Opioid Maintenance: Terminable or Interminable; Implications for Theory, Treatment and Policy Herbert D. Kleber, M.D. Professor of Psychiatry Director, Division on Substance Abuse Columbia University/NYSPI European and International Colloquium on Drug Addiction, Hepatitis and AIDS Biarritz, France 12 October, 2011
Whether individuals successfully maintained on Methadone can eventually be withdrawn and lead socially satisfactory and opiate free lives is a matter still not settled and open to vigorous debate. It is of course part of a larger issue, namely whether individuals dependent upon any opiate be it heroin or methadone can remain drug free and why or why not. Kleber HD, International J. Addiction, 1977
Early U.S. History 1900-1964 (Con t) At beginning of 20 th Century, opiate withdrawal considered adequate for treatment of narcotic addiction Patients who relapsed did it from choice not necessitythus, moral degenerates Frequency of relapse led cities to set up narcotic clinics to legally provide heroin or morphine to addicts But short acting opiates required either multiple visits to clinic or take-home Deemed failures because did not lead to abstinence, & diversion occurred By 1923, all clinics were closed
Early History 1900-1964 (Con t) 1914 Harrison Act interpreted as prohibiting maintenance of active addicts. Between 1919-1935, approximately 25,000 physicians indicted under the Harrison Act & 10% went to prison Physicians stop treating addicts for next 4 decades Treatment scarce, relapse common, prison frequent
Natural History 20 year follow-ups Vaillant 1973 Terms huezen 2005 Patients -100 NYC narcotics addicts 899 Amsterdam narcotics Admitted to Lexington 1962 addicts followed 1985-2002 Followed For 20 yrs recruited from low threshold MM Deaths 23% - mostly of unnatural causes 27% died within 20 yrs after starting regular drug use, half from HIV related causes Abstinence- 35-42% stable abstinence 27% abstinent from drugs + methadone Using 25% known to be using Unknown 10%
Methadone Maintenance 1964-2000 Dole & Nyswander begin methadone maintenance,1964, at Rockefeller Institute; with assistance of Kreek Federal agencies look for excuses to shut it but Methadone Maintenance Treatment (MMT) expands 1968 Yale, Chicago and Phila. programs begin In Phila., district attorney threatened to arrest any doctor prescribing methadone to addicts Concerned about increased crime, Pres. Nixon announces War on Drugs, 6/17/71 Creates SAODAP - Dr. Jaffe becomes 1 st Drug Czar 2/3 s of $750 million 1974 drug budget for treatment etc. especially MMT; now 2/3 s supply
Opposition to Methadone Maintenance Reaction against MMT began quickly Substituting one addiction for another Psychosocial programs oppose it as likely to reduce concerns about poverty & social ills Some black leaders saw it as genocide, chilling out the ghetto without doing anything about racism, jobs, housing, & other ills Director of a therapeutic community, I think methadone is a great idea. We should give money to bank robbers, women to rapists, & methadone to addicts (1966) IOM report: current policy puts too much emphasis on protecting society from methadone & not enough on protecting society from the epidemic of addiction, violence, & infections methadone can help reduce. (1995)
Opposition to Methadone Maintenance (Cont) He (Bill W.) suggested that in my future research, I should look for a medication to relieve the alcoholic s sometimes irresistible craving and enable him to progress in AA toward social and emotional recovery (Dole, 1991) but many AA + NA groups oppose 1990 - ONDCP states MMT both legitimate & important part of spectrum of drug abuse treatment Calls to dismantle or sharply curtail it continue from government officials
Methadone Maintenance 1964-2000 (Con t) MMT s successes marked improvement in reducing illicit opioid use, morbidity & mortality, crime & risk of HIV infection, & in improving social & vocational functioning Approximate 260,000 in MMT in US & more than 1 million in world but some countries, e.g., Russia, forbid it Dose above 80mg usually better (e.g. Caplehorn, 1991; Ball 1988) Above 120mg better (e.g. Nosyk, 2009)
Effect of Methadone Maintenance on I.V. Use for 368 Male Methadone Patients in 6 programs At end of 1 st year, I.V. use down to 63.3% At end of 3 rd year I.V. Use down to 41.7% At end of 4 th year I.V. use down to 28.9% Crime also sharply dropped In 105 dropouts, 82% relapsed to I.V. use in 1 year Ball & Ross The Effectiveness of Methadone Maintenance Treatment, 1991
Methadone Effectiveness Methadone maintenance therapy versus no opioid replacement therapy (Review) 11 studies met the criteria for inclusion, all were randomized clinical trials Total of 1969 participants. Main results Methadone significantly more effective than nonpharmacological approaches in retaining patients suppression of heroin use as measured by self report and urine/hair analysis Difference not as great in criminal activity and mortality Mattick RP, Cochrane Database of Systematic Reviews 2009, Issue 3
Annual Rate Death Rates in Treated and Untreated Heroin Addicts 8 7 6 5 6.91 7.20 4 3 2 1 0 0.15 0.85 1.65 Matched Cohort Methadone Voluntary Discharge Involuntary Discharge Untreated Gronbladh L, et al., Acta Psychiatr Scand, 1990
Methadone to Abstinence Tapering within a treatment environment supportive of both indefinite agonist treatment and medication tapering. records of (30) patients beginning a slow methadone taper were reviewed NONE successfully completed methadone tapering. 67% stopped taper 13% switched to bup 10% discharged, 10% continued taper Calsyn et al. 2006
Was difficulty to withdraw from MMT due to Detoxification Methods? 1980 s Clonidine (ROD) Rapid detoxification with clonidine and naltrexone 1990 s (UROD) ultra-rapid opiate detox under anesthesia; a number of deaths 2000 decade (BROD) Buprenorphine rapid detoxification Short Term Buprenorphine Taper No difference between 7 day and 28 day taper in those on Bup. only 1 month (Ling 2009) Adding Vivitrol post detoxification
Detoxification Although agonist maintenance therapies yield better outcomes most seek opioid withdrawal Primarily to lower cost of their habit or Pre-treatment before residential therapeutic community or opioid antagonist maintenance High relapse rates are probably less a function of withdrawal method & due more to reasons for seeking detoxification, post-withdrawal treatment, or brain changes developed during dependence Those who complete detoxification tend to have longer times to relapse than dropouts
Detoxification from heroin is good for many things but staying off heroin is not one of them Walter Ling
Reasons for Post-MMT Relapse Never achieved rehabilitated state - discharged Left program in good standing but Didn t feel ready to leave but under pressure from family or friends to do so Lack of employability skills and job Lack of non-using peer group While in treatment Comorbid psychiatric disorder not addressed Conditioned cues or coping with stress not addressed Dole Stupidity of thinking that just giving methadone will solve a complicated social problem seems to me beyond comprehension
Importance of Psychosocial Services in Methadone Maintenance Treatment 92 Male I.V. opiate users randomly assigned to one of 3 interventions when they entered the MMT 6 months Dose comparable in all groups at least 60 mg
Importance of Psychosocial Services in Methadone Maintenance Treatment (cont) Results MMS (methadone alone, no other services) had reduced opiate use but 69% had to be protectively transferred because of unremitting use of opiates or cocaine or medical / psychiatric emergencies SMS (Meth. + counseling) Treatment as usual 41% met criteria for transfer EMS (Enhanced services: Meth. + counseling and medical, psychiatric, employment and family therapy) 19% met criteria for transfer EMS>SMS>MMS in outcomes including employment, alcohol use, criminal activity and psychiatric status MMS patients transferred to SMS showed significant reductions in opiate and cocaine use in 4 weeks McLellan et al JAMA, 1993
Methadone Cash Cow CRC is Minting Money with Methadone CRC has become the country s largest dispenser of the drug by far, with 61 clinics scattered across many states. Jackson 2007 In 2008 half of M.M. pts. attended private for profit programs paying $13-$25/day Total spent for M.M.T.: 1992- $480 million year; 2010 - $1 billion /yr (approx) Harwood, 2011
Decreased Psychosocial Services Services decreased in many programs because of switch to for-profit status Both quantity and quality of staff decreased Also because of cutbacks in state and federal funding
Harm Reduction Dilemma Should pts be discharged from MMT if, in spite of therapeutic intervention, behavior persists such as Continued high level of illicit opioids or cocaine Frequent missed meds or criminal behavior Violence towards staff or other pts OR kept on, risking contagion to other pts, negative community attitudes, forced closure of programs In short, increased stigma, decreased funding, increased group harm vs decreased individual harm Informal consensus: continued use of illicit opiates should not be reason for discharge but violence or other criminal behaviors should
Buprenorphine High affinity partial mũ agonist & kappa antagonist available as S.L. tablet and strip Reduced opioid agonist effects, with less respiratory depression (ceiling effect at 24-32 mg) but need to be in withdrawal to begin. Users claim more clear-headed than methadone Possible relation to OPRL receptor 2 forms Mono (subutex) and Combo (suboxone) 4:1 ratio of bup/naloxone to reduce I.V. use Currently over 325K maintained, 40 K in detox, and 12 K prescribing Drs.
Buprenorphine 2000 - Present Drs. required to have 8-hours of special training & X number Initially, Drs. restricted to 30 pts, led to long waiting lists & emphasis on detox Now permitted 100 patients after 1 year & ratio has switched to 75% maintenance But many Drs. neither refer nor give support
Opposition to Buprenorphine Backlash against buprenorphine For profit MMT programs fought against buprenorphine & filed petitions Diversion initially by street addicts to treat withdrawal but injection increasing DEA initially and currently concerned about bup. diversion as a schedule III. Has begun to inspect all Drs with X number Increased diversion in countries with only mono form
Number remaining in treatment Buprenorphine Maintenance vs Detox. RCT of cumulative retention in treatment 20 15 0 deaths 10 5 Detox 1wk then Placebo 4 deaths 0 0 50 100 150 200 250 300 350 Time from randomization (days) Number at risk 20 19 18 17 17 16 15 15 20 1 0 0 0 0 0 0 Kakko, et al, Lancet, 2003
Addiction A chronic relapsing disease Genetic heritability, personal choice, and environmental factors involved in etiology and course as they are in type 2 diabetes and hypertension Addiction produces significant and lasting changes in brain chemistry and function but often treated as if it were an acute illness by Drs, family, insurers Relapse after detox. or other treatments is common There is no reliable cure for drug dependence Need to apply the strategies used in the treatment of other chronic illnesses to the treatment of drug dependence McLellan, et al JAMA, 2000 Could long term maintenance heal the brain? (Kreek)
Causes of Relapse Dole and Nyswander stress a metabolic deficiency either pre-existing or acquired Another major theory a conditioning model by Wikler (1971). O Brien, the heir to Wikler, showed in human lab studies that craving and withdrawal are conditioned responses with physiological concomitants (1977). Addiction is a learned response, a memory long after drugs were gone from the body Even slight W/D symptoms or anxiety can be relapse triggers. His group (1997) showed via brain imaging that drugrelated cues produce a conditioned limbic system activation and strong drug craving
Protracted Abstinence Syndrome (PAS) Chronic use of narcotic analgesics may induce physiological changes associated with an increased responsivity to stress responsible in part either directly or indirectly for relapse to narcotics use because of their capacity to diminish such responsivity 6-9 months are required before recovery from abstinence can be considered complete (May include dysphoria, fatigue, insomnia, irritability) William R. Martin Pathophysiology of Narcotic Addiction: Possible roles of Protracted Abstinence in Relapse -1972
The Reality of Terminable 50% of M.M. pts drop-out within 1 st year 1) Nearly 2/3 s of M.M. pts drop out within 1 st year 2) Those who drop out are likely to relapse quickly 3) 4) Most do so within 3 months after leaving 5) Reaching out to these pts after they leave led to many returning to treatment 6) 1) Simpson et al 1997, 2) Bell et al 2006, 3) Ball + Ross 1991, 4) Zanis et al 1996, 5) Hubbard and Marsden 1986, 6) Coviello et al 2011 About ½ of Bup. pts drop out by 6 months Withdrawal from last 2mg of bup. may be especially difficult
Terminable or Interminable Options Terminable Maintenance till socially rehabilitated (at least 1-3 years) followed by: Short term tapering or 6 month taper Either followed by long acting narcotic antagonist Indefinite Maintenance The optimal duration of M.M. or Bup.is not yet known and varies by individual For most patients, longer duration appears associated with better outcomes Alternatives: antagonist maintenance; T.C; AA.
Unresolved Questions Role of age of onset and duration of addiction Street heroin users vs prescription opioid abusers Role of comorbid and genetic factors Role of length of time on maintenance opioid
Recovery A voluntarily maintained lifestyle characterized by sobriety, personal health, and citizenship JSAT 2008 Recovery can be achieved without medication - and it can also be achieved with it. McLellan, 2010
The descent to Hell is easy; the gates stand open day and night; but to reclimb the slope, and escape to the upper air, this is labor. Virgil, The Aeneid Book VI, Line 126