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SAN DIEGO -- Despite being well aware that patients who take benzodiazepines while on buprenorphine are at increased risk for overdose and death, more than half of doctors surveyed still prescribed the two together, according to a study presented here.

Among surveyed physicians who prescribed the opioid partial agonist buprenorphine in 2015, 54.8% said they had also prescribed a benzodiazepine to the same patient. In 2016, 61.3% said they had prescribed the two together, reported Karen Gerlach, PhD, MPH, of Pinney Associates in Pittsburgh.

Recent FDA guidance could make this practice more common.

"We've been watching this for quite a few years," Gerlach told 番茄社区app. "We were already seeing a lot of co-prescribing and even from the same prescriber."

The researchers separately looked at buprenorphine-related deaths and found that benzodiazepine was also involved in 25.7% of the cases reported to the FDA's Adverse Event Reporting System, and in 49.3% of buprenorphine-related deaths in Florida, which has more detailed information than the FDA's database. In only one of 71 Florida autopsies was buprenorphine alone determined to be the cause of death.

"As you can see there are some serious outcomes," said Gerlach, during a poster session at the American Society of Addiction Medicine 49th Annual Conference.

The researchers looked at surveys from 2014 to 2016, taken in consecutive years by 1,214 doctors who prescribed buprenorphine. The surveys were conducted as part of the Buprenorphine-Containing Transmucosal Products for Opioid Dependence Treatment (BTOD) Risk Evaluation and Mitigation Strategy (REMS) program from the FDA -- approved in 2013 in order to reduce the risks of accidental overdose and death from buprenorphine-containing agents, and to raise awareness of the risks among patients, clinicians, and pharmacists.

They reported that the vast majority of doctors prescribing buprenorphine (97.3% to 98.3%) indicated they were aware of the increased overdose and mortality risk when patients also took a benzodiazepine, a central nervous system (CNS) depressant commonly used for treating anxiety.

Gerlach's group also examined healthcare utilization data from a cohort of 43,118 U.S. patients treated with buprenorphine, who were followed for 4 years. This data revealed that an alarming number of patients had prescriptions for the two drugs that overlapped (ranging from 33.5% in 2014 to 45.6% in 2016), and these were frequently from the same doctor. In 2015, 46.6% of these overlapping prescriptions were from the same physician, though in 2016 this rate dropped to 22.8%.

Overall, simultaneous use of the two drugs for 4 months or longer occurred in 26.0% to 44.0% of patients studied. The most recent data (2017) showed that in 51% of these cases the same doctor had prescribed the two drugs simultaneously.

Gerlach warned that recent guidance from the FDA could inadvertently lower the concerns over the risk of overdose and death. "We may actually start seeing more problems instead of fewer problems," she said.

When the FDA first approved the labelling for buprenorphine, benzodiazepines were contraindicated.

Last September, however, the FDA issued a Drug Safety Communication that, while acknowledging risks with the combination, advised that it could be legitimately prescribed because the risks of untreated opioid use disorder were even worse.

The FDA statement noted that "discharging patients from treatment because of use of benzodiazepines or CNS depressants is not likely to stop them from using these drugs together. Instead, the combined use may continue outside the treatment setting, which could result in more severe outcomes."

In light of this, the FDA went on to lay out a , for when patients on methadone or buprenorphine are treated with benzodiazepine or another CNS depressant. The plan included:

• Educating patients on the increased overdose and death risk with combined use -- "even when used as prescribed"
• Helping patients taper off benzodiazepines or CNS depressants until they are no longer taking them
• Verifying a diagnosis of anxiety or insomnia and considering alternate options instead of a benzodiazepine
• Making other prescribers aware that the patient is on buprenorphine or methadone
• Screening the patient with urine or blood to monitor illicit drug use

"We understand that there are a lot of patients that do need both medications, but be cautious," said Gerlach. "Be aware that this is a serious potential risk to patients."

Joseph Valdez, MD, an addiction medicine specialist at a Geisinger-Bloomsburg MAT Clinic in Pennsylvania, told 番茄社区app that the study findings on the frequent co-use of benzodiazepines and buprenorphine were "very relevant" to his clinical practice.

"This presents a dilemma to addiction treatment providers as it is well known that the co-use of these substances increases the risk of overdose death," Valdez said.

He noted that since the FDA report, more patients on benzodiazepines have been accepted onto treatment with buprenorphine.

"My approach involves educating the patient about the risks of concurrent use of these medications, coordinating with their benzodiazepine prescriber to discuss taper strategies and use of alternative medications, and frequent monitoring in the clinic," Valdez said. "Ultimately, we are trying to provide safe, evidence-based treatment for patients with a severe chronic disease."

Joseph Valdez, MD, an addiction medicine specialist at a Geisinger-Bloomsburg MAT Clinic in Pennsylvania, told 番茄社区app that the study findings on the frequent co-use of benzodiazepines and buprenorphine were “very relevant” to his clinical practice.

“This presents a dilemma to addiction treatment providers as it is well known that the co-use of these substances increases the risk of overdose death,” Valdez said.

He noted that since the FDA report, more patients on benzodiazepines have been accepted onto treatment with buprenorphine.

“My approach involves educating the patient about the risks of concurrent use of these medications, coordinating with their benzodiazepine prescriber to discuss taper strategies and use of alternative medications, and frequent monitoring in the clinic,” Valdez said. “Ultimately, we are trying to provide safe, evidence-based treatment for patients with a severe chronic disease.”

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