|Systematic (IUPAC) name|
|Trade names||Fanatrex, Gabarone, Gralise, Neurontin, Nupentin, Neogab|
|Licence data||US Daily Med:|
|Pregnancy cat.||B1 (AU) C (US)|
|Legal status||POM (UK) ℞-only (US) ℞ Prescription only|
|Bioavailability||Rapid, in part by saturable carrier-mediated L-amino acid transport system|
|Protein binding||Less than 3%|
|Metabolism||Not appreciably metabolized|
|Half-life||5 to 7 hours|
|Mol. mass||171.237 g/mol|
|(what is this?)|
Gabapentin (Neurontin) is a pharmaceutical drug, specifically a GABA analog. It was originally developed to treat epilepsy, and currently is also used to relieve neuropathic pain. It is also commonly prescribed by doctors for many off-label treatments, such as restless leg syndrome, insomnia, and bipolar disorder. There are, however, concerns regarding the quality of the trials conducted for a number of conditions.
- 1 Medical uses
- 2 Adverse effects
- 3 Pharmacology
- 4 Mechanism of action
- 5 Society and culture
- 6 Veterinary use
- 7 See also
- 8 References
- 9 External links
Gabapentin is used primarily to treat seizures, neuropathic pain, including concussions, and hot flashes. There are, however, concerns regarding the quality of the research on its use to treat migraines, bipolar disorders, and pain.
Gabapentin provides significant pain relief in about a third of people who take it for fibromyalgia or chronic neuropathic pain; however, there are side effects in two thirds of people. It is effective in reducing narcotic usage post operatively and is helpful in neuropathic pain due to cancer. It has not been shown useful for HIV-associated sensory neuropathy. When used for neuropathic pain it does not appear superior to carbamazepine. It appears as effective as pregabalin and costs less. It does not appear to provide benefit for complex regional pain syndrome or to be useful for migraine prevention.
Gabapentin is approved for treatment of focal seizures in a number of countries and evidence supports its use for treating partial and mixed seizure disorders however there is insufficient evidence for its use in generalized epilepsy.
There is some evidence of benefit in acquired pendular nystagmus and infantile nystagmus but not in periodic alternating nystagmus. Gabapentin may help with menopausal symptoms. It may be effective in reducing pain and spasticity in multiple sclerosis. Gabapentin is not supported for alcohol withdrawal, and treatment of smoking cessation has had mixed results. Gabapentin helps with itching due to renal failure, known as uremic pruritus.
Other off-label uses include treatment for mental health disorders. Numerous trials show that it is not effective alone 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 is useful in the treatment of anxiety associated with bipolar disorder and restless leg syndrome and for insomnia, but has limited usefulness in disorders such as social anxiety disorder and obsessive-compulsive disorder, and in treatment-resistant depression.
Gabapentin's most common side effects in adult patients include dizziness, fatigue, weight gain, drowsiness, and peripheral edema (swelling of extremities); these mainly occur at higher doses in the elderly. Also, in children 3 to 12 years of age, researchers observed susceptibility to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Though rare, the literature reports several cases of hepatotoxicity. 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 has been associated with an increased risk of suicidal acts or violent deaths. In 2009 the U.S. Food and Drug Administration 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.
Gabapentin should not be discontinued abruptly after long term use. Abrupt or over rapid withdrawal may provoke a withdrawal syndrome reminiscent to alcohol or benzodiazepine withdrawal. Gradual reduction over a period of weeks or months helps minimize or prevent the withdrawal syndrome.
Side effects upon discontinuation of gabapentin that have been reported in medical literature include insomnia, restlessness, agitation, anxiety, disorientation, confusion, light sensitivity, diaphoresis, headaches, palpitations, hypertension, chest pain, and flu-like symptoms. In one case, abrupt cessation of a high dose of gabapentin triggered a seizure in an individual with no history of epilepsy.
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.
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. The mechanism of action that leads to its rapid[dubious ] analgesic effect is simply unknown.
Some of its activity may involve interaction with voltage-gated calcium channels. Gabapentin binds to the α2δ subunit (1 and 2) and has been found to reduce calcium currents after chronic but not acute application via an effect on trafficking of voltage-dependent calcium channels in the central nervous system. Another possible mechanism of action, reported by Ben Barres and colleagues in Cell in 2009, is that gabapentin halts the formation of new synapses.
Mechanism of action
Gabapentin interacts with voltage-sensitive calcium channels in cortical neurons. Gabapentin increases the synaptic concentration of GABA, enhances GABA responses at non-synaptic sites in neuronal tissues, and reduces the release of mono-amine neurotransmitters. One of the mechanisms implicated in this effect of gabapentin is the reduction of the axon excitability measured as an amplitude change of the presynaptic fibre volley (FV) in the CA1 area of the hippocampus. This is mediated through its binding to presynaptic NMDA receptors. Other studies have shown that the antihyperalgesic and antiallodynic effects of gabapentin are mediated by the descending noradrenergic system, resulting in the activation of spinal alpha2-adrenergic receptors. Gabapentin has also been shown to bind and activate the adenosine A1 receptor.
Society and culture
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, Pfizer has come under heavy criticism and serious litigation for its marketing of Neurontin. They face allegations that, behind the scenes, Parke-Davis marketed the drug for at least a dozen supposed uses that the FDA had not approved. Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.
Gabapentin was originally approved by the U.S. Food and Drug Administration (FDA) in 1994, for use as an adjuvant 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).
Numerous cases have been brought against the makers of Neurontin, with convictions arising not only for the illegal promotion of off-label uses. In the first such case, Franklin v. Parke-Davis, whistleblower David Franklin sued under the False Claims Act on behalf of the Federal Government, and secured a $430 million settlement, of which the majority was incurred as fines and penalties in respect of guilty pleas to two felony counts of misbranding drugs under the Federal Food, Drug, and Cosmetic Act, some awarded for customer restitution schemes, and around $24m awarded personally to Franklin in recognition of his importance in revealing the matter.
Much of the popular use of Neurontin among physicians stems from the widespread illicit marketing that Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants' meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign. As part of a case brought by Kaiser Foundation Health Plan against Pfizer, it was noted that "The general neuropathic pain indication cannot be granted for Neurontin based on the clinical trials in painful diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN)."
Off label promotion
Off-label use of gabapentin for psychiatric off-label use also resulted in convictions. 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 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. In addition, the FDA black box warning states: "Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication."
Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. Often, it is tried as an alternative treatment when patients are unable to tolerate the side effects of more proven mood stabilizers such as lithium. More frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficient positive results.
Reuters reported on March 25, 2010, that "Pfizer Inc violated federal racketeering law by improperly promoting the epilepsy drug Neurontin ... Under federal RICO law the penalty is automatically tripled, so the finding will cost Pfizer $141 million." 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 (3/26/10, Van Voris, Lawrence) added 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."
The Wall Street Journal (3/26/10, Kamp) noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal." He would later add that "the verdict and the judge's rulings are not consistent with the facts and the law."
Franklin v. Pfizer case
By some estimates, off-label prescriptions account for roughly 90 percent of Neurontin sales. While off-label prescriptions are common for a number of drugs and are legal, marketing of off-label uses of a drug is 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 2004 settlement was one of the largest in U.S. history, and the first off-label promotion case brought successfully under the False Claims Act. 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 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.
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 and reduced anxiety. Larger doses can cause the user to become numb and even fully insensate. Tolerance to gabapentin occurs extremely rapidly with recreational use, with the user often needing to double the dosage within a day or two of the first recreational dose. Although it is widely regarded as having little or no potential for misuse, it is often a misused drug in Canadian Northern communities and among inmates in California State prisons. However, Pregabalin, a subsequent Pfizer spin-off, is a controlled substance under Schedule V of the United States' Controlled Substances Act.
Neurocognitive effects with other interactions
While symptoms of abrupt gabapentin withdrawal are many, a study has combined gabapentin and flumazenil—a benzodiazepine antagonist—to measure cognitive performance on individuals in the beginning stages of alcohol withdrawal. The research impetus came from the GABA and glutamate signaling that occurs during alcohol withdrawal. The study observed for improvement of response inhibitions between subjects that had received treatment versus a group receiving a placebo. Over 60 alcohol-dependent participants were evaluated. The results were moderate; the gabapentin and flumazenil treatment slightly improved response inhibition task during the early phases of abstinence, and this corresponds to many self-testimonials. However the quality of the overall impact was mixed and the medication cannot be said to improve avoidance of alcoholic relapse; however it has the potential to subdue early withdrawal discomforts when combined with the benzodiazepine receptor antagonist.
Frequently mentioned online in drug-experience sharing websites, Gabapentin has been considered for reducing cocaine use or assisting in cocaine withdrawal because of its GABAergic feedback properties. One study chose nine individuals with cocaine withdrawal symptoms from a clinical setting. Gabapentin presence was tested over a 24-week trial; the study concluded that Gabapentin may be a useful medicine for reducing cocaine usage in addicted patients, especially during the early weeks of any attempt to cease cocaine usage.
Various suppliers of gabapentin market it under a number of brand names, including Neurostil, Neurontin, Fanatrex, Gabarone, Gralise, Nupentin, and Gabrion.
Gabapentin comes as:
- 100 mg, 300 mg, and 400 mg capsules
- 300 mg, 600 mg, and 800 mg tablets
- a 250 mg/5 mL oral (by mouth) solution.
Inactive ingredients in the capsules include lactose, cornstarch, and talc.
- The 100-mg capsule shell also contains: gelatin and titanium dioxide.
- The 300-mg capsule shell also contains: gelatin, titanium dioxide, and yellow iron oxide.
- The 400-mg capsule shell also contains: gelatin, red iron oxide, titanium dioxide, and yellow iron oxide. The imprinting ink contains FD&C Blue No. 2 and titanium dioxide.
Inactive ingredients in the tablets include poloxamer 407, copolyvidonum, cornstarch, magnesium stearate, hydroxypropyl cellulose, talc, candelilla wax, and purified water.
Inactive ingredients in the oral solution include glycerin, xylitol, purified water, and artificial flavor.
Parke-Davis developed a drug called pregabalin as a successor to gabapentin. Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin. Another new drug atagabalin has been trialled by Pfizer as a treatment for insomnia.
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 veterinary use of the human version requires caution.
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- Neurontin collected news and commentary at The New York Times
- "Gabapentin" Drug Information Portal. U.S. National Library of Medicine.
- "Gabapentin" The Vaults of Erowid