Gabapentin

Gabapentin
Gabapentin
Systematic (IUPAC) name
2-[1-(aminomethyl)cyclohexyl]acetic acid
Clinical data
Licence data US FDA:link
Pregnancy cat. B1(AU) C(US)
Legal status POM (UK) ℞-only (US) ℞ Prescription only
Routes Oral
Pharmacokinetic data
Bioavailability Rapid, in part by saturable carrier-mediated L-amino acid transport system
Protein binding Less than 3%
Metabolism Not appreciably metabolized
Half-life 5 to 7 hours
Excretion Renal
Identifiers
CAS number 60142-96-3 YesY
ATC code N03AX12
PubChem CID 3446
DrugBank APRD00015
ChemSpider 3328 YesY
UNII 6CW7F3G59X YesY
KEGG D00332 YesY
ChEMBL CHEMBL940 YesY
Chemical data
Formula C9H17NO2 
Mol. mass 171.237 g/mol
SMILES eMolecules & PubChem
 YesY(what is this?)  (verify)

Gabapentin (brand names Fanatrex, Gabarone, Gralise, Neurontin, Nupentin) is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain. There are, however, concerns regarding the quality of the trials conducted.

Contents

Medical uses

A capsule of gabapentin

Gabapentin is used primarily for the treatment of seizures, neuropathic pain, and hot flashes.[1] There are, however, concerns regarding the quality of the research on its use to treat migraines, bipolar disorders, and pain.[2]

Pain

Gabapentin provides significant pain relief in about a third of people who take it for fibromyalgia or chronic neuropathic pain.[3] It is also effective in reducing narcotic usage post operatively[4] and is helpful in neuropathic pain due to cancer.[5] It has not been shown to be useful for HIV associated sensory neuropathy.[6] When used for neuropathic pain it does not appear superior to carbamazepine.[7] Further evidence is needed to determine if it is effective for migraine prevention.[8] It appears to be equally effective as pregabalin and is of lower cost.[9] It does not appear to be of benefit in treating complex regional pain syndrome.[10]

Seizures

Gabapentin is approved for treatment of focal seizures in a number of countries[11] and evidence supports it use for treating partial and mixed seizure disorders however there is insufficient evidence for it use in generalized epilepsy.[12] There is little data to support its initial use over older anticonvulsant medication for any type of seizure disorder.[13]

Other

There is some evidence of benefit in acquired pendular nystagmus and infantile nystagmus but not in periodic alternating nystagmus.[14][15] Gabapentin may help with menopausal symptoms.[16][17] It may be effective in reducing pain and spasticity in multiple sclerosis.[18] Gabapentin has been used to treat some symptoms of opiate withdrawal,[19] but tests for smoking cessation treatment have had mixed results.[20][21]

Negative

Gabapentin has been prescribed in the mental health context. Numerous trials show that it is not effective as a mood-stabilizing treatment for bipolar disorder and so has no therapeutic advantage in having fewer side-effects over better established 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.[22][23] Gabapentin can also cause weight gain.[24]

A double blind, randomized controlled trial found gabapentin ineffective for the treatment of idiopathic subjective tinnitus.[25]

Adverse effects

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities);[26] 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.[27][28] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[29][30]

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.[31]

Suicide

Gabapentin has been associated with an increased risk of suicidal acts or violent deaths.[32] In 2009, the FDA issued a warning of an increased risk of depression and suicidal thoughts and behaviors in patients taking gabapentin, along with other anticonvulsant drugs[33] modifying the packaging insert to reflect this.[26] In July 2009, the manufacturer of gabapentin (Pfizer) went to trial regarding the association between gabapentin and the increased risk of suicide.[34]

Withdrawal

Gabapentin should not be discontinued abruptly after long term use. Abrupt or over rapid withdrawal may provoke a withdrawal syndrome reminiscent to alcohol or benzodiazepine withdrawal.[35][36] Gradual reduction over a period of weeks or months helps minimize or prevents the withdrawal syndrome.[35]

Side effects upon discontinuation of gabapentin that have been reported in medical literature include insomnia, restlessness, agitation, anxiety, disorientation, confusion, light sensitivity, diaphoresis, headaches, palpitations, hypertension, chest pain, and flu-like symptoms.[35][37][38][39] In at least one case, abrupt cessation of a high dose of gabapentin triggered a seizure in an individual with no history of epilepsy.[38]

Overdosage

Persons who accidentally or intentionally ingested overdoses have manifested drowsiness, blurred vision, slurred speech and somnolence or coma. Serum gabapentin concentrations may be measured to confirm diagnosis.[24][40]

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.

One possible mechanism of action, reported by Ben Barres of Stanford University and colleagues in Cell in 2009, was that gabapentin halts the formation of new synapses.[41] 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[42] of voltage-dependent calcium channels in the central nervous system.[43] This effect on calcium channel trafficking is another possible mechanism of action of gabapentin, but the exact mechanism remains in dispute.

Related drugs

Parke-Davis developed a drug called pregabalin to be a successor of gabapentin.[44] Pregabalin was brought to market by Pfizer as Lyrica after the company acquired Warner-Lambert. Pregabalin is related in structure to gabapentin and is approved for treatment of epilepsy, neuropathic pain associated with diabetes, fibromyalgia, post-herpetic neuralgia, and generalized anxiety disorder. Compared to gabapentin, pregabalin is more potent, absorbs faster and has greater bioavailability. Higher potency means that less of the medication is required for the same effect. This does not necessarily result in fewer side effects.[45][46] Another new drug atagabalin has been trialled by Pfizer as a treatment for insomnia.[47] One must remain skeptical of industry run trials[48] as, despite significant monetary damages awarded in trials discussed below, there is no certainty the company is not still suppressing negative or equivocal data and news reports indicate this may be the case with pregabalin as well.[49]

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 is one of Pfizer's best-selling drugs, and was one of the 50 most-prescribed drugs in the United States in 2003. However, Pfizer has come under heavy criticism and serious litigation 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.[50][51] Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.[52]

FDA approval

Gabapentin was originally approved by the U.S. 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).[53]

Legal action

Numerous cases have been brought against the makers of Neurontin, with convictions arising not only for the illegal promotion of off-label uses. Much of the popular use of Neurontin among physicians stems from the widespread illicit marketing that Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants’ meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign.[54] The convictions for fraud set a new standard that goes beyond “scientific misconduct” and elevates the seriousness of the suppression of negative or unsupportive evidence as a form of fraud. As part of a case (CIVIL ACTION NO. 04-cv-10739-PBS) brought by Kaiser Foundation Health Plan against Pfizer, it was noted that "The general neuropathic pain indication cannot be granted for Neurontin based on the clinical trials in painful diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN)."[55]

While it is often prescribed off-label (that is, at the discretion of a physician) for various conditions, this use is probably frequently due to the widespread illicit marketing Pfizer was convicted of, which was communicated via promotional messages through advisory boards, consultants’ meetings, and accredited continuing medical education events posing as independent third-party organizations, co-opting opinion leaders, educational enterprises and academia in their marketing campaign.[54]

Off label promotion

Off-label use of gabapentin for psychiatric off-label use also resulted in convictions.[18] 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,[18] other more recent and better controlled studies have found it to be no more effective (and in one study, slightly less effective) than placebo.[56] 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. In addition, the FDA black box warning states: "Antiepileptic drugs (AEDs), including Neurontin, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication."[57]

Despite this controversy, many psychiatrists continue to prescribe it for a variety of off-label purposes. Oftentimes, it is tried as an alternative treatment when patients are unable to tolerate the side effects of more proven mood stabilizers such as lithium. More frequently, it is prescribed on a speculative basis as an auxiliary treatment, when single-drug therapy has consistently failed to yield sufficient positive results.[58]

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."[59] 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."[citation needed]

Bloomberg News (3/26/10, 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."[citation needed]

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."[citation needed] "The verdict and the judge's rulings are not consistent with the facts and the law," he added, according to Reuters (3/26/10, Berkrot).[citation needed]

Franklin v. Pfizer case

Main article: David Franklin (scientist)

By some estimates, off-label prescriptions account for roughly 90% of Neurontin sales.[60] 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.[61] 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.[62]

The University of California, San Francisco (UCSF) has archived[63] and studied[64] the documents made public by this case, which opens a unique 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.

Recreational use

Although gabapentin is not a controlled substance, it does produce psychoactive effects that cause it to have potential for recreational use. Even in low doses, gabapentin causes sensations of reduced acute pain, reduced anxiety and even a tendency to become overly social and talkative. Larger doses can cause the user to become numb and even fully insensate. Although it is widely regarded as having little or no potential for misuse, it is often a misused drug in Canadian Northern communities and among inmates in California State prisons[citation needed]. However, Pregabalin, a subsequent Pfizer spin-off, is a controlled substance under Schedule V of the United States' Controlled Substances Act.

Veterinary use

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 care must be taken if the human version is used for veterinary purposes.

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  58. ^ 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 (58): 85–91. doi:10.1176/appi.ps.58.1.85. 
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  63. ^ Drug Industry Document Archive
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External links

v · d · eAnalgesics (N02A, N02B)
Opioids
See also: Opioids template
Opium & alkaloids thereof

Codeine# • Morphine# • Opium • Laudanum • Paregoric
Semi-synthetic opium
derivatives
Synthetic opioids
Pyrazolones
Cannabinoids
Anilides
Non-steroidal
anti-inflammatories
See also: NSAIDs template
Propionic acid class
Oxicam class
Acetic acid class
Anthranilic acid
(fenamate) class

Meclofenamate • Mefenamic acid
Salicylates
Atypical, adjuvant and potentiators,
Metabolic agents and miscellaneous
Amitryptiline  • Befiradol • Bicifadine • Carisoprodol  • Camphor • Cimetidine • Clonidine • Chlorzoxazone • Cyclobenzaprine • Duloxetine • Esreboxetine • Flupirtine • Gabapentin • Glafenine • Hydroxyzine • Ketamine  • Menthol • Mephenoxalone • Methocarbamol • Nefopam • Orphenadrine • Pregabalin • Proglumide • Scopolamine • Tebanicline • Trazodone • Gabapentin enacarbil • Ziconotide

M: CNS

anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp

noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr

proc, drug(N1A/2AB/C/3/4/7A/B/C/D)
v · d · eAnticonvulsants (N03)
GABAA receptor agonist
Other GABA agents
Carbonic anhydrase inhibitor
Channel blockers
Primarily sodium
Carbamazepine# • Eslicarbazepine acetate • Oxcarbazepine • Oxitriptyline • Rufinamide
Primarily calcium
Unknown/ungrouped
Channel openers
Potassium
Retigabine
Indirect GABA agents

GABA transaminase inhibitor: Valproic acid# (Sodium valproate & Valproate semisodium) • Valpromide • Valnoctamide • Valproate pivoxil

GABA reuptake inhibitor: Tiagabine
Gabapentin • Pregabalin • Progabide • Tolgabide • Vigabatrin
Unknown/multiple/
unsorted
Propionates
#WHO-EM. ‡Withdrawn from market. Clinical trials: †Phase III. §Never to phase III

M: CNS

anat(n/s/m/p/4/e/b/d/c/a/f/l/g)/phys/devp

noco(m/d/e/h/v/s)/cong/tumr, sysi/epon, injr

proc, drug(N1A/2AB/C/3/4/7A/B/C/D)
v · d · eMood stabilizers
v · d · eMood disorder (F30–F39, 296)
History
Symptoms
Spectrum
Treatment
Non-pharmaceutical
Related

M: PSO/PSI

mepr

dsrd (o, p, m, p, a, d, s), sysi/epon, spvo

proc(eval/thrp), drug(N5A/5B/5C/6A/6B/6D)
v · d · eGABAergics
Receptor
ligands

Agonists: Main site: Bamaluzole • Gaboxadol • Ibotenic acid • Isoguvacine • Isonipecotic acid • Muscimol (Amanita Muscaria) • Progabide • SL 75102 • Thiomuscimol • Tolgabide; Positive allosteric modulators: Barbiturates • Benzodiazepines • Carbamates • Chlormezanone • Clomethiazole • Ethanol (Alcohol) • Etomidate • Kavalactones (Kava) • Loreclezole • Metomidate • Neuroactive steroids • Nonbenzodiazepines (β-Carbolines, Cyclopyrrolones, Imidazopyridines, Pyrazolopyrimidines, etc.) • Phenols • Piperidinediones • Propanidid • Pyrazolopyridines • Quinazolinones • ROD-188 • Skullcap • Stiripentol • Valerenic acid (Valerian)
* See Template:GABAAergics for a full list of GABAA positive allosteric modulators.

Antagonists: Main site: Bicuculline • Gabazine • Pitrazepin; Negative allosteric modulators: α5IA • Bilobalide • Cicutoxin • Cyclothiazide • DMCM • Flumazenil • Flurothyl • Furosemide • L-655,708 • Oenanthotoxin • Penicillin • Pentylenetetrazol • Picrotoxin • PWZ-029 • Ro15-4513 • Sarmazenil • Suritozole • Thujone (Absinthe) • Thiocolchicoside • ZK-93426
Agonists: Main site: 1,4-Butanediol • Baclofen • GBL • GHB • GHV • GVL • Lesogaberan • Phenibut • Progabide • SKF-97,541 • Tolgabide; Positive allosteric modulators: BHF-177 • BHFF • BSPP • CGP-7930 • GS-39783
Antagonists: Main site: CGP-35348 • Phaclofen • Saclofen • SCH-50911
Agonists: Main site: CACA • CAMP • GABOB • N(4)-chloroacetylcytosine arabinoside • Progabide • Tolgabide
Antagonists: Main site: Bilobalide • TPMPA
Reuptake
inhibitors
Plasmalemmal
GAT inhibitors
CI-966 • Deramciclane • EF-1502 • Gabaculine • Guvacine • Nipecotic acid • NNC 05-2090 • SKF-89976A • SNAP-5114 • Tiagabine
Enzyme
inhibitors
GAD inhibitors
Allylglycine
GABA-T inhibitors
3-Hydrazinopropionic acid • Aminooxyacetic acid • Gabaculine • Isoniazid • Phenelzine • Phenylethylidenehydrazine • Sodium valproate • Valnoctamide • Valproate pivoxil • Valproate semisodium (Divalproex sodium) • Valproic acid • Valpromide • Vigabatrin
Others
Glutamate • Glutamine
Others
Gabapentin • L-Theanine • Picamilon • Pregabalin

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