Gabapentin

Gabapentin

File:Gabapentin.svg
File:Gabapentin 3D.png
Systematic (IUPAC) name
2-[1-(aminomethyl)cyclohexyl]acetic acid
Clinical data
Pregnancy category	AU: B1 US: D (Evidence of risk) Benefit of treatment may outweigh risk to fetus. Risk of teratogenicity greater if more than one drug used
Routes of administration	Oral
Legal status
Legal status	UK: POM (Prescription only) ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Rapid, in part by saturable carrier-mediated L-amino acid transport system 60% for 0.9 g daily to 27% for 4.8 g daily dose Food increases absorption by 14%
Protein binding	Less than 3%
Metabolism	Not appreciably metabolized
Biological half-life	5 to 7 hours
Excretion	Renal
Identifiers
CAS Number	60142-96-3
ATC code	N03AX12 (WHO)
PubChem	CID 3446
DrugBank	APRD00015
ChemSpider	3328
Chemical data
Formula	C9H17NO2
Molar mass	171.237 g/mol[[]]
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Gabapentin (brand name Neurontin) is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain.

Pharmacology

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.

Results with human and rat brain NMR spectroscopy indicate that gabapentin increases GABA synthesis, probably by modulating, as it does in vitro, the action of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD) and the glutamate synthesizing enzyme, branched-chain amino acid transaminase.

Indications

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.

File:Gabapentin capsule.jpg

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.

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 cravings or desire to use methamphetamine. It also attenuates the severity of withdrawal symptoms experienced by those physically dependent on opioid analgesics, such as heroin, morphine, and oxycodone. One study also demonstrates a significant reduction in the severity of benzodiazepine withdrawal syndrome.

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 is a very promising medication in the treatment of post-herpetic neuralgia and pain. Because dermatological patients suffer pain from painful tumors, after surgery, in conjunction with neuropathic ulcers, during dressing changes involving serious medical conditions, its applications seem manifold.

Gabapentin has been used to treat some symptoms of opiate withdrawal, but tests for smoking cessation treatment have had mixed results.

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. Gabapentin may help deepen sleep, positively affecting deep, slow wave 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.

Negative

Gabapentin has been prescribed in the mental health context. Numerous trials have shown that it is not effective as a mood-stabilizing treatment for bipolar disorder and so has no therapeutic advantage in having fewer side-effects over better established bipolar drugs such as lithium and valproic acid. 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.

A double blind, randomized controlled trial found gabapentin ineffective for the treatment of idiopathic subjective tinnitus.

Relevant Legal Actions

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.A., Ph.D., a scholar of publication bias at Brown University..

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.

The Associated Press (3/26) reports that "a federal jury has found that Pfizer Inc. violated anti-racketeering laws in promoting its epilepsy drug Neurontin [gabapentin] for unapproved uses and must pay at least $142 million in damages." The case stems from a claim from Kaiser Foundation Health Plan Inc. that "it was misled into believing Neurontin was effective for off-label treatment of migraines, bipolar disorder and other conditions. Pfizer argued that Kaiser physicians still recommend the drug for those uses."

Bloomberg News (3/26, Voris, Lawrence) adds that "during the trial, Pfizer argued that Kaiser doctors continued to prescribe the drug even after the health insurer sued Pfizer in 2005. The insurer's website also still lists Neurontin as a drug for neuropathic pain, Pfizer lawyers said in closing argument." After their deliberation, "several jurors said they were strongly influenced by the testimony of former FDA Commissioner David Kessler and Kay Dickersin, a Johns Hopkins epidemiologist whose article casting doubt on clinical studies of Neurontin appeared in the New England Journal of Medicine last year."

The Wall Street Journal (3/26, Kamp) notes that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." "The verdict and the judge's rulings are not consistent with the facts and the law," he added, according to Reuters (3/26, Berkrot).

Franklin v. Pfizer case

Main article: David Franklin (scientist)

By some estimates, 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.

The University of California, San Francisco (UCSF) has archived and studied 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.

Precautions

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.

Withdrawal

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.

Adverse effects

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities); 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.

Overdosage

Persons who accidentally or intentionally ingested overdoses have manifested drowsiness, blurred vision, slurred speech and somnolence or coma. Serum gabapentin concentrations may be measured to confirm diagnosis.

Recreational use

Although gabapentin is not a controlled substance, it does produce psychoactive effects that cause it to have potential for recreational use. Even in low doses, Gabapentin causes sensations of reduced acute pain, reduced anxiety and even a tendency to become overly social and talkative. Larger doses can cause the user to become numb and even fully insensate. It has also been called upon to reduce opiate withdrawal symptoms. Although it is widely regarded as having little or no potential for misuse, it is often a misused drug in Canadian Northern communities. Pregabalin, a subsequent Pfizer spin-off, is however a controlled substance under Schedule V of the United States' Controlled Substances Act.

Suicide

Gabapentin has been associated with an increased risk of suicidal acts or violent deaths. In 2009 the FDA issued a warning of an increased risk of depression and suicidal thoughts and behaviors in patients taking gabapentin, along with other anticonvulsant drugs modifying the packaging insert to reflect this. In July 2009 the manufacturer of gabapentin (Pfizer) went to trial regarding the association between gabapentin and the increased risk of suicide.

Veterinary Use

Gabapentin is also used for some animal treatments, but formulations (especially liquid forms) for human use may contain the sweetener Xylitol which is toxic to dogs, so care must be taken if the human version is used for veterinary purposes.

Sales

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.

Related drugs

Parke-Davis developed a drug called pregabalin to be a successor of gabapentin, which was brought to market by Pfizer as Lyrica after they acquired Warner-Lambert. Pregabalin is related in structure to gabapentin and is approved for treatment of epilepsy, neuropathic pain associated with diabetes, fibromyalgia, post-herpetic neuralgia, and generalized anxiety disorder. Compared to gabapentin, pregabalin is more potent, absorbs faster and has greater bioavailability. Higher potency leads to less dose related adverse effects.

External links

• Gabapentin information from MedlinePlus
• News Article regarding Neurontin settlement and off-label marketing/use
• Website for the Greenstone subsidiary of Parke-Davis
• Website for the pending Class Action Lawsuit against Pfizer
• U.S. FDA information on safety of antiepileptics
• Bloomberg News on Neurontin lawsuit
• U.S. National Library of Medicine: Drug Information Portal - Gabapentin
• Erowid Gabapentin Vault

ar:جابابنتين tr:Gabapentin