Betty Ford Lecture Sharon Walsh - AMERSA

Prescription Opioid Abuse: TranslatingLaboratory Findings to Clinical PracticeSharon L. Walsh, Ph.D.Center on Drug and Alcohol ResearchUniversity of KentuckyAssociation for Medical Education andResearch in Substance AbuseNovember 3, 20111

Conflicts of Interest Served as an External Safety Advisor for MedaPharmaceuticals Received honoraria and travel reimbursementfor lectures from PCM Scientific (supported byan unrestricted grant from Reckitt Benckiser) Served as a consultant on protocol developmentfor Cephalon2

OutlineEpidemiology of prescription opioid abuseand dependenceLaboratory approaches in drug abuseAbuse liability studies of prescription opioidsMisuse of marketed formulationsUsing findings to inform clinical practice3

Global Consumption of Narcotics 2003-2005(defined daily doses/million inhabitants/day)#USA33532Canada14133Aus + NZ7284EU6450Japan662Eastern Europe191All others116WORLD22890 5000 10000 15000 20000 25000 30000 35000Courtesy of Dr. Jayadeep Patra, Centre for Addic-on and Mental Health, University of Toronto. 4

Number of New Nonmedical Users of PainRelievers: 1965-20093,000#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

Lifetime Heroin and Pain Relievers UsersAged 12 or Older: 2002-2005#Number of Lifetime Users(in Thousands)35,00030,00025,00020,00015,00010,00029,61131,207 31,76832,692HeroinPainRelievers5,0003,668 3,744 3,145 3,53402002 2003 2004 20056

Opioid AnalgesicPrescriptions in the U.S.Total Prescriptions - 176 millionIMS Health National Prescription Audit 7

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

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

Applications for the Human Laboratory inSubstance Abuse Evaluate and characterize behavioral factorsand pharmacological factors control drugtaking Drug safety and abuse potential of new agents(pharmacodynamics and pharmacokinetics) Consequences of misuse of marketed products Discover medications to use as treatments10

Abuse Potential vs. Abuse LiabilityAbuse Potential Characterizes the ability of a CNS-active drug toproduce positive psychic effects These effects are viewed as correlated with orpredictive of the risk of addiction11

How Are They Measured?13

General Methods Enroll as inpatients healthy adult volunteers withappropriate drug use histories Include tests of the appropriate control (positiveand negative if available) agents for comparisonwith the test drug of interest Collect of broad array of responses Physiological (safety) Subjective measures (abuse liability) Cognitive/psychomotor Self-administration14

RADARS System Opioid Abuse Trends,Populations Rates (Ranked Highest-Lowest)2010RankPoisonCenterOpioidTreatmentSKIPDrugDiversionCollegeSurvey1 Hydrocodone Oxycodone Oxycodone Oxycodone Oxycodone2 Oxycodone Hydrocodone Hydrocodone Hydrocodone Hydrocodone3 Tramadol Methadone Methadone Methadone Fentanyl4 Methadone Morphine Morphine Morphine Methadone5 Morphine Hydromorphone Hydromorphone Buprenorphine Morphine6 Buprenorphine Fentanyl Fentanyl Tramadol Tramadol7 Fentanyl Buprenorphine Buprenorphine Hydromorphone Buprenorphine8 Hydromorphone Tramadol Tramadol Fentanyl HydromorphoneCourtesy Dr. Richard Dart from Fifth Annual RADARS System Scientific Meeting, April 28, 2011.15

RADARS System Opioid Abuse Trends,Populations Rates (Ranked Highest-Lowest)2010RankPoisonCenterOpioidTreatmentSKIPDrugDiversionCollegeSurvey1 Hydrocodone Oxycodone Oxycodone Oxycodone Oxycodone2 Oxycodone Hydrocodone Hydrocodone Hydrocodone Hydrocodone3 Tramadol Methadone Methadone Methadone Fentanyl4 Methadone Morphine Morphine Morphine Methadone5 Morphine Hydromorphone Hydromorphone Buprenorphine Morphine6 Buprenorphine Fentanyl Fentanyl Tramadol Tramadol7 Fentanyl Buprenorphine Buprenorphine Hydromorphone Buprenorphine8HydromorphoneTramadol Tramadol Fentanyl HydromorphoneCourtesy Dr. Richard Dart from Fifth Annual RADARS System Scientific Meeting, April 28, 2011.16


“How HIGH Are You Right Now?”Oral AdministrationScore10050403020100Oxycodone Hydrocodone Hydromorphone0 mg10 mg20 mg40 mg0 mg15 mg30 mg45 mg0 mg10 mg17.5 mg25 mgB0 .5 1 1.5 2 2.5 3 3.5Time (hrs)4 4.5 5 5.5 6 B0 .5 1 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 B0 .5 1 1.5 2 2.5 3 3.5Time (hrs)Time (hrs)4 4.5 5 5.5 6Walsh, Nuzzo, Lofwall and Holtman (2008) Drug and Alcohol Dependence, 98: 191-202.18

Relative Potency Estimates Relative potency estimates based on analgesiawould suggest hydrocodone ≤ oxycodone

“How Much Do You LIKE the Drug?Intravenous AdministrationMorphine Oxycodone HydrocodoneConcentration (ng/mL)6050403020100 mg5 mg10 mg20 mg0BL 0 5 10 15 95185275 365 BL 0 5 10 15 95185 275 365 BL 0 5 10 15 95185 275 365Time (min)Time (min)Time (min)Stoops, Hatton, Lofwall, Nuzzo & Walsh (2010) Psychopharmacology, 212: 193-203.20

Summary All three drugs produced a similar profile of euphoriceffects in the absence of unpleasant effects Relative potency estimates suggest that oxycodone andhydrocodone are roughly equipotent with respect toabuse potential Oral hydromorphone was less than two-fold as potent asoxycodone and hydrocodone inconsistent with analgesicestimates These data suggest that relative potency estimatesbased upon analgesic response may not be comparableto those assessing relative abuse potential21

Treatment Admissions InvolvingOpioid Analgesics 1 1992-2006140#120#100#OxyContin® introduced80#60#40#20#0#1992# 1994# 1996# 1998# 2000# 2002# 2004# 2006#Ref: Deborah Trunzo, SAMHSAFDA Advisory Committee 5-5-081Includes admissions where primary, secondary, or tertiarysubstance was reported as Other opiates/synthetics. Excludesadmissions for non-prescription use of methadone. 22

Sustained Release?23

“How Much Do You Like the Drug?”605040Oxycontin® (intranasal)0 mg/70 kg15 mg/70 kg30 mg/70 kgOxycodone (p.o.)Placebo10 mg20 mg40 mgScore3020100B0 .25 .5 .75 1 1.25 1.5 BTime (hrs)0 .25 .5 .75 1 1.25 1.5Time (hrs)Lofwall, Nuzzo & Walsh (2011) under review.#Walsh, Nuzzo, Lofwall and Holtman (2008) Drug and Alcohol Dependence, 98: 191-202. 24

Oxycodone Plasma Concentrations6050IN OxyContin® 30 mg/70 kgIN OxyContin® 15 mg/70 kgIV oxycodone 5 mg/70 kgConcentration (ng/mL)403020100-0.50 0.5 1 1.5 24 8 1224Time (hrs)Lofwall, Moody, Fang, Nuzzo and Walsh (2011) Journal of Clinical Pharmacology, e-pub ahead of print 25

Oxycodone Plasma ConcentrationsConcentration (ng/mL)605040302010Intranasal Bioavailability+80%0-0.50 0.5 1 1.5 24 8 1224Time (hrs)Lofwall, Moody, Fang, Nuzzo and Walsh (2011) Journal of Clinical Pharmacology, e-pub ahead of print26


Oral Opioid Self-Administration:Progressive Ratio Drug vs. Money7Number of Ratios Completed for Drug6543210Placebo 20 40 200 400 100 200Oxycodone (mg) Tramadol (mg) Codeine (mg)Babalonis, Lofwall, Nuzzo and Walsh (2011) unpublished results28

Strategies to Reduce Opioid Abuse Prevention Education Peer approaches Media Deterrence Legal enforcement Prescription monitoring programs New drug engineering29

Development of Abuse-Deterrent orAbuse-Resistant Analgesics#Oxycontin® Reformulated (OP instead of OC)#• Mechanical deterrence##- Formulations resistant to extraction bycrushing, 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

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

Buprenorphine Sublingual buprenorphine, a partial mu opioidagonist, is available as buprenorphine alone(Subutex ® ) and buprenorphine/naloxone(Suboxone ® ) and both are effective treatmentsfor opioid dependence Subutex ® was introduced abroad in the 1990’sand following the passage of DATA 2000,Subutex ® and Suboxone ® were introduced in theUnited States (US)32

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

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

Abuse Potential Signal:Buprenorphine vs. Buprenorphine/NaloxoneRoute of Administration#Patient Type#Sublingual#Intranasal#(Snorting)#Parenteral#(Injecting)#Non-Dependent#BUP = BUP/NXModerateBUP > BUP/NXModerateBUP ≥ BUP/NXModerateDependent#BUP = BUP/NXLow?BUP > BUP/NXLow35

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

Buprenorphine For Sale?37


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 (

How Do Prescribing Practices Increase theRisk of Diversion? Inadequate screening- enrollment ofpseudopatients Poor quality of treatment – writing prescriptionsonly with no behavioral platform Improper Dosing- writing for too much, lack ofadequate supervision40

Introduction 19,668 doctors registered for DEA X-license as1of 5/11, but 1/3 do not prescribe Many doctors have limited experience Substance abusers can be a unique andchallenging population concerns about diversion/misuse ofmedication in Appalachia and Wisconsin (WI)Arfken, Johanson, di Menza and Schuster (2010) Journal of Substance Abuse Treatment, 39: 96-104.41

Definitions Diversion: an unauthorized rerouting orappropriation of a substance 1 Misuse: any use of a prescription drug thatvaries from accepted medical practice 2 Neither discuss motives, relatedness topatient illness, nor appropriate clinicalresponses42

Purpose Determine effectiveness of non-traditional CMEin improving pharmacology and legislativeknowledge and promoting quality practicebehaviors that should decrease risk of diversionand misuse of buprenorphine43

Methods – The Curriculum Gather all data, guidelines, and formulate acurriculum that all speakers agree upon Multiple handouts/forms generated Teach time- and cost-efficient concrete ways tostructure treatment Provide evidence, teach the pharmacology Discuss cases requiring skill set taught44

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 surveys45

Results CME attendees:BoardcertificationAppalachia(n=28) Mean # months with OBOT experience Appalachia (n=24): 21.9 months WI (n=32): 40.0 monthsWI(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

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

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 SiteAfter#1 Month#*3 Month#* Planned comparison 3 month vs. BL: p=0.001#48

What total buprenorphine dose do you allow a patient to take on InductionDay?#% 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

What % of your patients are in opioid withdrawal at the time on initiatingbuprenorphine dosing?:#100#% of doctors#90# BL80#1 Month3 Month70#60#50#40#30#20#10#0#0-20%# 21-40%# 41-60%# 61-80%# 81-100%#% of patients in withdrawal* Planned comparison 3 month vs. BL: p=0.013#50

100Average Daily Maintenance Dose#BL1 Month3 Month80% of doctors60402000-89-16 17-24 25-32 >32Buprenorphine (mg)Appalachia* Planned comparison 3 month vs. BL: p=0.021#51

100Average Daily Maintenance Dose#BL1 Month3 Month80% of doctors60402000-89-16 17-24 25-32 >320-89-16 17-24 25-32 >32Buprenorphine (mg)Buprenorphine (mg)AppalachiaWisconsin* Planned comparison 3 month vs. BL: p=0.021# Planned comparison 3 month vs. BL: p=NS#52

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 ofmaking 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 observesconcerning behavior53

Confessions of X-Licensed Doctors Honesty about poor practice Prescribing Temgesic (Schedule II) because patients preferredinjecting 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 prescriptionopioids54

Summary Baseline knowledge on average was not stellar All legislative & pharmacology knowledgeimproved & remained improved 3 months later Practice behaviors vary by location CME was effective in improving practicebehaviors & sustaining these changes Also on-line http://www.cecentral.com/BupreCME55

Conclusions Prescription opioid abuse is a national epidemicthat is showing no signs of abating A multi-pronged approach is needed thatincludes More education for patients and physicians Improved drug formulations to reduce abuse potentialwhile protecting availability of analgesics for treatment Increased availability of good treatment for opioiddependence and expansion of insurance coverage forsubstance abuse treatment56

AcknowledgementsCollaborators Drs. Michelle Lofwall, Lisa Middleton, Bill Stoops,Shanna Babalonis, Martha Wunsch, Art Van ZeeResearch Volunteers (including CME doctors)UK Center on Drug & Alcohol ResearchVan Ingram, Director Kentucky Drug Control Policy OfficeUK CME officeCRDOC 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

Betty Ford Lecture Sharon Walsh - AMERSA

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