|Systematic (IUPAC) name|
|Trade names||Gralise, Neurontin, Gabarone|
|Licence data||US Daily Med:|
|Bioavailability||27-60% (inversely proportional to dose; a high fat meal also increases bioavailability)|
|Protein binding||Less than 3%|
|Metabolism||Not significantly metabolised|
|Biological half-life||5 to 7 hours|
|ATC code||N03AX12 (WHO)|
|PDB ligand ID||GBN (, )|
|Molecular mass||171.237 g/mol|
Gabapentin, marketed under the brand name Neurontin among others, is a medication used to treat epilepsy, neuropathic pain, and hot flashes. It is also used for restless leg syndrome. It is recommended as a first line agent for the treatment of neuropathic pain arising from diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.
It is a lipophilic structural analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
- 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 and neuropathic pain. It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders, insomnia, and bipolar disorder. There are, however, concerns regarding the quality of the trials conducted and evidence for some such uses, especially in the case of its use as a mood stabilizer in bipolar disorder.
There is weak evidence that gabapentin provides pain relief for around 10% of people who take it for fibromyalgia, and for chronic neuropathic pain.[needs update] The evidence is stronger for effectiveness in postherpetic neuralgia and diabetic neuropathy. It may reduce opioid use following surgery, and may be helpful in neuropathic pain due to cancer.
Gabapentin does not ameliorate chronic pain after surgery. It is not effective in HIV-associated sensory neuropathy. When used for neuropathic pain it does not appear superior to carbamazepine. It appears to be as effective as pregabalin and costs less. It does not appear to provide benefit for complex regional pain syndrome
Gabapentin may be useful in the treatment of comorbid anxiety in bipolar patients, (however not the bipolar state itself). Gabapentin may be effective in acquired pendular nystagmus and infantile nystagmus, (but not periodic alternating nystagmus). It is effective in hot flashes. It may be effective in reducing pain and spasticity in multiple sclerosis. Gabapentin may reduce symptoms of alcohol withdrawal (but it does not prevent the associated seizures). Use for smoking cessation has had mixed results. Gabapentin is effective in alleviating itching in renal failure (uremic pruritus) and itching of other etiologies. It is well-established in the treatment of restless leg syndrome. (A prodrug form, gabapentin enacarbil, is also effective.) Gabapentin is effective in insomnia.
Gabapentin is not effective alone as a mood-stabilizing treatment for bipolar disorder. There is insufficient evidence to support its use in obsessive-compulsive disorder and treatment-resistant depression. Gabapentin does not appear effective for the treatment of tinnitus.
The most common side effects of gabapentin in adult patients include dizziness, fatigue, drowsiness, weight gain, and peripheral edema (swelling of extremities). Gabapentin may also produce sexual dysfunction in some patients, symptoms of which may include loss of libido, inability to reach orgasm, and erectile dysfunction. 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.
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. A 2010 meta analysis confirmed the increased risk of suicide associated with gabapentin use.
Persons who accidentally or intentionally ingested overdoses may have drowsiness, sedation, blurred vision, slurred speech, somnolence and possibly death, if a very high amount was taken, particularly if combined with alcohol. Serum gabapentin concentrations may be measured to confirm diagnosis.
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 is that gabapentin halts the formation of new synapses.
Mechanism of action
The mechanism of the anticonvulsant action of gabapentin has not been fully described. Though similar in structure to the endogenous neurotransmitter GABA, gabapentin has not been shown to bind to GABA receptors at concentrations at or below 1 mM. Gabapentin modulates the action of glutamate decarboxylase (GAD) and branched chain aminotransferase (BCAT), two enzymes involved in GABA biosynthesis. In human and rat studies, gabapentin was found to increase GABA biosynthesis, and to increase non-synaptic GABA neurotransmission in vitro.
Gabapentin (0.01-100 µM) has not been shown to interact with the sodium or L-type calcium ion channels targeted by the conventional anticonvulsant drugs phenytoin, carbamazepine and sodium valproate. Other neurophysiological findings indicate that gabapentin does not interact with glutamate, glycine, or NMDA receptors, further distinguishing its anticonvulsant mechanism from that of common antiepileptic medications.
Society and culture
In December 2004 the FDA granted final approval to a generic equivalent to Neurontin made by the Israeli firm Teva.
Neurontin began as one of Pfizer's best selling drugs; however, Pfizer was criticized and under litigation for its marketing of the drug. They faced allegations that Parke-Davis marketed the drug for at least a dozen supposed uses that the FDA had not approved. It has been used as 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 December 1993, for use as an adjuvant (effective when added to other antiseizure drugs) medication to control partial seizures in adults; that indication was extended to children in 2000. In 2004, its use for treating postherpetic neuralgia (neuropathic pain following shingles) was approved.
Although some small, non-controlled studies in the 1990s—mostly sponsored by gabapentin's manufacturer—suggested that treatment for bipolar disorder with gabapentin may be promising, the preponderance of evidence suggests that it is not effective. 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.
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 reported "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 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
While off-label prescriptions are common for a number of drugs and are legal, marketing of off-label uses of a drug is not. In 2004, Warner-Lambert (which subsequently was acquired by Pfizer) agreed to plead guilty for activities of its Parke-Davis subsidiary, and to pay $430 million in fines to settle civil and criminal charges regarding the marketing of Neurontin for off-label purposes. 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.
Various suppliers of gabapentin market it under a number of brand names, including Neurostil, Neurontin, Fanatrex, Gabarone, Gralise, Nupentin, Gabrion, Penral, Gabapin, Vultin.
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 trialed by Pfizer as a treatment for insomnia.
A prodrug form (gabapentin enacarbil) was approved in 2011 for the treatment of moderate-to-severe restless legs syndrome. and in 2012 for postherpetic neuralgia in adults. It was designed for increased oral bioavailability over gabapentin.
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