Robert G. Newman

Concerns about injectable naltrexone for opioid dependence

In The Lancet, Evgeny Krupitsky and colleagues report on the use of injectable naltrexone for treatment of opioid dependence. Their report comes some months after the US Food and Drug Administration (FDA) approved use of the preparation for opioid-dependent patients on the basis of the same fi ndings. The study by Krupitsky and colleagues suggests the strong potential of a oncemonthly, extended-release formulation of injectable naltrexone for opioid addiction—the median proportion of weeks of confi rmed abstinence was 90·0% in the depot naltrexone group compared with 35·0% in the placebo group (treatment eff ect 55% [95% CI 15·9–76·1], p=0·0002). The study is also striking, however, for the questions it raises about the FDA’s approval processes and clinical trial ethics. Factors requiring scrutiny include paucity of effi cacy data, adequacy of risk assessment (particularly of overdose risk in treatment dropouts), and the questionable ethics of a placebo-controlled trial when an accepted standard of treatment exists. The FDA’s assessment of depot naltrexone’s effi cacy was based on then-unpublished evidence from this trial in Russia, in which 250 eligible patients at 13 sites were randomly assigned to receive 380 mg depot naltrexone or placebo. This single study, in which 54% of patients did not complete the protocol and just over half of those on naltrexone received the full treatment course, was judged suffi cient proof by the FDA. For evidence on safety, the FDA accepted data from the Russian study and another in the USA in patients with alcohol or opioid dependence, or both. Strikingly, neither the materials provided to the FDA advisory committee nor the Lancet study make clear what follow-up was done to evaluate post-treatment opioid overdose in the participants in the Russian trial. Data from the US study are similarly vague on post-treatment adverse events. The FDA sometimes requires only a single clinical trial for new indications of an already approved drug. A single trial is not justifi ed, however, when there are questions about the safety of the drug as it will be prescribed or recommended. Although voluntary reporting captures only a small portion of serious adverse events that occur once a drug enters the marketplace, approval of depot naltrexone for alcoholism treatment has been followed by reports to the manufacturer of 19 fatalities, some necessary before a patient could be started on treatment for multidrug-resistant tuberculosis, which is longer, more expensive, more toxic, and less eff ective than is fi rst-line therapy. Thus strengthening and scale-up of laboratory capacity needs to go hand-in-hand with implementation of the MTB/RIF test. Finally, scaling up of testing needs to be accompanied by a rapid increase in access to treatment. In the past decade, about 5 million people developed drug-resistant tuberculosis but less than 1% had access to appropriate treatment, and 1·5 million died. The positive results with the MTB/RIF test are an urgent wake-up call to the international community that a substantial increase in capacity to manage multidrug-resistant tuberculosis at scale is needed, together with major improvements in the availability of high-quality aff ordable treatment.

Another Wall That Crumbled— Methadone Maintenance Treatment in Germany

During the past quarter-century there have been innumerable reports throughout the world documenting the effectiveness of methadone maintenance treatment. None have been as consistently positive as those from Germany, where just a few years ago methadone was effectively banned. The German accomplishments in the past 6 years in treating addicts with methadone confirm the experience elsewhere: Methadone treatment is a highly desired alternative to many who wish to escape the life of the street addict; it is very effective in benefiting the individual patient as well as the general community; and it can be expanded rapidly and on a large scale. What is needed today is not further discussion but a firm commitment to make treatment available on request to every addict willing to accept it. With methadone maintenance--one treatment approach among many--this goal is achievable. There is no justification for settling for less.

Advocacy for Methadone Treatment

After Drs. Nyswander and Dole initially reported their research findings with methadone treatment at the Rockefeller University in 1965 (1), its applicability on a very broad scale was quickly demo...

Attributing Fatal Cardiac Effects to Methadone : What's the Evidence?

Researchers in Oregon recently reported on a study comparing the frequency of cardiac pathology in two sudden-death cohorts.1 One comprised individuals in whom methadone, though found at autopsy, was not considered to have caused demise through overdose. The other decedents had negative toxicology for methadone. Cardiac pathology was found in 23% and 77% of the two groups, respectively. The authors concluded that “The significantly lower prevalence of cardiac disease in the [methadone] case group implicates methadone, even at therapeutic levels, as a likely cause of sudden death.” The key assumption on which the study and its conclusions are based, however, seems seriously flawed. The authors define non-overdose deaths as all those for which a postmortem blood concentration of methadone was found to be less than 1 mg/L. This arbitrary definition lacks support; indeed, any reliance on methadone concentrations for the purpose of establishing cause of death was explicitly rejected by a committee of experts convened in 2003 by the Department of Health and Human Services. The Department’s “Report of a National Assessment” of methadone-associated mortality presented the views of this “. . . multi-disciplinary group—including representatives from various Federal and State agencies, researchers, epidemiologists, pathologists, toxicologists, medical examiners, coroners, pain management specialists, addiction medicine experts, and others . . . .” (p. 3).2 Among the conclusions: “It is important to note that postmortem blood concentrations of methadone do not appear to reliably distinguish between individuals who have died from methadone toxicity and those in whom the presence of methadone is purely coincidental” (emphasis added). More recently, a study of 176 fatalities in Kentucky in which methadone was found alone or in combination with other drugs concluded that the interpretation of postmortem blood methadone concentrations “. . . requires consideration of the subject’s potential chronic use of and tolerance to the drug.”3 No such consideration is suggested in the analysis of the deaths in Oregon. Two additional points should be considered. First, not one of the 22 supposedly non-overdose “cases with methadone” that the Oregon group analyzed was found to involve methadone given for maintenance treatment of opiate dependence

Maintenance treatment of addiction: to whose credit, and why it matters.

It has been stated that credit for introducing methadone maintenance” treatment of opiate dependence does not belong o Drs. Vincent Dole and Marie Nyswander, but rather to a Canaian, Dr. Robert Halliday. One writer put it this way: “Halliday egan methadone treatment for heroin addiction in Vancouver, ritish Columbia, in the late 1950s and introduced a methadone aintenance program in 1963” (Bayes, 2007). Can and should e, in fact, be credited with first introducing the concept and ractice of “maintenance” treatment of addiction? The answer eems to be “no”. In a 1963 article Halliday wrote, “. . .it is now widely accepted hat the addict is a sick person physically, psychologically and ocially, and as such requires medical and other treatments” Halliday, 1963). Although even today the claim of “wide accepance” would seem – sadly – to overstate the case, Halliday did he field of addiction a great service by calling renewed attention o the view expressed 40 years earlier by the Rolleston Commitee in England: “. . .[A]ddiction to morphine and heroin should e regarded as a manifestation of a morbid state, and not as a ere form of vicious indulgence” (Ministry of Health, 1926); s such, the Committee concluded it should be considered “the esponsibility of doctors” (Berridge, 1980). With respect to the fundamental concept of addiction as a edical problem that falls squarely in the realm of the cliniian, Rolleston, Halliday and Dole were clearly of like mind. hey also shared another common perspective, expressed in the olleston Report as follows: “. . .the continued supply of drugs o a patient, either directly or by prescription, solely for the gratfication of addiction is unacceptable.” In precisely the same ein Halliday denounced as a “mistaken notion. . .the view that ddicts should be regularly supplied with drugs on a maintenance asis” (Halliday, 1963). What might surprise many supporters s well as critics of Dole and Nyswander, however, is that they ere no less emphatic on this score; in one of their earliest papers hey rebutted those who “. . .erroneously assume that we give ethadone to addicts as a legal substitute for heroin,” going on o state that they “. . .would not consider this to be proper medical ractice” (Dole & Nyswander, 1968).1

Opiate agonist treatment for addiction.

www.thelancet.com Vol 372 December 6, 2008 1951 examined correction factors available for Asian people on the Modifi cation of Diet in Renal Disease (MDRD) study equa tion, but such corrections were dis appoint ing and did not add value to our results. In a diff erent cohort from Taiwan, the mor tality risks of reduced GFR re mained unchanged when a verifi ed equa tion for Chinese popu lations was used. The MDRD study equation in this Asian popu lation yielded suffi ciently robust results to iden ti fy the group with an in creased mortality risk requiring early clinical inter vention. The long-held notion that there is a familial aggregation of CKD cases should be interpreted with caution, since family members also share similar life styles or environ mental risk factors. How ever, the husband/wife aggre gation, most prominent in our cohort, was clearly unrelated to genetics. Further more, we adjusted the prevalence according to the socio economic status of the general popu lation, minimising the eff ects of the some what affl uent status of the screened population. In summary, the CKD national prevalence in Asian people, carefully developed on the basis of a large cohort, has been corro borated with signi fi cant mor tal ity risks and with short ened lifespan. This outcome-based observation makes whether we over estimated the national pre valence a moot point.

Studying methadone’s appropriateness: enough already!

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Analysis supports methadone maintenance efficacy in Scotland

We welcome the opportunity to respond to the letter from your correspondent regarding our paper ‘‘Topping up Methadone: an analysis of patterns of heroin use among a treatment sample of Scottish drug users’’. The gist of the criticism set out in the letter is: that there are no conclusions that can be drawn from the research on which our paper is based; and that one of the authors has contradicted the conclusions set out in the paper in press coverage of the research in Scotland. It is hard to see how one can justifiably make both claims but, setting that aside, we will respond to the points raised. It should be no surprise that a study of this size and complexity cannot be comprehensively reported in a single 3,000-word article. There are 29 published reports of DORIS findings listed on the University website,2 including an extended summary paper of the methods and findings. We are happy to provide some additional information here. Firstly, on deaths, there were 38 deaths in the cohort at 33-month follow-up; a detailed analysis of the relevant mortality data is found in Bloor et al.4 Secondly, on exclusion of those inprison-based treatment, your correspondent perhaps over-looked our statement on p.1014 that these were excluded from analysis of methadone-maintained treatment because ‘very few prisoners in Scotland had access to methadone-maintenance treatment in 2001’ (the year of sample recruitment). Thirdly, on attrition, your correspondent perhaps also overlooked the information we previously gave on p.1015 on our logistic regression analysis of attrition bias: of the different treatment sub-groups, only those undergoing prison-based treatment at baseline were disproportionately lost to follow-up. Our follow-up rates in the DORIS study not only compare favourably with other cohort studies of drug users, they also compare favourably with panel studies of the general UK population. The second criticism set out in the letter has to do with the claim that one of the authors has contradicted the findings set out in the paper in comments covered by the Scottish media. The comments Analysis supports methadone maintenance efficacy in Scotland

Maintenance buprenorphine for opioid users

and noted by Kakko and colleagues, the generalisability of the results is limited. In view of the Declaration of Helsinki, use of placebo in this trial was unethical; placebo and buprenorphine are not clinically equivalent and no doubts exist about the differences in terms of efficacy and safety. The 1-year high mortality rate noted in the placebo group indicates the seriousness of heroin dependence and questions the use of placebo as a control. Finally, a 1-year maintenance trial for opioid dependence with a placebo control provides little clinically useful information. Doctors and therapists are interested in the results of trials that compare real alternatives, where efficacy and safety of new drugs are compared with proven active substances. Highdose methadone is the gold standard for maintenance therapy of opioid dependence. Buprenorphine could be an alternative if methadone programmes are limited. Kakko and co-workers should have compared high-dose buprenorphine with low-dose buprenorphine rather than placebo. *Magí Farré, Marta Torrens

Harm reduction : a common cause

In a field as complex as heroin addiction, controversy is useful in stimulating exchange of ideas. An appeal for action, however, based on what we already know to be enormously beneficial to addicts and to the general society, must be given higher priority than proselytizing for any given approach. We know that narcotic addiction takes a terrible toll and that, like alcoholism, we are currently unable to cure it. We also know that many addicts desperately seek methadone treatment, that many can be helped by it, and that many will die without it. The conclusion is clear: methadone treatment, one therapeutic approach among many, must be available upon request to all those who want it.