Correspondence

Diacetylmorphine versus Methadone for Opioid Addiction

N Engl J Med 2009; 361:2193-2195November 26, 2009

Article

To the Editor:

At least two important points warrant comment concerning the report by Oviedo-Joekes et al. (Aug. 20 issue).1 First, the findings suggest that there may be therapeutic value in administering a treatment medication by the same route through which the drug is abused. A discussion of this strategy is virtually absent from the treatment literature on substance abuse. Second, it is stated that the current study could not be conducted in the United States “because of financial and logistical barriers.” This statement seems peculiar given that dozens of clinical trials investigating potential pharmacotherapies for substance dependence (including opioid dependence) are conducted each year in the United States. Furthermore, multiple U.S. researchers have shown that it is safe to administer intravenous opioids (e.g., buprenorphine, heroin, and hydromorphone) to persons who are opioid-dependent in clinical settings.2-5 Nevertheless, we are encouraged by the current findings because they argue for broadening the scope of medications used for the treatment of opioid dependence.

Catalina Saldaña, B.A.
Carl L. Hart, Ph.D.
Columbia University, New York, NY
clh42@columbia.edu

5 References

1
Oviedo-Joekes E, Brissette S, Marsh DC, et al. Diacetylmorphine versus methadone for the treatment of opioid addiction. N Engl J Med 2009;361:777-786
Full Text | Web of Science | Medline

2
Comer SD, Sullivan MA, Whittington RA, Vosburg SK, Kowalczyk WJ. Abuse liability of prescription opioids compared to heroin in morphine-maintained heroin abusers. Neuropsychopharmacology 2008;33:1179-1191
CrossRef | Web of Science | Medline

3
Comer SD, Sullivan MA, Walker EA. Comparison of intravenous buprenorphine and methadone self-administration by recently detoxified heroin-dependent individuals. J Pharmacol Exp Ther 2005;315:1320-1330
CrossRef | Web of Science | Medline

4
Donny EC, Brasser SM, Bigelow GE, Stitzer ML, Walsh SL. Methadone doses of 100 mg or greater are more effective than lower doses at suppressing heroin self-administration in opioid-dependent volunteers. Addiction 2005;100:1496-1509
CrossRef | Web of Science | Medline

5
Walsh SL, Sullivan JT, Preston KL, Garner JE, Bigelow GE. Effects of naltrexone on response to intravenous cocaine, hydromorphone and their combination in humans. J Pharmacol Exp Ther 1996;279:524-538
Web of Science | Medline

To the Editor:

The North American Opiate Medication Initiative (NAOMI) proves only that many doctors don't know how to titrate methadone. The mean dose for the methadone group was only 96.0 mg per day — too low for heroin users who have already had methadone treatment that failed. There is compelling evidence that higher doses are more effective than lower doses in improving treatment retention and reducing heroin use.1-3 For example, a 10-year study showed that treatment retention was associated with a daily dose of 100 mg or more.3 The subjects in the methadone group in NAOMI had a mean of 12 days of heroin use in the previous month; their dose should have been increased until heroin use and cravings resolved. This is the recommended practice in current guidelines.4 In our experience, patients on doses of 120 to 140 mg or more rarely use heroin on a regular basis. The protocol for the Randomised Injecting Opiate Treatment Trial (RIOTT) calls for methadone doses of more than 100 mg.5 Until the results of this trial are published, the effectiveness of heroin treatment for heroin addiction remains uncertain.

Meldon Kahan, M.D.
Saint Joseph's Health Centre, Toronto, ON, Canada
kahanm@stjoe.on.ca

5 References

1
Kornor H, Waal H. Methadone dose, treatment duration and heroin use in drug-assisted rehabilitation. Tidsskr Nor Laegeforen 2004;124:332-334
Medline

2
Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: a receiver operating characteristic analysis. Drug Alcohol Depend 2006;81:129-136
CrossRef | Web of Science | Medline

3
Peles E, Schreiber S, Adelson M. Factors predicting retention in treatment: 10-year experience of a methadone maintenance treatment (MMT) clinic in Israel. Drug Alcohol Depend 2006;82:211-217
CrossRef | Web of Science | Medline

4
Methadone maintenance guidelines. Toronto: College of Physicians and Surgeons of Ontario, 2005.

5
Lintzeris N, Strang J, Metrebian N, et al. Methodology for the Randomised Injecting Opioid Treatment Trial (RIOTT): evaluating injectable methadone and injectable heroin treatment versus optimised oral methadone treatment in the UK. Harm Reduct J 2006;3:28-28
CrossRef | Medline

To the Editor:

I found the results of the NAOMI heroin prescription trial unimpressive, especially considering the cost of treatment, which although not specified was presumably considerable. The loss of participants from the two main study groups was sizable (33% and 60%), and the monthly expenditure on drugs was substantial. The methadone, delivered under what were optimal conditions, performed poorly. There were no significant improvements in terms of medical and psychiatric status, family and social relations, or alcohol use, and in 444 planned urine tests and 369 actual urine tests, only 14.6% and 17.6%, respectively, were morphine-free.

Given the reports from several nations on the accrual of chronic conditions in patients with opiate dependencies over decades of treatment,1-3 it is unfortunate that the NAOMI report did not include data on weight, blood pressure, lipid fractions, glycemia, or inflammatory markers, including high-sensitivity C-reactive protein. With recent data throughout the Western world showing many pathways to opiate dependency, such details may have provided a different risk–benefit analysis concerning the value of indefinite participation in maintenance programs. Depot antagonists such as naltrexone implants, which have recently been proved safe and highly effective,4,5 appear to be an under-resourced alternative; if a small fraction of the resources invested in maintenance programs were invested in antagonist programs, the clinical and research payoffs would be substantial.

A. Stuart Reece, M.B., B.S., M.D.
University of Queensland, Brisbane, QLD, Australia
sreece@bigpond.net.au

Dr. Reece reports that naltrexone implants were sold through his clinic. No other potential conflict of interest relevant to this letter was reported.

5 References

1
Darke S, Kaye S, Duflou J. Systemic disease among cases of fatal opioid toxicity. Addiction 2006;101:1299-1305
CrossRef | Web of Science | Medline

2
Hser YI, Gelberg L, Hoffman V, Grella CE, McCarthy W, Anglin MD. Health conditions among aging narcotics addicts: medical examination results. J Behav Med 2004;27:607-622
CrossRef | Web of Science | Medline

3
Rosen D, Smith ML, Reynolds CF III. The prevalence of mental and physical health disorders among older methadone patients. Am J Geriatr Psychiatry 2008;16:488-497
CrossRef | Web of Science | Medline

4
Tait RJ, Ngo HT, Hulse GK. Mortality in heroin users 3 years after naltrexone implant or methadone maintenance treatment. J Subst Abuse Treat 2008;35:116-124
CrossRef | Web of Science | Medline

5
Kunoe N, Lobmaier P, Vederhus JK, et al. Naltrexone implants after in-patient treatment for opioid dependence: randomised controlled trial. Br J Psychiatry 2009;194:541-546
CrossRef | Web of Science | Medline

Author/Editor Response

We agree with Saldaña and Hart that many trials investigating substitution treatment for opioid dependence have been conducted in the United States. However, there have been few studies of heroin substitution in the United States, particularly phase 3 studies with a large outpatient population. Of the four trials analyzed in the most recent Cochrane review of heroin-assisted therapy,1 not one was conducted in the United States. Our American collaborators in the NAOMI study group concluded, after several years of work, that they were unable to overcome regulatory barriers or to secure the funding necessary for a large-scale effectiveness trial.

Although many physicians may not use proper doses of methadone, this was not the case in the NAOMI trial. The mean of 12 days of illicit heroin use in the methadone group to which Kahan refers was calculated on an intention-to-treat basis; for patients who remained in the study the mean was 6 days. Study physicians followed best practices and titrated doses to the clinical needs of each patient. Doses in the range of 120 to 140 mg are recommended but only if tolerated. Low dosages were clearly not an issue in our trial, since the response rates of patients in the methadone group who received daily doses above or below 100 mg were similar (68% vs. 62%, P=0.63). Our findings mirrored those of a German heroin trial in which the overall average dose of methadone was 99 mg and did not differ significantly between those who did and those who did not respond to treatment (97 mg and 104 mg, respectively).2 We too await publication of the full results of the RIOTT study. However, the investigators have recently announced a positive result consistent with our findings — that is, three quarters of the participants for whom heroin was prescribed made substantial reductions in their use of street heroin, as compared with about a third of the participants in the groups receiving injectable methadone or optimized oral methadone.3

Reece is right to point out the important issue of cost. In a Dutch trial of heroin-assisted therapy, it was estimated that treatment, even though more expensive than methadone maintenance, led to an overall annual savings of approximately $18,900 in U.S. dollars.4 A formal pharmacoeconomic evaluation of our trial is under way. Meanwhile, it is noteworthy that the annual societal cost of each untreated heroin user in Canada in 1996 was estimated at approximately $41,700 in U.S. dollars.5 Optimized methadone maintenance, provided with adjunctive diacetylmorphine treatment when necessary, can be offered for less than a quarter of this amount.

Eugenia Oviedo-Joekes, Ph.D.
University of British Columbia School of Population, and Public Health, Vancouver, BC, Canada

David Marsh, M.D.
Vancouver Coastal Health, Vancouver, BC, Canada

Martin T. Schechter, M.D., Ph.D.
University of British Columbia School of Population, and Public Health, Vancouver, BC, Canada
martin.schechter@ubc.ca

5 References

1
Ferri M, Davoli M, Perucci CA. Heroin maintenance for chronic heroin dependents. Cochrane Database Syst Rev 2005;2:CD003410-CD003410
Medline

2
Haasen C, Vertheim U, Degkwitz P, et al. The German model project for heroin assisted treatment of opioid dependent patients: a multicentric, randomized, controlled treatment study. Hamburg, Germany: Centre for Interdisciplinary Addiction Research of Hamburg University (ZIS), 2006.

3
Siva N. Heroin clinics reduce street drug use and crime, shows study. BMJ 2009;339:b3845-b3845
CrossRef | Web of Science | Medline

4
Dijkgraaf MG, van der Zanden BP, de Borgie CA, Blanken P, van Ree JM, van den Brink W. Cost utility analysis of co-prescribed heroin compared with methadone maintenance treatment in heroin addicts in two randomised trials. BMJ 2005;330:1297-1297
CrossRef | Web of Science | Medline