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Published in final edited form as: Drug Alcohol Depend. 2023 Jun 1;249:109952. doi: 10.1016/j.drugalcdep.2023.109952

Trends in Overdose Deaths involving Gabapentinoids and Z-Drugs in the United States

David Powell 1, Kanaka D Shetty 2, Evan D Peet 3
PMCID: PMC10332434  NIHMSID: NIHMS1909896  PMID: 37301069

Abstract

Introduction:

As policies have been implemented to limit access to prescription opioids, other drugs have been prescribed off-label, sometimes concurrently with opioids, to manage pain. There are concerns about the use of gabapentinoids and “Z-drugs” with opioids. As the opioid crisis transitions to illicit opioids and polysubstance use, little work quantifies the concurrent involvement of non-opioid prescription drugs and illicit opioids in overdose deaths.

Methods:

Data from the census of deaths in the United States for 1999–2020 were used to understand trends in deaths involving gabapentinoids/Z-drugs and opioid co-involvement. These trends were studied overall and by sex, race, age, and education.

Results:

Per capita overdose deaths involving gabapentinoids/Z-drugs increased almost continuously since 1999, averaging 15.8% annual growth. This rate increased to 32% in 2020, primarily due to overdoses involving synthetic opioids. Women typically had higher rates of overdose deaths involving both opioids and gabapentinoids/Z-drugs, though this disparity disappeared in 2020. White Americans and American Indians/Alaskan Natives historically had higher rates than other racial groups; however, Black Americans experienced over 60% annual growth in recent years. Low education groups have been disproportionately impacted. The age incidence tends to be older than overdoses involving opioids more generally.

Conclusion:

Overdose deaths involving opioids and gabapentinoids/Z-drugs have tended to disproportionately affect women and older age groups compared to all opioid-involved overdoses. As deaths involving synthetic opioids likely reflect use of illicitly-obtained opioids, there may be less of a role for policies targeting the concurrent prescribing of gabapentinoids/Z-drugs with opioids to reduce these deaths.

Keywords: opioid crisis, concurrent prescriptions, fentanyl, disparities, illicit drug markets

Introduction:

As the opioid crisis worsens, the prescribing and use of non-opioid drugs concurrently with opioids has garnered significant attention (Bykov et al. 2020; Esechie et al. 2021; Guy Jr et al. 2019; Kuehn 2022; Macleod et al. 2019; Oueini et al. 2022; Peet et al. 2023; Ray et al. 2021; Szmulewicz et al. 2021; Tardelli et al. 2022). Specifically, concerns about misuse of gabapentinoids, which include gabapentin and pregabalin, have escalated over time (Evoy et al. 2021; Evoy, Morrison and Saklad 2017; Goodman and Brett 2017; Smith, Havens and Walsh 2016). Gabapentin, the 7th most dispensed medication in the United States in 2019 (IQVIA 2020), is a type of anti-convulsant intended to relieve pain associated with postherpetic neuralgia, control epileptic seizures, and treat restless leg syndrome. CDC guidelines recommended use of gabapentinoids as first- and second-line drugs for certain types of pain (Dowell, Haegerich and Chou 2016). Off-label prescribing is common, especially for pain-related diagnoses, partially due to their perceived lower risk potential relative to many opioids and due to restrictions on opioid access (Goodman and Brett 2019; Peckham et al. 2018; Zhao et al. 2022). Pregabalin (e.g., Lyrica) treats fibromyalgia and is also a standard off-label pain treatment medication (Bonnet and Scherbaum 2017; Calandre, Rico-Villademoros and Slim 2016).

Rates of gabapentinoid misuse among those also misusing opioids are high (Evoy et al. 2017; Smith et al. 2016), and concurrent gabapentin and opioid use is associated with increased risk of hospitalization (Gomes et al. 2017; Lyndon et al. 2017; Peckham et al. 2018; Zhou et al. 2021). The FDA issued a warning concerning the combined use of opioids with gabapentin or pregabalin (US Food & Drug Administration 2019). Similarly, “Z-drugs” – zaleplon, zolpidem, and eszopiclone – are commonly prescribed to prescription opioid users (Oueini et al. 2022; Vozoris 2019). A prior FDA warning cautioned against the use of opioids with benzodiazepines and Z-drugs (US Food & Drug Administration 2018). Z-drugs are used to treat insomnia and often taken by patients without informing their opioid prescriber (Mann et al. 2014). Concurrent prescribing of Z-drugs and opioids is associated with an increase in overdose risk (Szmulewicz et al. 2021).

Polysubstance use is driving a “fourth wave” of the opioid crisis with most attention from researchers and policymakers focused on opioids and illicit stimulants (Barocas et al. 2019; Ciccarone 2021; Compton, Valentino and DuPont 2021; Friedman and Shover 2022; Townsend et al. 2022). This paper examines non-opioid prescription drugs which are unlikely to be illicitly-manufactured. Gabapentinoids are diverted for non-medical use and even acquired through illicit markets (Buttram and Kurtz 2021; Hägg, Jönsson and Ahlner 2020; Smith, Lofwall and Havens 2015), but unlikely to be manufactured illicitly. Moreover, an analysis of a small set of gabapentin-related deaths found that 91.4% of decedents were prescribed the drug legitimately (Tharp, Hobron and Wright 2019). Previous work documented the national rise in overdose deaths involving opioids with gabapentinoids and/or Z-drugs in the United States through 2018 (Tardelli et al. 2022), before the recent escalation of the fentanyl and polysubstance crises and prior to the COVID-19 pandemic.

If gabapentinoid/Z-drug overdose deaths predominantly involve illicit fentanyl, different policy options are needed since prescribers are less likely to observe illicit opioid use. Policymakers would benefit from understanding demographic trends in overdose deaths involving opioids and gabapentinoids/Z-drugs since 2018.

Methods:

Data Source:

We used the National Vital Statistics System (NVSS) Mortality Multiple Cause-of-Death data, the census of deaths, for 1999–2020. Notably, not all current gabapentinoids and Z-drugs were available at the beginning of this sample period, but we study deaths involving any such drug. We coded deaths as overdoses using ICD-10 external cause of injury codes X40-X44, X60–64, X85, or Y10-Y14. We used ICD-10 codes for identification of substances found in the body at death. For opiates, we used T40.0 (opium), T40.1 (heroin), T40.2 (natural and semisynthetic opioids), T40.3 (methadone), T40.4 (synthetic opioids), and T40.6 (other and unspecified narcotics). We categorized overdoses as involving gabapentinoids and/or Z-drugs using T42.6 (Poisoning by, adverse effect of and underdosing of other antiepileptic and sedative-hypnotic drugs) or T42.7 (Poisoning by, adverse effect of and underdosing of unspecified antiepileptic and sedative-hypnotic drugs). These codes do not specify gabapentinoids/Z-drugs, but standard ICD lists include them (ICD 2022). These categories exclude benzodiazepines.

Race categorizations can be consistently aggregated into White, Black, American Indian or Alaskan Native (“AI/AN”), and Asian American or Pacific Islander (“AAPI”). We aggregated decedents into six age groups: 0–24, 25–34, 35–44, 45–54, 55–64, and 65+. Population sizes by race, sex, and age were derived from the Surveillance, Epidemiology, and End Results Program, which is based on Census data. We also stratified decedents ages 25+ into whether they ever attended college; educational attainment is missing for less than 3% of deaths. We used the Current Population Survey to calculate population counts by educational attainment. 95% confidence intervals for the main figures are provided in the Appendix.

Results:

Total overdose deaths involving reported gabapentinoids/Z-drugs increased almost continuously between 1999 and 2020 (Figure 1, Panel A), from 0.06 per 100,000 in 1999 to 1.51 per 100,000 in 2020, representing 15.8% annual growth. From 2018 to 2019, there was a 22% increase from (0.94 to 1.14 / 100,000), followed by a 32% increase from 2019 to 2020 (1.51 / 100,000). This growth was driven by overdoses concurrently involving opioids. Deaths involving gabapentinoids/Z-drugs but not classified as involving opioids rose at a slower rate: from 0.04 (1999) to 0.27 per 100,000 (2020). From 2019 to 2020, these deaths increased by 3.8%. Trends were similar when we defined opioid-involved deaths using T40.0-T40.4 (Supplemental Figure 1).

Figure 1:

Figure 1:

Open in a new tab

Trends in overdoses involving gabapentinoids/Z-drugs with and without opioids

Source: Authors’ analysis of NVSS data.

Notes: Gabapentinoid/Z-drug deaths are defined as overdoses (see text for definition) involving T42.6/T42.7. In Panel B, deaths may involve multiple types of opioids and be included more than once. Additional definitional details are provided in the “Methods” section. See Supplemental Table 1 for 95% confidence intervals.

Synthetic opioids drove this recent surge (Figure 1, Panel B), though we observe increases involving natural/semi-synthetic opioids and heroin too. Deaths may involve multiple types of opioids; these deaths are included multiple times. In 2020, synthetic opioids were involved in 56% of gabapentinoid/Z-drug overdose deaths. This large share reflects growing prevalence of synthetic opioids in gabapentinoid/Z-drug overdose deaths over time: 19% in 2015, 26% in 2016, 29% in 2017, 35% in 2018, and 44% in 2019. The rates of overdose deaths involving gabapentinoids/Z-drugs and synthetic opioids increased 41% from 2019 to 2020.

This growth was uneven across demographic groups. Overdose death rates involving opioids and gabapentinoids/Z-drugs among women outpaced those among men in every year until 2020 (Figure 2 Panel A). In 2020, the overdose death rate for these substances rose 46% among men to 1.30 per 100,000, and 37% among women to 1.26 per 100,000.

Figure 2:

Figure 2:

Open in a new tab

Demographic-specific trends in overdoses involving gabapentinoids/Z-drugs and opioids

Source: Authors’ analysis of NVSS data.

Notes: Gabapentinoid/Z-drug deaths are defined as overdoses (see text for definition) involving T42.6/T42.7. Additional definitional details are provided in the “Methods” section. The education analysis only uses ages 25+. See Supplemental Table 2 for 95% confidence intervals.

White Americans and AI/ANs experienced faster growth in overdose deaths involving opioids and gabapentinoids/Z-drugs relative to Black Americans and AAPIs for most of the sample period (Figure 2 Panel B). In 2020, there were 1.46 such overdose deaths among White Americans (per 100,000); AI/ANs 1.22; Black Americans 0.83; and AAPIs 0.12. However, Black Americans experienced a 60% increase from 2019 to 2020 (White Americans: 42%, AI/ANs: 12%, AAPIs: 50%).

The 45–54 age group consistently had the highest death rate for overdoses involving opioids and gabapentinoids/Z-drugs, followed by the 35–44 age group (Figure 2 Panel C). Lower rates are observed for the 0–24 and 65+ age groups. In 2020, each age group between 25 and 64 years experienced sharp growth.

Figure 2 Panel D provides trends by education. Those without any college education had higher rates of overdose deaths involving opioids and gabapentinoids/Z-drugs in every year. In 2020, those without any college education had 3.20 deaths involving opioids and gabapentinoids/Z-drugs per 100,000, compared to 0.97 per 100,000 for those with some college education. The 2020 rates represented 58% and 25% growth, respectively, relative to 2019.

In Appendix Figure 2, we replicate Figure 2 but plot deaths involving gabapentinoids/Z-drugs and synthetic opioids. The trends are similar, consistent with the fentanyl crisis driving the escalation in gabapentinoid/Z-drug overdose deaths.

Discussion:

Overdose deaths involving opioids and gabapentinoids/Z-drugs have escalated. The sharp national increases in 2019 and 2020 were driven by overdose deaths involving synthetic opioids, consistent with increases in illicitly-manufactured fentanyl (Kilmer et al. 2022a; Kilmer et al. 2022b). These steep trends preceded 2020, suggesting that they were not driven by the pandemic (Faust et al. 2021; Holland et al. 2021). While the literature has discussed concerns with the concurrent prescribing of opioids with gabapentinoids and Z-drugs (Gomes et al. 2017; Szmulewicz et al. 2021), the policy calculus changes as illicit opioids become the predominant type of substance involved in gabapentinoid/Z-drug overdoses.

The demographics of these overdose deaths are counter to many trends in opioid-involved overdose deaths. Despite higher opioid-involved overdose death rates overall (Hedegaard et al. 2022), men have typically had lower rates of overdoses deaths involving opioids and gabapentinoids/Z-drugs than women. This disparity disappeared in 2020, further evidence of the fentanyl crisis explaining trends in these deaths given the fentanyl crisis’s disproportionate impact on men (D’Orsogna, Böttcher and Chou 2023).

Overdose deaths involving opioids and gabapentinoids/Z-drugs peak for ages 45–54. The 55–64 age group had high rates of these overdoses as well. Among all opioid-involved overdose deaths, the 35–44 age group has typically experienced the highest mortality rates (Hedegaard et al. 2022). The sex and age composition of these deaths is consistent with gabapentin prescribing trends (Pauly et al. 2020; Peet et al. 2023).

We also observed large differences in death rates by race. We documented high rates of overdoses for White Americans and AI/ANs. Black Americans experienced the sharpest growth from 2018 to 2020. This steep growth for Black Americans mirrors recent escalation in overdose deaths involving synthetic opioids (Ciccarone 2021; Hedegaard et al. 2022).

The most striking stratification was by education. The overall growth in overdose deaths involving opioids and gabapentinoids/Z-drugs was driven by those with no college education, consistent with overdoses overall (Powell 2021).

The sharp increases in gabapentinoid/Z-drug deaths involving synthetic opioids paired with evidence that the demographics of these deaths began to shift are consistent with the escalating fentanyl crisis altering the nature of the opioid crisis. As fentanyl becomes more frequently mixed, often without consumer knowledge (Pardo et al. 2019), in illicit opioid markets, the incidence of polysubstance deaths will change.

This study has limitations. First, we relied on the accurate coding of overdose deaths and the substances involved, though the literature has expressed concerns about incomplete reporting (Boslett, Denham and Hill 2020; Ruhm 2017, 2018; Tote et al. 2019). Second, a motivation of this study was to understand trends in polysubstance use involving illicit opioids and non-opioid prescription drugs. However, we cannot distinguish between prescribed opioids such as tramadol and illicit opioids. Similarly, we do not observe how gabapentinoids and Z-drugs were acquired or manufactured. The combination of these drugs is suggestive of concurrent use of prescription drugs and illicit opioids, an important issue which has received little documentation. Third, we did not observe gabapentinoids or Z-drugs specifically and we cannot distinguish between gabapentin and pregabalin. A recent study using toxicology reports for 23 states (plus D.C.) for 2019–2020 reports 2975 deaths involving gabapentin specifically (Mattson, Chowdhury and Gilson 2022). We observed 4091 T42.6/T42.7 overdoses in those same state-years, implying that 73% of these deaths were gabapentin. More reliable methods are available using toxicology reports (Slavova et al. 2018), though typically only available for specific jurisdictions and time periods (Hargrove et al. 2018; Tharp et al. 2019). Fourth, cause of death can impact classification of race (Noymer, Penner and Saperstein 2011), and misclassification of AI/ANs typically leads to underestimates for this population (Arias, Heron and Hakes 2016; Joshi, Weiser and Warren-Mears 2018). There is evidence that individuals without a high school degree are coded in death records as having completed four years of high school (Rostron, Boies and Arias 2010; Sorlie and Johnson 1996). This concern is more relevant to the earlier 1989 revision of the death certificate. We stratified the education analysis by college attendance to minimize these concerns.

The incidence of deaths involving gabapentinoids/Z-drugs seems to be changing due to the worsening fentanyl crisis. More research is needed to understand whether policies targeting medical access to gabapentinoids and Z-drugs can curb these trends as illicit markets drive overdose deaths.

Supplementary Material

1

Highlights.

  • This study quantifies trends in overdose deaths involving gabapentinoids/Z-drugs.

  • These deaths have grown continuously since 1999, including 32% growth in 2020.

  • Synthetic opioids appear to be a major factor driving this recent growth.

  • The sex and age disparities of these deaths are different than those for opioid overdoses.

  • The fentanyl crisis is increasing deaths involving non-opioid prescription drugs.

Role of Funding Source

This research was supported by the National Institute on Drug Abuse grant 5R21DA052655. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the National Institutes of Health.

Funding:

We are grateful for funding from the National Institute on Drug Abuse, 5R21DA052655 (PIs: Dr. Peet and Dr. Powell). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIDA or the National Institutes of Health.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Declarations of Interest: The authors report grant funding from the National Institutes of Health and no other potential conflicts of interest.

Declaration of Competing Interest

No conflict declared.

CRediT authorship contribution statement

David Powell: Designed the present study, obtained funding for the study, conducted data analysis, drafted the manuscript. Evan Peet: Designed the parent study, designed the present study, obtained funding for the study, edited manuscript. Kanaka Shetty: Designed the present study, edited manuscript

Contributor Information

David Powell, RAND, 1200 S. Hayes St., Arlington, VA 22202.

Kanaka D. Shetty, RAND, 1776 Main St., Santa Monica, CA 90407.

Evan D. Peet, RAND, 4570 Fifth Ave., Pittsburgh, PA 15213.

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NIHMS1909896-supplement-1.pdf (800.2KB, pdf)

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