Introduced in 1993, gabapentin is a gamma-aminobutyric acid (GABA) analog that is classified as an anticonvulsant. Its FDA-approved uses are partial seizures in adults (1993) and children (2000), and postherpetic neuralgia (2002). An extended-release formulation is approved for restless legs syndrome (2011) and postherpetic neuralgia (2012). But outside of these indications, gabapentin has garnered a host of off-label uses, including anxiety, alcohol use disorder (AUD), alcohol withdrawal, and even hiccups. As these off-label uses accumulate, prescribing has skyrocketed. The 2016 release of the CDC Opioid Prescribing Guidelines, which emphasized non-opioid pain medications, has also likely been a driver of gabapentin prescriptions (Dowell D et al, MMWR 2016;65(1):1–49). At the same time, there are warning signs that gabapentin might be addictive and increase risk of opioid overdose death. Here, we’ll take a look at the data and put everything together to help you figure out how gabapentin can fit into your practice.

Prescribing trends

Gabapentin prescriptions are on the rise. Between 2009 and 2016, scripts went up by at least 44% in every state, and as of 2019, gabapentin was the seventh most prescribed medication in the US (Kuehn BM, JAMA 2022;327(24):2387). In addition, off-label prescribing is now the norm, with one study finding that <1% of gabapentin prescriptions are for an FDA-approved indication (Costales B and Goodin AJ, Psychiatr Serv 2021;72(11):1246–1253). That same study also found that gabapentin is prescribed along with one or more central nervous system depressant medications 60% of the time, with opioids and benzodiazepines being in the top three.

Pharmacology

While benzodiazepines and other sedative-hypnotics typically act as ligands at GABA receptors, gabapentin (despite its name) does not. Gabapentin inhibits voltage-gated calcium channels, reducing excitatory neurotransmitter release and thereby producing sedating effects. Gabapentin is excreted by the kidneys largely unmetabolized and has a half-life of five to seven hours. The dose should be adjusted in those with renal dysfunction.

Off-label indications: Reviewing the evidence

Off-label uses of gabapentin with the most evidence are AUD and alcohol detoxification. A recent meta-analysis of seven randomized controlled studies looking at gabapentin monotherapy in AUD found that it was more effective than placebo and significantly reduced the percentage of heavy drinking days (Kranzler HR et al, Addiction 2019;114(9):1547–1555). The authors of the study concluded that its potential clinical benefits outweighed any risks.

Another meta-analysis of 10 studies found that gabapentin was moderately effective in reducing cravings and withdrawal symptoms in alcohol detoxification—and, in cases of mild to moderate withdrawal, could be used as a benzodiazepine replacement (Ahmed S et al, Prim Care Companion CNS Disord 2019;21(4):19r02465). A potential added bonus is that gabapentin detoxification seems to reduce the probability of drinking, at least for the first week post-withdrawal, when compared to detoxification with benzos (Myrick H et al, Alcohol Clin Exp Res 2009;33(9):1582–1588).

There is also some evidence for gabapentin in anxiety disorders. While not a magic bullet, gabapentin appears to have a statistically significant, though clinically modest, effect in symptom reduction for generalized anxiety and social anxiety (Hong JSW et al, Mol Psychiatry 2022;27(3):1339–1349). It is also frequently prescribed for insomnia, an indication for which there is a modest amount of evidence (Atkin T et al, Pharmacol Rev 2018;70(2):197–245).

At one time, there was hope that gabapentin had mood-stabilizing properties; after all, many mood stabilizers, like gabapentin, started off as anticonvulsants. But multiple trials have yielded disappointing results, and it appears that gabapentin is ineffective in the treatment of mania either as monotherapy or as adjunctive treatment (Ng QX et al, Pharmaceuticals (Basel) 2021;14(9):834).

Can gabapentin be addictive?

Gabapentin can lead to tolerance and, if suddenly stopped, withdrawal. The time course of withdrawal can be highly variable, starting between 12 hours and seven days after cessation, with the most common occurrence between 24 and 48 hours (Mersfelder TL and Nichols WH, Ann Pharmacother 2016;50(3):229–233). Withdrawal symptoms include anxiety, irritability, and restlessness (which are the most frequently reported), along with confusion, disorientation, diaphoresis, tremor, tachycardia, hypertension, and insomnia. In a minority of cases, akathisia, catatonia, and even seizures can occur (Mersfelder and Nichols, 2016).

There is growing evidence that gabapentin can be reinforcing for some patients, possibly leading to misuse. According to one systematic review, people reported that gabapentin produced feelings of euphoria, increased sociability, and reduction in withdrawal symptoms or cravings from other substances, producing a “liking” effect (Evoy KE et al, Drugs 2021;81(1):125–156). Patients with comorbid substance use disorders, particularly opioid use disorder (OUD), seem to be particularly at risk for misusing gabapentin.

Associations with opioid overdose deaths

An additional concern with gabapentin is its association with opioid overdose mortality, which has become increasingly apparent in recent years. The mechanism is unclear, though two hypotheses have been proposed to explain it: 1) gabapentin may further opioid-induced respiratory depression, and 2) opioids may increase gabapentin bioavailability by slowing gastric motility (Gomes T et al, PLoS Med 2017;14(10):e1002396). It is likely that both mechanisms play a role.

The association has been established through several postmortem studies, with quite a bit of regional variability (Slavova S et al, Drug Alcohol Depend 2018;186:80–85). But it seems that gabapentin is being increasingly implicated in opioid overdose deaths all around the country (Mattson CL et al, MMWR Morb Mortal Wkly Rep 2022;71(19):664–666). Moreover, the association is not limited to illicit opioids; gabapentin prescribed alongside opioids has been found to increase odds of opioid-related deaths as well (OR=1.99 (95% CI 1.61–2.47, p<0.001); Gomes et al, 2017). This study also found a dose effect, with a nearly 60% increase in opioid-related mortality for doses ≥900 mg.

Summing it all up

Despite the risks when mixed with opioids, gabapentin still has its uses. There is evidence supporting its use in AUD, specifically in reduction of heavy drinking days, cravings, and management of withdrawal without benzodiazepines. Additionally, gabapentin can be used in the treatment of both generalized anxiety disorder and social anxiety disorder.

If you do choose to prescribe gabapentin, be sure that the patient has a good understanding of the risks and make an agreement beforehand about when the medication will be stopped. Carefully monitor the patient’s response and consider stopping if your patient starts taking more than prescribed, requests early refills, or reports having a euphoric response. When stopping, monitor for signs and symptoms of acute withdrawal for 24–48 hours, most commonly involving anxiety, irritability, and restlessness. If withdrawal does occur, you can taper the medication over a few weeks. Lastly, we recommend using caution when co-prescribing gabapentin with opioids or when there is a history of illicit opioid use, as this can lead to an increased risk of overdose and death.

CARLAT VERDICT 

Gabapentin prescribing has skyrocketed as its off-label uses have expanded. Though useful in some cases, namely AUD and anxiety disorders, it is not as harmless as once thought. Gabapentin has addictive potential and is associated with opioid overdose deaths, so use caution when prescribing to patients with a history of addiction, particularly to opioids. If prescribing gabapentin for a patient with OUD is unavoidable, have a thorough discussion of risks and benefits and make sure the patient has access to naloxone.