Prescription Opioid Abuse: Translating Laboratory Findings to Clinical Practice

Transcription

1 Prescription Opioid Abuse: Translating Laboratory Findings to Clinical Practice Sharon L. Walsh, Ph.D. Center on Drug and Alcohol Research University of Kentucky Association for Medical Education and Research in Substance Abuse November 3,

2 Conflicts of Interest Served as an External Safety Advisor for Meda Pharmaceuticals Received honoraria and travel reimbursement for lectures from PCM Scientific (supported by an unrestricted grant from Reckitt Benckiser) Served as a consultant on protocol development for Cephalon 2

3 Outline Epidemiology of prescription opioid abuse and dependence Laboratory approaches in drug abuse Abuse liability studies of prescription opioids Misuse of marketed formulations Using findings to inform clinical practice 3

4 Global Consumption of Narcotics (defined daily doses/million inhabitants/day)# USA Canada Aus + NZ 7284 EU 6450 Japan 662 Eastern Europe 191 All others 116 WORLD Courtesy of Dr. Jayadeep Patra, Centre for Addic-on and Mental Health, University of Toronto. 4

5 Number of New Nonmedical Users of Pain Relievers: ,000# All Ages# Under 18# 18 and Older# New Users (in thousands)# 2,500# 2,000# 1,500# 1,000# 500# 0# 1965# 1970# 1975# 1980# 1985# 1990# 1995# 2000# 2005# 2010# Year# SAMHSA-National Household Survey on Drug Use and Health# 5

6 Lifetime Heroin and Pain Relievers Users Aged 12 or Older: # Number of Lifetime Users (in Thousands) 35,000 30,000 25,000 20,000 15,000 10,000 29,611 31,207 31,768 32,692 Heroin Pain Relievers 5,000 3,668 3,744 3,145 3,

7 Opioid Analgesic Prescriptions in the U.S. Total Prescriptions million IMS Health National Prescription Audit 7

8 The Proliferation of Pain Clinics: Case Example - South Florida In 2007, there were a total of 4 pain clinics operating in South Florida This number increased from 4 to 176 by November 2009 From August 2008 to November 2009, one new pain clinic opened every third day in Broward and Palm Beach Counties alone During the last 6 months of 2008, these clinics prescribed 9 million dose units of oxycodone Satz MJ (2009) Interim report of the Broward County Grand Jury, State Attorney. 8

9 Broward Palm Beach New Times, Volume 13, Number 6, December 10-16, 2009.# 9

10 Applications for the Human Laboratory in Substance Abuse Evaluate and characterize behavioral factors and pharmacological factors control drug taking Drug safety and abuse potential of new agents (pharmacodynamics and pharmacokinetics) Consequences of misuse of marketed products Discover medications to use as treatments 10

11 Abuse Potential vs. Abuse Liability Abuse Potential Characterizes the ability of a CNS-active drug to produce positive psychic effects These effects are viewed as correlated with or predictive of the risk of addiction 11

12 Abuse Potential vs. Abuse Liability Abuse Liability Is similar and sometimes used interchangeably Includes abuse potential Captures other factors, including ease of synthesis and drug abuse/diversion history Describes abuse potential in a social and public health context 12

13 How Are They Measured? 13

14 General Methods Enroll as inpatients healthy adult volunteers with appropriate drug use histories Include tests of the appropriate control (positive and negative if available) agents for comparison with the test drug of interest Collect of broad array of responses Physiological (safety) Subjective measures (abuse liability) Cognitive/psychomotor Self-administration 14

15 RADARS System Opioid Abuse Trends, Populations Rates (Ranked Highest-Lowest) 2010 Rank Poison Center Opioid Treatment SKIP Drug Diversion College Survey 1 Hydrocodone Oxycodone Oxycodone Oxycodone Oxycodone 2 Oxycodone Hydrocodone Hydrocodone Hydrocodone Hydrocodone 3 Tramadol Methadone Methadone Methadone Fentanyl 4 Methadone Morphine Morphine Morphine Methadone 5 Morphine Hydromorphone Hydromorphone Buprenorphine Morphine 6 Buprenorphine Fentanyl Fentanyl Tramadol Tramadol 7 Fentanyl Buprenorphine Buprenorphine Hydromorphone Buprenorphine 8 Hydromorphone Tramadol Tramadol Fentanyl Hydromorphone Courtesy Dr. Richard Dart from Fifth Annual RADARS System Scientific Meeting, April 28,

16 RADARS System Opioid Abuse Trends, Populations Rates (Ranked Highest-Lowest) 2010 Rank Poison Center Opioid Treatment SKIP Drug Diversion College Survey 1 Hydrocodone Oxycodone Oxycodone Oxycodone Oxycodone 2 Oxycodone Hydrocodone Hydrocodone Hydrocodone Hydrocodone 3 Tramadol Methadone Methadone Methadone Fentanyl 4 Methadone Morphine Morphine Morphine Methadone 5 Morphine Hydromorphone Hydromorphone Buprenorphine Morphine 6 Buprenorphine Fentanyl Fentanyl Tramadol Tramadol 7 Fentanyl Buprenorphine Buprenorphine Hydromorphone Buprenorphine 8 Hydromorphon e Tramadol Tramadol Fentanyl Hydromorphone Courtesy Dr. Richard Dart from Fifth Annual RADARS System Scientific Meeting, April 28,

18 How HIGH Are You Right Now? Oral Administration Score Oxycodone Hydrocodone Hydromorphone 0 mg 10 mg 20 mg 40 mg 0 mg 15 mg 30 mg 45 mg 0 mg 10 mg 17.5 mg 25 mg B Time (hrs) B B Time (hrs) Time (hrs) Walsh, Nuzzo, Lofwall and Holtman (2008) Drug and Alcohol Dependence, 98:

19 Relative Potency Estimates Relative potency estimates based on analgesia would suggest hydrocodone oxycodone < hydromorphone by 4-fold Relative potency estimates based on abuse potential outcomes Hydrocodone: Hydromorphone = 0.77 mg/1 mg Oxycodone: Hydromorphone = 0.85 mg/1 mg 19

20 How Much Do You LIKE the Drug? Intravenous Administration Morphine Oxycodone Hydrocodone Concentration (ng/ml) mg 5 mg 10 mg 20 mg 0 BL BL BL Time (min) Time (min) Time (min) Stoops, Hatton, Lofwall, Nuzzo & Walsh (2010) Psychopharmacology, 212:

21 Summary All three drugs produced a similar profile of euphoric effects in the absence of unpleasant effects Relative potency estimates suggest that oxycodone and hydrocodone are roughly equipotent with respect to abuse potential Oral hydromorphone was less than two-fold as potent as oxycodone and hydrocodone inconsistent with analgesic estimates These data suggest that relative potency estimates based upon analgesic response may not be comparable to those assessing relative abuse potential 21

22 Treatment Admissions Involving Opioid Analgesics # 120# 100# OxyContin introduced 80# 60# 40# 20# 0# 1992# 1994# 1996# 1998# 2000# 2002# 2004# 2006# Ref: Deborah Trunzo, SAMHSA FDA Advisory Committee Includes admissions where primary, secondary, or tertiary substance was reported as Other opiates/synthetics. Excludes admissions for non-prescription use of methadone. 22

23 Sustained Release? 23

24 How Much Do You Like the Drug? Oxycontin (intranasal) 0 mg/70 kg 15 mg/70 kg 30 mg/70 kg Oxycodone (p.o.) Placebo 10 mg 20 mg 40 mg Score B B Time (hrs) Time (hrs) Lofwall, Nuzzo & Walsh (2011) under review.# Walsh, Nuzzo, Lofwall and Holtman (2008) Drug and Alcohol Dependence, 98:

25 Oxycodone Plasma Concentrations IN OxyContin 30 mg/70 kg IN OxyContin 15 mg/70 kg IV oxycodone 5 mg/70 kg Concentration (ng/ml) Time (hrs) Lofwall, Moody, Fang, Nuzzo and Walsh (2011) Journal of Clinical Pharmacology, e-pub ahead of print 25

26 Oxycodone Plasma Concentrations Concentration (ng/ml) Intranasal Bioavailability +80% Time (hrs) Lofwall, Moody, Fang, Nuzzo and Walsh (2011) Journal of Clinical Pharmacology, e-pub ahead of print 26

28 Oral Opioid Self-Administration: Progressive Ratio Drug vs. Money 7 Number of Ratios Completed for Drug Placebo Oxycodone (mg) Tramadol (mg) Codeine (mg) Babalonis, Lofwall, Nuzzo and Walsh (2011) unpublished results 28

29 Strategies to Reduce Opioid Abuse Prevention Education Peer approaches Media Deterrence Legal enforcement Prescription monitoring programs New drug engineering 29

30 Development of Abuse-Deterrent or Abuse-Resistant Analgesics# Oxycontin Reformulated (OP instead of OC)# Mechanical deterrence# #- Formulations resistant to extraction by crushing, heat, freezing, boiling # Embeda (morphine/naltrexone)# Addition of a deterrent agent# #if tampered with- it blocks its own effects# Other deterrents have included aversive agents# 30

31 Strategies to Reduce Opioid Abuse Treatment, Treatment, Treatment Drug Free (NA) Detoxification (not really treatment) Pharmacotherapies Naltrexone Opioid Agonist Substitution (methadone, buprenorphine/naloxone) 31

32 Buprenorphine Sublingual buprenorphine, a partial mu opioid agonist, is available as buprenorphine alone (Subutex ) and buprenorphine/naloxone (Suboxone ) and both are effective treatments for opioid dependence Subutex was introduced abroad in the 1990 s and following the passage of DATA 2000, Subutex and Suboxone were introduced in the United States (US) 32

33 Estimated Number of Patients by Month Nearly 350,000 patients in treatment May, 2011 Figure courtesy of Dr. Ed Johnson, Reckitt Benckiser (2/10)# 33

34 Buprenorphine Implementation Benefits: Increased access to treatment Reaching patients who would not consider methadone Decreased morbidity and mortality Risks: Diversion of buprenorphine Adverse outcomes (pediatric exposure, OD) 34

35 Abuse Potential Signal: Buprenorphine vs. Buprenorphine/Naloxone Route of Administration# Patient Type# Sublingual# Intranasal# (Snorting)# Parenteral# (Injecting)# Non-Dependent# BUP = BUP/NX Moderate BUP > BUP/NX Moderate BUP BUP/NX Moderate Dependent# BUP = BUP/NX Low? BUP > BUP/NX Low 35

36 Broward Palm Beach New Times, Volume 13, Number 6, December 10-16, 2009.# 36

37 Buprenorphine For Sale? 37

39 Sources of Misused BUP/NX U.S. treatment seeking opioid abusers (n=1000) 20-30% use to get high in last 30 days Buprenorphine is infrequently the drug of choice (<3%) BUP/NX (n=264) Other prescription opioids (n=799) Doctor source 57% 53% Friend source 23% 64% * Dealer source 35% 74% * Cicero, Surratt and Inciardi (2007) Journal of Opioid Management. 3:

40 How Do Prescribing Practices Increase the Risk of Diversion? Inadequate screening- enrollment of pseudopatients Poor quality of treatment writing prescriptions only with no behavioral platform Improper Dosing- writing for too much, lack of adequate supervision 40

41 Introduction 19,668 doctors registered for DEA X-license as 1 of 5/11, but 1/3 do not prescribe Many doctors have limited experience Substance abusers can be a unique and challenging population concerns about diversion/misuse of medication in Appalachia and Wisconsin (WI) Arfken, Johanson, di Menza and Schuster (2010) Journal of Substance Abuse Treatment, 39:

42 Definitions Diversion: an unauthorized rerouting or appropriation of a substance 1 Misuse: any use of a prescription drug that varies from accepted medical practice 2 Neither discuss motives, relatedness to patient illness, nor appropriate clinical responses 42

43 Purpose Determine effectiveness of non-traditional CME in improving pharmacology and legislative knowledge and promoting quality practice behaviors that should decrease risk of diversion and misuse of buprenorphine 43

44 Methods The Curriculum Gather all data, guidelines, and formulate a curriculum that all speakers agree upon Multiple handouts/forms generated Teach time- and cost-efficient concrete ways to structure treatment Provide evidence, teach the pharmacology Discuss cases requiring skill set taught 44

45 Methods Invited sample (n=123 Appalachia, n=188 WI) with DEA NTIS database IRB approval 4 surveys to evaluate outcomes Prior to CME Onsite immediately after CME 1 & 3 months after CME $99 Amazon gift card if completed all surveys 45

46 Results CME attendees: Board certification Appalachia (n=28) Mean # months with OBOT experience Appalachia (n=24): 21.9 months WI (n=32): 40.0 months WI (n=39) Psychiatry 7.1% 43.0% Family Medicine 25.0% 17.9% None 21.4% 10.3% Internal Medicine 10.7% 7.7% Other 35.8% 21.1% 46

47 If buprenorphine was reclassified as a Schedule II Controlled Substance, it would NOT be legal to prescribe it in an office-based setting for opioid dependence treatment:# 100# % Answering Definitely True# 90# 80# 70# 60# 50# 40# 30# 20# 10# * 0# BL# On Site After# 1 Month# 3 Month# GEE Site and Survey as Factors# * Planned comparison 3month vs. BL: p<0.0001# 47

48 Buprenorphine has an average half-life of approximately:# % Answering Correctly (37 hours)# 100# 90# 80# 70# 60# 50# 40# 30# 20# 10# 0# BL# On Site After# 1 Month# * 3 Month# * Planned comparison 3 month vs. BL: p=0.001# 48

49 What total buprenorphine dose do you allow a patient to take on Induction Day?# % Giving < 8 mg on Induction Day# 100# 90# 80# 70# 60# 50# 40# 30# 20# 10# 0# BL# 1 Month# 3 Month# *# * Planned comparison 3 month vs. BL: p=0.002# 49

50 What % of your patients are in opioid withdrawal at the time on initiating buprenorphine dosing?:# 100# % of doctors# 90# BL 80# 1 Month 3 Month 70# 60# 50# 40# 30# 20# 10# 0# 0-20%# 21-40%# 41-60%# 61-80%# %# % of patients in withdrawal * Planned comparison 3 month vs. BL: p=0.013# 50

51 100 Average Daily Maintenance Dose# BL 1 Month 3 Month 80 % of doctors >32 Buprenorphine (mg) Appalachia * Planned comparison 3 month vs. BL: p=0.021# 51

52 100 Average Daily Maintenance Dose# BL 1 Month 3 Month 80 % of doctors > >32 Buprenorphine (mg) Buprenorphine (mg) Appalachia Wisconsin * Planned comparison 3 month vs. BL: p=0.021# Planned comparison 3 month vs. BL: p=ns# 52

53 Other Practice Behaviors Have a PCSS Mentor Discuss diversion with patients # of urine drug tests in 1st 2 mo of trt Inform patients of trt components at time of making initial appointment refills for lost, washed, or stolen pills Use lock boxes Examine for track marks/intranasal erythema Engage pharmacist ask to call Dr. if observes concerning behavior 53

54 Confessions of X-Licensed Doctors Honesty about poor practice Prescribing Temgesic (Schedule II) because patients preferred injecting their medication Prescribing methadone in office-based practice Prescribing automatically at 24 or 32 mg (and on first day) Misbeliefs about buprenorphine Naloxone in the combination product is effective against alcohol (like naltrexone) Should dose multiple times per day like other prescription opioids 54

55 Summary Baseline knowledge on average was not stellar All legislative & pharmacology knowledge improved & remained improved 3 months later Practice behaviors vary by location CME was effective in improving practice behaviors & sustaining these changes Also on-line BupreCME 55

56 Conclusions Prescription opioid abuse is a national epidemic that is showing no signs of abating A multi-pronged approach is needed that includes More education for patients and physicians Improved drug formulations to reduce abuse potential while protecting availability of analgesics for treatment Increased availability of good treatment for opioid dependence and expansion of insurance coverage for substance abuse treatment 56

57 Acknowledgements Collaborators Drs. Michelle Lofwall, Lisa Middleton, Bill Stoops, Shanna Babalonis, Martha Wunsch, Art Van Zee Research Volunteers (including CME doctors) UK Center on Drug & Alcohol Research Van Ingram, Director Kentucky Drug Control Policy Office UK CME office CRDOC Nursing and Steve Sitzlar, Pharm.D. National Institute on Drug Abuse (T32 DA016176; R01- DA016718) Clinical Translation Science Award (UL1RR033173) Reckitt Benckiser (investigator-initiated CME project) 57