Although prescribing benzodiazepines concurrently with opioid analgesics has been shown to raise the risk for fatal overdose, new research documents a risk that is four times that of opioids taken alone, and even at low doses. The new study was published online in the British Medical Journal (2015;350:h2698).
Additionally, the authors found a dose-dependent association with overdose risk. This may “help prioritize how we address this risk,” said Roger Chou, MD, professor in the Departments of Medicine and Medical Informatics and Clinical Epidemiology at Oregon Health & Science University (OHSU) School of Medicine, and a staff physician in the Internal Medicine Clinic at OHSU, in Portland, who was not involved in the research. “Meaning, you can start by identifying patients on high doses of benzos, and go from there.”
David Juurlink, MD, PhD, professor and head of the Division of Clinical Pharmacology at the University of Toronto, noted that the investigators found a heightened risk for death even at low opioid doses, “which is extremely important.” Dr. Juurlink also was not involved in the research.
The study, said Dr. Chou, is consistent with prior case series and coroner series, but breaks new ground “by using a cohort design that enables calculation of risk estimates and adjustment for potential confounders.”
“This paper should remind physicians of the dangers of prescribing CNS [central nervous system] depressants such as benzodiazepines with opioids,” said Dr. Juurlink. “This is about as basic as drug interactions get, so the effect isn’t exactly a surprise. But the extent of coprescribing is incredible.”
In the study, Tae Woo Park, MD, assistant professor in the Departments of Medicine and Psychiatry and Human Behavior at the Warren Alpert Medical School of Brown University, in Providence, R.I., and his mentor and co-investigator, Amy S.B. Bohnert, of the U.S. Department of Veterans Affairs (VA), Health Services Research and Development Service, in Ann Arbor, Mich., identified 2,400 cases of death from drug overdose among 422,786 veterans receiving opioids for the treatment of acute, chronic and nonterminal cancer pain. Data were culled from VA claims data, VA pharmacy records and the National Death Index, which collects death records from individual states. Benzodiazepines were prescribed to about one-fourth of patients prescribed opioids (112,069). Roughly half of the overdose deaths (n=1,185) occurred in patients prescribed both opioids and benzodiazepines. The adjusted hazard ratio for patients with a previous benzodiazepine prescription compared with no prescription was 2.33 (95% CI, 2.05-2.64), whereas the adjusted hazard ratio for patients with a current prescription compared with no prescription was 3.86 (95% CI, 3.96-4.26).
Dr. Park advised physicians that “if you are going to prescribe benzodiazepines [to people on analgesic opioids], you should understand that there may be an increased risk of overdose, and you should consider what disorder you are attempting to treat. Typically, benzodiazepines are prescribed for anxiety disorders and insomnia, and these are pretty common in patients with pain problems. You want to ensure that you are prescribing in an evidence-based manner, and carefully weigh the risks and benefits of treatment.”
For example, said Dr. Park, there is little evidence that benzodiazepines adequately treat patients with post-traumatic stress disorder, “but evidence from the VA shows that they are commonly prescribed for that population.”
Dr. Park said safer alternatives are available, including the tetracyclic antidepressants trazodone and mirtazapine for sleep difficulties and selective serotonin reuptake inhibitors for anxiety. He also noted that psychotherapies such as cognitive-behavioral therapy have been shown to be effective for both anxiety and insomnia.
Mitigating Risk Factors
Dr. Park advises physicians to be alert for various factors outside of benzodiazepines that put patients on opioids at elevated risk for overdose. These include high opioid doses, mental health and substance abuse diagnoses, and having multiple prescribers of opioids and multiple pharmacies filling those prescriptions.
Dr. Juurlink advised physicians to keep the “big picture in mind” in their efforts to treat conditions ancillary to chronic pain, such as anxiety and insomnia.
“We should remember that the overarching goal of drug therapy is to afford benefits—in terms of quality and quantity of life—that exceed the risks of therapy,” he said. “This is a no-brainer, but it needs to be explicitly reiterated here. It’s my view that most benzodiazepine prescriptions don’t meet that goal, and many opioid prescriptions don’t either, particularly at high doses for patients with chronic pain. The combining of these two classes, particularly over the long term, is extremely difficult to justify and sometimes inexcusable. Before prescribing opioids and benzodiazepines, individually or together, I think doctors should step back and ask, ‘What am I really hoping to accomplish with this prescription?’ If we reflected on that question more often, we would save a lot of lives.”
Dr. Chou warned, “In clinical practice, it can be tough to get people off benzos—withdrawal can be life-threatening.”
He praised the paper’s quality, stating, “It attempted to adjust for covariates and used appropriate statistical techniques. Unlike other studies completely based on data from administrative databases, it appeared to use information from medical records to determine comorbidities, etc., which is a strength.”
He added, however, that he would have liked to have seen an analysis that was based on the duration of benzodiazepine use “to address whether the risk is as high in patients who have been co prescribed benzos and opioids for many years.”