Gabapentin (brand name Neurontin) is a GABA analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain.

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is not believed to act on the same brain receptors.

Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the α2δ subunit (1 and 2) of the voltage-dependent calcium channel in the central nervous system.Davies et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels.Trends Pharmacol Sci. 2007 May;28(5):220-8.

Due to the wide variety of conditions for which Gabapentin may be considered as a treatment, and the various claims and counterclaims surrounding it, this presentation of the indicated uses of Gabapentin has attempted to separate the FDA accepted uses, the putative uses, and the disputed uses of the drug.

A capsule of gabapentin

Proven

Gabapentin was originally approved in the U.S. by the Food and Drug Administration (FDA) in 1994 for use as an adjunctive medication to control partial seizures (effective when added to other antiseizure drugs). In 2002, an indication was added for treating postherpetic neuralgia (neuropathic pain following shingles), other painful neuropathies, and nerve related pain.Pfizer: Product Monograph Retrieved 14 August 2006

Gabapentin (administered orally) is one of two medications (the other being flumazenil, which is administered intravenously) used in the expensive Prometa Treatment Protocol for methamphetamine, cocaine and alcohol addiction. Gabapentin is administered at a dosage of 1200 mg taken at bedtime for 40–60 days. Though the combination of flumazenil infusions and gabapentin tablets is a licensed treatment, there is no prohibition against a physician prescribing gabapentin outside the Prometa protocol. There have been reports by methamphetamine addicts that gabapentin alone in doses of 1200 mg at bedtime taken for 40–60 days has been effective in reducing the withdrawal symptoms and almost eliminating cravings or desire to use methamphetamine.PROMETA Demonstrates Statisitcally Significant Reduction in Methamphetamine Cravings in Randomized Double-Blind Placebo Controlled Study It also helps those addicted to prescribed pain medications, and reduces withdrawal symptoms. Add-on gabapentin in the treatment of opiate withdrawal, Gabapentin-Assisted Benzodiazepine Withdrawal In A Multidrug Dependent Patient

Positive

Gabapentin is frequently used to treat various types of Neuralgia. It has been found to be effective in prevention of frequent migraine headaches, neuropathic pain and nystagmus, and is prescribed off-label (that is, without formal regulatory agreement) for these conditions. Gabapentin is widely believed to help patients with post-operative chronic pain (usually caused by nerves that have been severed accidentally in an operation and when grown back, have reconnected incorrectly) and nerve pain associated with spinal cord injury. It may be effective in reducing pain and spasticity in multiple sclerosis., and has also had success in treating certain instances of Complex Regional Pain Syndrome.Gabapentin: pharmacology and its use in pain management; Rose, M., Kam, P.Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1, Anton C van de Vusse , Suzanne GM Stomp-van den Berg , Alfons HF Kessels and Wim EJ Weber.

It is not uncommon for the prescription of Gabapentin to occur in a mental health context. It has been investigated as a mood-stabilizing treatment for bipolar disorder with the potential therapeutic advantage of having fewer side-effects than better established bipolar drugs such as lithium and valproic acid although numerous trials have shown that it is not effective. Gabapentin has limited usefulness in the treatment of anxiety disorders such as social anxiety disorder and obsessive-compulsive disorder, in treatment-resistant depression, and for insomnia.

Additionally, Gabapentin has been prescribed to menopausal patients being treated with anti-androgenic compounds to reduce the incidence and intensity of the accompanying hot flashes. It has occasionally been prescribed for treatment of idiopathic subjective tinnitus, although a double blind, randomized controlled trial has found this ineffective. Gabapentin may help deepen sleep, positively affecting stage 4 sleep, and reducing arousals during the night . It could potentially be helpful for both sleep onset and sleep maintenance. Gabapentin is sometimes prescribed for RLS (Restless Legs Syndrome). Finally, it may be effective in treating akathisia - a side effect of antipsychotics that causes severe agitation and anxiety.

Gabapentin has also been used to treat some symptoms of opiate withdrawal.

Negative

There has been a growing controversy regarding the psychiatric off-label use of Gabapentin. Although some small, non-controlled studies in the 1990s — mostly sponsored by gabapentin's manufacturer — suggested that gabapentin treatment for bipolar disorder may be promising, other more recent and better controlled studies have found it to be no more effective (and in one study, slightly less effective) than placebo. Subsequent to the corporate acquisition of the original patent holder, the pharmaceutical company Pfizer admitted that there had been violations of FDA guidelines regarding the promotion of unproven off-label uses for Gabapentin in the Franklin v. Pfizer case. Concerns about the distorting effects of Pfizer's research practices upon the represented efficacy of Gabapentin have been summarized for the Prescription Access Litigation project in an August 10, 2008 article written by Kay Dickersin, M.D, Ph.D, a scholar of publication bias at Brown University.Reporting and other biases in studies of Neurontin for migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic pain Retrieved 28 March 2009.

Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. It is often tried as an alternative treatment, when patients are unable to tolerate the side effect of more proven mood stabilizers such as lithium; as or more frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficiently positive results.

Gabapentin should not be discontinued abruptly after long term use. Abrupt or over rapid withdrawal may provoke a withdrawal syndrome similar to alcohol or benzodiazepine withdrawal. Gradual reduction over a period of weeks or months helps minimize or prevents the withdrawal syndrome.

Although the potential for serious withdrawal symptoms are very limited as described in official literature, there is increasing awareness among users about existence and sheer frequency of potentially serious withdrawal symptoms even after long tapering.

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities);Note that an updated labeling has been approved, but is not available online as of November 2006 these mainly occur at higher doses, in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity reported in the literature. Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.

An increase in formation of adenocarcinomas was observed in rats during preclinical trials, however the clinical significance of these results remains undetermined. Gabapentin is also known to induce pancreatic acinar cell carcinomas in rats through an unknown mechanism, perhaps by stimulation of DNA synthesis; these tumors did not affect the lifespan of the rats and did not metastasize.Gabapentin Official FDA information, side effects and uses

Although gabapentin is not a controlled substance, it does produce psychoactive effects that could lead to recreational use of the drug. However, it is widely regarded as having little or no potential for misuse. Pregabalin, a gabapentinoid with higher potency marketed for neuropathic pain, is a controlled substance, under Schedule V of the United States' Controlled Substances Act.

The FDA has issued a warning of an increased risk of suicidal thoughts and behaviors in patients taking gabapentin. An independent analysis by the FDA showed that anticonvulsant drugs, including gabapentin, can increase suicidal thoughts in patients. The approved label for Neurontin now includes a warning about an increased risk of suicidal thoughts or actions and a guide to help patients understand this riskSuicidal Behavior and Ideation and Antiepileptic Drugs.

In July 2009, the first case against Pfizer, the maker of Neurontin, went to trial, and there are an estimated 1200 pending cases regarding the safety of Neurontin. Although a Pfizer spokesperson noted that "the reliable scientific evidence does not demonstrate a causal association between Neurontin treatment and suicidal behavior," the FDA analysis found an 80 percent rise in suicidal thoughts and behavior in data from 199 studies of gabapentin and other anticonvulsantsPfizer Faces First Trial on Neurontin Suicide Claim.

Gabapentin is best known under the brand name Neurontin manufactured by Pfizer subsidiary Parke-Davis. A Pfizer subsidiary named Greenstone markets generic gabapentin.

In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by the Israeli firm Teva.

Neurontin is one of Pfizer’s best-selling drugs, and was one of the 50 most-prescribed drugs in the United States in 2003. However, in recent years, Pfizer has come under heavy criticism for its marketing of Neurontin, facing allegations that, behind the scenes, Parke-Davis marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved.

Franklin v. Pfizer case

By some estimates, so-called off-label prescriptions account for roughly 90% of Neurontin sales. While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal. In 2004, Warner-Lambert agreed to plead guilty and pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes, and further legal action is pending. The courts of New York State, for example, have refused to certify a class of injured parties who took Neurontin for off-label use, finding that they had failed to state that they had any injury.Baron v. Pfizer, Inc., 2007 N.Y. Slip Op. 05813 (App. N.Y., July 5, 2007)

The University of California, San Francisco (UCSF) has archivedDrug Industry Document Archive and studiedNarrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents - Steinman et al. 145 (4): 284 - Annals of Internal Medicine the documents made public by this case, which opens a unique window into the illegal promotion and marketing of pharmaceuticals. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Parke-Davis (through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people who had been prescribed gabapentin for off-label treatment of bipolar disorder later attempted or committed suicide.