INTRODUCTION
Several factors influence risk of harms associated with prescription opioids.1 One modifiable factor is co-prescription of medications, such as benzodiazepines, non-benzodiazepine sedative hypnotics, and gabapentinoids, which potentiate opioids’ respiratory depressant effects,2,3 slowing breathing and increasing risk of accidental overdose.4 Co-prescribing of benzodiazepines and opioids decreased after the U.S. Food and Drug Administration black box warning of 2016.5 However, it is unknown how co-prescription of opioids with other respiratory depressant potentiators has changed recently.6 To identify patterns of risky prescribing and raise awareness of the potential dangers of co-prescribing, this analysis provides the first U.S. national estimates of opioid co-prescribing with benzodiazepines, non-benzodiazepines, and gabapentinoids. The main hypothesis is that opioid–benzodiazepine co-prescribing had decreased, but other co-prescribing types had remained stable.
METHODS
Six waves of the 2007–2018 National Health and Nutrition Examination Survey, administered by the National Center for Health Statistics, were analyzed.7 Data were collected in April 2020, and analyzed from May to June 2020. This study of de-identified publicly available data was deemed exempt from review by the University of Connecticut School of Medicine’s IRB. Study procedures followed the STROBE reporting guideline.
Survey participants were asked to identify medications they were prescribed in the past 30 days. The outcome of interest was use of a prescription opioid plus ≥1 potentiator medications: benzodiazepines, non-benzodiazepine sedative hypnotics, or gabapentinoids. Changes in prevalence of such co-prescribing among U.S. adults aged ≥19 years (per 1,000 people), both overall and limited to those prescribed opioids, were estimated. To examine linear trends over time, the 6-level survey year variable was transformed from 0 (2007–2008) to 1 (2017–2018). ORs associated with this transformed variable represent change in odds of medication use across the study period. Stratified analyses by age, sex, race/ethnicity, and medication class were also performed. Covariates included age, sex, and race/ethnicity when estimating the association during the study period. Stata, version 15.1 MP/6-Core was used for all analyses, and the svy commands accounted for the complex sampling design including unequal probability of selection, clustering, and stratification.
RESULTS
The prevalence of U.S. adults who reported use of an opioid and potentiator increased significantly from 19.8 per 1,000 people in 2007–2008 to 26.8 per 1,000 people in 2015–2016, and then decreased to 18.4 per 1,000 people in 2017–2018 (AOR for time trends=1.38, 95% CI=1.14, 1.68) (Table 1). In 2007–2008, the most common type of co-prescribing was an opioid and benzodiazepine medication (11.5 per 1,000 people). By 2017–2018, this was replaced by opioid and gabapentinoid combinations (11.0 per 1,000 people), co-prescribing of which had increased significantly (AOR=1.63, 95% CI=1.07, 2.49). When stratified by age, co-prescribing increased significantly among adults aged ≥65 years (AOR=1.70, 95% CI=1.12, 2.58).
Table 1.
Trends in Co-Prescribing of Opioids and Opioid Potentiators per 1,000 Population in the U.S., 2007‒2018
| Variable | 2007–2008 | 2009–2010 | 2011–2012 | 2013–2014 | 2015–2016 | 2017–2018 | Period association AOR (95% CI) | p-value |
|---|---|---|---|---|---|---|---|---|
| Total, co-prescribing | 19.8 | 20.0 | 21.2 | 28.0 | 26.8 | 18.4 | 1.38 (1.14, 1.68) | 0.001 |
| Co-prescribing type | ||||||||
| Benzodiazepine and opioid | 11.5 | 11.0 | 12.3 | 16.1 | 15.0 | 8.7 | 1.01 (0.72, 1.42) | 0.949 |
| Non-benzodiazepine hypnotic and opioid | 4.5 | 4.6 | 4.2 | 5.7 | 4.2 | 2.7 | 0.73 (0.37, 1.43) | 0.355 |
| Gabapentinoid and opioid | 7.9 | 6.7 | 8.7 | 11.3 | 12.4 | 11.0 | 1.63 (1.07, 2.49) | 0.023 |
| Co-prescribing, number of potentiator classes | ||||||||
| Opioid and one potentiator | 16.3 | 18.1 | 17.6 | 23.2 | 22.2 | 14.9 | 1.06 (0.80, 1.39) | 0.725 |
| Opioid and two or more potentiators | 3.5 | 1.9 | 3.6 | 4.9 | 4.6 | 3.5 | 1.44 (0.71, 2.94) | 0.308 |
| Age, years | ||||||||
| 19–39 | 6.2 | 7.1 | 14.3 | 8.2 | 10.3 | 3.5 | 0.90 (0.48, 1.68) | 0.734 |
| 40–64 | 28.0 | 29.6 | 27.9 | 38.1 | 34.3 | 23.2 | 0.99 (0.72, 1.36) | 0.932 |
| ≥65 | 29.6 | 23.2 | 18.6 | 44.1 | 40.9 | 35.8 | 1.70 (1.12, 2.58) | 0.013 |
| Sex | ||||||||
| Male | 19.1 | 17.0 | 19.5 | 24.2 | 16.0 | 15.0 | 0.82 (0.53, 1.28) | 0.380 |
| Female | 20.5 | 22.7 | 22.8 | 31.6 | 36.8 | 21.6 | 1.35 (0.95, 1.92) | 0.092 |
| Race/Ethnicity | ||||||||
| White, non-Hispanic | 24.9 | 24.4 | 26.0 | 33.6 | 33.2 | 20.3 | 1.01 (0.76, 1.36) | 0.926 |
| Black, non-Hispanic | 6.6 | 12.6 | 18.3 | 20.4 | 16.2 | 10.8 | 1.24 (0.78, 1.97) | 0.356 |
| Hispanic | 6.9 | 11.8 | 9.5 | 9.8 | 11.2 | 11.4 | 1.20 (0.53, 2.71) | 0.661 |
| Other, non-Hispanic | 15.7 | 5.4 | 6.4 | 27.2 | 22.0 | 26.1 | 2.81 (0.76, 10.37) | 0.119 |
Note: Boldface indicates statistical significance (p<0.05). Data are from National Health and Nutrition Examination Survey (NHANES). Sample sizes are adjusted for populations in given years and reported as rates per 1,000 populations. Opioids include: codeine, fentanyl, droperidol-fentanyl, alfentanil, sufentanil, remifentanil, meperidine, methadone, hydromorphone, morphine, oxycodone, pentazocine, propoxyphene, opium, levorphanol, oxymorphone, butorphanol, nalbuphine, buprenorphine, hydrocodone, dihydrocodeine, tapentadol, tramadol, naltrexone, and their combined products. Benzodiazepines include: alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam, and triazolam. Non-benzodiazepine hypnotics include: eszopiclone, zaleplon, and zolpidem. Gabapentinoids include gabapentin and pregabalin. Analyses are adjusted for age, sex, and race/ethnicity.
Similar patterns were found when limited to prescription opioid users (Figure 1). Although linear trends were not significant, 29.9% of opioid users were prescribed a potentiator in 2007–2008, and this proportion increased to 46.6% in 2015–2016 before decreasing to 31.7% in 2017–2018. Co-prescribing of opioids and gabapentinoids increased significantly among prescription opioid users from 11.9% in 2007–2008 to 19.0% in 2017–2018 (AOR=2.02, 95% CI=1.20, 3.41).
Figure 1. Trends in use of opioid potentiators (weighted %) among opioid users by medication class in the U.S., 2007‒2018.
Notes: Data are from National Health and Nutrition Examination Survey (NHANES). Opioids include: codeine, fentanyl, droperidol-fentanyl, alfentanil, sufentanil, remifentanil, meperidine, methadone, hydromorphone, morphine, oxycodone, pentazocine, propoxyphene, opium, levorphanol, oxymorphone, butorphanol, nalbuphine, buprenorphine, hydrocodone, dihydrocodeine, tapentadol, tramadol, naltrexone, and their combined products. Benzodiazepines include: alprazolam, bromazepam, chlordiazepoxide, clobazam, clonazepam, clorazepate, diazepam, estazolam, flurazepam, lorazepam, nitrazepam, oxazepam, temazepam, and triazolam. Non-benzodiazepine hypnotics include: eszopiclone, zaleplon, and zolpidem. Gabapentinoids include gabapentin and pregabalin. Whiskers represent 95% CIs. The gabapentinoid use has significantly increased over time (AOR for period association, 2.02 and 95% CI=1.20, 3.41).
DISCUSSION
Co-prescribing of prescription opioids and respiratory depressant potentiators increased among U.S. adults over the 2007–2008 to 2017–2018 period, especially among adults aged ≥65 years and for co-prescribing involving gabapentinoids. Among prescription opioid users, more than 3 in 10 people received potentiators, most commonly a benzodiazepine in 2007–2008 and gabapentinoids in 2017–2018. The increasing trends might be partially explained by increasing prescriber perceptions of gabapentinoids as safer non-opioid alternative pain medications, particularly among older adults,8,9 during the opioid epidemic.10 These patterns underscore a need for close prescription monitoring,3,6 and increased attention to co-prescription of opioids and gabapentinoids.6
Although decreased benzodiazepine use among prescription opioid users may be explained in part by the Food and Drug Administration’s warning,5 further research on co-prescribing of opioids and gabapentinoids is needed as the Food and Drug Administration issued its warning on December 19, 2019.6 Study limitations include recall bias and lack of information about dosage forms, actual co-use (rather than co-prescribing), and treatment outcomes. Overall, the study suggests that co-prescribing remains common and prescribers should continually evaluate risks and benefits.
ACKNOWLEDGMENTS
In the past 3 years, Rhee was supported in part by the National Institute on Aging (#T32AG019134). Rhee is currently funded by the National Institute of Mental Health (#R21MH117438) and Institute for Collaboration on Health, Intervention, and Policy of the University of Connecticut. Olfson received funding support from the NIH (#R01MH107452, #R01DA039137, and #R01DA019606). Maust received funding support from the NIH (#R01DA045705). Fiellin has received grants from NIH and PCORI along with honoraria from Springer Nature, Boston Medical Center, Boston University, University of New South Wales, University of Alabama, Birmingham, U.S. Department of Justice, Tufts University, the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, and the University of Kentucky, outside of the submitted work.
The funding agency had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript, or decision to submit the manuscript for publication.
Further details of the data, including description, questionnaires, sampling methodology, and data sets, are publicly available on the website.
No financial disclosures were reported by the authors of this paper.
Footnotes
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