In 1993, the Food and Drug Administration (FDA) approved gabapentin (NEURONTIN) as an add-on treatment for focal (partial) seizures — a type of epilepsy that begins in one side of the brain — and subsequently approved the drug in 2002 to treat pain that occurs as a late complication of shingles (postherpetic neuralgia) in adults. The agency later approved two different formulations of the drug: one (GRALISE) to treat shingles pain and another (HORIZANT) to treat shingles pain and...
In 1993, the Food and Drug Administration (FDA) approved gabapentin (NEURONTIN) as an add-on treatment for focal (partial) seizures — a type of epilepsy that begins in one side of the brain — and subsequently approved the drug in 2002 to treat pain that occurs as a late complication of shingles (postherpetic neuralgia) in adults. The agency later approved two different formulations of the drug: one (GRALISE) to treat shingles pain and another (HORIZANT) to treat shingles pain and moderate-to-severe restless legs syndrome in adults.
Generic gabapentin and Neurontin should be used only for the treatment of partial seizures in combination with other antiepileptic drugs and for minimizing moderate-to-severe shingles pain. We recommend against using Gralise or Horizant for shingles pain because they are expensive and there are no studies that show them to be more effective than generic gabapentin. Do not use Gralise or Horizant for epilepsy, and do not use Gralise for restless legs syndrome. Finally, do not use any gabapentin formulation for off-label uses (uses not approved as safe and effective by the FDA).
Illegal promotion of unapproved uses
Gabapentin has been a top-selling drug for many years: It was the ninth-most commonly prescribed drug in the U.S. in 2016, totaling over 58 million prescriptions that year.
However, most of gabapentin’s prescriptions are for off-label uses. A study that used nationally representative data showed that gabapentin had, as of 2001, the highest proportion (83%) of off-label prescriptions of all outpatient prescription drugs. Gabapentin’s off-label uses include treatment of anxiety, bipolar disorder, borderline personality disorder, drug and alcohol addiction, insomnia, migraine, neuropathic pain associated with diabetes, and vertigo.
Pfizer, the company that acquired Warner-Lambert (the original maker of gabapentin) and its marketing division (Parke-Davis), agreed to pay a total of $755 million in 2004 and 2014 in criminal and civil settlements with the U.S. federal government for its long-standing illegal promotion of the drug for off-label uses.
Furthermore, a 2013 study revealed that information included in publications of industry-sponsored trials supporting the off-label uses of gabapentin was frequently “different” from what was actually described in internal industry reports, suggesting that gabapentin’s maker deliberately manipulated the published literature to make the drug appear more effective than it actually is for its off-label uses.
Limited Use: Epilepsy and shingles pain
Although the clinical trials supporting gabapentin’s initial approval showed that the drug is effective as an add-on treatment in people with drug-resistant partial epilepsy, these trials were of relatively short duration (lasting only three months) and did not provide any evidence regarding the long-term effectiveness of this drug.
A clinical trial that directly compared gabapentin with other drugs used for the treatment of partial epilepsy such as lamotrigine (LAMICTAL) and carbamazepine (CARBATROL, EPITOL, EQUETRO, TEGRETOL, TERIL) showed that gabapentin had a higher rate of treatment failure and a lower rate of remission at one year than these other drugs, respectively, due to inadequate seizure control. Importantly, gabapentin is ineffective for a type of seizures called absence seizures and can worsen certain types of generalized seizures.
Two small trials lasting between seven and eight weeks showed that gabapentin reduced, but did not eliminate, shingles pain: Subjects taking the drug had a mean pain score of around four (on a pain scale that ranged from 0 to 10) after treatment, compared with a not-much-higher pain score of nearly six before treatment.
Despite its modest effectiveness, gabapentin has one advantage: It does not interact with other antiepileptic drugs. Gabapentin, however, is primarily eliminated by the kidneys, so adverse reactions to the drug may be more likely in patients with impaired kidney function.
Do Not Use: Restless legs syndrome
Gabapentin enacarbil extended release (HORIZANT) is approved to treat restless legs syndrome. However, high doses of this formulation are absorbed more efficiently by the intestine than high doses of other gabapentin formulations are, potentially resulting in greater, more serious adverse events.
An FDA medical reviewer initially recommended against approving gabapentin enacarbil extended release because it causes pancreatic cancer in rats at doses relatively close to those used in humans, outweighing its potential benefit for restless legs syndrome.
Drug abuse potential
Historically, gabapentin was presumed to not have an abuse potential. However, there is growing evidence to the contrary. For example, a U.S. study showed an almost 3,000% increase in the recreational use of gabapentin from 2008 to 2014.
Moreover, a 2016 systematic review estimated that misuse of gabapentin occurs in approximately 1% of the general population, between 40% and 65% of gabapentin users with prescriptions for the drug, and between 15% and 22% of opioid abusers.
Importantly, as of November 2020, seven states already had classified gabapentin as a schedule V drug, while another 12 states had required gabapentin prescription monitoring. In the U.K., gabapentin has been scheduled as a controlled substance since 2019.
The Advisory Council on the Misuse of Drugs, an independent body of experts that advises the U.K. government, has highlighted concerns over the misuse of gabapentin in light of reports of abuse, dependence and involvement of gabapentin in opioid overdoses and opioid-related and other deaths. The council asserts that gabapentin products present a risk of addiction and that the abuse potential of gabapentin is similar to that of tramadol (CONZIP, ULTRAM), a controlled substance in the U.K. and the U.S. Therefore, the council had recommended that gabapentin should be classified as a controlled substance.
In October 2017, the Medicines and Healthcare products Regulatory Agency, an agency in the U.K. similar to the FDA, issued a warning that gabapentin was associated with a risk of severe respiratory depression (decreased breathing), a dangerous adverse effect seen with opioid drugs.
In February 2022, Public Citizen’s Health Research Group petitioned the Drug Enforcement Administration and the FDA to add gabapentin and gabapentin enacarbil to schedule V under the Controlled Substances Act to more tightly monitor and regulate use of these drugs because they are increasingly being misused, abused, and diverted, leading to dependence and overdose deaths.
Based on evidence from clinical trials, the FDA in 2008 required the makers of gabapentin, along with those of 10 other antiepileptic medications, to include a warning in their labeling and develop medication guides to inform patients of the risk of suicidal thoughts or actions associated with the drugs.
In 2020, Lancet published results of a randomized clinical trial indicating that gabapentin was not effective for treating chronic pelvic pain in women.
In April 2019, the Medicines and Healthcare products Regulatory Agency (a regulatory agency in the U.K. similar to the FDA) announced that gabapentin would be classified as a controlled substance in the U.K.
In September 2019, Health Canada (a regulatory agency in Canada similar to the FDA) issued an advisory that there is an increased risk of adverse effects, including opioid overdose, when gabapentin or pregabalin (LYRICA) is used together with opioid medications.
In December 2019, the FDA issued an advisory that serious breathing problems can occur when gabapentin or pregabalin is used in the elderly and in patients who are at risk of breathing difficulties, including those taking opioids and other drugs that depress breathing through their effects on the central nervous system. The product labeling for the drug was subsequently updated in April 2020 to include a warning about this risk.