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.
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]
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]
Gabapentin is approved for treatment of focal seizures in a number of countries[11] and evidence supports its use for treating partial and mixed seizure disorders however there is insufficient evidence for its 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]
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 is not supported for alcohol withdrawal,[19] and treatment of smoking cessation have had mixed results.[20][21]
Gabapentin has been prescribed in the mental health context. Numerous trials show that it is not effective alone 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 is useful in the treatment of anxiety associated with bipolar disorder, but has limited usefulness in disorders such as social anxiety disorder and obsessive-compulsive disorder, in treatment-resistant depression, and for insomnia.[22][23]
A double blind, randomized controlled trial found gabapentin ineffective for the treatment of idiopathic subjective tinnitus.[24]
Gabapentin's most common side effects in adult patients include dizziness, fatigue, weight gain, drowsiness, and peripheral edema (swelling of extremities);[25] 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.[26][27] Gabapentin should be used carefully in patients with renal impairment due to possible accumulation and toxicity.[28][29]
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.[30]
Gabapentin has been associated with an increased risk of suicidal acts or violent deaths.[31] 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[32] modifying the packaging insert to reflect this.[25] In July 2009 the manufacturer of gabapentin (Pfizer) went to trial regarding the association between gabapentin and the increased risk of suicide.[33]
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.[34][35] Gradual reduction over a period of weeks or months helps minimize or prevents the withdrawal syndrome.[34]
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.[34][36][37][38] In at least one case, abrupt cessation of a high dose of gabapentin triggered a seizure in an individual with no history of epilepsy.[37]
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.[39]
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. The mechanism of action that leads to its rapid analgesic effect is simply unknown.
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[40] of voltage-dependent calcium channels in the central nervous system.[41] Another possible mechanism of action, reported by Ben Barres and colleagues in Cell in 2009, is that gabapentin halts the formation of new synapses.[42]
Parke-Davis developed a drug called pregabalin to be a successor of gabapentin.[43] 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.[44][45] Another new drug atagabalin has been trialled by Pfizer as a treatment for insomnia.[46] One must remain skeptical of industry run trials[47] 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.[48]
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.[49][50] Today it is a mainstay drug for migraines, even though it was not approved for such use in 2004.[51]
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).[52]
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.[53] As part of a case[54] 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 may partially stem from the illicit marketing mentioned above.[53]
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."[60]
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."[61]
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."[62] He would later add that "the verdict and the judge's rulings are not consistent with the facts and the law."[59]
[edit] Franklin v. Pfizer case
By some estimates, off-label prescriptions account for roughly 90 percent of Neurontin sales.[63] 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.[49] 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.[64]
The University of California, San Francisco (UCSF) has archived[65] and studied[66] 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.
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[citation needed]. Larger doses can cause the user to become numb and even fully insensate. Tolerance to gabapentin occurs extremely rapidly with recreational use, with the user often needing to double the dosage within a day or two of misuse. Although it is widely regarded as having little or no potential for misuse, it is often a misused drug in Canadian Northern communities[citation needed] and among inmates in California State prisons.[67] However, Pregabalin, a subsequent Pfizer spin-off, is a controlled substance under Schedule V of the United States' Controlled Substances Act.
Staggering
Because of perceived low bioavaliability, a commonly reported method of Gabapentin usage is "staggering", as reported on drug-experience sharing websites such as Bluelight and Erowid[68][unreliable source?] 1. Staggering involves taking more than the prescribed daily amount of drug, often over an interval of half hours or longer. The method sometimes include food with the repeated dosings. Users have reported mixed feelings; ranging from euphoria to nausea and chest tension.[69][unreliable source?] Gastrointestinal side effects of very high doses of gabapentin are extremely common. Profuse diarrhea is common with doses of gabapentin exceeding 4800 mg at a time, or perhaps more over the course of a day. It is likely that the large quantities of binders and fillers in gabapentin tablets cause diarrhea,[dubious – discuss][citation needed] although the sheer volume of the alkaloid itself needed to produce recreational effects may irritate the GI tract causing the diarrhea. The effects of staggering are intended to maximize the saturation along its main transporter. Because gabapentin's mechanism for action remains relatively unknown, especially because additional research is needed into its effects on bipolar and psychological disorders, the tendency of users to experiment and self-regulate the acceptable levels of gabapentin in them should be considered when examining its adverse effects.[70] It is actively absorbed via the L amino acid transporter system.[71] Because it is a non-plasma-bound renally excreted drug, it is entirely eliminated by the kidneys.[70] Other methods of recreational gabapentin abuse are chewing the time-released pills into a powder that can be absorbed through swallowing or absorption into the lining of the mouth. Snorting a powdery residue of chopped-up gabapentin is reported as well, although highly ill-advised.[72][unreliable source?] Such abuse led to the removal of gabapentin in certain California correctional facilities.[67][73]
Neurocognitive effects with other interactions
Alcohol dependence
While symptoms of abrupt gabapentin withdrawal are many-fold, a study has combined gabapentin and flumazenil, a benzodiapazine antagonist, in order to measure cognitive performance on individual's in the beginning stages of alcohol withdrawal. The research impetus came from the GABA and glutamate signaling that occurs during alcohol withdrawal. The study observed for improvement of response inhibitions between subjects that had received treatment versus a group receiving a placebo; over 60 alcohol-dependent participants were evaluated. The results were moderate; the gabapentin and flumazenil treatment slightly improved response inhibition task during the early phases of abstinence, and this corresponds to many self-testimonials. However the quality of the overall impact was mixed and the medication cannot be said to improve alcoholic relapse; however it has the potential to subdue early withdrawal discomforts when combined with the benzodiapazine receptor antagonist.[74]
Cocaine
Frequently mentioned online in drug-experience sharing websites, Gabapentin has been considered for reducing cocaine use or assisting in cocaine withdrawal because of its GABAergic feedback properties. One study chose nine individuals with cocaine withdrawal symptoms from a clinical setting. Gabapentin presence was tested over a 24-week trial; the study concluded that Gabapentin may be a useful medicine for reducing cocaine usage in addicted patients, especially during the early weeks of any attempt to come clean.[75]
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.[76]
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- ^ 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. DOI:10.1034/j.1399-5618.2000.20305.x. PMID 11249802.
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- ^ 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". Psychiatric Services 58 (58): 85–91. DOI:10.1176/appi.ps.58.1.85. PMID 17215417. http://ps.psychiatryonline.org/data/Journals/PSS/3790/07ps85.pdf.
- ^ a b Berkrot, Bill (2010-03-25). "US jury's Neurontin ruling to cost Pfizer $141 mln". Reuters. http://www.reuters.com/article/2010/03/25/pfizer-neurontin-idUSN259778920100325.
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- ^ Never Snorting This Stuff Again Erowid Experience Vaults https://www.erowid.org/experiences/exp.php?ID=77321
- ^ Del Paggio D. Psychotropic medication abuse in correctional facilities. Bay Area Psychopharmacology Newsletter. 2005;8(2):1,5.)
- ^ Schacht, JP; Randall, PK; Waid, LR; Baros, AM; Latham, PK; Wright, TM; Myrick, H; Anton, RF (November 2011). "Neurocognitive Performance, Alcohol Withdrawal, and Effects of a Combination of Flumazenil and Gabapentin in Alcohol Dependence". Alcoholism: Clinical and Experimental Research 35 (11): 2030–8. DOI:10.1111/j.1530-0277.2011.01554.x. PMC 3166540. PMID 21631542. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3166540.
- ^ Raby WN; Coomaraswamy S (January 2004). "Gabapentin reduces cocaine use among addicts from a community clinic sample". The Journal of Clinical Psychiatry 65 (1): 84–6. DOI:10.4088/JCP.v65n0114. PMID 14744174.
- ^ Barbara Forney. "Gabapentin for Veterinary Use". http://www.wedgewoodpetrx.com/learning-center/professional-monographs/gabapentin-for-veterinary-use.html.
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