Methadone Maintenance 4 Decades Later

Methadone Maintenance 4 Decades Later Thousands of Lives Saved But Still Controversial Commentary by Herbert D. Kleber, MD JAMA 2008 (November 19);300(19):2303-2305
SUMMARY OF THE ORIGINAL ARTICLE

A Medical Treatment for Diacetylmorphine (Heroin) Addiction: A Clinical Trial With Methadone Hydrochloride Vincent P. Dole, MD, and Marie Nyswander, MD JAMA. 1965;193(8):646-650

Twenty-two male patients, addicted to heroin 9.5 years (median), were stabilized using oral methadone hydrochloride and then observed for approximately 1 to 15 months (median, 3 months). The medication had 2 main effects: (1) relief of narcotic hunger (craving); and (2) induction of sufficient tolerance to block the average illegal dose of heroin.

A combination of the methadone treatment and a comprehensive program of rehabilitation was associated with marked improvement in patient problems such as jobs, returning to school, and family reconciliation. No adverse effect other than constipation was found.

The authors note that "careful medical supervision and many social services" were necessary and stressed that "both the medication and supporting program were essential." The small size of the group studied and short duration of the follow-up would best describe this as a promising and exciting but preliminary report.

See PDF for full text of the original JAMA article.

Commentary

The effects of the article by Dole and Nyswander1 are best understood by knowing what preceded it. The current scientific consensus is that opioid dependence is a chronic and severe medical disorder, and withdrawal alone is usually followed by rapid relapse.2 A century ago, however, withdrawal was often considered adequate to treat narcotic addiction, with methods used often more dangerous than withdrawal. Individuals who relapsed were viewed as doing so out of choice rather than necessity.

The frequency of relapse, however, led to the establishment of narcotic clinics to legally provide heroin or morphine to individuals with addiction. By 1923, all these clinics had closed, deemed failures because they did not lead to abstinence. Federal agencies interpreted the 1914 Harrison Act as prohibiting maintenance of individuals with active addiction and threatened or prosecuted physicians doing so. Between 1919 and 1935, approximately 25,000 physicians were indicted under the Harrison Act and 10% were imprisoned. Despite 1921 and 1926 Supreme Court rulings that the act did not forbid such prescribing, most physicians avoided it, ending the role of the medical profession in treating patients with addiction for 4 decades.

Heroin became the street narcotic of choice. During World War II, with heroin scarce and purity as low as 1%, addiction hit a record low. By the late 1940s, the flow of smuggled heroin had resumed, but addicts were more likely younger, from a racial or ethnic minority group, and living in northern impoverished communities. Treatment was scarce, prison common, and relapse likely.3

Methadone Maintenance

Forty years after the last maintenance clinics closed, the 1965 article by Dole and Nyswander landed with a bang.1 Dole, an internist, believed narcotic addiction was a metabolic disease, not very different from diabetes; Nyswander, a psychiatrist, had frustrating years of treating individuals with narcotic addiction with psychotherapy only to see them relapse. Their study,1 conducted in New York City first at the Rockefeller Institute and later moving to Manhattan General Hospital, included 22 participants with heroin addiction. One year later, Dole et al reported empirical data on the induced narcotic blockade.4 Long-term follow-up studies later confirmed that therapeutic success on a larger scale was possible.

Methadone replaced morphine as the preferred agent for heroin withdrawal. As a maintenance agent for treating addiction, methadone prevents withdrawal for 24 to 36 hours, enabling a system in which addicted patients come for treatment once a day, in contrast to the 1920s clinics using short-acting opioids.

Following the 1965 article,1 scientists systematically expanded the science behind methadone maintenance treatment (MMT). Large-scale programs using more cost-effective induction methods opened in New York City, and the US Food and Drug Administration approved a limited use of methadone in large research programs.5

In 1970, the federal government faced 2 major heroin-related problems: heroin use and associated crime was increasing, especially in urban areas; and soldiers in Vietnam were using heroin. Concerned about possible increased crime when these soldiers returned home and influenced by the early success of DuPont's Narcotics Treatment Administration in reducing crime by treating individuals with heroin addiction,6 President Nixon announced the war on drugs on June 17, 1971, created the Special Action Office for Drug Abuse Prevention (SAODAP), and hired Jerome Jaffe to be its first director. This new federal structure was charged with coordinating and rapidly expanding drug treatment, including changing existing regulations.5

Even as SAODAP and New York City moved to expand MMT, strong reaction began against it, fueled partly by reports of methadone-related deaths and diversion, but primarily by its substituting one addiction for another. Psychosocial program advocates opposed MMT as likely to reduce concerns about poverty and social ills. The director of a therapeutic community remarked, "I think methadone is a great idea. We should give money to bank robbers, women to rapists, and methadone to addicts."7

In those first 2 years, more federally supported treatment capacity developed than in the previous 50 years. In 1974, two-thirds of the $750 million drug budget was devoted to treatment, research, and prevention, compared with the recent 25 years during which two-thirds of the budget targeted supply reduction.5

Positive Outcomes of MMT

Numerous studies have demonstrated the effectiveness of MMT for reducing illicit opioid use, morbidity and mortality, risk of human immunodeficiency virus (HIV) infection, illegal activities, and improving overall functioning. Patients in MMT had a 1-year mortality rate of 1% compared with 8% among patients who discontinued treatment.8 In a 1993 prospective study conducted in Philadelphia, Pennsylvania, HIV seroconversion rates were 4 times higher among individuals who were actively using street heroin compared with patients receiving MMT.9 Risk decreased in relation to length of time continuously receiving MMT; risk of hepatitis B and hepatitis C also was reduced but to a much lower extent.9

In a 1991 study, crime days per year among individuals addicted to narcotics decreased more than 70% while receiving MMT.10 In a random assignment study, patients in the standard and enhanced treatment groups had marked reductions in illicit opiate use and improvements in overall functioning compared with the minimal counseling group.11 However, the increase of for-profit MMT centers (often realizing very large profits), and decreased funding for nonprofit centers left many programs inadequately staffed. This remains a major unresolved public health problem.

Average methadone maintenance doses of 60 to 120 mg or higher have consistently better results than use of lower average doses, especially because heroin purity is now often greater than 40%. Methadone's plasma half-life, once stabilized, averages 24 to 36 hours with a range of 13 to 56 hours. However, as many as 10 days may be needed to reach a steady state, and new patients, either to MMT or given methadone for analgesia, are at risk for fatal overdose. Most deaths have been from methadone prescribed for pain rather than from methadone treatment programs.

Although MMT has been lifesaving for thousands of individuals, it is not a panacea. High levels of psychopathology remain. Abuse of cocaine and benzodiazepines and disruptive behavior are problems in many programs. Many patients do not change their behavior even when services are available. What to do under such circumstances remains contentious, given the likely severe postdischarge consequences vs the effect on other patients and the possibility that more intensive residential intervention might be helpful.

During the past 2 decades, evidence has accumulated regarding the neurobiology of opiate dependence. Opiate dependence is now seen as a brain-related disorder with genetic and environmental overlays characteristic of a medical illness. The endorphin system and opioid receptors have now been discovered. Dole was ahead of his time.1, 4, 12

Safety

Studies on MMT in the 1970s by Kreek found no long-term damage to the heart, kidneys, liver, or lungs.13 Long-acting maintenance medications normalized the neuroendocrine alterations induced by short-acting opioids12 with minimal psychoactive impairment. MMT has been shown not to impair driving ability. In the past decade, it was found that methadone, especially at high doses, when beginning treatment, or when combined with certain drugs, may lead to QTc prolongation and possibly to torsade de pointes, a potentially fatal cardiac arrhythmia. A black box warning was added to the prescribing information for methadone in December 2006. However, the clinical significance of this abnormality is not yet clear regarding deaths.

Federal Regulations

MMT is one of the most heavily regulated medical treatments in the United States.5 With few exceptions, methadone may only be dispensed for opioid withdrawal or maintenance by certified opioid treatment programs. An increasing number of take-home doses is permitted, depending on the patient's history of illicit drug use and employment, with a maximum 1-month supply after 2 years. Regulations and decreased public financing have made it more difficult to start or expand programs. An Institute of Medicine review14 concluded, " . . . current policy puts too much emphasis on protecting society from methadone, and not enough on protecting society from the epidemic of addiction, violence, and infections that methadone can help reduce." However, regulation that is too lenient may lead to worsened problems and increased hostility; a balance is needed.

Stigma

In the late 1980s, the backlash against MMT became stronger. Community complaints about loitering and bartering of drugs outside clinics exacerbated the hostile environment. Complaints often coincided with decreased ancillary supports.

In 1988, the White House Conference for a Drug-Free America, vehemently antimethadone, demonized methadone and the National Institute on Drug Abuse and called for a congressional investigation.7 In 1990, the Office of National Drug Control Policy reversed this position, and its White Paper on treatment stated clearly that methadone maintenance was both legitimate and an important part of the spectrum of drug abuse treatment.7 Ironically, even though 12-step programs have often been hostile to MMT,15 Dole, a friend of the cofounder of Alcoholics Anonymous recounted, "He [Bill W.] suggested that in my future research, I should look for an analogue of methadone, a medication that would relieve the alcoholic's sometimes irrestible craving and enable him to progress in AA toward social and emotional recovery. . . . "15

In the United States, approximately 260 000 individuals are currently receiving MMT (M. Perrino, written communication, October 2008), although it is estimated that fewer than 10% of individuals who are addicted to heroin and prescription opioids are receiving MMT. Worldwide, about 1 million individuals are receiving MMT; in some countries such as Russia, government opposition to agonist maintenance prevents its use even when high HIV rates exist.

The long-acting sublingual partial agonist buprenorphine, a Schedule III opioid, has been available since 2002 for office-based prescribing by physicians with special training5 and with current limits of 100 patients per physician. Approximately 140 000 patients are now receiving maintenance using buprenorphine (R.E. Johnson, written communication, October 2008) and results to date appear comparable to MMT albeit with somewhat different populations. It is not clear whether it will be any easier to remain abstinent after withdrawal from buprenorphine treatment than from MMT, especially if inadequate ancillary support is provided. While buprenorphine's formulation makes overdose or diversion to parenteral use less likely, like all µ agonists, this drug has that possibility and limited diversion is already occurring.

Methadone: Terminable or Interminable

The benefits of long-term methadone maintenance are borne out by data.2 Two years of MMT appears to be the minimum duration before attempting withdrawal.5 Even patients receiving maintenance for long periods with substantial lifestyle changes often relapse after leaving treatment, and death rates are much higher than for individuals who remain in treatment. For many patients, therefore, years or even lifetime maintenance may be needed, but there is often patient and family opposition. Office-based medical maintenance has been used on a limited basis for patients stable at least a few years with generally successful results, although some patients increased their use of illicit drugs. This approach avoids the clinic problem of mixing stable and unstable patients but the number of eligible stable patients appears limited. Ultimately, the problem of interminable maintenance vs relapse may require learning how to reverse the brain changes associated with addiction. Until then, long-term agonist treatment remains a reasonable alternative.

Review: Electrocardiogram Characteristics of Methadone and Buprenorphine Maintained Subjects

Byrne Review: Electrocardiogram characteristics of methadone and buprenorphine maintained subjects
Comments by A. Byrne
September 22, 2008

Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35

These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a ‘normal’ addiction clinic setting.

We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 (39%) were female.

No significant difference in QT interval was found between the three groups. There were 2 methadone patients and one control with long QT when defined as 430ms or longer for males (450 for females). None was over 475ms (the threshold at which risk of torsades occurs is believed to be 500ms). There was a trend for longer QT intervals in those on >60mg daily as well as some increased U waves reported in methadone patients. These findings are consistent with Lipsky’s findings from 1973, but the clinical significance, if any, is unclear. Like other prospective studies on this subject, these authors do not report any cases of torsades.

The authors conclude: “Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.”

As an exercise I contacted two prominent addiction experts in Adelaide on this subject. One had seen no cases and the other was aware of one possible case some years ago. This is on a long background of good quality methadone treatment, both private and public, in that city.

It may be timely to examine the evidence for claims that methadone treatment in addiction is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports (or perhaps because of it) a number of authors attempted to assess methadone’s role in cardiotoxicity by using indirect and unconventional methods.

For example, Fanoe (ref below) prefers QT/torsades as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsades is 0-1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics). Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. His deduction for QT changes without a single case report seems hard to understand. Wedam (ref below) wrote “To compare the effects of …[methadone] … on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.” [our italics] In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsades cases were reported in the study groups.

A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing ‘normal’ clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold ‘normal’ doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).

I believe that it is now possible to restate unequivocally that ‘normal’, guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). A pre-treatment cardiograph would not have detected any of these cases.

As well as a dearth of relevant case reports, some have given advice without due consideration of the benefits of methadone treatment in the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone induced torsades may indeed occur, it must be in extremely low numbers and would probably be swamped statistically by reductions in endocarditis cases alone (as reported by Krantz in 2001 - ref below).

In practical terms, this means that existing methadone patients needing other medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should have a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.

We need to ensure that as clinicians we continue to ask the question: what is the evidence?

Comments by Andrew Byrne.
Redfern Clinic.com News

References:

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055.

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71.

Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473.

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006;101:1333-1338.

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282–285.

Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803.

Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Available from: Addiction Treatment Forum 2001 No 4