By Brenda L. Mooney
PROVIDENCE, RI — Researchers are urging VA clinicians to be cautious about prescribing benzodiazepines to veterans already taking opioid painkillers.
That’s in light of a new study, published online recently by the British Medical Journal, finding that nearly half of all veterans who died from drug overdoses while on opioids were also receiving higher doses of benzodiazepines, often used for anxiety, insomnia or alcohol withdrawal.
“Although the design of this study does not allow for the determination of the extent to which benzodiazepines cause deaths from overdose,” write the authors from Rhode Island Hospital in Providence, Boston Medical Center and the VA Ann Arbor, MI, Healthcare System, “it does indicate a need for clinicians to be aware of the increased risk among patients currently receiving benzodiazepines and opioids and that the risk might be higher among those receiving higher doses of either or both drugs.”
“The risk of receiving both opioids and benzodiazepines during this six-year period was approximately four times higher than in those who received opioids alone,” added lead author Tae Woo Park, MD, attending physician at Rhode Island Hospital. “From a public health perspective, this is deeply troubling, because drug overdoses are a leading cause of death in the U.S., and prescribing benzodiazepines to patients taking opioids for pain is quite common. In 2010, 75% of pharmaceutical-related drug-overdose deaths involved opioids. As we learn more about pharmaceuticals and how they interact with each other, we can try to reduce the risk of harm to patients.”
For the study, the research team reviewed patient records of 2,400 veterans who died from drug overdoses while receiving medical services as an outpatient at the VHA between October 2004 and September 2009. The review focused on the relationship between the opioids and benzodiazepines when prescribed concurrently.
Results indicate that, during the study period, 27% of a random sample 420,386 of veterans who received opioid analgesics also received benzodiazepines, and about half of the deaths from drug overdose – involving 1,185 veterans — occurred with concurrent benzodiazepines and opioid prescriptions.
Benzodiazepine types included in the study were alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam, temazepam, estazolam, flurazepam, oxazepam, quazepam and triazolam. The most commonly prescribed benzodiazepines were those on the VHA drug formulary (i.e., alprazolam, chlordiazepoxide, clonazepam, diazepam, lorazepam and temazepam). The other benzodiazepines included in the study were prescribed during the study period but at lower rates, the researchers write.
Women were more likely to receive benzodiazepines than men — 33% vs. 26%. Recipients also were more likely to be middle aged, white and living in wealthier areas. Additionally, they were more likely to have had a recent hospital admission for mental health or substance use disorder, to have a diagnosis of a substance use disorder or several psychiatric disorders, including post-traumatic stress disorder, other anxiety disorders, depression and bipolar or psychotic disorders and to use other drugs, according to the article.
The report indicates that the risk of death from drug overdose increased with history of benzodiazepine prescription; adjusted hazard ratios were 2.33 for former prescriptions vs. no prescription and 3.86 for current prescriptions vs. no prescription.
Furthermore, the risk of death from drug overdose increased as daily benzodiazepine dosage increased. Compared with clonazepam, the researchers note, temazepam was associated with a decreased risk of death from drug overdose of 0.63.
Benzodiazepine dosing schedule was not associated with risk of death from drug overdose.
Part of the problem is the older age of the cohort treated by the VA, according to background information in the study.
“Although the toxicity of benzodiazepines used in isolation is generally considered mild in young and middle-aged adults, the risks from over-sedation are believed to be magnified when they are combined with other substances with sedating properties, such as opioids,” the authors point out. “Also, receipt of benzodiazepines could be a marker of the presence of a severe anxiety disorder, which carries its own risk for death from intentional and unintentional overdose.”
Researchers also point out that benzodiazepines are more likely to be prescribed to patients with substance misuse and other psychiatric disorders — conditions that carry their own risk for death from overdose.
“Although we were unable to determine whether benzodiazepine prescribing patterns are the direct cause of death from drug overdose because of the observational design of this study,” the authors conclude, “we found that receipt of concurrent benzodiazepines was associated with an increased risk of death from overdose in this large national sample of veterans who received opioid analgesics.”
1Park TW, Saitz R, Ganoczy D, Ilgen MA, Bohnert AS. Benzodiazepine prescribing patterns and deaths from drug overdose among US veterans receiving opioid analgesics: case-cohort study. BMJ. 2015 Jun 10;350:h2698. doi: 10.1136/bmj.h2698. PubMed PMID: 26063215; PubMed Central PMCID: PMC4462713.