Gabapentin
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Gabapentin
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| Systematic (IUPAC) name | |
| 2-[1-(aminomethyl)cyclohexyl]acetic acid | |
| Identifiers | |
| CAS number | |
| ATC code | N03 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C9H17NO2 |
| Mol. mass | 171.237 g/mol |
| Pharmacokinetic data | |
| Bioavailability | Rapid, in part by saturable carrier-mediated L-amino acid transport system 60% for 0.9 g daily to 27% for 4.8 g daily dose Food increases absorption by 14% |
| Protein binding | Less than 3% |
| Metabolism | Not appreciably metabolized |
| Half life | 5 to 7 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. |
D(AU) D(US) Benefit of treatment may outweigh risk to fetus. Risk of teratogenicity greater if more than one drug used[1] |
| Legal status | |
| Routes | Oral |
Gabapentin (brand name Neurontin) is a GABA analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain.
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[edit] Pharmacology
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.
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 (1 and 2)[2] of the voltage-dependent calcium channel in the central nervous system.[3]
[edit] Indications
Due to the wide variety of conditions for which Gabapentin may be considered as a treatment, and the various claims and counterclaims surrounding it, this presentation of the indicated uses of Gabapentin has attempted to separate the FDA accepted uses, the putative uses, and the disputed uses of the drug.
[edit] Proven
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, an indication was added for treating postherpetic neuralgia (neuropathic pain following shingles), other painful neuropathies, and nerve related pain.[4]
Gabapentin (administered orally) is one of two medications (the other being flumazenil, which is administered intravenously) used in the expensive Prometa Treatment Protocol for methamphetamine, cocaine and alcohol addiction. Gabapentin is administered at a dosage of 1200 mg 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 1200 mg at bedtime taken for 40–60 days has been effective in reducing the withdrawal symptoms and almost eliminating cravings or desire to use methamphetamine.[5]
[edit] Positive
Gabapentin is frequently used to treat various types of Neuralgia. It has been found to be effective in prevention of frequent migraine headaches,[6] neuropathic pain[7] and nystagmus,[8] and is prescribed off-label (that is, without formal regulatory agreement) for these conditions. Gabapentin is widely believed 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) and nerve pain associated with spinal cord injury. It may be effective in reducing pain and spasticity in multiple sclerosis.[9], and has also had success in treating certain instances of Complex Regional Pain Syndrome.[10][11]
It is not uncommon for the prescription of Gabapentin to occur in a mental health context. It has been seriously investigated as a treatment for bipolar disorder; it is widely assumed to act as a mood stabilizer and has the advantage of having fewer side-effects than more conventional bipolar drugs such as lithium and valproic acid. 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.[12][13]
Additionally, Gabapentin has been prescribed to patients being treated with anti-androgenic compounds to reduce the incidence and intensity of the accompanying hot flushes.[14]. It has occasionally been prescribed for treatment of idiopathic subjective tinnitus, although a double blind, randomized controlled trial has found this ineffective.[15] Gabapentin may help deepen sleep, positively affecting stage 4 sleep, and reducing arousals during the night. It could potentially be helpful for both sleep onset and sleep maintenance. Finally, it may be effective in treating akathisia - a rare side effect of atypical antipsychotics that causes severe agitation and anxiety.
[edit] Negative
There has, unfortunately, been a growing controversy regarding the psychiatric off-label use of Gabapentin.[9] 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,[9] other more recent and better controlled studies have found it to be no more effective (and in one study, slightly less effective) than placebo.[16] 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. Concerns about the distorting effects of Pfizer's research practices upon the represented efficacy of Gabapentin have been summarized for the Prescription Access Litigation project in an August 10th, 2008 article written by Kay Dickersin, M.D, Ph.D, a scholar of publication bias at Brown University.[17].
Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. It is often tried as an alternative treatment, when patients are unable to tolerate the side effect of more proven mood stabilizers such as lithium; as or more frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficiently positive results. [18]
[edit] Precautions
Gabapentin should not be discontinued abruptly after long term use. Abrupt or over rapid withdrawal may provoke a withdrawal syndrome similar to alcohol or benzodiazepine withdrawal. Gradual reduction over a period of weeks or months helps minimise or prevents the withdrawal syndrome.[19]
[edit] Adverse effects
Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities);[20] these mainly occur at higher doses, in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity reported in the literature.[21] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[22][23]
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.[24]
[edit] Recreational use
Although gabapentin is not a controlled substance, it does produce psychoactive effects that could lead to recreational use of the drug. However, it is widely regarded as having little or no potential for misuse. Pregabalin, a gabapentinoid with higher potency marketed for neuropathic pain, is a controlled substance, under Schedule V of the United States' Controlled Substances Act.
Recreational use of gabapentin produces a varying number of effects including euphoria, appetite stimulation, incessant talking, physical and mental stimulation which results in varying degrees of drug induced productivity. Diarrhea/stomach discomfort is commonly reported with heavy use.
[edit] 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 Israeli firm Teva.
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.
[edit] Franklin v. Pfizer case
By some estimates, so-called off-label prescriptions account for roughly 90% of Neurontin sales.[25] 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.[26] 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 any injury.[27]
The University of California, San Francisco (UCSF) has archived[28] and studied[29] the documents made public by this case, which opens a unique window into pharmaceutical marketing and their illegal promotion. 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, prescribed gabapentin for off-label treatment of bipolar disorder, attempted or committed suicide.
[edit] Related drugs
Pfizer has developed a successor to gabapentin, called pregabalin (being marketed as Lyrica). Related in structure to gabapentin, pregabalin is effective for neuropathic pain associated with diabetes, fibromyalgia, and shingles, as well as for the treatment of epilepsy and seizures.
[edit] References
- ^ BNF (March 2003) 45
- ^ Hendrich J, Van Minh AT, Heblich F, et al (March 2008). "Pharmacological disruption of calcium channel trafficking by the alpha2delta ligand gabapentin". Proc. Natl. Acad. Sci. U.S.A. 105 (9): 3628–33. doi:. PMID 18299583. PMC: 2265195. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=18299583.
- ^ Davies et al. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels.Trends Pharmacol Sci. 2007 May;28(5):220-8.
- ^ Pfizer: Product Monograph NeurontinPDF (251 KB) Retrieved 14 August 2006
- ^ PROMETA Demonstrates Statisitcally Significant Reduction in Methamphetamine Cravings in Randomized Double-Blind Placebo Controlled Study
- ^ Mathew, NT; Rapoport A, Saper J, Magnus L, Klapper J,hello Ramadan N, Stacey B, Tepper S (2001). "Efficacy of gabapentin in migraine prophylaxis". Headache 41 (2): 119–28. doi:. ISSN 0017-8748. PMID 11251695. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=11251695&itool=pubmed_citation. Retrieved on 2006-08-14.
- ^ Backonja, MM; Serra J (2004). "Pharmacologic management part 1: better-studied neuropathic pain diseases". Pain Med 5 (Suppl 1): S28–47. doi:. ISSN 1526-2375. PMID 14996228.
- ^ Choudhuri, I; Sarvananthan N, Gottlob I (May 26, 2006). "Survey of management of acquired nystagmus in the United Kingdom". Eye 21: 1194. doi:. ISSN 0950-222X. PMID 16732211.
- ^ a b c Mack, Alicia (2003). "Examination of the evidence for off-label use of gabapentin" (PDF). Journal of Managed Care Pharmacy 9 (6): 559–68. http://www.amcp.org/data/jmcp/Contemporary%20Subject-559-568.pdf. Retrieved on 2006-08-14.
- ^ Gabapentin: pharmacology and its use in pain management; Rose, M., Kam, P.
- ^ Randomised controlled trial of gabapentin in Complex Regional Pain Syndrome type 1, Anton C van de Vusse , Suzanne GM Stomp-van den Berg , Alfons HF Kessels and Wim EJ Weber.
- ^ 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. ISSN 1180-4882. PMID 16699602.
- ^ Frye, Mark A.; et al (2000). "A Placebo-Controlled Study of Lamotrigine and Gabapentin Monotherapy in Refractory Mood Disorders" (Abstract). Journal of Clinical Psychopharmacology 20 (6): 607–14. doi:. http://www.psychopharmacology.com/pt/re/jclnpsychopharm/abstract.00004714-200012000-00004.htm. Retrieved on 2006-08-14.
- ^ Guttuso, T Jr; Kurlan R; McDermott MP; Kieburtz K (February 2003). "Gabapentin's effects on hot flashes in postmenopausal women: a randomized controlled trial". Obstet Gynecol 101 (2): 337–45. doi:.
- ^ Piccirillo, JF; Finnell J, Vlahiotis A, Chole RA, Spitznagel E (2007). "Relief of idiopathic subjective tinnitus: is gabapentin effective?". Arch Otolaryngol Head Neck Surg 133 (4): 390–7. doi:. PMID 17438255.
- ^ Pande, AC; Crockatt JG, Janney CA, Werth JL, Tsaroucha G. (2000). "Gabapentin in bipolar disorder: a placebo-controlled trial of adjunctive therapy" (Abstract). Bipolar Disorders 2 (3 Pt 2): 249–55. doi:. PMID 11249802.
- ^ Reporting and other biases in studies of Neurontin for migraine, psychiatric/bipolar disorders, nociceptive pain, and neuropathic pain [1]PDF (251 KB) Retrieved 28 March 2009
- ^ Baldessarini, Ross J.; Leahy L, Arcona S, Gause D, Zhang W, Hennen J. (2007). "Patterns of Psychotropic Drug Prescription for U.S. Patients With Diagnoses of Bipolar Disorders" (Abstract). Psychiatric Serv[ices] (58): 85-91. doi:.
- ^ Tran KT, Hranicky D, Lark T, Jacob Nj (June 2005). "Gabapentin withdrawal syndrome in the presence of a taper". Bipolar Disord 7 (3): 302–4. doi:. PMID 15898970. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1398-5647&date=2005&volume=7&issue=3&spage=302.
- ^ "FDA approved labeling for Neurontin capsules, tablets, and oral solution." (PDF). February 2005. http://www.fda.gov/cder/foi/label/2005/20235s029,20882s015,21129s016lbl.pdf. Retrieved on 2008-12-30. Note that an updated labeling has been approved, but is not available online as of November 2006
- ^ Maria C Lasso-de-la-Vega Pharm.D (2001). "Gabapentin-associated hepatotoxicity" (Abstract). Am J Gastroenterol 96 (12): 3460–3462. doi:. http://www.blackwell-synergy.com/links/doi/10.1111/j.1572-0241.2001.05357.x/abs. Retrieved on 2007-02-14.
- ^ Ayhan DOGUKAN (2006). "Gabapentin-induced coma in a patient with renal failure" (Abstract). Hemodialysis International 10 (2): 168–169. doi:. http://www.blackwell-synergy.com/doi/abs/10.1111/j.1542-4758.2006.00089.x?journalCode=hdi. Retrieved on 2007-02-14.
- ^ Bookwalter T, Gitlin M (2005). "Gabapentin-induced neurologic toxicities" (Abstract). Pharmacotherapy 25 (12): 1817–9. doi:. PMID 16305301. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16305301&query_hl=4&itool=pubmed_docsum. Retrieved on 2007-02-14.
- ^ Gabapentin Official FDA information, side effects and uses
- ^ "Huge penalty in drug fraud, Pfizer settles felony case in Neurontin off-label promotion.". San Francisco Chronicle. 2004-05-14. p. C-1. http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2004/05/14/BUGKK6L0LB1.DTL.
- ^ Jane E. Henney, MD (2006). "Editorial: Safeguarding Patient Welfare: Who's In Charge?". Annals of Internal Medicine 145 (4): 305–307. PMID 16908923. http://www.annals.org/cgi/content/full/145/4/305?etoc. Retrieved on 2006-08-14.
- ^ Baron v. Pfizer, Inc., 2007 N.Y. Slip Op. 05813 (App. N.Y., July 5, 2007)
- ^ Drug Industry Document Archive
- ^ Narrative Review: The Promotion of Gabapentin: An Analysis of Internal Industry Documents - Steinman et al. 145 (4): 284 - Annals of Internal Medicine
[edit] External links
- Gabapentin information from MedlinePlus
- News Article regarding Neurontin settlement and off-label marketing/use
- Website for the Greenstone subsidiary of Parke-Davis
- Website for the pending Class Action Lawsuit against Pfizer
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