Patients on opioid replacement therapy have an increased risk of death early on in treatment, and again when they come off, researchers have found.

The risk was greatest — eight to nine times as high as that during treatment — immediately after coming off methadone or buprenorphine, Matthew Hickman, MD, of the University of Bristol in England, and colleagues reported in BMJ.

„The overall risk of death during opiate substitution treatment was lower than the risk of death out of treatment,“ they wrote.

The researchers conducted a prospective cohort study among primary care patients diagnosed with substance abuse and prescribed methadone or buprenorphine between 1990 and 2005.

A total of 5,577 patients given 267,003 prescriptions were followed up until one year after the expiration date of their last prescription.

Overall, the researchers found that the crude mortality rates were almost double for those who came off treatment: 0.7 per 100 person-years while on treatment and 1.3 per 100 person-years after coming off.

However, in the first two weeks of opiate substitution, the crude mortality rate was 1.7 per 100 person-years — just over three times higher than the rate during the rest of the time on treatment, the researchers said.

The first two weeks was a critical time period after treatment was stopped, too. Crude mortality rates were 4.8 per 100 person-years during the first two weeks post-treatment and 4.3 per 100 person-years during the third and fourth weeks.

That’s nine and eight times the risk of death when being on treatment, the researchers said.

Those rates fell to 0.95 during the rest of the time off treatment — a figure that was still nearly twice as high as patients‘ baseline risk.

The researchers said they were cautious about the potential mechanisms at work because they didn’t directly assess those factors in this study.

But, they said, the findings are generally consistent with the literature, which holds that risk of overdose is higher when opiate tolerance has temporarily fallen — after a patient has gone through an induction phase to start treatment, for instance.

So if, after ending replacement therapy, the patient goes back to using his drug of choice, „the first few occasions of opiate use pose the greatest risk of precipitating fatal overdose before tolerance has been re-established,“ according to the researchers.

They also observed that substitution therapy’s mortality benefits may relate to the duration of treatment, as opiate substitution treatment has more than an 85% chance of reducing overall mortality if patients are on it for at least 12 months.

They said that further research is needed to investigate the effect of average duration of opiate substitution treatment on drug-related mortality.

They also called for closer supervision of the induction phase of treatment, and for ongoing monitoring of the impact of opiate substitution treatment on mortality in the U.K. and other countries.