Gabapentin  

Gabapentin
Systematic (IUPAC) name
2-[1-(aminomethyl)cyclohexyl]acetic acid
Identifiers
CAS number	60142-96-3
ATC code	N03AX12
PubChem	3446
DrugBank	APRD00015
Chemical data
Formula	C9H17NO2
Mol. mass	171.237 g/mol
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
Half life	5 to 7 hours
Excretion	Renal
Therapeutic considerations
Pregnancy cat.	B1(AU) D(US) Benefit of treatment may outweigh risk to fetus. Risk of teratogenicity greater if more than one drug used[1]
Legal status	POM(UK) Prescription only
Routes	Oral
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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.

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 2 subunit (1 and 2)^[2] of the voltage-dependent calcium channel in the central nervous system.^[3]

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.

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.^[4]

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 4060 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 4060 days has been effective in reducing the withdrawal symptoms and almost eliminating cravings or desire to use methamphetamine.^[5] It also helps those addicted to prescribed pain medications, and reduces withdrawal symptoms.^{[citation needed]}

Positive

Gabapentin is frequently used to treat various types of Neuralgia. It has been found to be effective in prevention of frequent migraine headaches,^[6] neuropathic pain^[7] and nystagmus,^[8] 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.^[9], and has also had success in treating certain instances of Complex Regional Pain Syndrome.^[10][11]

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.^[12][13]

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^[14]. It has occasionally been prescribed for treatment of idiopathic subjective tinnitus, although a double blind, randomized controlled trial has found this ineffective.^[15] Gabapentin may help deepen sleep, positively affecting stage 4 sleep, and reducing arousals during the night ^[16].^{[citation needed]} It could potentially be helpful for both sleep onset and sleep maintenance.^{[citation needed]} Gabapentin is sometimes prescribed for RLS (Restless Legs Syndrome). Finally, it may be effective in treating akathisia - a rare side effect of typical antipsychotics that causes severe agitation and anxiety.^{[citation needed]}

Gabapentin has also been used to treat some symptoms of opiate withdrawal.^[17]

Negative

There has been a growing controversy regarding the psychiatric off-label use of Gabapentin.^[9] 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,^[9] other more recent and better controlled studies have found it to be no more effective (and in one study, slightly less effective) than placebo.^[18] 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.^[19].

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. ^[20]

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.^[21]

Adverse effects

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities);^[22] these mainly occur at higher doses, in the elderly. Also, children 312 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.^[23] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.^[24][25]

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.^[26]

Recreational use

Although gabapentin is not a controlled substance, it does produce psychoactive effects that could lead to recreational use of the drug.^{[citation needed]} 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.

Risk of Suicide

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 risk^[27].

In July of 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 anticonvulsants^[28].

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 Pfizers 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.^[29] 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.^[30] 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.^[31]

The University of California, San Francisco (UCSF) has archived^[32] and studied^[33] 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.

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.

References

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
• [2]
• [3]

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Gabapentin For the past 2 years I have been using a cpac machine to sleep but lately I will wake 5 or more times a night. My doctor prescribe medication for RLS, but did not work, now he has prescribed Gabapentin 300 mg to help me sleep. What I have been reading about the med. I can't find no where that it is for sleeping. Friday, 6/5/2009 7:53:15 PM  1 Reply

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