1. Pain Management and Addiction Medicine Russell K. Portenoy, MD Chairman, Department of Pain Medicine and Palliative Care Gerald J. Friedman Chair in Pain Medicine and Palliative Care Beth Israel Medical Center Professor of Neurology and Anesthesiology Albert Einstein College of Medicine New York, New York

2. Pain Management and Addiction Medicine  Role of opioid therapy in pain management  Risk management during opioid therapy for pain  Other issues –New formulations

3. 3 Opioid Therapy: 2011  Acute pain l consensus that opioid therapy is first line for moderate to severe acute pain –International consensus that opioid therapy is first line for moderate to severe acute pain  Chronic pain related to active cancer or other advanced illness l consensus that opioid therapy is first line for moderate to severe pain –International consensus that opioid therapy is first line for moderate to severe pain

4. 4 Opioid Therapy: 2011  Long-term opioid therapy for so-called chronic non-cancer pain –Pain specialists agree that long-term opioid therapy is safe and effective for some patients –Risks are significant and must be understood and managed –No consensus about the positioning of this therapy, patient selection, or treatment guidelines

5. Chronic Pain: Immense Public Health Problem  Persistent pain in primary care: WHO Study –5438 primary care patients from 15 sites in 14 countries assessed by interview and questionnaires –22% had persistent pain (>6 months + care or disability) More likely to have anxiety or depressive disorder (OR=4.14) –Pain-distress relationships were more consistent across cultures than pain-disability Gureje et al, JAMA, 1998:280:147

6. Chronic Pain: Immense Public Health Problem

7. Approach to the Patient with Chronic Pain Pain Assessment Comorbidities Primary Therapy? Symptomatic Therapies? PharmacotherapyOther Approaches Opioids Interventional Nonopioid Rehabilitative “Adjuvant Psychologic Analgesics” Neurostimulatory CAM Etiology

8. Key Issue in Positioning Opioid Therapy: Effectiveness  Many RCTs and systematic reviews yield mixed findings and provide little help in developing evidence-based therapy

9. Key Issue in Positioning Opioid Therapy: Effectiveness Opioids for chronic noncancer pain  Meta-analysis of RCTs through May, 2005  41 RCTs (N=6019) of any oral opioid therapy for any type of pain, with study duration averaging 5 weeks (range 1-16)  Opioids outperformed placebo for pain and functional outcomes in nociceptive and neuropathic pain, and fibromyalgia  “Strong” opioids were superior to naproxen and nortriptyline only for pain relief Furlan AD et al., CMAJ. 2006 May 23;174(11):1589-94

10. Key Issue in Positioning Opioid Therapy: Effectiveness Opioids for chronic noncancer pain  Conclusion: There is short-term efficacy for pain and function in all types of pain; opioids are better than other drugs for pain, but not functional outcomes. There are insufficient data to judge long-term outcomes. Furlan AD et al., CMAJ. 2006 May 23;174(11):1589-94

11. Key Issue in Positioning Opioid Therapy: Effectiveness Opioid treatment for chronic back pain  Systematic review and meta-analysis through 2005  Studies of oral, topical, or transdermal opioids for chronic back pain, with study duration less than 16 weeks  Meta-analysis of 4 studies of opioids vs. placebo or nonopioid did not show efficacy (p=0.136)  Meta-analysis of 5 studies of different opioids did not show reduced baseline pain (p=0.055)  Abuse behaviors ranged from 5% to 24% Martell BA et al.Ann Intern Med. 2007;146:116-27

12. Key Issue in Positioning Opioid Therapy: Effectiveness Opioid treatment for chronic back pain  CONCLUSIONS: Opioids have limited, if any, short-term value in chronic low back pain. Evidence about substance abuse is too limited to draw any conclusions. There are insufficient data to judge long- term outcomes. Martell BA et al.Ann Intern Med. 2007;146:116-27

13. Opioids for noncancer pain: surveys  Systematic review of open-label prospective studies through April, 2007  17 studies (N=3079) of oral, transdermal or neuraxial opioid, with study duration at least 6 months  Many patients stopped treatment due to AEs or poor response (oral 32.5%, transdermal 17.5%, neuraxial 6.3%)  Signs of addiction in 0.05%; abuse in 0.43%  Small but significant pain reduction for oral therapy (mean 1.99 points) and neuraxial therapy (mean 1.33 points); too few data to judge transdermal Noble M et al., JPSM. 2008;35:214-228 Key Issue in Positioning Opioid Therapy: Effectiveness

14. Opioids for noncancer pain: surveys  Conclusion: Many patients stop therapy but there is weak evidence that those who continue have pain relief over time. There are insufficient data to judge other long- term outcomes, including function and drug abuse. Noble M et al., JPSM. 2008;35:214-228 Key Issue in Positioning Opioid Therapy: Effectiveness

15.  Conclusions –RCTs suggest efficacy but have very limited relevance to long-term therapy –Observational studies provide weak evidence that many patients stop therapy due to side effects or poor response, but those who continue may benefit –Other outcomes, including those related to risk, are poorly characterized

16. Positioning Opioid Therapy  Despite limited evidence, APS-AAPM evidence-based guidelines: –Support consideration of an opioid trial for all patients with severe pain, but case-by-case decision based on an analysis: What is conventional practice? Are there reasonable alternatives? Is there relatively high risk of adverse effects? Is the patient likely to be a responsible drug-taker? Chou R et al. J Pain 2009;10:113-130

17. Positioning Opioid Therapy  Trends over two decades –Rapid increase in opioid use by pain specialists and primary care physicians –Rapid increase in adverse outcomes Abuse, addiction and diversion Unintentional overdose –Evolving responses by the Clinical community Regulatory and law enforcement communities

18. Trends in Long-Term Opioid Use  Study of health care claims data –From 1997 to 2005, age-gender groups had an increased incidence of long-term opioid use by 16% to 87% prevalence of long-term opioid use by 61% to 135% –Women used more opioids than men and older women had the highest prevalence (8%-9%) –Sedative-hypnotics commonly used with opioids Campbell CI et al.Am J Public Health 2010;100:2541-7

19. Trends in Opioid Use: Patients with SUD  Study of health care claims data –From 1997 to 2005, prevalence of long-term opioid use Increased from 7.6% to 18.6% in patients with SUD Increased from 2.7% to 4.2% in those w/o SUD Dx of opioid disorder among those treated increased from 15.7% to 52.4% Those with prior SUD received higher doses, more Schedule II and long-acting opioids, and more sedative-hypnotics Weisner, et al. Pain 2009;145:287-93.

20. Trends in Opioid Use: Commercial vs M’Caid  Study of health care claims data in a MCO and a Medicaid population –In 2000, chronic opioid therapy MCO population: 8% in those with mental health disorder (MHD) or SUD vs 3% w/o MHD or SUD Medicaid: 20% with MHD or SUD vs 13% w/o MHD or SUD –From 2000 to 2005, chronic opioid therapy MCO population: increased 34.9% in those with MHD or SUD vs. 27.8% w/o MHD or SUD Medicaid: increased 55.4% in those with MHD or SUD vs. 39.8% w/o MHD or SUD Edlund MJ, et al. Clin J Pain. 2010;26(1):1-8

21. Trends in Risk: Increasing Prescription Drug Abuse National HouseholdSurvey On Drug Use and Health Drug Abuse Warning Network

22. New Illicit Drug Use in the United States: 2005 SAMHSA. Results From the 2005 National Survey on Drug Use and Health. DHHS Publication No. SMA 06-4194, 2006. *526,000 new nonmedical users of OxyContin ®. Pain Relievers* TranquilizersCocaineEcstasyLSDPCP MarijuanaInhalantsStimulantsSedativesHeroin 77 108 243 247 615 647 872 877 1286 2114 2193 0 500 1000 1500 2000 2500 Numbers in Thousands

23. Source of Opioids for Nonmedical Use Reported by Users *Source of drugs for the most recent nonmedical use of pain relievers reported by persons aged 12 or older in the United States 2005. SAMHSA. Results From the 2005 National Survey on Drug Use and Health. DHHS Publication No. SMA 06-4194, 2006. 59.8 16.8 4.3 0.8 0 10 20 30 40 50 60 70 Friend/RelativeOne DoctorDealer/StrangerInternet Percent

24. Management of Risk Is a “Package Deal”  Best practice requires –Skills to optimize pharmacological outcomes –Skills to minimize risk  Risk is defined –Side effects –Abuse, addiction and diversion –Unintentional overdose

25. Management of Risk Is a “Package Deal”  Understanding laws and regulations  Screening & risk stratification: “Universal Precautions’  Compliance monitoring commensurate with risk stratum  Dealing with problems over time  Education about drug storage & sharing

26. Risk: Laws and Regulation  Federal: Controlled Substances Act –Prescribing is legal if it is consistent with Usual professional practice Legitimate medical purpose –Must stop prescribing if diversion occurs  State criminal statutes concerned with diversion: role for prescription monitoring programs  State civil laws/regulations concerned with physician practice

27. Prescription Monitoring Programs

28. Practical Considerations in Risk Management  Patient selection based on assessment  Distinguishing a trial from long-term therapy  Stratifying risk  Structuring therapy commensurate with risk  Educating  Assessing appropriate outcomes  Adjusting over time  Document and communicate

29. Stratify Risk Gourlay DL, et al. Pain Med. 2005;6:107-112. ♦No past/current history of substance abuse ♦Noncontributory family history of substance abuse ♦No major or untreated psychological disorder ♦History of treated substance abuse ♦Significant family history of substance abuse ♦Past/comorbid psychological disorder ♦Active substance abuse ♦Active addiction ♦Major untreated psychological disorder ♦Significant risk to self and practitioner Low Risk Moderate RiskHigh Risk

30. Measures for Screening  CAGE AID  Opioid Risk Tool  SOAPP  Many others

31. Structuring Therapy Based on Risk  May include –Written agreement –Frequent visits –Prescribing small quantities –Long-acting drugs with no rescue doses –One pharmacy –Pill counts, no replacements or early scripts –Urine toxicology screening –Coordination with addiction medicine specialist, psychotherapist, others

32. Structuring Therapy: Role of Urine Drug Screening  Low threshold for urine drug screening Urine ToxicologyAberrant Behaviors YesNoTotal Positive10 (8%)26 (21%)36 (29%) Negative17 (14%)69 (57%)86 (71%) Total27 (22%)95 (78%)122 Katz N, Fanciullo GJ. Clin J Pain. 2002;18:S76-S82.

33. Opioid Therapy: Monitoring Outcomes  Critical outcomes: The 4 A’s –Analgesia –Adverse effects –Activities –Aberrant drug-related behaviors

34. Monitoring Aberrant Drug- taking Behaviors  Probably more predictive –Selling prescription drugs –Prescription forgery –Stealing or borrowing another patient’s drugs –Injecting oral formulation –Obtaining prescription drugs from non-medical sources –Concurrent abuse of related illicit drugs –Multiple unsanctioned dose escalations –Recurrent prescription losses  Probably less predictive –Aggressive complaining about need for higher doses –Drug hoarding during periods of reduced symptoms –Requesting specific drugs –Acquisition of similar drugs from other medical sources –Unsanctioned dose escalation 1–2 times –Unapproved use of the drug to treat another symptom –Reporting psychic effects not intended by the clinician Passik and Portenoy, 1998.

35. Aberrant Behaviors (n = 388) (n = 215) (n = 98) (n = 33)(n = 26) (n = 16) Number of Behaviors Reported Patients Exhibiting Behaviors (%) (Passik, Kirsh et al, 2005)

36. Unintentional Overdose  Factors poorly understood  Methadone for pain significantly contributes  Probably multifactorial –Prescribing to patients at risk Axis I and Axis II: impulsivity and suicidality Predisposed to opioid-induced sleep-disordered breathing Predisposed to methadone-induced QTc prolongation –Lacking knowledge of drug-specific risks

37. Deaths with Mention of Methadone by Intent 1999-2003 Minino AM, et al. Deaths: Injuries, 2002. NVSR 54:10. NCHS. 2006. Accessed April 19, 2007 at: http://www.cdc.gov/nchs/data/nvsr/nvsr54/nvsr54_10.pdf. Anderson RN, et al. Deaths: Injuries, 2001. NVSR 52:21. NCHS. 2004. Accessed April 19, 2007 at: http://www.cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_21acc.pdf. Accessed April 19, 2007. *Includes intent categories homicide and legal intervention 0 500 1,000 1,500 2,000 2,500 3,000 3,500 19992000200120022003 Year Methadone Mentions All injury*UnintentionalSuicideUndetermined

38. Opioid-Induced Sleep Disordered Breathing Events per Hour Percent of Patients * *Bars indicate hi/lo of 95% CI; AHI = apnea-hypopnea index; CAI = central apnea index; OMAI = obstructive and mixed apnea index Webster LR, et al. Pain Med, 2009 0 10 20 30 40 50 60 70 80 90 AHI > 5 AHI > 15 AHI > 30 CAI > 5 CAI > 15 CAI > 30 OMAI > 5 OMAI > 15 OMAI > 30 Obstructive sleep apnea Central sleep apnea Both central and obstructive sleep apnea Sleep apnea: type indeterminate n = 140

39. Formulations and Risk  Risk of abuse may vary with drug and formulation –Higher concern: Short-acting drugs, including the rapid onset fentanyl drugs for breakthrough pain –Higher concern: Higher street value drugs, e.g. oxycodone, hydromorphone –Lower concern: Transdermal fentanyl and methadone

40. Formulations and Risk  Emergence of abuse deterrent formulations –May reduce unintentional overdose during recreational or impulsive use –May reduce diversion if less attractive to those with addiction –Benefits not yet demonstrated and will be difficult to track

41. Formulations and Risk  Mechanical abuse deterrent formulations –Oxycontin ™ and Remoxy™ Deters dose dumping: as gelatin capsule dissolves, SR oxycodone released via GI tract Difficult to crush, break, dissolve Cannot inject or snort

42. Formulations and Risk  Chemical abuse deterrent formulations –EMBEDA™

43. Conclusion  Despite lack of consensus, there is growing use of opioid therapy for chronic pain –Some is good –Some does harm  Reducing harm requires education and balanced policies based on best practice approaches