Polysubstance Use Common in Buprenorphine Deaths

Deaths among people who use buprenorphine often also involve benzodiazepines, gabapentinoids, alcohol, and illicit substances, a study in Drug and Alcohol Dependence suggests. The findings signal a need to both screen for polysubstance use in people with substance use disorder and monitor carefully those patients who receive buprenorphine to treat opioid use disorder (OUD) who are also prescribed medications that can interact with the drug and raise the risk of accidental death.

“The importance of sedatives [in the deaths] was far greater than we could have imagined,” senior author Ilkka Ojanperä, Ph.D., a professor of forensic toxicology in the Department of Forensic Medicine at the University of Helsinki, told Psychiatric News. “It was clearly shown that buprenorphine alone does not cause deaths.”

Ojanperä and colleagues analyzed the autopsy records of 792 people aged 15 to 64 years who died in Finland between 2016 and 2019 wherein buprenorphine or norbuprenorphine was found in the decedents’ blood, urine, vitrous humor, liver, or muscle. In more than a third of these cases, buprenorphine was implicated in a fatal poisoning without other opioids. Among those, benzodiazepines were found in 94%, illicit drugs in 63%, gabapentinoids in 50%, and alcohol in 41%. Clonazepam was the most common benzodiazepine found in this group, present in 53%, while pregabalin was the most common gabapentinoid, present in 41%.

That buprenorphine was the sole opioid in so many of the fatal poisonings may seem unusual to Americans when opioid deaths in the United States largely involve synthetic opioids such as fentanyl and fentanyl analogs, prescription opioids such as oxycodone or hydrocodone, or heroin. Although the study was not designed to determine the source of the buprenorphine found in the autopsies, the researchers noted that more than 80% of people in Finland who use opioids illicitly use buprenorphine as their main substance. Furthermore, only 1% of those who receive medication treatment with buprenorphine in Finland take buprenorphine-only medications such as Subutex, yet 85% to 95% of the buprenorphine administered illicitly by injection originates from buprenorphine-only drugs, Ojanperä explained.

“Buprenorphine is used in opioid agonist treatment in our country mainly as a buprenorphine-naloxone combination [such as] Suboxone, but the poisoning deaths involving buprenorphine are mainly due to Subutex tablets smuggled from France,” Ojanperä said.

Buprenorphine was implicated along with other opioids in roughly 13% of the 792 deaths. Among those, benzodiazepines were found in 94%, gabapentinoids in 65%, and alcohol in 32%.

“The study found that the differences in substance findings between user groups were quite small,” Ojanperä said. “It is important to recognize the unsafe patterns of drug use and drug combinations and inform the patient.”

“Many patients with OUD also use other substances besides opioids. Ideally, it makes sense to monitor patients on buprenorphine for use of other substances either through clinical observation or toxicology testing or both,” said Andrew J. Saxon, M.D., a professor in the Department of Psychiatry and Behavioral Sciences at the University of Washington and director of the Center of Excellence in Substance Addiction Treatment and Education at the VA Puget Sound Health Care System. Saxon, who was not involved in the research, is a member of APA’s Council on Addiction Psychiatry.

“When other substance use is occurring, address it using the best evidence-based interventions,” Saxon said. “However, do not discontinue treatment for OUD with buprenorphine even if other substance use is occurring. Overall, staying on buprenorphine is more protective against overdose than discontinuing it.”

Ojanperä and colleagues noted that medications that may enhance the respiratory depressant effects of opioids and increase the risk of overdose death are often prescribed to patients with OUD, even though guidelines advise against it. Indeed, earlier this year, a study in Addiction revealed that 24% of adults who received buprenorphine treatment for OUD in Massachusetts between 2012 and 2015 filled at least one benzodiazepine prescription during buprenorphine treatment. During that time, 183 patients in the study died of opioid overdose, and nearly a third of those deaths occurred when patients received benzodiazepines during buprenorphine treatment.

Saxon said that prescribing benzodiazepines for patients on buprenorphine should be rare.

“In general, except for treating acute alcohol withdrawal, benzodiazepines are best avoided in most patients. We generally have better and safer treatments for anxiety disorders and insomnia disorders than benzodiazepines, primarily cognitive-behavioral therapy, but also medications such as a variety of antidepressants and buspirone for anxiety,” said Saxon. “In rare cases patients do not respond to any other intervention, and then, as a last resort, benzodiazepines could be prescribed with very careful monitoring at low or modest doses for patients on buprenorphine for OUD.”

Ojanperä’s study was supported in part by a personal grant to one of the researchers from the Häme Students Foundation in Helsinki, Finland. ■