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Gabapentin

Clinical data
Trade names	Neurontin, Gabarone, Gralise
AHFS/Drugs.com	Monograph
MedlinePlus	a694007
License data	US DailyMed: 52049 US FDA: Gabapentin
Pregnancy category	AU: B1
Routes of administration	Oral
ATC code	N03AX12 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	27-60% (inversely proportional to dose; a high fat meal also increases bioavailability)
Protein binding	Less than 3%
Metabolism	Not significantly metabolised
Elimination half-life	5 to 7 hours
Excretion	Renal
Identifiers
IUPAC name 1-(aminomethyl)cyclohexaneacetic acid
CAS Number	60142-96-3
PubChem CID	3446
DrugBank	DB00996
ChemSpider	3328
UNII	6CW7F3G59X
KEGG	D00332
ChEBI	CHEBI:42797
ChEMBL	ChEMBL940
PDB ligand	GBN (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID0020074
ECHA InfoCard	100.056.415
Chemical and physical data
Formula	C9H17NO2
Molar mass	171.237 g/mol g·mol
3D model (JSmol)	Interactive image
SMILES O=C(O)CC1(CN)CCCCC1
InChI InChI=1S/C9H17NO2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10H2,(H,11,12) Key:UGJMXCAKCUNAIE-UHFFFAOYSA-N
(verify)

Gabapentin, marketed under the brand name Neurontin among others, is a medication used as an anticonvulsant and analgesic. Originally it was developed to treat epilepsy, and is currently used to relieve neuropathic pain and 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 structural analogue of the inhibitory neurotransmitter γ-aminobutyric acid (GABA).

Medical uses

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.

Pain

There is weak evidence that gabapentin provides pain relief for around 10% of people who take it for fibromyalgia, and for chronic neuropathic pain. 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

There is no evidence that it is useful for migraine prevention.

Seizures

Gabapentin is approved for treatment of focal seizures, partial seizures and mixed seizures. There is insufficient evidence for its use in generalized epilepsy.

Anxiety disorders

Gabapentin is effective in social anxiety disorder, panic disorder and generalized anxiety disorder.

Other uses

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.

Adverse effects

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.

Suicide

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.

Overdose

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.

Pharmacology

Gabapentin was initially synthesized to mimic the chemical structure of the neurotransmitter gamma-aminobutyric acid (GABA), but is believed to act on different brain receptors.

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 1000 µM. 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

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 began as one of Pfizer's best selling drugs; however, Pfizer has been criticized and under litigation for its marketing of the drug. They face allegations that 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.

FDA approval

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.

Off-label promotion

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 (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 (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 illegal 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.

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 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.

Brand names

Various suppliers of gabapentin market it under a number of brand names, including Neurostil, Neurontin, Fanatrex, Gabarone, Gralise, Nupentin, Gabrion, Penral, Gabapin.

Forms

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.

Related drugs

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.

Veterinary use

Gabapentin is also used for some animal treatments, but some formulations (especially liquid forms) for human use contains the sweetener xylitol, which is toxic to dogs.

See also

• Atagabalin
• Phenibut
• Baclofen
• Pregabalin (Lyrica)

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External links

• DrugBank: gabapentin
• Gabapentin information from MedlinePlus
• "Gabapentin" PubMed Health. National Center for Biotechnology Information (NCBI)
• "Suicidal Behavior and Ideation and Antiepileptic Drugs" U.S. Food and Drug Administration (FDA)
• Neurontin collected news and commentary at The New York Times
• "Gabapentin" Drug Information Portal. U.S. National Library of Medicine.

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