Journal Club Alcohol, Other Drugs, and Health: Current Evidence September–October 2009

Featured Article Diacetylmorphine versus Methadone for the Treatment of Opioid Addiction Oviedo-Joekes E, et al. N Engl J Med. 2009; 361(8):777–786.

Study Objective To determine whether diacetylmorphine, the active ingredient in heroin, can be an effective treatment for chronic, relapsing opioid dependence.

Study Design Open-label phase-3 randomized controlled trial. Long-term heroin users from 2 Canadian sites who had not benefited from ≥2 previous attempts at treatment (including at least 1 methadone treatment) were randomly assigned to: –injectable diacetylmorphine (n=115), or –oral methadone maintenance therapy (n=111). * Outcomes assessed at 12 months included: –retention in treatment, and –reduction in illicit-drug use or other illegal activity. *An additional 25 subjects were randomized to receive injectable hydromorphone to facilitate validation of self-reported heroin use by urine tests.

Assessing Validity of an Article about Therapy Are the results valid? What are the results? How can I apply the results to patient care?

Are the Results Valid? Were patients randomized? Was randomization concealed? Were patients analyzed in the groups to which they were randomized? Were patients in the treatment and control groups similar with respect to known prognostic variables?

Are the Results Valid? (cont.) Were patients aware of group allocation? Were clinicians aware of group allocation? Were outcome assessors aware of group allocation? Was follow-up complete?

Were patients randomized? Yes. –Computer-generated randomization was used to assign patients to treatment groups.

Was randomization concealed? Yes. –Randomization was concealed.

Were patients analyzed in the groups to which they were randomized? Yes. –Retention and response rates were calculated on an intention-to-treat basis.

Were the patients in the treatment and control groups similar? Yes. –Baseline characteristics of the groups were similar.

Were patients and clinicians aware of group allocation? Yes, for the main comparison. –Investigators and participants knew whether the prescribed drug was oral methadone or an inject- able medication. –Neither investigators nor participants knew whether the injectable medication was diacetyl- morphine or hydromorphone.

Were outcome assessors aware of group allocation? Outcomes were assessed at research offices that operated independently from the treatment clinics. No information is pre- sented that indicates that assessors were not aware of group allocation.

Was follow-up complete? Of the 111 patients who received methadone, –106 had retention data available. –104 had response data available. Of the 115 patients who received diacetylmorphine, –114 had retention data available. –111 had response data available. Of the 25 patients who received hydromorphone, –25 had retention and response data available.

What Are the Results? How large was the treatment effect? How precise was the estimate of the treatment effect?

How large was the treatment effect and how precise was the estimate of treatment effect? The rate of retention in treatment in the diacetylmorphine group was 87.8% compared with 54.1% in the methadone group (rate ratio, 1.62; 95% CI, 1.35 to 1.95; p<0.001). For the outcome of a reduction in illicit-drug use or other illegal activities, 67% of the patients in the diacetylmor- phine group were classified as having a response compared with 47.7% of patients in the methadone group (rate ratio, 1.40; 95% CI, 1.11 to 1.77; p=0.004). Twenty-three patients (20%) originally assigned to diacetylmorphine switched to methadone.

How Can I Apply the Results to Patient Care? Were the study patients similar to the patients in my practice? Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harm and costs?

Were the study patients similar to those in my practice? Participants were largely middle-aged men who were marginally housed, did not complete high school, had a record of illegal activities, and reported opioid use for 16 to 19 years.

Were all clinically important outcomes considered? The primary outcomes, retention in treatment at 12 months and reduction in illicit-drug use or other illegal activities, are clinically important.

Are the likely treatment benefits worth the potential harm and costs? A total of 24 adverse events occurred among patients in the diacetylmorphine group (including 11 overdoses and 7 seizures). None occurred in the methadone group. This raises substantial concerns regarding the potential harms associated with diacetylmorphine treatment.