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Benzodiazepines Raise Overdose Risk — and Prolong Life-Saving Treatment for Opioid Use Disorder

In an effort to reduce harmful interactions, providers may be going too far in steering people with opioid use disorder away from anxiety meds.
The class of anxiety drugs called benzodiazepines interact with buprenorphine to cause dangerous effects, but the risks might be worth it to keep people in treatment for opioid use disorder.
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Many people with opioid use disorder (OUD) — nearly 1 in 3, by some estimates — also experience co-occurring anxiety or insomnia. Benzodiazepines are highly effective for both anxiety and sleep problems, but some providers have hesitated to prescribe benzos to patients with OUD because the medications can be addictive.

But that’s not the only concern. Many people in treatment for OUD are taking the drug buprenorphine, an opioid agonist that can decrease cravings and withdrawal symptoms. While benzodiazepines and buprenorphine are both remarkably safe when taken as indicated, there are significant dangers associated with mixing them. Physiologically, the drugs interact to eliminate the mechanism of action that makes each safe, increasing a person’s likelihood of central nervous system depression and ultimately, overdose death.

As a result, some patients with anxiety don’t get treatment for their OUD with buprenorphine, and other patients with OUD are refused benzodiazepine treatment for their anxiety.

The reluctance among providers to prescribe these drugs in combination was partly due to a so-called black box warning issued by the FDA in 2016 that warned the drugs could be fatal when used together. In response, the FDA issued a report the following year that cautioned providers not to withhold opioid use disorder medications simply because patients were taking central nervous system depressants such as benzodiazepines.

“The feeling is that it’s better to increase the potential harms of doing something, like prescribing benzodiazepines, and keep patients in treatment as opposed to losing them to treatment entirely,” says Tae Woo Park, MD, an addiction psychiatrist at Boston Medical Center. “The philosophy has changed.”

Park explains that there are distinct benefits to co-prescribing the drugs when patients take them as indicated, including better control over their anxiety that may allow for better engagement in treatment for their opioid addiction — which may be more likely to kill them than any benzo and buprenorphine interaction. Three years after the FDA’s advisory came out, addiction providers have begun shifting toward a harm reduction mindset, he says, but there’s still a way to go.

Research adds to the picture

In an effort to shed light on the benefits and risks of co-prescribing benzodiazepines and buprenorphine, Park and colleagues recently examined the connections between benzodiazepine prescriptions, overdose death, and buprenorphine continuation using data from the Massachusetts Public Health Data Warehouse, which combines opioid-related data from multiple state agencies.

In the study, published in Addiction, 24% of 63,389 individuals who received buprenorphine had filled at least one prescription for benzodiazepines during their buprenorphine treatment. Researchers found that benzodiazepine receipt during buprenorphine treatment was associated with greater risk of a fatal and nonfatal opioid overdose. However, patients were also less likely to discontinue buprenorphine treatment if they also received a benzodiazepine.

These results suggest that the benefits of prescribing benzodiazepines alongside buprenorphine may outweigh the risks for some patients if it keeps them in OUD treatment, Park says. The study found that fatal opioid overdose during buprenorphine treatment was rare, representing less than 4% of the estimated total opioid overdoses that occurred in Massachusetts over the course of the study.

The potential benefits and dangers of co-prescribing

Treating patients’ underlying anxiety disorders may be the driving force behind the continuation of buprenorphine. Resolving these symptoms may encourage people with opioid use disorder to stay on buprenorphine.

While evidence-based psychotherapy is a useful alternative, many patients with opioid use disorder are resistant to engaging with a therapist, says Park, or don’t complete enough sessions to create meaningful change. Trained practitioners who offer these sessions are also in short supply, and first-line anxiety medications — like SSRIs — aren’t effective for certain individuals, sometimes causing intolerable side effects. Benzodiazepines may be some people’s best option.

The benefits of prescribing benzodiazepines alongside buprenorphine may outweigh the risks for some patients if it keeps them in OUD treatment.

Some people take advantage of the interaction between the medications to create a dangerous drug cocktail that causes blackouts and numbs reality. However, Park says this type of misuse is likely the exception, not the rule, likening the trend of withholding benzos to the pattern of prescription opioid stewardship that has left many patients with legitimate need in pain.

“The majority of people who are taking prescribed opioids for their pain are taking them safely and they're getting some benefit from it,” says Park. “It's the same idea with benzos. You know there are risks, but you know that some people are benefiting. We just need to figure out a better way of assessing whether a certain patient can take them safely or not.”

A shift toward harm reduction: 'We should do a better job'

He adds that providers should always clearly communicate risk to their patients, monitor them carefully for signs of medication misuse, and be mindful of the consequences associated with stopping prescriptions.

“If you take benzodiazepines away from somebody who is stable in buprenorphine treatment, then you run the risk of them dropping out of treatment,” says Park.

The takeaway from the study, Park explains, is that benzodiazepine co-prescriptions for people on buprenorphine can both hurt or help them. The task now, then, is figuring out which patients fall in which category.

Going forward, we need further research to determine which patient populations are likely to benefit from buprenorphine-benzodiazepine co-prescriptions and which are more likely to be harmed. Until then, the researchers argue, we shouldn’t cut off a patient population from benzodiazepines when we have so few effective treatments available.

“Knowing that there are risks, we should learn how to prescribe them safely,” Park says. “We should do a better job of it, instead of just saying no.”

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Kerry Benson


Kerry is a freelance writer holding a master’s in science writing from Johns Hopkins University. Her work has appeared in Boston University’s The Brink, Northeastern University’s [email protected], and Hippocampus Magazine, among others. She has also authored three nonfiction books, most recently about the opioid epidemic.