Diacetylmorphine versus methadone for the treatment of opioid addiction

N Engl J Med. 2009 Aug 20;361(8):777-86. doi: 10.1056/NEJMoa0810635.


Background: Studies in Europe have suggested that injectable diacetylmorphine, the active ingredient in heroin, can be an effective adjunctive treatment for chronic, relapsing opioid dependence.

Methods: In an open-label, phase 3, randomized, controlled trial in Canada, we compared injectable diacetylmorphine with oral methadone maintenance therapy in patients with opioid dependence that was refractory to treatment. Long-term users of injectable heroin who had not benefited from at least two previous attempts at treatment for addiction (including at least one methadone treatment) were randomly assigned to receive methadone (111 patients) or diacetylmorphine (115 patients). The primary outcomes, assessed at 12 months, were retention in addiction treatment or drug-free status and a reduction in illicit-drug use or other illegal activity according to the European Addiction Severity Index.

Results: The primary outcomes were determined in 95.2% of the participants. On the basis of an intention-to-treat analysis, the rate of retention in addiction treatment in the diacetylmorphine group was 87.8%, as compared with 54.1% in the methadone group (rate ratio for retention, 1.62; 95% confidence interval [CI], 1.35 to 1.95; P<0.001). The reduction in rates of illicit-drug use or other illegal activity was 67.0% in the diacetylmorphine group and 47.7% in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; P=0.004). The most common serious adverse events associated with diacetylmorphine injections were overdoses (in 10 patients) and seizures (in 6 patients).

Conclusions: Injectable diacetylmorphine was more effective than oral methadone. Because of a risk of overdoses and seizures, diacetylmorphine maintenance therapy should be delivered in settings where prompt medical intervention is available. (ClinicalTrials.gov number, NCT00175357.)

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adult
  • Cocaine-Related Disorders / epidemiology
  • Double-Blind Method
  • Drug Overdose
  • Female
  • Heroin / administration & dosage
  • Heroin / adverse effects
  • Heroin / therapeutic use*
  • Heroin Dependence / drug therapy*
  • Heroin Dependence / epidemiology
  • Humans
  • Hydromorphone / adverse effects
  • Hydromorphone / therapeutic use
  • Illicit Drugs
  • Injections
  • Male
  • Methadone / administration & dosage
  • Methadone / adverse effects
  • Methadone / therapeutic use*
  • Substance Abuse Detection
  • Substance Abuse, Intravenous / drug therapy


  • Illicit Drugs
  • Heroin
  • Hydromorphone
  • Methadone

Associated data

  • ClinicalTrials.gov/NCT00175357

Grants and funding