The amino acid gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system (CNS). The main GABA receptor complexes are referred to as GABA-A, GABA-B, and GABA-C. GABAergic function has been investigated in psychiatric disorders and substance abuse. Because of the important role of GABA in the CNS, some drugs have been developed as structural analogs of GABA (Bryans & Wustrow, 1999). GABAergic neurons and receptors are the target of a wide range of drugs, including anti-anxiety, sedativehypnotic, general anesthetic, and anticonvulsant drugs. In this article, I will review the use of the GABA analog drug gabapentin for the treatment of substance use disorders (SUDs).
What Is Gabapentin?
Gabapentin is available in three manufactured products: gabapentin tablets, capsules, and oral solution (Neurontin®); gabapentin once-daily tablets (Gralise®); and gabapentin enacarbil extended-release tablets (Horizant®).
The product Neurontin is approved by the U.S. Food and Drug Administration (FDA) for use as adjunctive therapy (together with other anticonvulsant drugs) in the treatment of partial seizures and for the management of postherpetic neuralgia (PHN). Bioequivalent tablets, capsules, and oral solutions are available as FDA-approved generic formulations of Neurontin. Gabapentin tablets and capsules are used more commonly in clinical practice than the other branded gabapentin products. Gabapentin is used extensively off-label for a variety of clinical reasons: migraine and other headaches, various types of acute and chronic pain syndromes, hot flashes, pruritis (especially in hemodialysis patients), anxiety, and insomnia. Depending on the indication, the dose range is 300 to 3,600 mg per day. Gabapentin bioavailability (absorption) is not dose proportional (i.e., as the dose is increased, bioavailability decreases). According to the product package insert, the bioavailability is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1,200, 2,400, 3,600, and 4,800 mg per day (when given in three divided doses), respectively. The reason for this is that the intestinal transporter mechanism (the large, neutral amino acid transporter referred to as “system L”) responsible for the absorption of gabapentin is saturable—only so much gabapentin can be transported at one time (Stewart, Kugler, Thompson, & Bockbrader, 1993). Food has only a slight effect on drug absorption. Because gabapentin has a short half-life and its absorption is not dose-proportional, it is typically given in divided doses three times daily. For insomnia, however, bedtime doses of 100 mg or higher are used. Gabapentin is not metabolized by the liver, nor does it affect the hepatic metabolism of other drugs, but it is excreted unchanged through the kidneys. For all clinical uses, gabapentin is generally considered a safe and well-tolerated drug. Potential adverse effects include sedation, fatigue, ataxia, dizziness, nystagmus, and peripheral edema.
The product Gralise is FDA approved for the management of PHN, but it is not available in generic formulations and it is not bioequivalent to or interchangeable with other gabapentin products. Gralise is used in doses of 300 to 1,800 mg, given once per day. Its bio-availability is much greater with food, so it should be taken during an evening meal.
The Horizant product is FDA approved for the treatment of restless legs syndrome (RLS) and for the management of PHN. Generic formulations are not available. Gabapentin enacarbil is a transported prodrug of gabapentin, designed to overcome the pharmacokinetic limitations of gabapentin (i.e., its short half-life and lack of dose-proportional absorption). Prodrugs are pharmacologically inactive compounds that must be converted to biologically active metabolites. Gabapentin enacarbil is absorbed by high-capacity nutrient transporters distributed in the gastrointestinal system, where it then undergoes rapid hydrolysis (cleavage) by nonspecific esterases to release gabapentin. Horizant’s bioavailability is greater with food. It is used in doses of 600 mg at night for RLS or 600 mg twice per day for PHN.
How Does Gabapentin Work?
Although structurally related to GABA, gabapentin does not modify GABA-A or GABA-B binding, it is not converted metabolically into GABA or a GABA receptor agonist, and it is not an inhibitor of GABA uptake or degradation (Taylor et al., 1998). Gabapentin does not exhibit affinity for other CNS receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, glycine, adrenergic, adenosine, cholinergic, dopamine, histamine, serotonin, opioid, and cannabinoid receptors. Preclinical studies have shown that gabapentin binds with high affinity to the alpha-2-delta subunit of voltage-activated calcium channels, an effect that may regulate glutamate and GABA signaling in the CNS (Yoshizumi, Eisenach, & Hayashida, 2012). Modulation of neuronal calcium channels is a mechanism that may explain the analgesic effects of certain drugs, including gabapentin and the GABA analog pregabalin (Lyrica®). The FDA-approved drug ziconotide (Prialt®) is also a calcium channel blocker indicated for treating chronic pain. Regulation of glutamate and GABA signaling within brain reward systems has been used to justify investigations into the use of drugs such as gabapentin for treating addictions.
Gabapentin for Substance Use Disorders
Preclinical and clinical studies have investigated the effects of gabapentin on alcohol consumption. Gabapentin (600 mg per day) was significantly more effective than placebo in reducing alcohol consumption and craving in a 4-week randomized study of 60 alcohol dependent participants who had just completed detoxification treatment (Furieri & Nakamura-Palacios, 2007). In a small 6-week randomized pilot study of 21 participants with alcohol dependence, gabapentin (1,500 mg per day) significantly delayed the onset to heavy drinking compared to placebo, and this differential effect favoring gabapentin-treated patients persisted for an additional 6 weeks after the end of the double-blind study (Brower et al., 2008).
In a 16-week randomized double-blind study of 150 participants with alcohol dependence, Anton et al. (2011) compared three treatment groups: naltrexone (Revia®; an FDA-approved treatment for alcohol dependence) (50 mg per day) plus placebo-gabapentin; naltrexone (50 mg per day) plus gabapentin (1200 mg per day for the first 6 weeks and then replaced by placebo-gabapentin for the last 6 weeks); and double-placebo (placebo-naltrexone plus placebo-gabapentin). During the first 6 weeks, the naltrexone/gabapentin group had (a) a significantly longer delay to heavy drinking than the naltrex-one alone group, which was similar to the double-placebo group; (b) had significantly less heavy drinking days than naltrexone alone, which did worse than double-placebo; and (c) had significantly less drinks per drinking day than naltrexone alone and double-placebo. These significant differences faded during the last 6 weeks of the study (after gabapentin was switched to placebo-gabapentin).
Most recently, a 12-week double-blind controlled randomized clinical trial of gabapentin (900 mg per day or 1,800 mg per day) versus placebo in 150 participants with alcohol dependence demonstrated that gabapentin was significantly effective on measures of alcohol dependence and relapse-related symptoms of insomnia, dysphoria, and craving (Mason et al., 2013). Both gabapentin doses were effective, but especially at the higher dose.
Controlled and open-label studies have also found gabapentin safe and effective for the treatment of alcohol withdrawal syndromes (Bonnet et al., 2010; Mariani, Rosenthal, Tross, Singh, & Anand, 2006; Myrick et al., 2009; Stock, Carpenter, Ying, & Greene, 2013).
Gabapentin has been investigated for the treatment of other SUDs. A 12-week randomized double-blind pilot study of 50 participants with cannabis dependence demonstrated that compared to placebo, gabapentin (1,200 mg per day) was associated with significantly less marijuana use and marijuana withdrawal symptoms and significantly greater overall improvement in marijuana-related cognitive impairment (Mason et al., 2012). By contrast, randomized controlled studies have not found any significant benefit for gabapentin in the treatment of methamphetamine dependence or cocaine dependence (Berger et al., 2005; Bisaga et al., 2006; González et al., 2007; Heinzerling et al., 2006). Some work has suggested that gabapentin may be associated with reduced opioid drug use in patients taking buprenorphine or methadone (González et al., 2007; Moghadam & Alavinia, 2013; Sanders et al., 2013). The use of gabapentin for treating benzodiazepine abuse has not been reported in the literature. One ongoing trial of gabapentin for benzodiazepine dependence is listed on the ClinicalTrials.gov website (trial NCT01893632). A second study (trial NCT00420771) of gabapentin treatment for benzodiazepine abuse in methadone-treated patients has been completed, but no results are posted on ClinicalTrials.gov.
Three medications are FDA approved for alcohol dependence: disulfiram (Antabuse®), naltrexone (Revia), and acamprosate (Campral®). Four controlled studies found gabapentin effective for alcohol dependence, although its long-term efficacy is unknown. Gabapentin may also be safe and effective for treating alcohol withdrawal syndromes. A pilot study found gabapentin beneficial for cannabis dependence, but several controlled studies found no benefit for cocaine or methamphetamine dependence. Whether gabapentin is effective for other SUDs is unknown. Nurses who work with alcohol-dependent patients should become familiar with the use of gabapentin. I have frequently prescribed gabapentin for the treatment of anxiety, insomnia, pain, and/or headaches in psychiatric patients, especially those patients who have comorbid SUDs or those patients I consider at high risk for substance abuse. In these cases, gabapentin is intended as an alternative to the use of benzodiazepine drugs. Whether the use of gawwbapentin is entirely safe and appropriate for SUDs will be addressed in next month’s Psychopharmacology article.
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