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Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine.

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Presentation on theme: "Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine."— Presentation transcript:

1 Pharmacological Treatment of Addiction David A. Fiellin, M.D. Professor of Medicine Yale University School of Medicine

2 Overview Epidemiology of opioid dependence Treatment of opioid dependence –Buprenoprhine –Office-based treatment Epidemiology of alcohol problems Treatment of alcohol problems –Naltrexone, acamprosate, disulfiram

3 Physical Dependence –Tolerance –Withdrawal Loss of control (addiction) –Larger amounts/longer period than intended –Inability to/persistent desire to cut down or control –Increased amount of time spent in activities necessary to obtain opioids –Social, occupational and recreational activities given up or reduced –Opioid use is continued despite adverse consequences Opioid Dependence (DSM-IV, 3 or more within one year )

4 Epidemiology Prescription opioids –National Survey on Drug Use and Health, 2006 > 12 million reported non-medical use of prescription opioids Estimated 1.6 million met criteria for prescription opioid abuse or dependence Heroin –National Household Survey on Drug Abuse, 2006 > 500,000 reported past year heroin use Approximately 323,000 individuals met criteria for heroin abuse or dependence Combined, 2 million opioid dependent in U.S. –In 2005 only 331,000 individuals entered treatment for opioid dependence

5 Prescription of Opioids Between 1994 & 2003, prescriptions for: –Non-controlled drugs increased by 57% –Controlled substances increased by 154%. Trescot et al. Pain Physician, 2008; 11: S5-62.

6 0.1 0.2 0.6 0.7 0.6 2.0 6.2 14.6 0 0 1 1 3 3 5 5 7 7 9 9 11 13 15 LSD Heroin Inhalants Meth Ecstasy Crack Cocaine Prescription Drugs Marijuana (incl. crack) Past Month Users, Ages 12 and Older (in Millions) Source: SAMHSA, 2002 National Survey on Drug Use and Health. Nonmedical Use of Prescription Drugs Nonmedical Use of Prescription Drugs


8 Annual sales of prescription opioids and unintentional overdose death 1990 - 2006 Source: Paulozzi, CDC, Congressional testimony, 2007

9 Brains Reward pathways


11 Changes in Neurobiology Repeated exposure to short acting opioids leads to neuronal adaptations –Mesolimbic dopaminergic system adaptations in G protein-coupled receptors up regulation of cyclic cAMP second messenger pathway changes in transcription and translation Adaptations –Mediate tolerance, withdrawal, craving, self-adminstration –Provide insight into the chronic and relapsing nature of opioid dependence –Form basis of pharmacotherapies to stabilize neuronal circuits

12 Opioid Treatment

13 Pharmacologic Treatment of Opioid Dependence Pharmacologic withdrawal - detoxification Opioid antagonist treatment –Naltrexone Opioid agonist treatment –Methadone –Buprenorphine

14 Poor results with detoxification Kakko, Lancet 2003 Treatment duration (days) Remaining in treatment (nr) 0 5 10 15 20 050100150200250300350 Detoxification Maintenance

15 Opioid Agonist Treatment Rationale –Cross-tolerance prevent withdrawal relieve craving for opioids –Narcotic blockade block or attenuate euphoric effect of exogenous opioids

16 How effective is opioid agonist treatment?

17 Buprenorphine, Methadone, LAAM: Treatment Retention Percent Retained 0 20 40 60 80 100 1234567891011121314151617 20% Lo Meth 58% Bup 73% Hi Meth 53% LAAM Study Week




21 HIV Seroconversion Metzger, 1993: –2 cohorts of patients 103 out-of-treatment intravenous opiate users 152 subjects receiving methadone treatment –HIV antibody conversion, 18-months 22% of those out-of-treatment 3.5% of those receiving methadone treatment

22 Treatment vs. Addiction MarkedAbsent Euphoria 3-6 hours24-36 hours Duration Immediate30 minutes Onset IV, IN Oral, sublingual Route Heroin Methadone or buprenorphine

23 Buprenorphine Partial agonist at mu receptor Low abuse and diversion potential, especially when combined with naloxone Can be prescribed from the office by a physician Sub-lingual tablet Daily or thrice weekly dosing

24 -10-9-8-7-6-5-4-4 0 10 20 30 40 50 60 70 80 90 100 Intrinsic Activity Log Dose of Opioid Full Agonist (Methadone, oxycodone) Partial Agonist (Buprenorphine) Antagonist (Naltrexone) Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone)

25 Bup 00 mg Bup 02 mg Bup 16 mg Bup 32 mg 0 - 4 - MRI Binding Potential (Bmax/Kd) Effects of Buprenorphine Dose on µ-Opioid Receptor Availability in a Representative Subject

26 Federal Efforts to Increase Access Fiellin and OConnor, NEJM 2002 Congress (2000) Drug Addiction Treatment Act Allows qualifying physicians to use approved schedule III-V medications Qualifying physician either certified in Addiction Medicine/Psychiatry or complete 8 hour training FDA and DEA (2002) Approves buprenorphine and buprenorphine/naloxone for treatment of opioid dependence, schedule III

27 How effective is office-based buprenorphine treatment?

28 Self-Reported Frequency of Illicit Opioid Use in Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care Fiellin D et al. N Engl J Med 2006;355:365-374

29 Retention among Opioid-Dependent Patients Receiving Buprenorphine- Naloxone in Primary Care Fiellin D et al. N Engl J Med 2006;355:365-374

30 6 Weeks of Opioid Abstinence Moore, JGIM, 2007

31 66 Physicians and 31 Treatment Programs listed in Minnesota

32 Trained, Registered and Prescribing Physicians U.S. January 2009 8295

33 Alcohol Treatment

34 Patterns of Alcohol Use: Epidemiology

35 Terminology For Alcohol Use Behaviors

36 What is a drink? 14 grams of alcohol –12 ounces of beer –5 ounces of wine –1.5 ounces of distilled spirits

37 Alcohol Treatment Pharmacotherapy

38 Disulfiram Ethanol AcetaldehydeAcetate ADH ALDH Build up of acetaldehyde causes: -Flushing -Headache -Nausea -Dizziness -Palpitations

39 Disulfiram Efficacy In a large double-blinded study, disulfiram was no better than placebo in helping patients remain abstinent A subset of relapsed patients, who were older and more socially stable, drank less frequently when given disulfiram Greater efficacy has been shown with supervised disulfiram administration Fuller PK, et al. JAMA 1986;256:1449-55

40 Prescribing Disulfiram Start at 250mg daily and titrate to 500mg daily Contraindications: –Recent alcohol use –Pregnancy –Cognitive impairment Side effects: –Hepatotoxicity –Neuropathy

41 Naltrexone 1. Mechanism of Action: opioid receptor blockade 2. Effects: decreased craving and alcohol consumption 3. Dose: 50 mg/day 4. Side Effects: nausea (10%), headache 5. Contraindications: opioid dependence severe liver disease

42 Combined Analysis of Yale and U Penn Studies of Naltrexone 12 week, double-blind, placebo controlled Concurrent Psychotherapy: – Once weekly individual therapy (Yale) – Day Hospital (1 month), twice weekly group (2 months) (U Penn) Abstinence rates: Naltrexone:54% Placebo: 31% ------------- OMalley et al., Psychiatric Annals 1995;25:681-88.

43 Naltrexone: Efficacy Meta-analysis of 14 studies* –Relapse to heavy drinking Naltrexone 428/1142 (37%), control 445/930 (48%) –Odds ratio for relapse 0.62 (95% CI 0.52,0.75) COMBINE Study (Naltrexone X 16 w, n=302) –Increased abstinence over placebo (81% vs. 75%) –Reduced risk of a heavy drinking day (HR 0.72, p<0.02) *Carmen B, Addiction 2004; Anton RF, JAMA, 2004

44 Prescribing Naltrexone 25 to 50 mg daily taken after a meal for at least 3-4 months Depot form available doses studied 190-380 mg –25% reduction in heavy drinking days Contraindications: –Opioid use –Pregnancy Side Effects: –Nausea Garbutt JC, JAMA, 2005, Anton R, NEJM, 2008

45 Anton, R. F. et al. JAMA 2006;295:2003-2017. Project Combine: Design

46 Copyright restrictions may apply. Anton, R. F. et al. JAMA 2006;295:2003-2017. Project Combine: Effect Size Estimates and Hazard Ratios for Primary Outcomes

47 Garbutt, J. C. et al. JAMA 2005;293:1617-1625. Injectable Naltrexone: Mean Heavy Drinking Event Rate

48 Acamprosate Alcohol is an agonist at the inhibitory GABA receptors and antagonist at excitatory glutamate receptors Acamprosate modulates alcohol effects: –GABA-analogue –Modulates action at NMDA receptor

49 Acamprosate: Efficacy Meta-analysis of 7 placebo controlled trials* –Acamprosate (n=1195), placebo (n=1027) –Proportion of patients continually abstinent at one year 23% for acamprosate group, 15% for placebo group COMBINE study (Acamprosate arm, n=300) –No significant effect on drinking over placebo *Carmen B, Addiction 2004; Anton, RF, JAMA 2004

50 Prescribing Acamprosate 666 mg po TID; start after a period of abstinence Contraindications –CrCl < 30 cc/min –Pregnancy Side effects –Diarrhea

51 Topiramate Reduces corticomesolimbic dopamine release –Agonist at GABA –Antagonist at glutamate Not FDA approved

52 Topiramate: Efficacy N=371, double blind randomized placebo controlled trial Intention-to-treat analysis TopiramatePlacebop Reduction in number of heavy drinking days 44%52%0.002 Increase in abstinence days (baseline wk 14) 10% to 38%9% to 29%0.002 Johnson BA, JAMA 2007

53 Summary Opioid and alcohol problems are common Effective therapies for opioid dependence and alcohol use disorders exist Office-based treatment of addictive disorders may help increase access to treatment and decrease stigma

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