Last month, I reviewed the use of the gamma-aminobutyric acid (GABA) analog drug gabapentin (Neurontin®, Gralise®, Horizant®) for the treatment of substance use disorders (Howland, 2013). Four placebo-controlled studies demonstrated that gabapentin is safe and efficacious for the treatment of alcohol dependence. One of my colleagues thought this was interesting, but she wondered about the risk of diversion of gabapentin. This comment prompted two other colleagues (who work primarily in addiction patient populations) to say they would “hesitate to prescribe gabapentin for patients with concurrent opiate or sedative addiction, as there is a huge problem in Pittsburgh [Pennsylvania] with abuse and diversion of gabapentin in this population” (personal communication, November 2013). Patients tell them gabapentin increases the sensation of getting high if they combine it with opiate agents and that there is a street market for selling it. Because I often prescribe gabapentin for anxiety, insomnia, headaches, and/or pain, especially as an alternative to benzodiazepine drugs in patients who have comorbid substance use disorders (SUDs) or who are at high risk of substance abuse, I was intrigued by this reported misuse. In this column, I will review the potential for misuse of gabapentin.
Controlled Substances Classification of Gabapentin
The U.S. Controlled Substance Act (1970) classifies all drugs regulated under federal law into one of five schedules (Schedules I–V). This classification is based on the drug’s medical use, potential for abuse, and safety or dependence liability. The classification of a drug is made by the U.S. Drug Enforcement Agency (DEA), based on a DEA investigative process that also requires the U.S. Department of Health and Human Services (USDHHS) to conduct a medical and scientific evaluation of the drug, to recommend whether the drug should be controlled, and to recommend on what schedule the drug should be placed.
Gabapentin is not a scheduled drug. According to information contained in the product package insert (PPI) (Pfizer Inc., 2013), gabapentin does not exhibit affinity for benzodiazepine, opiate, or cannabinoid receptors. The PPI also indicates that a small number of postmarketing cases report gabapentin misuse and abuse. These individuals were taking higher than recommended doses of gabapentin for unapproved uses. Most of the individuals described in these reports had a history of polysubstance abuse or used gabapentin to relieve symptoms of withdrawal from other substances. The PPI also mentions rare postmarketing reports of individuals experiencing withdrawal symptoms shortly after discontinuing higher than recommended doses of gabapentin used to treat illnesses for which the drug is not approved. Such symptoms included agitation, disorientation, and confusion after suddenly discontinuing gabapentin that resolved after restarting gabapentin. Most of these individuals also had a history of polysubstance abuse or used gabapentin to relieve symptoms of withdrawal from other substances.
Similar to gabapentin, pregabalin (Lyrica®) is a GABA analog drug that strongly binds to the alpha-2-delta subunit of voltage-activated calcium channels, although its pharmacological effects are considered more potent than gabapentin (Bockbrader et al., 2010; Sills, 2006). Pregabalin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of fibromyalgia, postherpetic neuralgia, diabetic neuropathic pain, neuropathic pain associated with spinal cord injury, and partial seizures. Based on controlled studies, it has an approved indication for generalized anxiety disorder by the European Medicines Agency (but not by the FDA). Unlike gabapentin, pregabalin is classified as a Schedule V drug, which means that it has a low potential for abuse and limited physical or psychological dependence compared to Schedule IV drugs. Clonazepam (Klonopin®), alprazolam (Xanax®), and other benzodiazepine drugs are classified as Schedule IV drugs. Opioid and stimulant drugs are classified as Schedule II drugs (having a high potential for abuse and severe physical or psychological dependence).
Misuse of Gabapentin
Consistent with the product labeling, there are indeed anecdotal reports of gabapentin abuse as well as withdrawal symptoms associated with abrupt cessation of gabapentin (Canadian Agency for Drugs and Technologies in Health, 2010; “Gabapentin and pregabalin,” 2012; Mah & Hart, 2013; Webb, 2008). The total number of patients involved in these reports is rather small, however, and such reports have not prompted the DEA to reclassify gabapentin as a controlled drug.
Based on concerns about online availability and recreational misuse of pregabalin, Schifano et al. (2011) conducted an analysis of online information about pregabalin by monitoring 108 websites. For comparison, they analyzed online information about gabapentin and clonazepam by monitoring 32 other websites. They found that all three drugs are commonly offered for sale online. Users posting their experiences online described pregabalin as being associated with sedative and/or psychedelic effects. Although perceived as less powerful than pregabalin, gabapentin misuse was associated with similar descriptions of sedative and/or psychedelic effects. Clonazepam misuse was described by users as inducing sedation or stimulation, depending on the dose.
In a recent online survey (completed anonymously by 1,500 individuals in the United Kingdom), Kapil, Green, Le Lait, Wood, and Dargan (2013) compared misuse of baclofen (Lioresal®; a GABA-B receptor agonist drug), gabapentin, and pregabalin. Respondents’ self-reported lifetime prevalence of gabapentin misuse (1.1%) was similar to pregabalin (0.8%) and baclofen (1.3%). By contrast, the respondents’ self-reported lifetime prevalence of cocaine use was 8.1%, cannabis use 28.1%, and methamphetamine use 8.2%. Frequency of misuse of baclofen, gabapentin, or pregabalin was less than once per month in 37% and between once per month and once per week in 50%. Hence, only 13% misused any of these drugs more than once per week.
A questionnaire-based survey completed by 129 respondents attending six substance misuse clinics in Scotland found that 25 (22%) patients admitted to using nonprescribed gabapentin (Baird, Fox, & Colvin, 2013). For comparison, nonprescribed use of pregabalin was 3%, methadone 15%, benzodiazepine drugs 47%, buprenorphine 2%, heroin 5%, and cannabis 43%. Of the 29 patients taking nonprescribed gabapentin or pregabalin, 22 used them to become intoxicated and 11 used them to potentiate the “high” they obtained from taking methadone.
In a pharmacoepidemiological study using the Norwegian Prescription Database, Bramness, Sandvik, Engeland, and Skurtveit (2010) measured benzodiazepine drug use before and after initiation of treatment with pregabalin and gabapentin. Psychiatric patients who started pregabalin were able to reduce the amount of benzodiazepine drugs they used by 48%, compared to a reduction of only 14% among gabapentin users. Although the methodology of this study precludes a definitive comparison between gabapentin and pregabalin, this finding suggests a possibly greater degree of cross-tolerance between pregabalin and benzodiazepine drugs. Consistent with this possibility, data from the Swedish spontaneous adverse drug reaction (ADR) reporting system identified 16 cases of pregabalin abuse, but none for gabapentin (Schwan, Sundström, Stjernberg, Hallberg, & Hallberg, 2010). An analysis of data from the French Pharmacovigilance Database found a slightly higher rate of neuropsychiatric ADRs for pregabalin (35%) compared to gabapentin (29%) (Fuzier, Serres, Guitton, Lapeyre-Mestre, & Montastruc, 2013). Somnolence, confusion, and dizziness were identified as the most common neuropsychiatric ADRs, but there were no reports of overdose, misuse, or abuse of either drug.
In the United Kingdom, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the functional equivalent of the FDA. Complete listings of all suspected ADRs reported to the MHRA are compiled in Drug Analysis Prints (DAPs), which are available to review on the MHRA website (MHRA, n.d.). The DAP for gabapentin (covering the 20 years from 1993 to September 2013) reports only eight cases of abuse, dependence, or misuse and 24 cases of withdrawal syndromes. By contrast, the DAP for pregabalin (covering the approximate 10 years from 2004 to September 2013) reports 80 cases of abuse, dependence, or misuse and 48 cases of withdrawal syndromes. It is notable that 10 times as many cases of drug misuse have been reported in half the time period for pregabalin compared to gabapentin.
Drug Abuse Warning Network
The Drug Abuse Warning Network (DAWN) is a program of the Substance Abuse and Mental Health Services Administration (SAMHSA) within the USDHHS. DAWN, a public health surveillance system that reports on drug-related visits to hospital emergency departments (EDs), is used to monitor trends in drug misuse and abuse, identify the emergence of new substances and drug combinations, assess health hazards associated with drug use and abuse, and estimate the effect of drug use, misuse, and abuse on the health care system.
Data from the National Estimates of Drug-Related Emergency Department Visits (NEDREDV) for the years 2004–2011 are available to review as Microsoft® Excel® files on the DAWN website (SAMHSA, n.d.). NEDREDV data (on all drug misuse and abuse) reveal that the ED visit rates (per 100,000 population) for gabapentin rose from 2.7 in 2004 to 4.9 in 2011. To put these gabapentin rates in perspective, alcohol ED visit rates were 230.5 (in 2004) and 232.5 (in 2011), opioid drugs were 67.7 (2004) and 178.6 (2011), benzodiazepine drugs were 58.2 (2004) and 136.6 (2011), antidepressant drugs were 28 (2004) and 34.8 (2011), bupropion (Wellbutrin®) was 3.6 (2004) and 3.2 (2011), and atypical antipsychotic drugs were 11.1 (2004) and 20.1 (2011).
In another analysis of NEDREDV data (on nonmedical use of pharmaceuticals), the ED visit rate for gabapentin rose from 2.4 (in 2004) to 4.2 (in 2011). By comparison, rates for opioid drugs were 59 (2004) and 156.6 (2011), benzodiazepine drugs were 49 (2004) and 114.8 (2011), antidepressant drugs were 22.9 (2004) and 28.6 (2011), bupropion was 3.1 (2004) and 2.6 (2011), and atypical antipsychotic drugs were 9.1 (2004) and 16.2 (2011).
Both of these NEDREDV analyses demonstrate that rates of gabapentin-related ED visits are considerably lower than for other psychotropic drug classes. Among benzodiazepine drugs, alprazolam and clonazepam were by far associated with the highest ED visit rates in both analyses. Gabapentin rates are not much different than for the commonly used antidepressant drug bupropion, which has been associated with misuse and diversion (Hilliard, Barloon, Farley, Penn, & Koranek, 2013).
There is some evidence of gabapentin misuse and abuse. Withdrawal symptoms also have been described in cases where gabapentin was abruptly discontinued, although discontinuation symptoms can be associated with many different psychotropic drugs (Howland, 2010a, 2010b, 2010c, 2010d). Because gabapentin is a commonly prescribed medication, nurses should be aware of the potential risks for its misuse and for discontinuation symptoms. In my opinion, however, the risk of gabapentin misuse is inconsistent, the magnitude of the risk is small, and the risk is not comparable to the much higher risks associated with alcohol use, certain prescription drugs (e.g., benzodiazepine, opioid, and stimulant drugs), or illicit drugs. Moreover, reports of gabapentin misuse are not unique to this drug. Misuse of prescription medications not typically considered “drugs of abuse” can also occur (Hilliard et al., 2013). I will touch on this topic next month, when I address the safety and appropriateness of using gabapentin in patients with SUDs.
- Baird, C.R., Fox, P. & Colvin, L.A. (2013). Gabapentinoid abuse in order to potentiate the effect of methadone: A survey among substance misusers. European Addiction Research, 20, 115–118. doi:10.1159/000355268 [CrossRef]
- Bockbrader, H.N., Wesche, D., Miller, R., Chapel, S., Janiczek, N. & Burger, P. (2010). A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clinical Pharmacokinetics, 49, 661–669. doi:10.2165/11536200-000000000-00000 [CrossRef]
- Bramness, J.G., Sandvik, P., Engeland, A. & Skurtveit, S. (2010). Does pregabalin (Lyrica®) help patients reduce their use of benzodiazepines? A comparison with gabapentin using the Norwegian Prescription Database. Basic and Clinical Pharmacology and Toxicology, 107, 883–886. doi:10.1111/j.1742-7843.2010.00590.x [CrossRef]
- Canadian Agency for Drugs and Technologies in Health. (2010). Gabapentin tablets versus capsules: A review of the evidence regarding appropriate use. Retrieved from http://www.cadth.ca/media/pdf/htis/L0169%20Gabapentin%20Tablets%20Versus%20Capsules%20final.pdf
- Controlled Substances Act, 21 U.S.C. §801 (1970).
- Fuzier, R., Serres, I., Guitton, E., Lapeyre-Mestre, M. & Montastruc, J.L. (2013). Adverse drug reactions to gabapentin and pregabalin: A review of the French pharmacovigilance database. Drug Safety, 36, 55–62. doi:10.1007/s40264-012-0006-6 [CrossRef]
- Gabapentin and pregabalin. (2012). Abuse and addiction. Prescrire International, 21, 152–154.
- Hilliard, W.T., Barloon, L., Farley, P., Penn, J.V. & Koranek, A. (2013). Bupropion diversion and misuse in the correctional facility. Journal of Correctional Health Care, 19, 211–217. doi:10.1177/1078345813486448 [CrossRef]
- Howland, R.H. (2010a). Potential adverse effects of discontinuing psychotropic drugs. Part 1: Adrenergic, cholinergic, and histamine drugs. Journal of Psychosocial Nursing and Mental Health Services, 48(6), 11–14. doi:10.3928/02793695-20100506-01 [CrossRef]
- Howland, R.H. (2010b). Potential adverse effects of discontinuing psychotropic drugs. Part 2: Antidepressant drugs. Journal of Psychosocial Nursing and Mental Health Services, 48(7), 9–12. doi:10.3928/02793695-20100527-98 [CrossRef]
- Howland, R.H. (2010c). Potential adverse effects of discontinuing psychotropic drugs. Part 3: Antipsychotic, dopaminergic, and mood stabilizing drugs. Journal of Psychosocial Nursing and Mental Health Services, 48(8), 11–14. doi:10.3928/02793695-20100708-01 [CrossRef]
- Howland, R.H. (2010d). Potential adverse effects of discontinuing psychotropic drugs. Part 4: Benzodiazepine, glutamate, opioid, and stimulant drugs. Journal of Psychosocial Nursing and Mental Health Services, 48(9), 11–14. doi:10.3928/02793695-20100730-04 [CrossRef]
- Howland, R.H. (2013). Gabapentin for the treatment of substance use disorders. Journal of Psychosocial Nursing and Mental Health Services, 51(12), 11–14. doi:10.3928/02793695-20121219-01 [CrossRef]
- Kapil, V., Green, J.L., Le Lait, C., Wood, D.M. & Dargan, P.I. (2013). Misuse of the GABA-analogues baclofen, gabapentin and pregabalin in the United Kingdom. British Journal of Clinical Pharmacology. Advance online publication. doi:10.1111/bcp.12277 [CrossRef]
- Mah, L. & Hart, M. (2013). Gabapentin withdrawal: Case report in an older adult and review of the literature. Journal of the American Geriatrics Society, 61, 1635–1637. doi:10.1111/jgs.12427 [CrossRef]
- Medicines and Healthcare Products Regulatory Agency. (n.d.) Download Drug Analysis Prints (DAPs). Retrieved from http://www.mhra.gov.uk/Safetyinformation/Howwemonitorthesafetyofproducts/Medicines/TheYellowCardScheme/YellowCarddata/Druganalysisprints/index.htm
- Pfizer Inc. (2013, May). Neurontin medication guide. Retrieved from http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020235s036,020882s022,021129s022lbl.pdf
- Schifano, F., D’Offizi, S., Piccione, M., Corazza, O., Deluca, P., Davey, Z. & Scherbaum, N. (2011). Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data. Psychotherapy and Psychosomatics, 80, 118–122. doi:10.1159/000321079 [CrossRef]
- Schwan, S., Sundström, A., Stjernberg, E., Hallberg, E. & Hallberg, P. (2010). A signal for an abuse liability for pregabalin—Results from the Swedish spontaneous adverse drug reaction reporting system. European Journal of Clinical Pharmacology, 66, 947–953. doi:10.1007/s00228-010-0853-y [CrossRef]
- Sills, G.J. (2006). The mechanisms of action of gabapentin and pregabalin. Current Opinion in Pharmacology, 6, 108–113. doi:10.1016/j.coph.2005.11.003 [CrossRef]
- Substance Abuse and Mental Health Services Administration. (n.d.). Drug Abuse Warning Network. Retrieved from http://www.samhsa.gov/data/DAWN.aspx
- Webb, J. (2008). Gabapentin—Another drug of misuse? Retrieved from the British Columbia Drug and Poison Information Centre website: http://dpic.org/article/professional/gabapentin-abuse