Medically Prescribed Heroin Superior to Methadone for Severe, Refractory Opioid Dependence

Caroline Cassels

August 20, 2009

August 20, 2009 — A new Canadian study, which was not conducted in the United States because of potential funding and approval barriers, shows that treatment with injectable diacetylmorphine — also known as medically prescribed heroin — is more effective than oral methadone for chronic, refractory opioid addiction.

The phase 3 randomized controlled trial conducted by investigators at the University of British Columbia shows that the rate of retention in addiction treatment at 12 months among individuals taking medically prescribed heroin was 87.8% compared with 54.1% among subjects in the methadone group.

Furthermore, diacetylmorphine was associated with reduced rates of illicit drug use or other illegal activity compared with methadone, with rates of 67% vs 47.7%, respectively.

"We've shown that for those that need it, medically prescribed heroin can help us reach individuals who were previously considered to be beyond help and who can actually do remarkably well with this type of treatment," principal investigator Martin T. Schechter, MD, PhD, told Medscape Psychiatry.

In addition, said Dr. Schechter, the results support the idea that medically prescribed heroin is a viable treatment alternative. "Medically prescribed heroin adds another weapon to the treatment arsenal that we can use to treat heroin addiction," he said.

The study is published in the August 20 issue of the New England Journal of Medicine.

United States Lags Behind Canada

Methadone has been shown to reduce major risks associated with opioid addiction. However, the authors note that 15% to 25% of the most severely affected individuals do not respond well to methadone treatment.

European studies have suggested that Injectable diacetylmorphine can be an effective adjunctive treatment for chronic, relapsing opioid dependence.

To examine this as a potential treatment in North America, investigators conducted the North American Opiate Medication Initiative (NAOMI), an open-label, phase 3 randomized controlled trial, in Montreal and Vancouver from March 2005 to July 2008.

According to Dr. Schechter, financial and logistical barriers in the United States meant the study could only be conducted in Canada.

"When we were first planning this study in the late 1990s, it became increasingly clear that the American researchers in our group weren't going to be able to find the funding from the National Institutes of Health, and that they would not be able to get the necessary government approvals to conduct the study in the United States. At that point, we in the Canadian group decided to see if we could go it alone in Canada, and that's exactly how it turned out," said Dr. Schechter.

He went on to say that on the whole, the United States lags behind Canada in terms of its approach to the problem of injection drug dependence and is generally averse to needle exchange programs, safe injection sites, and harm reduction as treatment strategies.

Hardest to Reach, Hardest to Treat

The trial included long-term injectable heroin users who had not benefited from at least 2 previous attempts at treatment for addiction, including at least 1 methadone treatment. In addition to long histories of opioid dependence, participants had extensive involvement in criminal activity and multiple attempts at treatment.

"These are people chronically addicted to heroin. They had tried treatment multiple times in the past and on average had tried methadone 3 to 4 times. They were completely outside the system and not receiving any treatment, so they were the hardest patients to reach and the hardest to treat," said Dr. Schechter.

Subjects were randomly assigned to receive either methadone (111 participants) or diacetylmorphine (115 participants). In addition, 25 subjects were randomly assigned to receive injectable hydromorphone instead of diacetylmorphine.

Investigators and participants were aware of whether they were receiving oral methadone or injectable medications, but diacetylmorphine and hydromorphone were administered in a double-blind fashion. The injectable medications were self-administered in treatment clinics under supervision, with a maximum daily dose of 1000 mg for diacetylmorphine.

The rationale for the hydromorphone group, said Dr. Schechter, was to provide validation that study participants were not using street heroin. A licensed drug that is frequently used in hospitals to manage pain, hydromorphone behaves like heroin but is distinct from heroin on urine testing.

"We were relying on self-report of whether individuals were using street heroin, but we needed a scientifically objective way of determining whether their information was accurate. Urine testing of this small group of 25 individuals on hydromorphone provided us with that validation," he said.

Significant Reduction in Illicit Drug Use

The study's 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.

Study treatments were provided for 12 months, followed by a 3-month tapering-off period of the injectable drugs, during which patients were switched to conventional therapies such as oral methadone.

Participants receiving injectable medications could switch to oral methadone — either partially or wholly — any time during the study period if it was acceptable to the patient and their physician. In addition to drug therapy, subjects were offered a range of psychosocial and primary care services.

Overall, patients received diacetylmorphine a median of twice per day. The average daily dose was 392.3 mg when prescribed alone. Subjects in the methadone group received a mean daily dose of 96.0 mg.

Thirty patients were prescribed diacetylmorphine with methadone at some point during the study period. In this group, the mean daily dose of diacetylmorphine was 365.5 mg, and the mean daily dose of methadone was 34.0 mg.

The composite scores for drug use and illegal activities were reduced in both groups.

In addition to superior retention and response rates for diacetylmorphine compared with oral methadone, the investigators found a significant reduction in the mean number of days of illicit heroin use, from 26.6 to 5.3 days for diacetylmorphine vs 27.4 to 12 days in the methadone group.

Safety Data Require Careful Interpretation

Medically prescribed heroin was associated with 51 serious adverse events compared with 18 such events in the methadone group. For hydromorphone, there were 10 serious adverse events. However, said Dr. Schechter, these safety data must be interpreted with caution.

Dr. Schechter pointed out that during the 12-month study period there were a total of 89,924 diacetylmorphine injections. Serious adverse events in the diacetylmorphine included overdoses in 10 patients and seizures in 6 individuals. All of the overdoses were treated with naloxone, and there were no long-term effects.

"We gave people medically prescribed heroin 90,000 times, and we had a handful of overdoses and seizures. In each case they were treated right away [with naloxone], and there were no hospitalizations or long-term effects. My view, based on this experience with almost 90,000 treatments, is that this is a very safe and effective treatment if used properly," said Dr. Schechter.

Interestingly, he added, those in the hydromorphone group appeared to do as well as subjects on medically prescribed heroin, although, he pointed out, the study was not designed to test this drug as a potential treatment for opioid dependence.

However, he said, his team is currently planning a study to test this hypothesis in an upcoming study. If it turns out that hydromorphone is as effective as medically prescribed heroin, "this could provide us with another potential treatment alternative," he said.

Will "Homegrown" Results Be Better Received?

In an accompanying editorial, Virginia Berridge, PhD, from the London School of Hygiene and Tropical Medicine, University of London, United Kingdom, points out that "the prescription of heroin is now recognized in some European countries as the optimal treatment for patients for whom options are running out and in whom methadone maintenance has not worked, and it keeps the user in contact with drug services."

She adds that time will tell whether the "homegrown" results from the current NAOMI trial will have a greater effect in North America than findings from the European studies.

"We will now wait to see what political or professional factors will support or oppose the conclusions of this study in its home territory, and whether the historical legacy of heroin will matter."

N Engl J Med. 2009;361:777–786.

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