice

Massachusetts College of Pharmacy and Health Sciences – Boston

Clinical Pharmacy Specialist in Pain Management

Brigham and Women’s Hospital

Disclosure

Michele L. Matthews reports no relevant financial relationships.

Learning Objectives

At the end of this program, the participant will be able to:

Analyze the risk of overdose in patients receiving high dose opioids




What is High-Dose Opioid Use?

Washington State

Guidelines*

Veterans Affairs/

DoD Guidelines±

COT in CNCP

Guidelines (Chou et al)†

Canadian Guidelines on COT in

CNCP‡

Morphine Milligram ≥ 120 ≥ 200Milligram

Equivalents ≥ 120 ≥ 200

Does our patient meet this criteria?

Which patients are candidates for high-dose opioid therapy?

*Washington State Pain Management Guidelines. Available at: www.doh.wa.gov± VA/DoD Chronic Opioid Therapy Guidelines. Available at: http://www.healthquality.va.gov/Chronic_Opioid_Therapy _COT.asp†Chou et al. J Pain 2009; 10(2):113-130‡ Canadian Guidelines on COT in CNCP. Available at: http://nationalpaincentre.mcmaster.ca/opioid/

Who Gets High-Dose Opioid Therapy?

TROUP Study (2008)• Population

• Arkansas residents with CNCP

• Correlates

Morasco et al (2010)• Population

• Military veterans in the Pacific Northwest

• Correlates • Age between 41-60

years• Medicaid• Multiple pain diagnoses• Mental health diagnosis• Concomitant sedative-

hypnotic

• Male gender• Multiple pain diagnoses• Multiple comorbidities• Mental health diagnosis• Concomitant sedative-

hypnotic • Nicotine dependence

Sullivan MD et al. Trends in use of opioids for non-cancer pain conditions 2000–2005 in Commercial and Medicaid insurance plans: The TROUP study Pain 2008; 138:440–449Morasco BJ et al. Clinical characteristics of veterans prescribed high doses of opioid medications for chronic non-cancer pain. PAIN 2010; 151: 625–632

Opioid Prescriptions and ED Visits

TROUP Study (2010)• Highest rates of ED visits in:

• Younger age

• Females

• Multiple comorbidities

• Presence of back pain

• Presence of headaches

• Correlation with daily dose• Doses between 35 to 120 mg/day were significantly associated with

ED visits in commercially-insured patients

• Doses higher than 120 mg/day were not associated with ED visits but were associated with doubling of risk of adverse effects in all patients

Braden JB et al Emergency department visits among recipients of chronic opioid therapy. Arch Intern Med. 2010;170(16):1425-32.

Opioid Prescriptions and Risk of Overdose

CONSORT Study (2010)• Overdose rates

• 148 per 100,000 person-years (fatal and nonfatal combined)

• 17 per 100,000 person-years (fatal alone)

• Relationship between dose and overdose

H d R i f AllDaily Opioid Dose (MME)

Overdose Rate (95% CI) Per 100,000 Person-Years

Hazard Ratio for All Overdose Events

(95% CI)

1 to < 20 160 (100 – 233) 1.00

20 to < 50 260 (95 – 505) 1.44 (0.57 – 3.62)

50 to <100 677 (249 – 1317) 3.73 (1.47 – 9.50)

≥ 100 1791 (894 – 2995) 8.87 (3.99 – 19.72)

Any opioid use 256 (187 – 336) 5.16 (2.14 – 12.48)

Dunn KM et al. Opioid prescriptions for chronic pain and overdose: a cohort study. Ann Intern Med. 2010;152:85-92.

Opioid Prescriptions and Risk of Overdose (cont’d)

Bohnert et al (2011)• Unadjusted rate of prescription opioid overdose death by opioid

dose

Daily Opioid Dose (MME)

Overdose Deaths

Person-Months

Overdose Death Rateper 1000 Person-Months (95%CI)

0 243 2,729,022.7 0.09 (0.08-0.10)

1 - < 20 44 395,205 0.11 (0.08-0.15)

20 - < 50 108 458,296.2 0.24 (0.19-0.28)

50 - < 100 86 129,491.6 0.66 (0.53-0.82)

≥ 100 125 100,479.3 1.24 (1.04-1.48)Bohnert ASB et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305(13):1315-21.


Bohnert et al (2011)• Risk of death by prescription opioid overdose


CNCP(n=111,759)

Cancer (n=36,803)

Substance Use Disorder (n=15,491)( )

20 - < 50 1.88 (1.33-2.67) 1.74 (0.69-4.35) 1.42 (0.85-2.38)

50 - < 100 4.63 (3.18-6.74) 6.01 (2.29-15.78) 2.76 (1.54-4.94)

≥ 100 7.18 (4.85-10.65) 11.99 (4.42-32.56) 4.54 (2.46-8.37)

Bohnert ASB et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011;305(13):1315-21.





Gomes et al (2011)• Association between opioid-related death and overdose


Cases (n/N)

Controls (n/N)

Adjusted OR (95% CI)

20 49 118/498 514/1714 1 32 (0 94 1 84)20 – 49 118/498 514/1714 1.32 (0.94-1.84)

50 – 99 97/498 273/1714 1.92 (1.30-2.85)

100 – 199 82/498 181/1714 2.04 (1.28-3.24)

≥ 200 116/498 223/1714 2.88 (1.79-4.63)

Gomes T et al. Opioid dose and drug-related mortality in patients with nonmalignant pain. Arch Intern Med 2011;171(7):686-91.

Risk of Unintentional Drug Overdose Death

Paulozzi et al (2012)


Case Deaths (%)

Control Patients (%)

OR (95%CI)

Single peak > 40 54.7 26.6 3.3 2.6-4.1

Single peak > 120 29.7 5.2 7.6 5.8-10

True peak > 40 65.3 30 4.3 3.4-5.5

True peak > 120 36.3 6.4 8.4 6.5-10.8

Average > 40 34.3 4.3 12.2 9.2-16

Average > 120 20 2.1 11.3 8.1-15.8Paulozzi LJ et al. A history of being prescribed controlled substances and risk of drug overdose death.Pain Medicine. 2012;13:87-95.

Percentage of Patients and Prescription Drug Overdoses, by Risk Group

CDC Grand Rounds: Prescription Drug Overdoses — a U.S. Epidemic. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6101a3.htm

Malpractice Cases Involving Fatal Opioid Overdose

Rich and Webster (2011)

Observation N = 20 (%)

MME > 60 20 (100)

Last documented pain level > 6/10 (NRS) 20 (100)Last documented pain level > 6/10 (NRS) 20 (100)

Taking opioids for > 6 months 20 (100)

History of mental health disorder 14 (70)

History of snoring 12 (60)

Current or past substance abuse disorder

8 (40)

Rich BA, Webster LR. A review of forensic implications of opioid prescribing with examples from malpractice cases involving opioid-related overdose. Pain Medicine 2011; 12: S59–S65.

Risk Factors Beyond Dose

Provider error due to knowledge deficits

Patient non-adherence

Psychological variables• Catastrophizing • Impulsivity• Chemical coping

Unanticipated comorbidities

Presence of additional centrally-acting drugs

• Lack of acceptance • Personality disorders • Demoralization and

existential distress• Sensation seeking• Escapism

Passik SD, Lowery A. Psychological variables potentially implicated in opioid-related mortality as observed in clinical practice. Pain Medicine. 2011;12:S36-S42.

Clinical Implications

Guidelines for COT in CNCP

Risk Evaluation and Mitigation Strategies (REMS) for ER/LA opioids

Expansion of substance abuse resources

Role of the insurer

(REMS) for ER/LA opioids

Prescription drug monitoring programs (PDMPs)

Opioid overdose prevention initiatives

Does regulation mean education?




Summary

Opioid dose has been correlated to increased risk of overdose in patients with CNCP• Limitations to available data

• Need to identify better ways to gather data related to opioid-related overdose deaths

Need for balance between the “epidemics” • Undertreatment of pain vs. risk of opioid misuse/abuse/overdose

Back to the Case

Is this patient at risk of opioid overdose? If so, what are her risk factors?

What are your recommendations for safe and effective pain management?




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