Full length articlePrevalence of gabapentin in drug overdose postmortem toxicology testing results
Introduction
Gabapentin is an anticonvulsant and nerve pain medication available in many countries worldwide under different generic or brand names (Kamerman et al., 2016). In the United States (U.S.), gabapentin is approved by the Food and Drug Administration (FDA) for the management of postherpetic neuralgia and as adjunctive therapy in the treatment of partial seizures. According to the FDA-approved labeling of Neurontin® (gabapentin), “gabapentin is structurally related to the neurotransmitter GABA but it does not modify GABAA or GABAB radioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation” (Pfizer, 2011). It was reported that gabapentin had been increasingly promoted and prescribed for off-label uses with limited scientific evidence in support for such use (Chen et al., 2005; Hamer et al., 2002; Radley et al., 2006; Steinman et al., 2006). It was estimated that the off-label prescribing of gabapentin in the U.S. in 2001 was 83% (Radley et al., 2006). The number of gabapentin prescriptions in the U.S. nearly doubled from 33 million in 2011–57 million in 2015, making gabapentin the 11th most prescribed medication in 2015 (IMS, 2016). Gabapentin use in the general U.S. population has not been well studied. Among the commercially insured U.S. population, approximately 2.3% of the beneficiaries had at least one gabapentin prescription in 2014, with a significantly higher percentage of gabapentin users among females (2.7%) vs. males (1.8%) (Pauly et al., 2017). A comparison of gabapentin users and non-users in the same study demonstrated that gabapentin users were more likely to have a diagnosis of mental health conditions (5.3% vs. 0.6%), neuropathic pain (1.7% vs. 0.1%), substance use disorders (2.6% vs. 0.3%), or seizures (0.7% vs. 0.1%) compared with non-users.
Studies have reported that gabapentin had analgesic and opioid-sparing effects when used in conjunction with opioids in pre- or post-operative pain management, thus improving the analgesic efficacy of opioids and decreasing cumulative morphine consumption (Mao et al., 2016; Zhai et al., 2016). Information on the synergistic effects of gabapentin and opioids and the increased risk for addiction and overdose has recently emerged in the literature. In a population-based nested case-control study of opioid users in Ontario, Canada, concomitant use of gabapentin and opioids increased the risk for a fatal opioid overdose by 49% among the 1256 cases matched to 4619 controls (Gomes et al., 2017). The authors also found that moderate (900–1799 mg daily) and high (≥1800 mg daily) doses of gabapentin increased the adjusted odds of a fatal opioid overdose by 60% compared to those without concomitant gabapentin and opioid use. Gabapentin uses among people with histories of opioid abuse has increasingly been identified among decedent populations through postmortem toxicology testing (Evoy et al., 2017). Similarly, a systematic review of 106 gabapentinoid-related studies determined that patients with current or past substance use disorders, particularly opioid use disorders, had an increased risk of addiction to gabapentinoids such as pregabalin and gabapentin (Bonnet and Scherbaum, 2017). Peckham et al., 2017a, Peckham et al., 2017b found that gabapentin use exhibited a similar abuse pattern to other abusable drugs such as opioids and zolpidem among patients (Peckham et al., 2017b). Lastly, in a study of opioid-exposed pregnant women, 11.4% of infants whose mothers were co-prescribed gabapentin and opioids experienced neonatal drug withdrawal compared to 1% of infants who were exposed in utero to opioids alone (Huybrechts et al., 2017).
A systematic review of gabapentin misuse, abuse, and diversion found evidence that suggested gabapentin was misused intentionally, especially among individuals with a known history of drug abuse (Smith et al., 2016). Increased problematic use of gabapentin was also reported in Canada, Scotland, and other countries (Smith et al., 2012; Zhang and Sproule, 2015). In England and Wales, the number of death certificates mentioning gabapentoids increased from fewer than one annually prior to 2009–137 in 2015, demonstrating a strong correlation with increased prescribing (Lyndon et al., 2017). A study on gabapentin abuse using postmortem toxicology testing in Finland from 2010 to 2011 reported that poisoning deaths attributed to gabapentin represented 12.5% of deaths among decedents with a known history of drug abuse (Hakkinen et al., 2014). Currently, there are no national estimates on the extent of gabapentin involvement in drug overdose deaths in the U.S. To the best of our knowledge, gabapentin was not among the top 10 drugs identified as being involved in drug overdose deaths as of 2014 (Warner et al., 2016).
This study is intended to raise awareness among public health and safety professionals in the U.S. and other countries about the possible intentional use and misuse of gabapentin in populations with substance use disorders and highlight the need to monitor the involvement of gabapentin in drug overdose deaths. The goal of this study was to establish and compare baseline data on the prevalence of gabapentin identified through postmortem toxicology testing among drug overdose decedents in several geographically diverse states/jurisdictions with differing levels of drug overdose fatality burdens in 2015.
Section snippets
Methods
Five geographically diverse U.S. states/jurisdictions participated in this study: 1) Kentucky, North Carolina, and West Virginia; 2) Maricopa County, Arizona, the 4th largest county in the U.S. in 2015, where Phoenix is the county seat, capital of Arizona, and among the top 10 most populous cities in the U.S.; and 3) Northeast Tennessee, a 7-county jurisdiction with a population of 350,101 in 2015. According to the National Center for Health Statistics (NCHS), West Virginia had the highest
Results
The crude rates of resident drug overdose deaths with available toxicology results are presented in Fig. 1. The crude drug overdose fatality rate ranged from 40/100,000 in West Virginia to 16/100,000 in North Carolina and Maricopa County, Arizona. The presence of opioids in resident overdose deaths with available toxicology results ranged from 93% in Kentucky (23/100,000 overdose deaths involving opioids, 25/100,000 overall overdose rate; Fig. 1) to 66% in Maricopa County (10/100,000
Discussion
Five geographically diverse U.S. states/jurisdictions participated in this study to ensure that regional specificity did not limit any interpretations and conclusions made. The participants in this study provided data from states/jurisdictions serving nearly 21 million residents in total, representing approximately 6.5% of the total population of the United States. The results of this study suggest significant variation in the prevalence of gabapentin in drug overdose postmortem toxicology
Conclusions
The results of this study support the possible intentional use and misuse of gabapentin among individuals with substance use disorders and highlight the need to monitor the involvement of gabapentin in drug overdose deaths. As the extent to which gabapentin contributes to drug overdose deaths is unclear, further research is needed at state and local levels to evaluate the patterns of gabapentin prescribing, misuse, and diversion among populations with substance use disorders, as well as among
Role of funding source
This research did not receive any specific support from funding agencies in the public, commercial, or not-for-profit sectors.
Contributors
We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us. We confirm that we have given due consideration to the protection of intellectual property associated with this work and that there are no impediments to publication, including the timing of publication, with respect to
Conflict of interest
We wish to confirm that there are no known conflicts of interest associated with this publication (Prevalence of Gabapentin in Drug Overdose Postmortem Toxicology Testing Results) and there has been no significant financial support for this work that could have influenced its outcome.
Acknowledgments
The authors would like to thank the Council of State and Territorial Epidemiologists (CSTE); Barbara Gabella, Megan Toe, and Dr. Michael Landen, CSTE Overdose Subcommittee; Dr. Holly Hedegaard from the National Center for Health Statistics; Kentucky Department for Public Health; Kentucky Office of Vital Statistics; Kentucky Office of the Chief Medical Examiner; Dr. Kenneth E. Ferslew from the William L. Jenkins Forensic Center, East Tennessee State University; Tennessee Department of Health;
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