Presentation on theme: "Pharmacological Treatment of Addiction"— Presentation transcript:
1 Pharmacological Treatment of Addiction David A. Fiellin, M.D.Professor of MedicineYale University School of Medicine
2 Overview Epidemiology of opioid dependence Treatment of opioid dependenceBuprenoprhineOffice-based treatmentEpidemiology of alcohol problemsTreatment of alcohol problemsNaltrexone, acamprosate, disulfiram
3 Opioid Dependence (DSM-IV, 3 or more within one year) Physical DependenceToleranceWithdrawalLoss of control (addiction)Larger amounts/longer period than intendedInability to/persistent desire to cut down or controlIncreased amount of time spent in activities necessary to obtain opioidsSocial, occupational and recreational activities given up or reducedOpioid use is continued despite adverse consequences
4 Epidemiology Prescription opioids Heroin National Survey on Drug Use and Health, 2006> 12 million reported non-medical use of prescription opioidsEstimated 1.6 million met criteria for prescription opioid abuse or dependenceHeroinNational Household Survey on Drug Abuse, 2006> 500,000 reported past year heroin useApproximately 323,000 individuals met criteria for heroin abuse or dependenceCombined, 2 million opioid dependent in U.S.In 2005 only 331,000 individuals entered treatment for opioid dependence4
5 Prescription of Opioids Between 1994 & 2003, prescriptions for:Non-controlled drugs increased by 57%Controlled substances increased by 154%.With increased attention to the treatment of pain, there has been a significant increase in perscriptions.Between 1994 and 2003, prescriptions for noncontrolled drugs increased by 57%, while prescriptions for controlled substances increased by 154%.Data from the DEA presented on this graph demonstrates grams of therapeutic opioid use in the United States per 100,000 people between 1997 and Notable that all show dramatic increase in use; oxycodone with less than 3000 grams/100,000 to more than 12,000 over this time period.Trescot et al. Pain Physician, 2008; 11: S5-62.5
6 Nonmedical Use of Prescription Drugs Past Month Users, Ages 12 and Older (in Millions)Marijuana14.6Prescription Drugs6.2Cocaine2.0(incl. crack)Crack0.6Ecstasy0.7Meth0.6Inhalants0.6Heroin0.2LSD0.113579111315Source: SAMHSA, 2002 National Survey on Drug Use and Health.
8 Annual sales of prescription opioids and unintentional overdose death 1990 - 2006 Sources: unintentional drug poisoning mortality is from the National Vital Statistics System.. The drug poisoning mortality category is defined by E850-E858 in 1990 through 1998 and by X40-X44 in 1999 through The rate for 2005 is estimated as 95% of the unintentional poisoning death rate.Total sales are from DEA ARCOS. Opioid sales are in total morphine equivalents for all major opioids combined except codeine. The conversions are the same as those used in Paulozzi and Budnitz, Pharmacoepidemiology and Drug Safety, Sales data for 2006 is estimated from the first 3 quarters of 2006.Source: Paulozzi, CDC, Congressional testimony, 20078
9 Brain’s Reward pathways The ubiquity of the mu opioid receptor in the central nervous system has a double-edged sword if you will because opioids agonists are not only potent analgesics but because of the mu receptor’s presence in the midbrain, opioids are very effective and efficient stimulators of reward pathways. What do I mean by reward pathways? Typically, endogenous opioids are released when we engage in pleasurable activities and these endogenous opioids stimulate the production of dopamine in the so-called reward center of the midbrain. Dopaminergic neurons project to the cortex to stimulate repeated behavior and then recurrent pleasurable feelings that the brain perceives as linked to and caused by the original activity. In the case of opioid analgesics, these medications directly agonize the mu receptors that cause the dopamine release that project to the cortex. So, the pleasurable activity that the brain begins to crave is taking the medication itself and this is how addiction arises. The seeking of and taking of opioids supercedes virtually every other activity for the patient including even eating. Now to be clear I am in no way saying that addiction is an inevitable consequence of opioid-taking. In fact, we know that it is a small minority of patients, probably with a genetic susceptibility related to mu receptor polymorphisms and other genetic variability that contributes to the risk of addiction.
11 Changes in Neurobiology Repeated exposure to short acting opioids leads to neuronal adaptationsMesolimbic dopaminergic systemadaptations in G protein-coupled receptorsup regulation of cyclic cAMP second messenger pathwaychanges in transcription and translationAdaptationsMediate tolerance, withdrawal, craving, self-adminstrationProvide insight into the chronic and relapsing nature of opioid dependenceForm basis of pharmacotherapies to stabilize neuronal circuits
21 HIV Seroconversion Metzger, 1993: 2 cohorts of patients 103 out-of-treatment intravenous opiate users152 subjects receiving methadone treatmentHIV antibody conversion, 18-months22% of those out-of-treatment3.5% of those receiving methadone treatment
22 Treatment vs. Addiction MarkedAbsentEuphoria3-6 hours24-36 hoursDurationImmediate30 minutesOnsetIV, INOral, sublingualRouteHeroinMethadone or buprenorphine
23 Buprenorphine Partial agonist at mu receptor Low abuse and diversion potential, especially when combined with naloxoneCan be prescribed from the office by a physicianSub-lingual tabletDaily or thrice weekly dosing
24 Intrinsic Activity: Full Agonist (Methadone), Partial Agonist (Buprenorphine), Antagonist (Naloxone) 10090Full Agonist(Methadone, oxycodone)8070Intrinsic Activity60Partial Agonist50(Buprenorphine)40302010Antagonist (Naltrexone)-10-9-8-7-6-5-4Log Dose of Opioid
25 Effects of Buprenorphine Dose on µ-Opioid Receptor Availability in a Representative Subject MRIBup 00 mgBindingPotential(Bmax/Kd)Bup 02 mg4 -Bup 16 mgBup 32 mg0 -
26 Federal Efforts to Increase Access Fiellin and O’Connor, NEJM 2002 Congress (2000)Drug Addiction Treatment ActAllows qualifying physicians to use approved schedule III-V medicationsQualifying physician either certified in Addiction Medicine/Psychiatry or complete 8 hour trainingFDA 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 CareFiellin D et al. N Engl J Med 2006;355:
29 Retention among Opioid-Dependent Patients Receiving Buprenorphine-Naloxone in Primary Care Fiellin D et al. N Engl J Med 2006;355:
38 Disulfiram Disulfiram ADH ALDH Ethanol Acetaldehyde Acetate Build up of acetaldehyde causes:-Flushing-Headache-Nausea-Dizziness-PalpitationsAn old standby for alcoholism treatment since the 1940s has been disulfiram, an inhibitor of aldehyde dehydrogenase, ALDH, that results in increased levels of acetaldehyde and an unpleasant reaction after consumption of ethanol. In one of the largest studies of this medication, disulfiram was no better than placebo in achieving abstinence. But it is not clear that a placebo controlled trial is the best way to test a drug whose efficacy depends on the patient knowing that they may experience a very unpleasant reaction. Of note, in post hoc analyses, the drug was more effective in those who were adherent to it.In controlled studies, 4 trials (conducted in the 1970s and early 1980s) have shown significantly improved abstinence rates when disulfiram is taken under direct monitoring by a concerned other.
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 administrationFuller PK, et al. JAMA 1986;256:
40 Prescribing Disulfiram Start at 250mg daily and titrate to 500mg dailyContraindications:Recent alcohol usePregnancyCognitive impairmentSide effects:HepatotoxicityNeuropathyOf all of the approved, efficacious medications, disulfiram may be the most difficult to use since it is an aversive therapy that works best when its administration is monitored.Disulfiram should be started at 250 mg a day, up to a dose of 500 mg. The drug can be used daily or just prior to risky situations, and it lasts 4-7, and up to 14 days. Tell the monitor and the patient they are to take the medication as prescribed. The monitor should observe the patient as he or she takes the pill and call you if the patient is non-adherent.The main contraindications are recent alcohol use, pregnancy, rubber, nickel cobalt allergy, cognitive impairment (since awareness of the risk of the reaction is essential), and as a relative contraindication, conditions that would increase the risk of harm from the disulfiram ethanol reaction, for example, coronary artery disease, esophageal varices. Disulfiram also has numerous drug interactions, including warfarin and anticonvulsants. The main side effect is an idiosyncratic sometimes fulminant hepatitis, and neuropathy seen at higher doses. Regular monitoring of liver enzymes is advised, as is a clear recommendation to avoid alcohol even in over-the-counter medications.
41 Naltrexone 1. Mechanism of Action: opioid receptor blockade 2. Effects: decreased craving and alcohol consumption3. Dose: 50 mg/day4. Side Effects: nausea (10%), headache5. Contraindications: opioid dependencesevere 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 weeklygroup (2 months) (U Penn)• Abstinence rates: Naltrexone: 54% Placebo: %O’Malley et al., Psychiatric Annals 1995;25:
43 Naltrexone: Efficacy Meta-analysis of 14 studies* Relapse to heavy drinkingNaltrexone 428/1142 (37%), control 445/930 (48%)Odds ratio for relapse0.62 (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)This meta-analysis included 14 clinical trials, in which relapse was decreased significantly, from 48% to 37%. The odds ratio favored naltrexone, 0.62, suggesting a 38% decrease in heavy drinking. In one study, patients were not abstinent before beginning naltrexone. In another study, the drug was effective in a primary care setting. In a third study, naltrexone was effective for reducing heavy drinking in nondependent heavy drinkers. In a fourth study, the combination of naltrexone and acamprosate was as safe and more effective than either alone.COMBINE study 1383 participants from 11 academic sites with EtOH dependence and at least 4 days of abstinenceNaltrexone only arm vs. placebo 302*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 monthsDepot form available doses studied mg25% reduction in heavy drinking daysContraindications:Opioid usePregnancySide Effects:NauseaNaltrexone can be started at 12.5 or 25 mg a day and advanced to 50 mg a day. Its main contraindication is opiate dependence or need for opioids. The main side effects are nausea and dizziness, which can be avoided by starting at a low dose and increasing it to the therapeutic dose of 50 mg per day over time as tolerated, usually after a few days. Liver enzymes should be monitored because of hepatitis seen at much higher than the doses recommended for alcoholism (for example, >300 mg a day). The main difficulty with the use of naltrexone is that it can complicate pain management, leading to a need to give very high dose opioids in the event of acute pain, or stopping and restarting therapy perioperatively.DEPOT:Naltrexone has modest efficacy for treating alcohol dependence. So why focus ona single clinical trial of naltrexone? This trial was well done: it employed advancedstatistical techniques and had excellent external validity, enrolling 70% of the eligiblepopulation and not requiring abstinence for study entry. The study found efficacy fora novel injectable preparation that may have adherence advantages over oral tablets.How do we interpret the results? The higher dose of extended-release naltrexonecombined with psychosocial therapy was associated with a 25% greater decrease inheavy drinking than was the combination of placebo and psychosocial therapy. Althoughthe relative effects are of interest, absolute numbers (as displayed in Figure 3 of theoriginal article, for example) are of greater interest. This figure suggests (by roughinspection) that after treatment, the 380-mg naltrexone group drank heavily on a medianof about 3 days per month compared with about 6 days per month for the placebo group.In a subgroup analysis, naltrexone had a more impressive effect in those with a weekof abstinence prior to study entry—the 190-mg and 380-mg subgroups, however, hadonly 17 patients each. In another subgroup analysis, the drug had efficacy in men butnot women. Subgroup analyses such as these should be interpreted with caution. Mytake is that extended-release naltrexone has efficacy, but that future research with thisdrug should address improving outcomes in women and in those who do not initiallyestablish abstinence.A more significant consideration is whether the drinking decreases were clinicallyimportant. Clearly, on each additional heavy drinking day, people are at risk for acuteadverse consequences, and over time, the more heavy drinking days, the more negativehealth consequences. So the effects are likely meaningful, though trials that look athealth outcomes beyond surrogate measures (consumption) would certainly be welcome.Unlike most other chronic diseases, alcohol dependence is characterized by loss ofcontrol and impaired motivation, which make adherence to treatment particularlydifficult. Does the new injectable preparation represent an advance over oral naltrexone?A monthly injection might be easier to adhere to than a daily pill, but this is not yetknown to be the case in alcohol dependence. Many people may prefer pills to avoidinjections and/or the office visits to receive them. And it will be a challenge for thehealthcare system to get these injections to where people with alcohol dependencecan receive them from qualified personnel. So the adherence advantages remain to beseen. The niche for injectable extended-release naltrexone also remains to be seen. Itwill likely make sense for those who prefer it or find it easier to adhere to. But for mostpeople with alcohol dependence, the key issue is not which preparation of a medicationthey choose. The issue for them is getting as many known efficacious therapies aspossible: pharmacotherapy (eg, naltrexone or acamprosate), psychosocial therapyincluding support for treatment adherence, and mutual help.BRENDA (Biopsychosocial, Report, Empathy, Needs, Direct advice, andAssessment)Garbutt JC, JAMA, 2005, Anton R, NEJM, 2008
45 Project Combine: Design Anton, R. F. et al. JAMA 2006;295:
46 Project Combine: Effect Size Estimates and Hazard Ratios for Primary Outcomes Anton, R. F. et al. JAMA 2006;295:Copyright restrictions may apply.
47 Injectable Naltrexone: Mean Heavy Drinking Event Rate Garbutt, J. C. et al. JAMA 2005;293:
48 AcamprosateAlcohol is an agonist at the inhibitory GABA receptors and antagonist at excitatory glutamate receptorsAcamprosate modulates alcohol effects:GABA-analogueModulates 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 groupCOMBINE study† (Acamprosate arm, n=300)No significant effect on drinking over placeboCOMBINE study 1383 participants from 11 academic sites with EtOH dependence and at least 4 days of abstinenceWhy was combine not positive for acamprosate?Required only 4 days abstinence while other trials required longer pretreatment abstinence*Carmen B, Addiction 2004; †Anton, RF, JAMA 2004
50 Prescribing Acamprosate 666 mg po TID; start after a period of abstinenceContraindicationsCrCl < 30 cc/minPregnancySide effectsDiarrheaAcamprosate is dosed three times a day, 666 mg. The main issue with Acamprosate is that it is contraindicated in renal insufficiency (Cr CL <30 ml/min, half dose for ml/min) and its main side effect is diarrhea. Acamprosate and all other alcohol dependence pharmacotherapies are pregnancy category C, meaning that there are no controlled studies in pregnant women, and that they should be prescribed during pregnancy only if clearly needed and the benefits are likely to outweigh the risks.
51 Topiramate Reduces corticomesolimbic dopamine release Not FDA approved Agonist at GABAAntagonist at glutamateNot FDA approved
52 Topiramate: EfficacyN=371, double blind randomized placebo controlled trialIntention-to-treat analysisTopiramatePlacebopReduction in number of heavy drinking days44%52%0.002Increase in abstinence days (baselinewk 14)10% to 38%9% to 29%Johnson BA, JAMA 2007
53 Summary Opioid and alcohol problems are common Effective therapies for opioid dependence and alcohol use disorders existOffice-based treatment of addictive disorders may help increase access to treatment and decrease stigma