Gabapentin

Gabapentin
Clinical data
Trade names Neurontin, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a694007
License data
Pregnancy
category
  • AU: B1
  • US: C (Risk not ruled out)
Routes of
administration		 By mouth
ATC code N03AX12 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 27–60% (inversely proportional to dose; a high fat meal also increases bioavailability)[2][3]
Protein binding Less than 3%[2][3]
Metabolism Not significantly metabolised[2][3]
Biological half-life 5 to 7 hours[2][3]
Excretion Renal[2][3]
Identifiers
CAS Number 60142-96-3 YesY
PubChem (CID) 3446
IUPHAR/BPS 5483
DrugBank DB00996 YesY
ChemSpider 3328 YesY
UNII 6CW7F3G59X YesY
KEGG D00332 YesY
ChEBI CHEBI:42797 YesY
ChEMBL CHEMBL940 YesY
PDB ligand ID GBN (PDBe, RCSB PDB)
ECHA InfoCard 100.056.415
Chemical and physical data
Formula C9H17NO2
Molar mass 171.237 g/mol
3D model (Jmol) Interactive image
  (verify)

Gabapentin (GPN) marketed under the brand name Neurontin among others, is a medication used to treat epilepsy, neuropathic pain, hot flashes, and restless leg syndrome.[4][5] In epilepsy it may be used for those with partial seizures.[4] It is recommended as one of a number of first line medications for the treatment of neuropathic pain in diabetic neuropathy, post-herpetic neuralgia, and central neuropathic pain.[6] A 2014 review of its use for diabetic neuropathy and postherpetic neuralgia found about 14% of people have a meaningful benefit.[7]

Common side effects include sleepiness and dizziness. Serious side effects may include an increased risk of suicide, aggressive behaviour, and drug reaction with eosinophilia and systemic symptoms.[4] It is unclear if it is safe during pregnancy or breastfeeding.[8] Lower doses should be used in people with kidney problems. Gabapentin affects the inhibitory neurotransmitter γ-aminobutyric acid (GABA) but how it works is otherwise unclear.[4]

Gabapentin was first approved for use in 1993.[9] The wholesale price in the developing world is about US$40.50 per month.[10] In the United States it has been available as a generic medication since 2004.[4] As of 2015 the cost for a typical month of medication in the United States is US$100 to US$200.[11] During the 1990s Parke-Davis, a sub-company of Pfizer, used a number of techniques to encourage physicians in the United States to use gabapentin for unapproved uses.[12]

Medical uses

Gabapentin is used primarily to treat seizures and neuropathic pain.[13] It is also commonly prescribed for many off-label uses, such as treatment of anxiety disorders,[14][15] insomnia, and bipolar disorder.[14] 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.[16]

Seizures

Gabapentin is approved for treatment of focal seizures,[17] partial seizures and mixed seizures. There is insufficient evidence for its use in generalized epilepsy.[18]

Pain

A 2010 European Federation of Neurological Societies task force clinical guideline based on available evidence recommended gabapentin as a first-line treatment for diabetic neuropathy and postherpetic neuralgia with its highest level of evidence; it also recommended gabapentin as a first-line treatment for central pain but with lower evidence. It also found good evidence that a combination of gabapentin and morphine or oxycodone or nortriptyline worked better than either drug alone; the combination of gabapentin and venlafaxine may be better than gabapentin alone.[6]

A Cochrane review published in 2014 found that evidence of moderate quality shows that gabapentin can reduce pain by 50% for some people with postherpetic neuralgia (34% of people taking gabapentin in clinical trials versus 21% taking placebo) and for some people with painful diabetic neuropathy (38% versus 21%) and that there was not sufficient evidence to draw conclusions about other pain conditions; it also found no difference among various formulations or doses of gabapentin.[7]

A 2010 review found that it may be helpful in neuropathic pain due to cancer.[19] It is not effective in HIV-associated sensory neuropathy[20] and does not appear to provide benefit for complex regional pain syndrome.[21]

A 2009 review found gabapentin may reduce opioid use following surgery, but does not help with chronic pain after surgery.[22] A 2016 review found it does not help with pain following a knee replacement.[23]

It appears to be as effective as pregabalin and costs less.[24]

Migraine

The American Headache Society (AHS) and American Academy of Neurology (AAN) guidelines classify gabapentin as a drug with "insufficient data to support or refute use for migraine prophylaxis."[25] Furthermore, a 2013 Cochrane review concluded that gabapentin was not useful for the prevention of episodic migraine in adults.[26] Some have suggested that gabapentin may be effective for chronic migraine.[27]

Anxiety disorders

Gabapentin is effective in social anxiety disorder, panic disorder,[28][29] and generalized anxiety disorder.[14][15]

Other uses

Gabapentin may be useful in the treatment of comorbid anxiety in bipolar patients, (however not the bipolar state itself).[16][30][31] Gabapentin may be effective in acquired pendular nystagmus and infantile nystagmus, (but not periodic alternating nystagmus).[32][33] It is effective in hot flashes.[34][35][36] It may be effective in reducing pain and spasticity in multiple sclerosis.[37] Gabapentin may reduce symptoms of alcohol withdrawal (but it does not prevent the associated seizures).[38] Use for smoking cessation has had mixed results.[39][40] Gabapentin is effective in alleviating itching in kidney failure (uremic pruritus)[41] and itching of other causes.[42] It is an established treatment of restless leg syndrome.[43] Gabapentin may help sleeping problems in people with restless leg syndrome and partial seizures.[44][45] Gabapentin may be an option in essential or orthostatic tremor.[46][47][48]

Gabapentin is not effective alone as a mood-stabilizing treatment for bipolar disorder.[14] 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.[49]

Adverse effects

The most common side effects of gabapentin include dizziness, fatigue, drowsiness, ataxia, peripheral edema (swelling of extremities), nystagmus, and tremor.[50] Gabapentin may also produce sexual dysfunction in some patients, symptoms of which may include loss of libido, inability to reach orgasm, and erectile dysfunction.[51][52] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[53]

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.[54]

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[55] modifying the packaging insert to reflect this.[50] A 2010 meta analysis confirmed the increased risk of suicide associated with gabapentin use.[56]

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.[57]

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[58] of voltage-dependent calcium channels in the central nervous system.[59] Another possible mechanism of action is that gabapentin halts the formation of new synapses.[60]

Mechanism of action

The mechanism of the anticonvulsant action of gabapentin has not been fully described. Several possible mechanisms for pain improvement have been discussed.[61] 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.[62] 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.[63]

Gabapentin has been shown to bind to the α2δ-1 subunit of voltage gated calcium ion channels, which contributes to its pain attenuation effects in diabetic neuropathy and post-herpetic neuralgia. Other neurophysiological findings indicate that gabapentin also interacts with NMDA receptors, protein kinase C, and inflammatory cytokines.[62][64]

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 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.[12][65] It has been used as a mainstay drug for migraines, even though it was not approved for such use in 2004.[66]

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.[67] In 2004, its use for treating postherpetic neuralgia (neuropathic pain following shingles) was approved.[67][68]

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,[37] the preponderance of evidence suggests that it is not effective.[69] 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."[70] 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."[71]

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."[72]

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."[73] He would later add that "the verdict and the judge's rulings are not consistent with the facts and the law."[70]

Franklin v. Pfizer case

According to the San Francisco Chronicle, off-label prescriptions accounted for roughly 90 percent of Neurontin sales.[74]

While off-label prescriptions are common for a number of drugs and are legal, marketing of off-label uses of a drug is not.[12] 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.

Brand names

Gabapentin was originally marketed under the brand name Neurontin and since it became generic, it has been marketed under many other brand names.[1]

A capsule of gabapentin

Parke-Davis developed a drug called pregabalin as a successor to gabapentin.[75] Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin.[76] Another new drug atagabalin has been trialed by Pfizer as a treatment for insomnia.[77]

A prodrug form (gabapentin enacarbil)[78] was approved in 2011 for the treatment of moderate-to-severe restless legs syndrome[79] and in 2012 for postherpetic neuralgia in adults.[80] It was designed for increased oral bioavailability over gabapentin.[81][82]

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.[83]

References

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