Gabapentin’s Impact on Drug-related Overdose Deaths

Gabapentin’s Impact on Drug-related Overdose Deaths
Lucas Cannon, PharmD
Community-University Health Care Center

Background: Gabapentin is a medication approved by the Food and Drug Administration (FDA) for two clinical indications: postherpetic neuralgia and as an adjunctive therapy for partial seizures. Gabapentin is structurally similar to the inhibitory neurotransmitter GABA, however the exact mechanism of action is not known. It has been suggested it may decrease the effects of an excitatory synapse while also increasing the synthesis of the GABA neurotransmitter. Non-FDA approved (i.e. off-label) indications include maintenance of abstinence with alcohol dependence, fibromyalgia, hemodialysis-associated pruritus, hot sweats, neuropathy due to diabetes mellitus, preemptive therapy for acute postoperative pain, and trigeminal neuralgia. This list has continued to grow over the last several years, and according to Pauly et al., prescribing rates of gabapentin have doubled from 2009 to 2016. Moreover, according to IQVIA Institute, in 2019 it was the seventh most prescribed medication in the US.

Due to the overall inhibitory nature of gabapentin, some of the most common side effects include somnolence, ataxia, fatigue and dizziness. Gabapentin is generally considered safe on its own and can potentially have only mild to moderate toxicity even at doses as high as 35 to 40 grams. However, when used with other prescribed and non-prescribed central nervous system (CNS) depressants, such as an opioid like fentanyl or hydromorphone, CNS depression can become fatal. 

Evidence: Over the last few years, there has been an increase in patient death related to gabapentin usage, driven partly by misuse. Buttram et al. states gabapentin is being misused to assist in opioid withdrawal management, self-detoxification from opioids, and the self-management of mental health or pain-related stress. Misuse of gabapentin often occurs at doses between 3600 mg and 12,000 mg. The Centers for Disease Control and Prevention analyzed data from the State Unintentional Drug Overdose Reporting System (SUDORS) and found there were 58,362 overdose deaths with toxicology reports in the 24 jurisdictions that use the reporting system (23 states and the District of Columbia) in 2019 and 2020. Of these overdose deaths, 5,687 (9.7%) had gabapentin detected in postmortem toxicology, and of those deaths, gabapentin was determined to be the cause of death in 49% of people at the beginning of 2019, with an increase to 55% by the end of 2020. This report also collected information on concomitant medication use. Of the 58,362 overdose deaths, 90% also involved opioids as the cause of death and this percentage remained stable from 2019 to 2020. Interestingly, prescribed opioid involvement decreased during this time period while illicit opioid use, particularly fentanyl, increased. An important limitation from this review: gabapentin is not always included on death certificates. This leads to an unknown amount of overdose deaths not indicated as associated with or caused by gabapentin which could potentiate an underestimate of gabapentin involvement. 

Discussion and Clinical Impact: As health care professionals, we must find a way to decrease these overdose deaths. One way to find a solution to this is by looking at the patient care process and the indication, effectiveness, safety, and convenience (IESC) framework. For patients seen during day-to-day appointments, ensure gabapentin is a medication that is indicated for their condition and consider all alternative options for the condition. From a broader view, off-label indications for gabapentin need to be reevaluated and stronger recommendations need to be made in favor of or against the use of gabapentin. The other crucial part of the IESC framework is, of course, safety. Regular monitoring of adverse effects needs to be assessed in patients, especially those taking concomitant opioids. With the use of collected data and effective patient-provider relationships, we can help reduce these types of overdose deaths. 

Bonus note: According to Premont, et al., as of July 2022, gabapentin is a C-V in Alabama, Kentucky, Michigan, North Dakota, Tennessee, Virginia, and West Virginia. Also, states that require gabapentin to be included in PDMP monitoring include Connecticut, Kansas, Massachusetts, Indiana, Washington DC, New Jersey, Minnesota, Nebraska, Ohio, Utah, Wyoming, and Oregon.

References:

  1. Pauly NJ, Delcher C, Slavova S, et al. Trends in gabapentin prescribing in a commercially insured U.S. adult population, 2009-2016. J Manag Care Spec Pharm. 2020;26(3):246-252. doi: 10.18553/jmcp.2020.26.3.246
  2. Medicine spending and affordability in the U.S. IQVIA. Published August 4, 2020. Accessed August 21, 2022. https://www.iqvia.com/insights/the-iqvia-institute/reports/medicine-spending-and-affordability-in-the-us
  3. Mattson C, Chowdhury F, Gilson T. Notes from the Field: Trends in Gabapentin Detection and Involvement in Drug Overdose Deaths — 23 States and the District of Columbia, 2019–2020. MMWR Morb Mortal Wkly Rep 2022;71:664–666. doi:10.15585/mmwr.mm7119a3
  4. Buttram M, Kurtz S. Descriptions of gabapentin misuse and associated behaviors among a sample of opioid (mis)users in South Florida. J Psychoactive Drugs. 2021;53(1):47-54. doi:10.1080/02791072.2020.1802087
  5. Schifano F, D'Offizi S, Piccione M, et al. Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychother Psychosom. 2011;80(2):118-122. doi: 10.1159/000321079
  6. Premont M, Aungst C. Is gabapentin a controlled substance? In some states, yes. Updated July 26, 2022. Accessed August 21, 2022. https://www.goodrx.com/gabapentin/is-gabapentin-a-controlled-substance