Diacetylmorphine versus Methadone for the Treatment of Opioid Addiction

Opioid dependence, most commonly manifested as heroin dependence, is a chronic relapsing condition that is estimated to affect more than 1 million persons in North America. The risks of opioid dependence include fatal overdoses, infections (including endocarditis, human immunodeficiency virus infection, and hepatitis C virus infection), social disintegration, violence, and crime. The associated burdens on communities include medical, public health, and criminal-justice costs as well as public disorder and crimes against property.

Methadone, the standard opioid-substitution treatment, has been shown to reduce major risks associated with untreated opioid dependence in patients who are willing to undergo and are successfully retained in treatment. However, 15 to 25% of the most adversely affected persons do not have a good response to this treatment. Such persons are either not retained in methadone maintenance treatment for very long or continue to use illicit opioids while in treatment. European studies have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive maintenance treatment for such persons. To investigate this possibility in North America, we conducted a randomized, controlled trial comparing injectable diacetylmorphine with oral methadone. Because of financial and logistical barriers in the United States, the trial could be conducted only in Canada.

DISCUSSION
In this trial, patients assigned to receive injectable diacetylmorphine were more likely to stay in treatment and to reduce their use of illegal drugs and other illegal activities than patients assigned to receive oral methadone. These findings are consistent with the results of European studies that suggest greater effectiveness of diacetylmorphine than methadone as maintenance treatment for long-term, treatment-refractory opioid use. Two of these trials showed no differences between groups in the rate of retention in treatment for addiction. However, the fact that control patients were eligible to receive diacetylmorphine at the end of the study period may have introduced a bias in the observed retention rates. In addition, patients currently enrolled in methadone maintenance treatment were eligible for the European trials but not for the present study. Although the definitions of clinical response varied among the trials, all of them considered the same variables (drug use, illegal activities, health, and social adjustment) and showed greater effectiveness of diacetylmorphine than of methadone for maintenance treatment.

Secondary analyses showed that both groups had significant improvement in many of the variables that were evaluated. The diacetylmorphine group had greater improvements with respect to medical and psychiatric status, economic status, employment situation, and family and social relations. These results are particularly noteworthy in view of the nature of the population and the time frame. The fact that patients who received diacetylmorphine had significant improvement in these areas suggests a positive treatment effect beyond a reduction in illicit-drug use or other illegal activities.

The lack of effective pharmacologic treatments for cocaine addiction poses a considerable challenge for the treatment of opioid addiction in patients who use more than one drug. One argument against diacetylmorphine maintenance is that patients receiving free diacetylmorphine might increase their spending on cocaine, other drugs, or both. Such an increase has not been reported in other studies. Moreover, we observed an important overall reduction in the money spent on illicit drugs in both groups.

Overdoses and seizures were the two most common serious adverse events related to diacetylmorphine. Sixteen of the 115 patients randomly assigned to receive diacetylmorphine had a life-threatening overdose or seizure during the study. Because the study included close medical supervision, these serious adverse events were promptly treated, and all patients recovered. Heroin is a respiratory depressant, and heroin injection is less safe than oral treatments. When injected opioids are taken under the supervision of health care staff, overdoses and seizures have been shown to be effectively treated. Had these overdoses occurred under circumstances in which no medical help was immediately available, as would be the case with the use of illicit heroin, the outcomes might have been worse. Our safety data suggest that diacetylmorphine should be delivered in settings where prompt medical intervention is available.

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Eugenia Oviedo-Joekes, Ph.D., Suzanne Brissette, M.D., David C. Marsh, M.D., Pierre Lauzon, M.D., Daphne Guh, M.Sc., Aslam Anis, Ph.D., and Martin T. Schechter, M.D., Ph.D.
N Engl J Med 2009; 361:777-786

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Heroin (diacetylmorphine, diamorphine) is a semi-synthetic opioid synthesized from morphine, a derivative of the opium poppy. It is the 3, 6-diacetyl ester of morphine (hence diacetylmorphine). The white crystalline form is commonly the hydrochloride salt diacetylmorphine hydrochloride.

As with other opiates, heroin is used both as a pain-killer and a recreational drug.

One of the most common methods of heroin use is via intravenous injection. When taken orally, heroin undergoes extensive first-pass metabolism via deacetylation, making it a prodrug for the systemic delivery of morphine. When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the blood-brain barrier due to the presence of the acetyl groups, which render it much more lipid-soluble than morphine itself. Once in the brain, it is deacetylated into 3- and 6-monoacetylmorphine and morphine, which bind to μ-opioid receptors resulting in intense euphoria with the feeling centered in the gut.