Therapy with supervised hydromorphone (multiple brands) injections shows noninferiority to therapy with diacetylmorphine hydrochloride (the active ingredient in heroin) in the treatment of severe opioid dependence, suggesting a potentially effective alternative treatment for severe, treatment-refractory patients, new research shows.
“Our study shows that a licensed medication, hydromorphone, is as good as diacetylmorphine at reducing the injection of street opioids, including street heroin,” senior author Eugenia Oviedo-Joekes, PhD, of the Centre for Health Evaluation and Outcome Sciences, Providence Health Care, St Paul’s Hospital, in Vancouver, Canada, told Medscape Medical News.
“For many contexts where diacetylmorphine is not licensed, hydromorphone offers an alternative,” she said.
The study was published April 6 in JAMA Psychiatry.
Those contexts of supervised opioid therapy, particularly employing heroin, are indeed few. The drug is not available in most countries, including the United States.
However, the treatment approach is used in several countries in Europe, including Germany, the Netherlands, Switzerland, and Denmark, where it is reserved for those with severe dependencies who are refractory to standard oral maintenance therapy with methadone or buprenorphine, according to the authors.
Importantly, six randomized trials have shown that treatment with supervised diacetylmorphine is more clinically effective and more cost-effective than oral methadone for the subgroup of severely addicted patients, the authors note.
In a subgroup analysis of patients treated with supervised hydromorphone, which is licensed as an analgesic, the authors reported being surprised that “participants were unable to detect that they were receiving hydromorphone [instead of diacetylmorphine].” In addition, hydromorphone appeared to be as effective as diacetylmorphine, although the investigators note that the study was not powered to make that comparison.
For the new phase 3, double-blind Study to Assess Longer-term Opioid Medication Effectiveness (SALOME), the researchers enrolled 202 long-term users of injection opioids in Vancouver from December 2011 to December 2013. Participants were randomly assigned to treatment either with injectable diacetylmorphine (n = 102) or hydromorphone (n = 100) up to three times daily, under supervision, for 6 months.
Among the patients, 30.7% were women; the mean age was 44 years.
A per protocol (PP) analysis showed noninferiority of hydromorphone compared with diacetylmorphine (-1.44; 90% confidence interval [CI], -3.22 to 0.27) in terms of the number of days of street heroin use, although the margin of 4 days was not observed in a separate intent-to-treat (ITT) analysis (-2.34; 90% CI, -4.14 to -0.52).
In terms of the outcome of total days for any street opioid use among the patients, both analyses confirmed noninferiority between the two treatments for the use of any street opioids (ITT analysis: -0.85; 90% CI, -2.97 to 1.25; PP analysis: -0.15; 90% CI, -2.09 to 1.76).
There were five reports of serious adverse events linked to the injection medication in the hydromorphone group, compared with 24 in the diacetylmorphine group (rate ratio, 0.21; 95% CI, 0.06 to 0.69), with seizures and overdoses accounting for 25 of the 29 adverse events. None of the seizures occurred in the patients receiving hydromorphone.
There were significantly fewer reports of drowsiness and overdoses in the hydromorphone arm. Treatment retention was high, at more than 80%, and was nearly identical in both groups.
The findings underscore the potential value of hydromorphone as an alternative treatment, said Dr Oviedo-Joekes.
“Treatment with injectables in specialized clinics has a very small, but very important, role in the addiction treatment system,” she said.
“Injectable diacetylmorphine ― and now hydromorphone ― has shown to attract and retain the most vulnerable patients into treatment and give us the opportunity to care for them. There is no single answer to the drug problem, and we need to build a wide array of options so no one is left behind.”
In an accompanying editorial, coauthors Richard Schottenfield, MD, and Stephanie S. O’Malley, PhD, both of the Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, said the study is particularly important in light of the opioid addiction epidemic ― and low treatment rates.
“One of the great values of this study is its focus on developing and evaluating treatments for some of the most difficult-to-reach and difficult-to-treat persons who inject heroin,” they write.
“Only approximately 21% are treated for opioid dependence in the United States, and approximately 50% are treated in Europe, with rates of treatment penetration substantially lower in some European countries and across most of the rest of the world.”
In comments to Medscape Medical News, the editorialists cautioned that the diacetylmorphine (or hydromorphone) treatment model is recommended only for patients with the most severe, injection-heroin addictions, and that it can pose risks for those with less severe dependencies.
“There is no evidence that diacetylmorphine treatment is as or more effective than treatment with methadone or buprenorphine for the vast majority of people with opioid use disorder,” they said. “There is evidence that diacetylmorphine is associated with greater risks than methadone or buprenorphine.”
The editorialists noted, however, that stepped-up treatment efforts are needed for all levels of opioid addiction, from mild to severe.
“The most important public health priority is to expand availability and accessibility of established effective treatments with methadone, buprenorphine, and naltrexone,” they said.
“However, it is also important to focus on ways of improving treatment outcomes for patients who do not benefit optimally from standard treatments and to develop alternative treatments or other harm-reduction approaches for people who do not engage in treatment with methadone, buprenorphine, or naltrexone.
“This study is a possible step along the way to developing alternative treatments for people who do not engage in or benefit from current treatments.”
“Resistance to methadone and buprenorphine treatment in many countries and regions has prevented or hindered efforts to scale up treatment, and it seems likely that opposition to supervised injection programs, even those using hydromorphone, would make it difficult to gain support.”
Stuart Gitlow, MD, MPH, a psychiatrist based in Woonsocket, Rhode Island, and past president of the American Society of Addiction Medicine, said he was not familiar with the approach of treating severe opioid addiction with heroin or hydromorphone, but that the therapy appears reasonable.
“I suppose in a highly controlled and supervised setting, there’s nothing wrong with the approach,” he told Medscape Medical News.
“It’s simply a taper, as used to be done with alcohol for those with alcoholism. In a highly controlled setting, this would be perfectly reasonable. And there would, in that case, be no (expected) difference whether dilaudid is used vs heroin. That makes sense as well.”
The study received funding from the Canadian Institutes of Health Research in partnership with Providence Health Care, with additional financial support from the Inner Change Foundation, the Providence Health Care Research Institute, St Paul’s Hospital Foundation, Vancouver Coastal Health, the Michael Smith Foundation for Health Research Career Award, the Canada Institutes of Health Research New Investigator Award, and the Canada Research Chairs Program. The editorial was supported by grants from the National Institute on Drug Abuse of the National Institutes of Health and by the Connecticut Department of Mental Health and Addiction Services. The authors and Dr Gitlow report no relevant financial relationships. Dr Schottenfeld received donated study medications from Indivior and Reckitt Benckiser. Dr O’Malley is a member of an American Society of Clinical Psychopharmacology work group for the Alcohol Clinical Trials Initiative, which is supported with funding from Abbott Laboratories, Alkermes, Eli Lilly, Lundbeck, Pfizer, and Ethyphama; she is a consultant or advisory board member for Alkermes, Cerecor Inc, and Amygdala; she has a site contract for a multisite study with Eli Lilly; she has received donated study medications from Pfizer and AstraZeneca; and she has served as a scientific panel member for the Hazelden Betty Ford Foundation.