7 The Lexington Narcotic Farm The first facility opened on May 25, 1935, outside Lexington, Ky. The 1,050-acre site included a farm and dairy, working on which was considered therapeutic for patients.With the increased availability of state and local drug abuse treatment programs, the hospital was closed in February 1974.Drs. Kolb, Himmelsbach, Wikler, Jaffe, Kleber, Vaillant
9 JAMA Classics: Celebrating 125 Years Methadone Maintenance 4 Decades Later Thousands of Lives Saved But Still ControversialCommentary by Herbert D. Kleber, MD JAMA. 2008;300(19):JAMA. 1965;193(8):
10 Exclusion: non-opioid addiction/misuse, severe psychiatric problems
11 Opiate Addiction Treatment Outcome* Methadone Maintenance – 80%Naltrexone Maintenance – 20%“Drug Free” (non-pharmacotherapeutic) 5 – 30%LAAM Maintenance – 80%Buprenorphine-Naloxone Maintenance %**Short-term Detoxification (any mode) – 20% (limited data)* One year retention in treatment and/or follow-up with significant reduction or elimination of illicit use of opiates** Maximum effective dose (24mgsl) equal to 60 to 70 mg/d methadone. Data base on 6 month follow-up only.Kreek, 1996; 2001
12 Methadone Synthetic Opioid 1937 Germany T ½ 24—36 hrs. Inherent Onset of Action 30 min. Peak 3-4 hrs.R/S(l/d) racemic mixture mu/NMDA antagCYP3A4, 2D6 Drug/Drug No Active MetabRenal and biliary excretionDosing QD for addiction, Q6H for Pain
13 Functional State (Heroin) Functional State (Methadone) Impact of Short-Acting Heroin versus Long-Acting Methadone Administered on a Chronic Basis in Humans Study"High"Functional State (Heroin)(overdose)"Straight""Sick"AMPMAMPMAMDays"High"Functional State (Methadone)"Straight""Sick"AMPMAMHPMAMDaysDole, Nyswander and Kreek, 1966
16 Molecular and Cellular Basis of Addiction Science 3 October 1997:Eric J. Nestler,George K. AghajanianFigure 2. Scheme illustrating opiate actions in the locus coeruleus. Opiates acutely inhibit locus coeruleus neurons by increasing the conductance of an inwardly rectifying K+ channel through coupling with subtypes of Gi/o, as well as by decreasing a Na+-dependent inward current through coupling with Gi/o and the consequent inhibition of adenylyl cyclase. Reduced concentrations of cAMP decrease PKA activity and the phosphorylation of the responsible channel or pump. Inhibition of the cAMP pathway also decreases phosphorylation of numerous other proteins and thereby affects many additional processes in the neuron. For example, it reduces the phosphorylation state of CREB, which may initiate some of the longer-term changes in locus coeruleus function. Upward bold arrows summarize effects of chronic morphine administration in the locus coeruleus. Chronic morphine increases concentrations of types I and VIII adenylyl cyclase (AC I and VIII), PKA catalytic (C) and regulatory type II (RII) subunits, and several phosphoproteins, including CREB. These changes contribute to the altered phenotype of the drug-addicted state. For example, the intrinsic excitability of locus coeruleus neurons is increased by enhanced activity of the cAMP pathway and Na+-dependent inward current, which contributes to the tolerance, dependence, and withdrawal exhibited by these neurons. Up-regulation of type VIII adenylyl cyclase is mediated by CREB, whereas up-regulation of type I adenylyl cyclase and of the PKA subunits appears to occur by means of a CREB-independent mechanism not yet identified.
17 39wk137wk39 wkCerebral phosphorus metabolite abnormalities in opiate-dependent polydrug abusers in methadone maintenancePsychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999, PagesKaufman,MPhosphorous MR SpectroscopyFig. 3. Metabolite levels in control subjects (n=16) and in short- (n=7) and long-term (n=8) methadone maintenance treatment (MMT) subgroups. Shown are means±S.D. of percent metabolite measures. Post hoc Scheffé test results: *P<0.05 vs. control subjects; **P<0.01 vs. control subjects; ***P< vs. control subjects ;†P<0.05 vs. long-term MMT group
18 From these data, we conclude that polydrug abusers in MMT have 31P-MRS results consistent with abnormal brain metabolism and phospholipid balance. The nearly normal metabolite profile in long-term MMT subjects suggests that prolonged MMT may be associated with improved neurochemistry.Psychiatry Research: Neuroimaging Volume 90, Issue 3 , 30 June 1999, Pages
19 Distribution of Opioid Treatment Programs (OTPs) 2002SAMHSA/CSAT
20 581 Male Heroin Addicts Followed for 33yrs The natural history of narcotics addiction among a male sample (N = 581).From: Yih-Ing, et. al., A 33-Year Follow-up of Narcotics Addicts. Archives of General Psychiatry, 58: )
23 Medical Maintenance Admission Criteria At least 4 years in MMTPNegative urines for last 3 yearsWorking/School etc.Adequate income for feesRecommendation from clinicNot in military reservesStable and safe storage environment
24 Medical Maintenance Procedures Patient given 28 day supply of methadone, by MD,in disket form, every 4 weeks.Medication prepared by hospital pharmacy in usual Rx type bottle and labelRoutine urine toxicologiesPatient returns before “run out” datePrimary care provided
25 Methadone Maintenance Total duration in years N = 233 patients 4/05Duration in years
26 Medical Maintenance Total Duration in Years N= 233 patients 4/05Duration in years
27 Medical Maintenance--Dosage Average = 75mg./dayMedian = 80mg./dayRange = 5mg mg./day30% Split Dose04/ N=223
30 Prevalence of HIV-1 (AIDS Virus) Infection in Intravenous Drug Users New York City: Study: Protective Effect of Methadone Maintenance Treatment50 – 60% Untreated, street heroin addicts:Positive for HIV-1 antibody9% Methadone maintained since<1978(beginning of AIDS epidemic):less than 10% positive for HIV-1 antibodyKreek , 1984; Des Jarlais et al., 1984; 1989
33 STIGMA--METHADONE“My Wife’s Opinion Is That Methadone Maintenance Treatment Is As Close To Evil As You Can Get, Without Killing Someone.”A “successful” methadone patient quoting his wife’s attitudetoward methadone treatment
34 U.S. Drug Enforcement Administrative Agent Joanne Masur, one of the last government witnesses in the case against Shinderman, took the stand Friday in U.S. District Court in Portland. Masur, whose job is preventing the diversion of prescription drugs to the black market, said she consulted with Shinderman on at least two occasions. But she said she had no bias against him or his clients, although she said she may have referred to them as "dirt bags." "That is a term I use," she said. "But it's not necessarily derogatory."Portland Press Herald, 7/15/06
35 Crane collapses in busy New York street, killing seven in worst construction accident in recent memory'
36 SUBSTITUTION TREATMENT SUBSTITUTION TREATMENT ??????? Helpful/Harmful “Substituting one addiction for another”
37 3/19/08Critics say methadone simply replaces one dependency with another, and some say methadone can be even harder to quit than heroin.Scottish Conservative Party justice spokesman, Bill Aitken, recently described many of those in methadone programmes in Scotland as “sitting fat, dumb and happy" on the drug.
38 Percent Change in Distribution of Methadone and Three Comparison Drugs, 1998--2002 Percent Change from Baseline Year 1998This slide illustrates the recent increase in distribution of methadone. MMT programs for addiction and pain therapy are the two uses of methadone. Distribution of methadone through MMT programs remained relatively flat during this period suggesting the increase in distribution was primarily for analgesia.Center for Substance Abuse Treatment, Methadone-Associated Mortality: Report of a National Assessment, May 8-9, SAMHSA Publication No Rockville, MD: Center for Substance Abuse Treatment, SAMHSA, 2004.
40 Methadone Deaths Not Linked to Misuse of Methadone from Treatment Centers The consensus report, “Methadone-Associated Mortality, Report of a National Assessment”, concludes that “although the data remain incomplete, National Assessment meeting participants concurred that methadone tablets and/or diskettes distributed through channels other than opioid treatment programs most likely are the central factor in methadone-associated mortality.”The panel based it conclusion that methadone is coming from other sources on data showing that the greatest growth in methadone distribution in recent years is associated with its use as a prescription analgesic prescribed for pain, primarily in solid tablet or diskette form, and not in the liquid formulations that are the mainstay of opioid treatment programs that treat patients with methadone for abuse of heroin or prescription pain killers.The experts surmise that current reports of methadone deaths involve one of three scenarios: illicitly obtained methadone used in excessive or repetitive doses in an attempt to achieve euphoric effects; methadone, either licitly or illicitly obtained, used in combination with other prescription medications, such as benzodiazepines (anti-anxiety medications), alcohol or other opioids; or an accumulation of methadone to harmful serum levels in the first few days of treatment for addiction or pain, before tolerance is developedSAMHSA--2004
42 Survival Function by Treatment Group Sees, K. L. et al. JAMA 2000;283:Copyright restrictions may apply.
43 Proportion of Participants Using Heroin and Mean Days of Heroin Use in Previous 30 Days Sees, K. L. et al. JAMA 2000;283:Copyright restrictions may apply.
44 Buprenorphine Maintenance/Withdrawal: Retention 2015Remaining in treatment (nr)101. This figure shows treatment retention, which was significantly better for the maintenance (buprenorphine) vs. control (withdrawal followed by placebo) group. All placebo patients who dropped out did so following relapse to drug use (as determined by urine testing). In the maintenance group, one patient dropped out of treatment, and four were discharged due to relapse in their drug use.2. Urine results showed that 74.8% of samples were negative for drugs in the buprenorphine maintenance group over the course of the year.5ControlBuprenorphine50100150200250300350Treatment duration (days)(Kakko et al., 2003)
45 Kakko et al, Lancet Feb 22, 2003Buprenorphine Maintenance/Withdrawal: MortalityPlaceboBuprenorphineCox regressionDead4/20 (20%)0/20 (0%)2=5.9; p=0.0151. While not the primary goal of the study, the study noted that four of the patients who underwent a withdrawal (which was inpatient, and lasted six days) had died after one year -- compared to none of the patients in the buprenorphine maintenance group.
46 Transitioning Stable Methadone Maintenance Patients to Buprenorphine Maintenance Edwin A. Salsitz, M.D., FASAMBeth Israel Medical CenterNew York City46
47 Why Transition From Methadone? Office-based availabilityLess than monthly visitsDifferent side effect profilePossible diminished stigmaGeographic Flexibility
48 Why Not Transition? May not be as effective for individual Fear of destabilizationTransition difficultOpioid withdrawal requiredMay precipitate withdrawalLess social and psychological servicesInsurance/costSatisfied with methadone“If it Ain’t Broke….”
49 Subjects MMM eligibility requirements 4 years in Methadone Maintenance Treatment Program (MMTP)3 years of illicit drug abstinenceNo excessive drinkingEmployment/Education, etc.Emotional stability6/03 - 1/08 patients on methadone ≤ 80 mg/day offered transition to buprenorphineJohnson RE, Chutuape MA, et al. A comparison of levomethadyl acetate, buprenorphine, and methadone for opioid dependence. N Engl J Med. 2000;343:1290–1297.49
50 Transfer Patients given option to taper methadone to 30-40 mg/day Standard protocol usedPatients abstained from methadone for hoursFirst buprenorphine/naloxone dose given when Clinical Opiate Withdrawal Scale (COWS) score indicated withdrawalStabilized over following weekCenter for Substance Abuse Treatment. Clinical guidelines for the use of buprenorphine in the treatment of opioid addiction. Treatment Improvement Protocol Series (TIPS) 40. Department of Health and Human Services Publication #SMA Rockville, MD: Substance Abuse and Mental Health Services Administration, 2004.50
51 Study Participants 102 MMM patients offered buprenorphine 23 (22.5%) acceptedTwo stable MMTP patients referred104 patients total-25 (24.0%) acceptedReasons for not wanting to switchno perceived advantage of switchingconcern about efficacyconcern about side effects (withdrawal)
52 Outcomes25/25 patients successfully stabilized on buprenorphine (100%)Average buprenorphine dose mg (S.D. 7.6)Average time on buprenorphine maintenance months (S.D. 16.5)
53 Methadone Dose Compared to Buprenorphine Dose 40353025Final buprenorphine dose mg/day2015105102030405060708090Baseline methadone dose mg/dayLow-moderate correlation - Spearman rank order coefficient = 0.46, p = 0.0253
54 Positive ExperiencesNo stabilized subjects elected to return to methadoneLess frequent office visitsevery months, not monthlyseveral patients moved further away from program24/25 patients reported feeling “clearer”
55 Unsuccessful Transfers 5 initially reluctant patients agreed to attempt conversionAll unsuccessfulDuration of buprenorphine treatment - 1 dose to 5 daysReturned to methadone without event2 cases - “dysphoria”3 cases – no reason listed55
56 Study Strengths Subjects Unique population in researchFindings applicable to stable methadone maintained patients seeking transfer to BuprenorphineVery long follow-up period - absence of negative outcomes56
57 CONCLUSIONSBuprenorphine is viable maintenance treatment for stable patients on methadone doses up to 80 mg/dayTransitioning generally well toleratedBuprenorphine efficacious and safe long-termLow to moderate association between methadone and buprenorphine doses
62 Russia Scorns Methadone for Heroin Addiction Science Times 7-22-08, Michael Schwartz After the conference in February, which Dr. Mendelevich helped organize, Moscow’s legislature began an inquiry into whether he had engaged in “drug propaganda,” and it called on prosecutors to open a case against him, he saidAt the same AIDS conference, Dr. Gennady G. Onishchenko, the country’s chief sanitary doctor, the equivalent of surgeon general, said health officials “are not convinced that this is effective,” and added, “There is little optimism for legalizing methadone therapy in the near future.”“Scientific arguments, evidence-based data, are not convincing them,” said Evgeny M. Krupitsky, the head of a laboratory that conducts research on drug addiction at St. Petersburg State Pavlov Medical University. Russian methodology regarding opiate addiction “is not evidence-based,” but relies on “subjective opinions of major leaders in this field.
63 DRUG PROBLEM Patients in a program for heroin addiction in Yekaterinburg, Russia, run by a nongovernmental group.