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Gabapentin chemical structure
Gabapentin

2-[1-(aminomethyl)cyclohexyl]acetic acid
IUPAC name
CAS number
60142-96-3
ATC code

N03AX12

PubChem
3446
DrugBank
APRD00015
Chemical formula {{{chemical_formula}}}
Molecular weight 171.237 g/mol
Bioavailability Rapid, in part by saturable carrier-mediated L-amino acid transport system
60% for 0.9g daily to 27% for 4.8g daily dose
Food increases absorption by 14%
Metabolism not appreciably metabolized
Elimination half-life 5 to 7 hours
Excretion Renal
Pregnancy category Benefit of treatment outweighs risk to fetus. Risk of teratogenicity greater if more than one drug used[1]
Legal status Rx-only
Routes of administration Oral


Gabapentin (brand name: Neurontin) was initially synthesized to mimic the structure of GABA for the treatment of epilepsy. Presently, gabapentin is widely used as a medication to relieve pain, especially neuropathic pain. Gabapentin is well tolerated in most patients, has a relatively mild side-effect profile, and passes through the body unmetabolized.

Gabapentin is similar in structure to the neurotransmitter GABA but is not believed to act on the same brain receptors. Its exact mechanism of action is unknown, but its therapeutic action on neuropathic pain is thought to involve voltage-gated N-type calcium ion channels. It is thought to bind to the α2δ subunit of the voltage-dependent calcium channel in the central nervous system.

Clinical uses

Gabapentin was originally approved in the U.S. by the Food and Drug Administration (FDA) in 1994 for use as an adjunctive medication to control partial seizures (effective when added to other antiseizure drugs). In 2002, approval was added for treating postherpetic neuralgia (neuropathic pain following shingles, other painful neuropathies, and nerve related pain).[2]

Although not "indicated" (i.e., not FDA-approved), gabapentin has been found to be effective in prevention of frequent migraine headaches,[3] neuropathic pain[4] and nystagmus.[5]

Gabapentin has also been used in the treatment of bipolar disorder. However, its off-label use for this purpose is increasingly controversial.[6] Some claim gabapentin acts as a mood stabilizer and has the advantage of having fewer side-effects than more conventional bipolar drugs such as lithium and valproic acid. Some small, non-controlled studies in the 1990s, most sponsored by gabapentin's manufacturer, suggested that gabapentin treatment for bipolar disorder may be promising.[6] However, more recently, several larger, controlled, and double-blind studies have found that gabapentin was no more effective than (and in one study, slightly less effective than) placebo.[7] Despite this scientific evidence that gabapentin in the treatment of bipolar disorder is not an optimal treatment, many psychiatrists continue to prescribe it for this purpose.

Gabapentin has limited usefulness in the treatment of anxiety disorders such as social anxiety disorder and obsessive-compulsive disorder, in treatment-resistant depression, and for insomnia.[8][9] Gabapentin may be effective in reducing pain and spasticity in multiple sclerosis.[6]

Gabapentin has also been found to help patients with post-operative chronic pain (usually caused by nerves that have been severed accidentally in an operation and when grown back, have reconnected incorrectly). Symptoms of this include a tingling sensation near or around the area where the operation was performed, sharp shooting pains, severe aches after much movement, constant 'low ache' all day and sometimes a general 'weak' feeling. These symptoms can appear many months after an operation, and therefore the condition can go unnoticed.

Gabapentin is also prescribed to patients being treated with anti-androgenic compounds to reduce the incidence and intensity of the accompanying hot flushes.[10]

Gabapentin (administered orally) is one of two medications (the other being Flumazenil, which is administered intraveniously) used in the expensive Prometa Treatment Protocol for methamphetamine, cocaine and alcohol addiction. Gabapentin is administered at a dosage of 1200mg. taken at bedtime for 40-60 days. Though the combination of Flumazenil infusions and Gabapentin tablets is a licensed treatment, there is no prohibition against a physician prescribing Gabapentin outside the Prometa protocol. There have been reports by methamphetamine addicts that Gabapentin alone in doses of 1200mg. at bedtime taken for 40-60 days has been effective in reducing the withdrawal symptoms and almost eliminating cravings or desire to use methamphetamine.

Marketing of gabapentin

Gabapentin is best known under the brand name Neurontin manufactured by Pfizer subsidiary Parke-Davis. In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by Israeli firm Teva Pharmaceutical Industries, Ltd.

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, in recent years Pfizer has come under heavy criticism for its marketing of Neurontin, facing allegations that behind the scenes Parke-Davis marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved[1].

By some estimates, so-called off-label prescriptions account for roughly 90% of Neurontin sales.[11] While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal.[12] 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 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 had any injury.[13]

The University of California, San Francisco (UCSF) has archived [2]and studied [3] the documents made public by this case which opens a unique window into pharmaceutical marketing and illegal drug promotion. However, Pfizer maintains that the illegal activity originated in 1996, well before it accquired Parke-Davis (through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people prescribed gabapentin for off-label treatment of bipolar disorder attempted or committed suicide.

Pfizer has developed a successor to gabapentin, called pregabalin (being marketed as Lyrica®). Structurally related to gabapentin, Pregabalin is effective for neuropathic pain associated with diabetes, fibromyalgia, and shingles, as well as for the treatment of epilepsy and seizures.

Side effects

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities).[14] Children 3–12 years of age were also observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. An increase in formation of adenocarcinomas (a type of cancer) was observed in rats during preclinical trials, however the clinical significance of these results remains undetermined. Although rare, there are several cases of hepatotoxicity reported in the literature.[15] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[16][17]

Abuse potential

Though gabapentin is not a controlled substance, it does produce psychoactive effects that could lead to abuse of the drug. However, it is widely regarded as having little or no abuse potential. Pregabalin, a gabapentinoid with higher potency marketed for neuropathic pain, is a controlled substance, under the DEA Schedule V of the US Controlled substances act.

References

  1. BNF (March 2003) 45
  2. Pfizer: Product Monograph Neurontin®PDF (254 KiB) Retrieved 14 August 2006
  3. Mathew, NT, Rapoport A, Saper J, Magnus L, Klapper J, Ramadan N, Stacey B, Tepper S (2001). Efficacy of gabapentin in migraine prophylaxis. Headache 41 (2): 119-28.
  4. Backonja, MM, Serra J (2004). Pharmacologic management part 1: better-studied neuropathic pain diseases. Pain Med 5 (Suppl 1): S28-47.
  5. Choudhuri, I, Sarvananthan N, Gottlob I (May 26, 2006). Survey of management of acquired nystagmus in the United Kingdom. Eye.
  6. 6.0 6.1 6.2 Mack, Alicia (2003). Examination of the evidence for off-label use of gabapentin. Journal of Managed Care Pharmacy 9 (6): 559-68.
  7. Pande, AC, Crockatt JG, Janney CA, Werth JL, Tsaroucha G. (2000). Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy. Bipolar Disorders 2 (3 Pt 2): 249-55.
  8. Chouinard, G (May 2006). The search for new off-label indications for antidepressant, antianxiety, antipsychotic and anticonvulsant drugs. J Psychiatry Neurosci 31 (3): 168-176.
  9. Frye, Mark A., et al (2000). A Placebo-Controlled Study of Lamotrigine and Gabapentin Monotherapy in Refractory Mood Disorders. Journal of Clinical Psychopharmacology 20 (6): 607-14.
  10. Guttuso, T Jr, Kurlan R; McDermott MP; Kieburtz K (Feb 2003). Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 101 (2): 337-45.
  11. includeonly>"Huge penalty in drug fraud, Pfizer settles felony case in Neurontin off-label promotion.", San Francisco Chronicle, 2004-05-14, p. C-1.
  12. Jane E. Henney, MD (2006). Editorial: Safeguarding Patient Welfare: Who's In Charge?. Annals of Internal Medicine 145 (4): 305-307.
  13. Baron v. Pfizer, Inc., 2007 N.Y. Slip Op. 05813 (App. N.Y., July 5, 2007)
  14. FDA approved labeling for Neurontin capsules, tablets, and oral solution.. Note that an updated labeling has been approved, but is not available online as of November 2006
  15. Maria C Lasso-de-la-Vega Pharm.D (2001). Gabapentin-associated hepatotoxicity. Am J Gastroenterol 96 (12): 3460–3462.
  16. Ayhan DOGUKAN (2006). Gabapentin-induced coma in a patient with renal failure. Hemodialysis International 10 (2): 168–169.
  17. Bookwalter T, Gitlin M (2005). Gabapentin-induced neurologic toxicities. Pharmacotherapy 25 (12): 1817–9.

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