Gabapentin

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Gabapentin
Gabapentin2DACS.svg
Gabapentin3Dan.gif
Systematic (IUPAC) name
2-[1-(aminomethyl)cyclohexyl]acetic acid
Clinical data
Trade names Fanatrex, Gabarone, Gralise, Neurontin, Nupentin, Neogab
AHFS/Drugs.com monograph
MedlinePlus a694007
Licence data US Daily Med:link
Pregnancy cat. B1 (AU) C (US)
Legal status Prescription Only (S4) (AU) -only (CA) POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 27-60% (inversely proportional to dose; a high fat meal also increases bioavailability)[1][2]
Protein binding Less than 3%[1][2]
Metabolism Not significantly metabolised[1][2]
Half-life 5 to 7 hours[1][2]
Excretion Renal[1][2]
Identifiers
CAS number 60142-96-3 YesY
ATC code N03AX12
PubChem CID 3446
DrugBank DB00996
ChemSpider 3328 YesY
UNII 6CW7F3G59X YesY
KEGG D00332 YesY
ChEBI CHEBI:42797 YesY
ChEMBL CHEMBL940 YesY
PDB ligand ID GBN (PDBe, RCSB PDB)
Chemical data
Formula C9H17NO2 
Mol. mass 171.237 g/mol
 YesY (what is this?)  (verify)

Gabapentin (Neurontin) is an anticonvulsant and analgesic drug. It was originally developed to treat epilepsy, and is currently also used to relieve neuropathic pain. 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.[3]

Gabapentin is also commonly prescribed for many off-label uses, such as treatment of restless leg syndrome, anxiety disorders,[4][5] insomnia, and bipolar disorder.[4] 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.[6]

A prodrug form with a longer duration of action and improved pharmacokinetics, gabapentin enacarbil, has recently been introduced.

Medical uses[edit]

Gabapentin is used primarily to treat seizures and neuropathic pain.[7] There are, however, concerns regarding the quality of the research on its use to treat migraines, bipolar disorder, and pain.[6]

Pain[edit]

Gabapentin appears to provide pain relief for slightly more than 10% of people who take it for fibromyalgia or chronic neuropathic pain; however, the evidence for this conclusion is not very good.[8] With respect to neuropathic pain there is greater evidence in postherpetic neuralgia and diabetic neuropathy and little evidence for other types of pain.[8] There are side effects in nearly two thirds of people.[8] It may reduce opioid use following surgery.[9] There; however, is not evidence that it prevents chronic pain after surgery.[10]

It may be helpful in neuropathic pain due to cancer.[11] It has not been shown useful for HIV-associated sensory neuropathy.[12] When used for neuropathic pain it does not appear superior to carbamazepine.[13] It appears as effective as pregabalin and costs less.[14] It does not appear to provide benefit for complex regional pain syndrome[15] or to be useful for migraine prevention.[16]

Seizures[edit]

Gabapentin is approved for treatment of focal seizures in a number of countries[17] and evidence supports its use for treating partial and mixed seizure disorders however there is insufficient evidence for its use in generalized epilepsy.[18]

Anxiety disorders[edit]

A variety of research has supported the use of gabapentin in the treatment of certain anxiety disorders.[19] Evidence exists for its effectiveness in the treatment of social anxiety disorder and panic disorder.[19][20] In addition, pregabalin, an analog of gabapentin with the same mechanism of action, has demonstrated effectiveness in the treatment of social anxiety disorder and generalized anxiety disorder, and is an approved treatment for the latter.[21] Gabapentin is likely similarly effective for these conditions, and has the advantage of being significantly less expensive in comparison.[21] Indeed, it is frequently prescribed off-label as a treatment for generalized anxiety disorder.[5]

Other uses[edit]

There is some evidence of benefit in acquired pendular nystagmus and infantile nystagmus but not in periodic alternating nystagmus.[22][23]

Gabapentin may help with certain menopausal symptoms, such as hot flashes.[24][25][26] It may be effective in reducing pain and spasticity in multiple sclerosis.[27] Gabapentin may reduce symptoms of alcohol withdrawal but it does not prevent the seizures often associated with this condition.[28] Use for smoking cessation has had mixed results.[29][30] Gabapentin helps with itching (pruritus) associated with renal failure (uremic pruritus)[31] and other conditions.[32]

Other off-label uses of gabapentin include treatment of, in addition to anxiety disorders, various other psychiatric disorders. However, the evidence for its use in many of these conditions has not been demonstrated. Numerous trials show that it is not effective alone as a mood-stabilizing treatment for bipolar disorder.[4] It may be useful in the treatment of comorbid anxiety in bipolar patients, however.[33][34] There is also insufficient evidence to support the use of gabapentin in disorders such as obsessive-compulsive disorder and treatment-resistant depression. However, it is well-established in the treatment of restless leg syndrome, which a prodrug form, gabapentin enacarbil, is indicated for.[35] In addition, there is data in support of the effectiveness of gabapentin as a therapy for insomnia.[36][37]

Gabapentin does not appear effective for the treatment of tinnitus.[38]

Adverse effects[edit]

The most common side effects of gabapentin in adult patients include dizziness, fatigue, drowsiness, weight gain, and peripheral edema (swelling of extremities).[39] Gabapentin may also produce sexual dysfunction in some patients, symptoms of which may include loss of libido, inability to reach orgasm, and erectile dysfunction.[40][41] In children three to twelve 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.[42][43] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[44][45]

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.[46]

May cause adverse effects to patient decision making ability.[citation needed]

Suicide[edit]

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[47] modifying the packaging insert to reflect this.[39] In July 2009 the manufacturer of gabapentin (Pfizer) went to trial regarding the association between gabapentin and the increased risk of suicide.[48]

Overdose[edit]

Persons who accidentally or intentionally ingested overdoses have manifested drowsiness, sedation, blurred vision, slurred speech and somnolence or coma. Serum gabapentin concentrations may be measured to confirm diagnosis.[49]

Pharmacology[edit]

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.

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[50] of voltage-dependent calcium channels in the central nervous system.[51] Another possible mechanism of action, reported by Ben Barres and colleagues in Cell in 2009, is that gabapentin halts the formation of new synapses.[52]

Mechanism of action[edit]

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 alpha-2 adrenergic receptors. Gabapentin has also been shown to bind and activate the adenosine A1 receptor.[citation needed]

Society and culture[edit]

Sales[edit]

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 come under heavy criticism and serious litigation for its marketing of the drug. 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.[53][54] Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.[55]

FDA approval[edit]

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).[56]

Off-label promotion[edit]

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,[27] the preponderance of evidence suggests that it is not effective.[57] 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."[58] 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."[59]

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."[60]

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."[61] He would later add that "the verdict and the judge's rulings are not consistent with the facts and the law."[58]

Franklin v. Pfizer case[edit]

By some estimates, off-label prescriptions account for roughly 90 percent of Neurontin sales.[62]

While off-label prescriptions are common for a number of drugs and are legal, marketing of off-label uses of a drug is illegal.[53] 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.[63]

The University of California, San Francisco (UCSF) has archived[64] and studied[65] 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.

Brand names[edit]

Various suppliers of gabapentin market it under a number of brand names, including Neurostil, Neurontin, Fanatrex, Gabarone, Gralise, Nupentin, Gabrion,[66] Penral, Gabapin.

Forms[edit]

A capsule of gabapentin

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.[67]

Related drugs[edit]

Parke-Davis developed a drug called pregabalin as a successor to gabapentin.[68] Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin.[69] Another new drug atagabalin has been trialed by Pfizer as a treatment for insomnia.[70]

Veterinary use[edit]

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.[71]

Synthesis[edit]

Process For Synthesis Of Gabapentin: U.S. Patent 20,080,103,334

See also[edit]

References[edit]

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