Dangerous Prescribing Practice May Boost Overdose Risk

Caroline Cassels

March 14, 2017

Concurrent prescribing of opioids and benzodiazepines – a dangerous practice that is associated with a significantly increased risk for overdose – is on the rise, new research shows.

A retrospective analysis conducted by investigators at Stanford University in California showed that for patients who used both drug types concurrently, there was a more than twofold increased risk for an emergency department (ED) visit or inpatient admission for opioid overdose in comparison with patients who used opioids but who did not also use benzodiazepines.

Furthermore, the investigators found a significant increase in concurrent prescribing of opioids and benzodiazepines over a 12-year period.

"From 2001 to 2013, concurrent benzodiazepine/opioid use sharply increased in a large sample of privately insured patients in the US and significantly contributed to the overall population risk of opioid overdose," the authors, led by Eric C Sun, MD, PhD, write.

The study was published online March 14 in the BMJ.

Prescribe With Caution

The investigators note that during the past 15 years, opioid prescriptions have increased nearly threefold, a trend that parallels a concurrent increase in opioid-related overdoses and deaths.

Research also shows that nearly one third of fatal opioid overdoses also involve benzodiazepines, suggesting that concurrent opioid/benzodiazepine use may be hazardous and may be a contributor to opioid overdose and/or death.

"Although benzodiazepines have received less public safety attention than opioids, the combination of the two drugs is dangerous because benzodiazepines potentiate the respiratory depressant effects of opioids," the authors write.

The aim of the study was to identify trends in concurrent opioid and benzodiazepine use and determine the impact of these trends on hospital admissions and ED visits for opioid overdose.

The study included claims data from 315,428 privately insured individuals aged 18 to 64 years who filled at least one prescription for an opioid between 2001 and 2013.

The main outcome measures were the annual percentage of opioid users with concurrent benzodiazepine use and the annual incidence of visits to EDs and inpatient admissions for opioid overdose.

The investigators found that 9% of opioid users also used a benzodiazepine in 2001. In 2013, this increased to 17% ― a relative increase of 80%. The researchers note that this increase was mainly driven by increases among intermittent vs long-term opioid users.

The researchers also found that compared to opioid monotherapy, combined use of both drug types was linked to an increased risk for an ED visit or inpatient admission for opioid overdose (adjusted odds ratio [AOR], 2.14, 95% confidence interval [CI], 2.05 - 2.24; P < .001) among all opioid users.

The AOR for an ED visit or inpatient admission for opioid overdose was 1.42 (95% CI, 1.33 - 1.51; P < .001) for intermittent opioid users and 1.81 (95% CI, 1.67 - 1.96; P < .001) for long-term opioid users.

"If this association is causal, elimination of concurrent benzodiazepine/opioid use could reduce the risk of emergency room visits related to opioid use and inpatient admissions for opioid overdose by an estimated 15%," the researchers write.

The investigators note that the study findings have several implications for clinical practice and healthcare policy. First, healthcare providers need to "exercise caution in prescribing opioids for patients who are already using benzodiazepines (or vice versa) even in a non-chronic setting.

"Indeed, we note that the association between concurrent benzodiazepine/opioid use and the risk of opioid overdose was broadly similar for both intermittent and chronic opioid users. Therefore, opioids should be prescribed cautiously ― even if only for a short term course ― among patients who are also using benzodiazepines."

From a policy perspective, the authors suggest that prescribers and patients be educated about the potential risks of combined use of opioids and benzodiazepines.

Guidelines Not Enough

In an accompanying editorial, Pnar Karaca-Mandic, PhD, Division of Health Policy and Management, School of Public Health, University of Minnesota, Minneapolis, along with Ellen Meara, PhD, and Nancy E Morden, MD, MPH, both from the DartmouthInstitute for Health Policy and Clinical Practice, Lebanon, New Hampshire, call for a comprehensive approach to change clinical behavior.

"[A] multi-pronged effort from both regulators and experts writing clinical guidelines, along with extensive expansion in warnings about the hazards of drug-drug interactions, are essential to reduce low value, potentially dangerous care," they write.

They note that in 2016, the Centers for Disease Control and Prevention issued guidelines on opioid prescribing in which physicians were urged to avoid concurrent prescribing with benzodiazepines. In addition, the US Food and Drug Administration now requires black box warnings on product labels and patient-focused medication guides for opioids and benzodiazepines.

"Warnings and guidelines, while important to defining problematic practice, are not likely to change clinical behavior, at least not quickly," the editorialists write.

They suggest that use of performance metrics that target hazardous prescribing practices would help hold clinicians and healthcare facilities accountable. In addition, optimizing use of safety alerts in electronic health records "could prove effective but only if they appropriately notify prescribers of hazardous combinations and only if prescribers are held accountable for over-riding warnings."

However, they also point out that opioids are often prescribed by multiple providers, and they highlight the need for a centralized approach to care.

"Unless systems are set up to push information to providers...busy clinicians will struggle to keep up with their patients' use of different prescriptions."

The authors and editorialists have disclosed no relevant financial relationships.

BMJ. Published online March 14, 2017. Full text, Editorial

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