A weekly subcutaneous buprenorphine depot could improve adherence and reduce the potential for misuse, according to a study presented at the annual meeting of the College on Problems of Drug Dependence and published simultaneously June 22 in JAMA Psychiatry.
In a phase II, double-blind, randomized study, 47 adults with moderate to severe opioid use disorder were randomized to a weekly dose of the subcutaneous buprenorphine depot CAM2038 – either 24 mg or 32 mg – for 2 weeks. They also underwent five 3-day test sessions to evaluate their response to 6 mg and 18 mg doses of intramuscular hydromorphone and a 0 mg control. One qualification session was held before randomization and the remaining four sessions after.
The primary outcome of the study was drug liking, and both doses of CAM2038 were associated with immediate, sustained, and dose-related suppression of participants’ response to hydromorphone (JAMA Psychiatry. 2017 June 22. doi:10.1001/jamapsychiatry.2017.1874).
The depot also appeared to block the dose-dependent increase in drowsiness that was seen in response to hydromorphone in the qualification session.
However, there was a reversal of the dose-dependent response in participants’ desire to use opioids, with greater suppression seen at the lower depot dose.
Buprenorphine is known to be safer than methadone for the treatment of opioid use disorders, but Sharon L. Walsh, PhD, of the Center on Drug and Alcohol Research at the University of Kentucky, Lexington, and her coauthors said sublingual buprenorphine itself has become an abuse liability in some countries.
“Sublingual formulations of buprenorphine can be injected or snorted to enhance euphoric effects,” they wrote. “Unintentional overdose with buprenorphine has been reported, leading to toxicity and fatality in children and those who coingest buprenorphine with benzodiazepines or alcohol.”
The results mean the formulation meets the U.S. Food and Drug Administration criteria for complete opioid blockade.
CAM2038 achieved complete suppression of opioid withdrawal at both doses, and Clinical Opiate Withdrawal Scale (COWS) remained suppressed for the entire duration of the study.
“During treatment initiation, it is important that withdrawal symptoms are well-controlled,” the authors wrote. “The COWS and [Objective Opioid Withdrawal Scale] scores were reduced to near zero on the first dosing day with suppression thereafter.”
The mean COWS preinjection score was 11, which did not include five participants who accidentally were inducted with CAM2038 before they had achieved the prespecified criteria of a COWS score of 8 or above.
They also noted that the pharmacokinetic profile of CAM2038 showed gradually increasing buprenorphine concentrations, reaching maximum at around 24 hours after the dose was given. Perhaps because of this effect – which they likened to a de factor induction procedure mimicking the recommended induction with sublingual buprenorphine – the authors suggested that patients using CAM2038 could likely be inducted directly using the depot.
Researchers also looked at some key physiological outcomes before and after treatment with the depot. They found that, while patients showed significant dose-dependent reductions in oxygen saturation with hydromorphone before receiving depot treatment, these were significantly attenuated after treatment with CAM2038.
One subject withdrew from the study because of ventricular extrasystoles, and one showed abnormal liver function at discharge that was later attributed a hepatitis C diagnosis. Neither event was linked to the study drug.
However, 81% of patients experienced at least one adverse event, with significantly more events reported in the higher dose group. The most common reported events that were possibly related to the study drug were constipation, injection site pain and erythema, and headache. Most were rated as mild.
The College on Problems of Drug Dependence, a nonprofit corporation, is holding its annual meeting in Montreal. The study was supported by research contracts from Braeburn Pharmaceuticals, with additional support from the National Institute on Drug Abuse, the National Center for Research Resources, and the National Center for Advancing of Translational Sciences. Two authors are employees of study sponsor Braeburn Pharmaceuticals, and one is an employee of Camurus – a partner to the sponsor. Three authors also received research contract support from Braeburn, four research consultant fees from Braeburn, and two received consulting fees or partial salary support from Camurus, and other pharmaceutical companies.