Clinical Research Study
Opioid and Benzodiazepine Substitutes: Impact on Drug Overdose Mortality in Medicare Population

https://doi.org/10.1016/j.amjmed.2022.02.039Get rights and content

Abstract

Introduction

Gabapentinoids (GABAs) and serotonergic drugs (selective serotonin reuptake inhibitors [SSRIs]/serotonin and norepinephrine reuptake inhibitors [SNRIs]) are increasingly being prescribed as potential substitutes to opioids and benzodiazepines (benzos), respectively, to treat co-occurring pain and anxiety disorders. The toxicities of these drug classes and their combinations are not well understood.

Methods

We conducted a matched case-control study using 2013-2016 Medicare files linked to the National Death Index. Cases were enrollees who died from drug overdose. Controls were enrollees who died from other causes. Cases and controls were matched on patient characteristics and prior chronic conditions. Possession of any opioids, GABAs, benzos, and SSRIs/SNRIs in the month prior to death was defined as drug use. Combination drug use was defined as possessing at least 2 types of these prescriptions for an overlapping period of at least 7 days in the month prior to death.

Results

Among 4323 matches, benzo possession was associated with twice the risk for drug overdose death in cases vs controls. Compared with opioid-benzo co-prescribing, combinations involving SSRIs/SNRIs and opioids (or GABAs) were associated with decreased risk (adjusted odds ratio 0.55; 95% confidence interval, 0.44-0.69 for opioids and SSRIs/SNRIs; adjusted odds ratio 0.59; 95% confidence interval, 0.44-0.79 for GABAs and SSRIs/SNRIs). Fatal drug overdose risk was similar in users of GABA-opioid, GABA-benzo, and opioid-benzo combinations.

Conclusions

Benzodiazepines, prescribed alone or in combination, were associated with an increased risk of drug overdose death. SSRIs/SNRIs were associated with lower risk of overdose death vs benzodiazepines. GABAs were not associated with decreased risk compared with opioids, raising concerns for GABAs’ perceived relative safety.

Introduction

Opioid and benzodiazepine (benzo) co-prescribing is common in patients with co-occurring pain and anxiety disorders.1., 2, 3, 4, 5, 6 Co-prescribing these 2 central nervous system (CNS)-active drug classes is linked to high risk of emergency department visits and drug overdose mortality.4,7, 8, 9, 10, 11, 12 Data from the Centers for Disease Control (CDC) showed benzodiazepine co-use in 21% of people who died from opioid overdose in 2017.11 The CDC issued guidelines in 2016 for clinicians to avoid opioid-benzo co-prescribing.13 The US Food and Drug Administration (FDA) also issued similar warnings in 2019.14 These changes have subsequently been associated with decreases in opioid-benzo co-prescribing.15,16

As opioid-benzo co-prescribing decreases, non-opioid (eg, gabapentinoids) and non-benzo (serotonergic drugs) substitutes are increasingly being prescribed as potentially safer alternatives.17, 18, 19 Data support gabapentinoid (GABA)—specifically pregabalin and gabapentin—effectiveness for peri- and postoperative pain as well as chronic, neuropathic pain.20,21 Serotonergic anxiolytic drugs—selective serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors (SSRIs/SNRIs)—are FDA-approved treatments for anxiety disorders and depression.22,23 Despite known side effects for GABAs (somnolence, risk of drug abuse) and SSRIs/SNRIs (insomnia, withdrawal symptoms, fracture), prescribing rates for these 2 drug classes have steadily grown, as they are perceived to have lower risk of drug overdose death.17,21,24, 25, 26, 27

Although toxicities from certain co-prescribing combinations of CNS-active drug classes are known (eg, opioids + GABAs, opioids + SSRIs/SNRIs, benzos + GABAs), the effects of every possible drug combination have not been fully investigated.28, 29, 30, 31, 32, 33 Data from investigating toxicity profiles of different CNS-active drug combinations can guide therapeutic decision-making for patients with co-occurring pain and anxiety disorders. We thus investigated specific pharmacologic classes and their various combinations, and their relationships to risk of drug overdose mortality. Because drug overdose death is a rare outcome, we conducted a matched case-control study to isolate the toxicity of a given drug or drug combination with this outcome. We hypothesized that co-prescribing of opioids, benzos, and GABAs would be associated with the greatest risk of drug overdose deaths, and co-prescribing of GABAs and SSRIs/SNRIs with a lower risk of drug overdose death compared with co-prescribing of opioids and benzos.

Section snippets

Study Population

This matched case-control study used Medicare files linked to the National Death Index from a 20% national sample of Medicare enrollees in 2013-2016. Drug overdose deaths were identified using the International Statistical Classification of Diseases 10th Revision (ICD-10) codes. Cases were enrollees who died from drug overdose with ICD-10 codes as cause of death (X40-44, X60-64, X85, or Y10-Y14).34 We excluded cases without Part D enrollment in the 3 months prior to death to capture

Results

From our study cases of 4625 Medicare enrollees who died from drug overdose in 2013-2016 (Supplementary Table 3, available online), the mean age was 53.0 (standard deviation 13.0) years, 48.9% were women, and 83.9% were white. The majority (87.3%) had original disability entitlement, and more than two-thirds (67.5%) were eligible for Medicaid. Depression (62.1%), chronic pain (55.4%), and drug use disorder (45.3%) were highly prevalent conditions, and 40.6% of cases had more than 3 chronic

Discussion

We found that benzo prescription alone was associated with almost twice the odds of drug overdose death. Co-prescribing of opioids, GABAs, and benzos was associated with an increased risk of drug overdose death, when compared with opioid-benzo co-prescribing—a practice already established as a potentially lethal combination. Co-prescribing SSRIs/SNRIs with either opioids or GABAs was associated with a lower overdose risk compared with opioid-benzo co-prescribing.

Possessing any CNS-active

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    Funding: Y-FK and MAR are supported by the National Institute on Drug Abuse (R01‐DA039192; Kuo, Raji, MPI). The content is solely the authors' responsibility and does not necessarily represent the official views of the National Institutes of Health. XY is supported by a research career development award (K12HD052023: Building Interdisciplinary Research Careers in Women's Health Program-BIRCWH; Berenson, PI) from the National Institutes of Health/Office of the Director (OD)/National Institute of Allergy and Infectious Diseases (NIAID), and Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD).

    Conflicts of Interest: All the authors listed on the manuscript have fulfilled the criteria for authorship, reviewed and approved the paper, and attested to the integrity of this paper. We have no conflict of interest. The sponsors had no role in the design, methods, subject recruitment, data collection, analysis, or preparation of this manuscript.

    Authorship: All authors had access to the data and all the authors had a key role in writing the manuscript.

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