Gabapentin was first approved for use in the United Kingdom in 1993.[18] It has been available as ageneric medication in the United States since 2004.[19] It is the first of several other drugs that are similar in structure and mechanism, calledgabapentinoids. In 2023, it was the ninth most commonly prescribed medication in the United States, with more than 45million prescriptions.[20][21] During the 1990s,Parke-Davis, a subsidiary ofPfizer, used several illegal techniques to encouragephysicians in the United States to prescribe gabapentin forunapproved uses.[22] They have paid out millions of dollars to settle lawsuits regarding these activities.[23]
Gabapentin is recommended for use infocal seizures andneuropathic pain.[7][10] Gabapentin is prescribedoff-label in the US and the UK,[24][25] for example, for the treatment of non-neuropathic pain,[24]anxiety disorders, sleep problems andbipolar disorder.[26] In recent years, gabapentin has seen increased use, particularly in the elderly.[27] There is concern regarding gabapentin's off-label use due to the lack of strong scientific evidence for its efficacy in multiple conditions, its proven side effects and its potential for misuse and physical/psychological dependency.[13][14][3] Some harms, including nervous system harms, have been underreported in published trials of gabapentin, potentially resulting in the underestimation of harms in guidelines for the use of gabapentin.[28]
Gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities.[10][11][31][32] This is a general recommendation applicable to all neuropathic pain syndromes except fortrigeminal neuralgia, where it may be used as a second- or third-line agent.[11][32]
Gabapentin shows substantial benefit (at least 50% pain relief or a patient's global impression of change (PGIC) "very much improved") for neuropathic pain (postherpetic neuralgia or peripheral diabetic neuropathy) in 30–40% of subjects treated as compared to those treated withplacebo.[12]
Gabapentin is effective in treating sleep disorders such as insomnia andrestless legs syndrome that are the result of an underlying illness, but comes with some risk ofdiscontinuation andwithdrawal symptoms after prolonged use at higher doses.[39]
Gabapentin enhancesslow-wave sleep in people with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneousarousal.[40]
Gabapentin is moderately effective in reducing the symptoms ofalcohol withdrawal and associated craving.[41][42][43] The evidence in favor of gabapentin is weak in the treatment ofalcoholism: it does not contribute to the achievement of abstinence, and the data on the relapse of heavy drinking and percent of days abstinent do not robustly favor gabapentin; it only decreases the percent days of heavy drinking.[44]
Gabapentin is ineffective in cocaine dependence and methamphetamine use,[45] and it does not increase the rate ofsmoking cessation.[46] While some studies indicate that gabapentin does not significantly reduce the symptoms ofopiate withdrawal, there is increasing evidence that gabapentinoids are effective in controlling some of the symptoms during opiate detoxification. A clinical study in Iran, where heroin dependence is a significant social and public health problem, showed gabapentin produced positive results during an inpatient therapy program, particularly by reducing opioid-inducedhyperalgesia anddrug craving.[47][45] There is insufficient evidence for its use incannabis dependence.[48]
Gabapentin is recommended as a first-line treatment of the acquiredpendular nystagmus, torsional nystagmus, and infantile nystagmus; however, it does not work in periodic alternating nystagmus.[49][50][51]
Gabapentin decreases the frequency ofhot flashes in both menopausal women and people with breast cancer. However, antidepressants have similar efficacy, and treatment withestrogen more effectively prevents hot flashes.[52]
Gabapentin should be used carefully and at lower doses in people withkidney problems due to possible accumulation and toxicity. It is unclear if it is safe duringpregnancy orbreastfeeding.[7]
In a systematic review analysing data from 5 cohort studies having 10,85,488 patients, use of gabapentinoids (gabapentin and pregabalin) was associated with an increased risk of thrombotic events (deep venous thrombosis and pulmonary thrombo-embolism) as early as three months of use, and with increased risk of cardiovascular events on prolonged use of more than a year duration. Heart failure was not increased with the use of gabapentinoids.[66]
Gabapentin Orion 100 mg, bottle and pills in Sweden
Dizziness andsomnolence are the most frequentside effects.[7]Fatigue,ataxia,peripheral edema (swelling of extremities), andnystagmus are also common.[7] A 2017 meta-analysis found that gabapentin also increased the risk of difficulties inmentation and visual disturbances as compared to a placebo.[33] Gabapentin is associated with a weight gain of 2.2 kg (4.9 lb) after 1.5 months of use.[67] Case studies indicate that it may causeanorgasmia anderectile dysfunction,[68] as well asmyoclonus[69][70] that disappear after discontinuing gabapentin or replacing it with other medication. Fever, swollen glands that do not go away, eyes or skin turning yellow, unusual bruises or bleeding, unexpected muscle pain or weakness, rash, long-lasting stomach pain which may indicate aninflamed pancreas,hallucinations,anaphylaxis,respiratory depression, and increasedsuicidal ideation are rare but serious side effects.[71]
As with all antiepileptic drugs approved in the US, gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors.[7] This warning is based on a meta-analysis of all approved antiepileptic drugs in 2008, and not with gabapentin alone.[72] According to an experimental meta-analysis of insurance claims databases, gabapentin use is associated with an approximately 40% increased risk ofsuicide,suicide attempt, and violent death as compared with a referenceanticonvulsant drugtopiramate. The risk is increased for people withbipolar disorder orepilepsy.[72] Another study has shown an approximately doubled rate of suicide attempts andself-harm in people with bipolar disorder who are taking gabapentin versus those takinglithium.[73] A large Swedish study suggests that gabapentinoids are associated with an increased risk of suicidal behaviour, unintentional overdoses, head/body injuries, and road traffic incidents and offences.[74] On the other hand, a study published by the Harvard Data Science Review found that gabapentin was associated with a significantly reduced rate of suicide.[75]
Serious breathing suppression, potentially fatal, may occur when gabapentin is taken together withopioids,benzodiazepines, or otherdepressants, or by people with underlying lung problems such asCOPD.[76] Gabapentin and opioids are commonly prescribed or abused together, and research indicates that the breathing suppression they cause is additive. For example, gabapentin use beforejoint replacement orlaparoscopic surgery increased the risk ofrespiratory depression by 30–60%.[76] A Canadian study showed that use of gabapentin and other gabapentinoids, whether forepilepsy,neuropathic pain or other chronic pain was associated with a 35–58% increased risk for severe exacerbation of pre-existingchronic obstructive pulmonary disease.[77]
Withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin (almost unambiguously due to extended use and during a very short-termrebound phenomenon) — similar to, albeit less intense than most benzodiazepines.[78] Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more raretremor,tachycardia,hypertension andinsomnia.[78] In some cases, users experience withdrawal seizures after chronic or semi-chronic use in the absence of periodic cycles or breaks during repeating and consecutive use.[79] All these symptoms subside when gabapentin is re-instated[78] ortapered off gradually at an appropriate rate.[citation needed]
On its own, gabapentin appears not to have a substantial addictive power. In human and animal experiments, it shows limited to norewarding effects. The vast majority of people abusing gabapentin are current or former abusers of opioids or sedatives.[79] In these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety.[80]
Gabapentin is increasingly recognized to cause a range of psychiatric and behavioral adverse effects that extend beyond its more common neurological side effects. Systematic reviews have documented atypical manifestations such asaggression,agitation,irritability, mood instability, andsuicidal ideation, with some cases noting the emergence ofmania,hallucinations, andpsychosis, particularly in pediatric populations and individuals with preexisting psychiatric conditions.[81][82][83]
Largecohort studies and post-marketing surveillance indicate that neuropsychiatric symptoms—including confusion, depression, and behavioral disturbances—can occur in up to 29% of gabapentin users. Most reactions are mild to moderate and often dose-dependent.[84] There is also evidence associating gabapentin with an increased risk of suicidal behavior, especially in younger patients, and rare reports of violent or aggressive behavior. Causality is difficult to establish, and such events remain uncommon.[85][86]
Through excessive ingestion, accidental or otherwise, persons may experience overdose symptoms including drowsiness, sedation, blurred vision, slurred speech,somnolence, uncontrollable jerking motions, and anxiety. A very high amount taken is associated with breathing suppression, coma, and possibly death, particularly if combined withalcohol oropioids.[79][87]
Gabapentin preventsseizures in adose-related manner in several laboratoryanimal models.[88] These models include spinal extensor seizures from low-intensity electroshock to theforebrain in mice, maximal electroshock in rats, spinal extensor seizures in DBA/2 mice with a genetic sensitivity to seizures induced by loud noise, and in rats "kindled" to producefocal seizures by repeated prior electrical stimulation of thehippocampus. Gabapentin slightly increased spontaneousabsence-like seizures in a genetically susceptible strain recorded withelectroencephalography. All of these effects of gabapentin were seen at dosages at or below thethreshold for producingataxia.
Gabapentin has also been tested in a wide variety of animal models that are relevant foranalgesic actions.[89] Generally, gabapentin is not active to prevent pain-related behaviors in models of acutenociceptive pain. It prevents pain-related behaviors when animals are made sensitive by prior peripheralinflammation or peripheral nerve damage (inflammatory orneuropathic conditions).
Gabapentin is not a direct calciumchannel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins. Gabapentin reduces delivery of intracellular calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling to lead to neurotransmitters release, and disrupts interactions of α2δ with voltage gated calcium channels but also withNMDA receptors,neurexins, andthrombospondin.[15][16][17] These proteins are found as mutually interacting parts of the presynapticactive zone, where numerous protein molecules interact with each other to enable and to regulate the release ofneurotransmitters frompresynaptic vesicles into the synaptic space.[citation needed]
Out of the four known isoforms of α2δ protein, gabapentin binds with similar highaffinity to two:α2δ-1 andα2δ-2.[91] All of the pharmacological properties of gabapentin tested to date are explained by its binding to just one isoform – α2δ-1.[91][16]
Theendogenousα-amino acidsL-leucine andL-isoleucine, which resemble gabapentin inchemical structure, bind α2δ with similar affinity to gabapentin and are present in humancerebrospinal fluid at micromolar concentrations.[93] They may be the endogenous ligands of the α2δ subunit, and theycompetitively antagonize the effects of gabapentin.[93][94] Accordingly, while gabapentin hasnanomolar affinity for the α2δ subunit, its potencyin vivo is in the lowmicromolar range, and competition for binding by endogenousL-amino acids is likely to be responsible for this discrepancy.[16]
Gabapentin is a potent activator of voltage-gated potassium channelsKCNQ3 andKCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of gabapentin's therapeutic effects.[95]
Gabapentin is structurally similar to the neurotransmitter glutamate and competitively inhibitsbranched-chain amino acid aminotransferase (BCAT), slowing down the synthesis of glutamate.[96] In particular, it inhibits BCAT-1 at high concentrations (Ki = 1 mM), but not BCAT-2.[97] At very high concentrations, gabapentin can suppress the growth of cancer cells, presumably by affecting mitochondrial catabolism; however, the precise mechanism remains elusive.[97]
Even though gabapentin is a structuralGABA analogue, and despite its name, it does not bind to theGABA receptors, does not convert intoGABATooltip γ-aminobutyric acid or anotherGABA receptor agonistin vivo, and does not modulate GABAtransport ormetabolism within the range of clinical dosing.[90] In vitro gabapentin has been found to very weakly inhibit theGABA aminotransferase enzyme (Ki = 17–20 mM); however, this effect is so weak that it is not clinically relevant at prescribed doses.[96]
Theoral bioavailability of gabapentin is approximately 80% at 100 mg administered three times daily once every 8 hours, but decreases to 60% at 300 mg, 47% at 400 mg, 34% at 800 mg, 33% at 1,200 mg, and 27% at 1,600 mg, all with the same dosing schedule.[7][99] Drugs that increase the transit time of gabapentin in thesmall intestine can increase its oral bioavailability; when gabapentin was co-administered with oralmorphine, the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.[99]
Gabapentin at a low dose of 100 mg has aTmax (time topeak levels) of approximately 1.7 hours, while the Tmax increases to 3 to 4 hours at higher doses.[91] Food does not significantly affect the Tmax of gabapentin and increases the Cmax andarea-under-curve levels of gabapentin by approximately 10%.[99]
Gabapentin is generally safe in people with livercirrhosis.[104]
Gabapentin iseliminatedrenally in theurine.[99] It has a relatively shortelimination half-life, with the reported average value of 5 to 7 hours.[99] Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels.[105] Gabapentin XR (brand name Gralise) is taken once a day.[106]
Chemical structures of GABA and gabapentin, with commonalities highlighted
Gabapentin is a 3,3-disubstitutedderivative of GABA. Therefore, it is aGABA analogue, as well as aγ-amino acid.[107][108] It is similar to several other compounds that collectively are calledgabapentinoids. Specifically, it is a derivative of GABA with a pentyl disubstitution at 3 position, hence, the name - gabapentin, in such a way as to form a six-membered ring. After the formation of the ring, theamine andcarboxylic groups are not in the same relative positions as they are in the GABA;[109] they are moreconformationally constrained.[110]
Although it has been known for some time that gabapentin must bind to the α2δ-1 protein in order to act pharmacologically (see Pharmacodynamics), the three-dimensional structure of the α2δ-1 protein with gabapentin bound (or alternatively, the native amino acid, L-Isoleucine bound) has only recently been obtained bycryo-electron microscopy.[111] A figure of this drug-bound structure is shown in the Chemistry section of the entry ongabapentinoid drugs. This study confirms other findings to show that both compounds alternatively can bind at a single extracellular site (somewhat distant from the calcium conducting pore of thevoltage gated calcium channel α1 subunit) on the calcium channel and chemotaxis (Cache1) domain of α2δ-1.
A process forchemical synthesis and isolation of gabapentin with high yield and purity[112] starts with conversion of 1,1-cyclohexanediacetic anhydride to 1,1-cyclohexanediacetic acid monoamide and is followed by a 'Hofmann' rearrangement in an aqueous solution ofsodium hypobromite prepared in situ.
GABA is the principal inhibitoryneurotransmitter in mammalian brains. By the early 1970s, it was appreciated that there are two main classes ofGABA receptors,GABAA andGABAB and also thatbaclofen was anagonist of GABAB receptors. Gabapentin was designed, synthesized, and tested in mice by researchers at the pharmaceutical company Goedecke AG in Freiburg, Germany (a subsidiary ofParke-Davis). It was meant to be ananalogue of theneurotransmitter GABA that could more easily cross theblood–brain barrier. It was first synthesized in 1974/75 and described in 1975[113] by Satzinger and Hartenstein.[109][114]
The first pharmacology findings published were sedating properties and prevention ofseizures in mice evoked by theGABA antagonist,thiosemicarbazide.[113] Shortly after, gabapentin was shown in vitro to reduce the release of the neurotransmitterdopamine from slices of ratcaudate nucleus (striatum).[115] This study provided evidence that the action of gabapentin, unlike baclofen, did not arise from the GABAB receptor.
Initialclinical trials utilizing small numbers of subjects were for treatment ofspasticity[116] andmigraine[117] but neither study had statistical power to allow conclusions. In 1987, the first positive results with gabapentin were obtained in a clinical trial using three dose groups versus pre-treatment seizure frequency for 75 days, as add-on treatment in patients who still had seizures despite taking other medications.[118] This study did not show statistically significant results. It did show a strong dose-related trend to decreased frequency of seizures.
Under the brand name Neurontin, it was first approved in the United Kingdom in May 1993, for the treatment of refractory epilepsy.[119] Approval by theU.S. Food and Drug Administration followed in December 1993, also 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.[120][7] Subsequently, gabapentin was approved in the United States for the treatment of pain frompostherpetic neuralgia in 2002.[121] Ageneric version of gabapentin first became available in the United States in 2004.[19] An extended-release formulation of gabapentin for once-daily administration, under the brand name Gralise, was approved in the United States for the treatment of postherpetic neuralgia in January 2011.[122][123]
In recent years, gabapentin has been prescribed for an increasing range of disorders and is one of the more common medications used, particularly in elderly people.[124]
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,[137] the preponderance of evidence suggests that it is not effective.[138]
After 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 theFranklin v. Parke-Davis case.
While off-label prescriptions are common for many drugs, marketing of off-label uses of a drug is not.[22] 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 wasone of the largest in U.S. history up to that point, and thefirst off-label promotion case brought successfully under the False Claims Act.[139]
Gabasync, a treatment consisting of a combination of gabapentin and two other medications (flumazenil andhydroxyzine) as well as therapy, is an ineffective treatment promoted formethamphetamine addiction. It had also been claimed to be effective fordependence on alcohol orcocaine.[146] It was marketed as PROMETA. While the FDA has approved individual drugs, they have not approved their off-label use for addiction treatment.[147] Gabasync was marketed by Hythiam, Inc., which is owned byTerren Peizer, a formerjunk bond salesman who has since been convicted of securities fraud relative to another company.[148][149][150][146] Hythiam charges up to $15,000 per patient to license its use (of which half goes to the prescribing physician, and half to Hythiam).[151]
In a November 2005 article entitled "Curb Your Cravings For This Stock",Barrons wrote: "If the venture works out for patients and the investing public, it'll be a rare success for Peizer, who's promoted a series of disappointing small-cap medical or technology stocks ... since his days at Drexel".[152]60 Minutes,NBC News, andThe Dallas Morning News criticized Peizer after the company bypassedclinical studies and government approval when bringing to market Prometa; the addiction drug proved to be completely ineffective.[153][154][146][155]CBS News journalistScott Pelley said to Peizer in 2007: "Depending on who you talk to, you're either a revolutionary or asnake oil salesman."[156][152] JournalistAdam Feuerstein opined: "most of what Peizer says is dubious-sounding hype".[157]
In November 2011, the results of adouble-blind,placebo-controlled study (financed by Hythiam and carried out atUCLA) were published in thepeer-reviewed journalAddiction. It concluded that Gabasync is ineffective: "The PROMETA protocol, consisting of flumazenil, gabapentin, and hydroxyzine, appears to be no more effective than placebo in reducing methamphetamine use, retaining patients in treatment, or reducing methamphetamine craving."[158]
The consumption of gabapentinoids rose significantly between 2008 and 2018. A study published in Nature Communications in 2023 highlights this trend, demonstrating a notable escalation in sales of gabapentinoids. The study, which analyzed healthcare data across 65 countries/ regions, found that the consumption rate of gabapentinoids had doubled over the decade, driven by their use in a wide range of indications.[159]
Gabapentin was originally marketed under the brand name Neurontin. Since it became generic, it has been marketed worldwide using over 300 different brand names.[1] Anextended-release formulation of gabapentin for once-daily administration was introduced in 2011 for postherpetic neuralgia under the brand name Gralise.[160]
When taken in excess, gabapentin can induce euphoria, a sense of calm, improved sociability, and reduced alcohol or cocaine cravings.[167][168][169] Also known on the streets as "Gabbies",[170] gabapentin was reported in 2017 to be increasingly abused and misused for these euphoric effects.[171][172] About 1 percent of the responders to an Internet poll and 22 percent of those attending addiction facilities had a history of abuse of gabapentin.[78][173] Gabapentin misuse, toxicity, and use in suicide attempts among adults in the US increased from 2013 to 2017.[174]
After Kentucky implemented stricter legislation regarding opioid prescriptions in 2012, there was an increase in gabapentin-only and multi-drug use from 2012 to 2015. The majority of these cases were from overdose in suspected suicide attempts. Increases in abuse and recreational use accompanied these rates.[175]
Withdrawal symptoms, often resembling those ofbenzodiazepine withdrawal, play a role in the physical dependence some users experience.[79] Its misuse predominantly coincides with the usage of otherCNS depressant drugs, namely opioids, benzodiazepines, and alcohol.[176]
In cats, gabapentin can be used as an analgesic in multi-modal pain management,[177] anxiety medication to reduce stress during travel or vet visits,[178] and anticonvulsant.[179]
Veterinarians may prescribe gabapentin as an anticonvulsant and pain reliever in dogs.[180][179] It has beneficial effects for treatingepilepsy, different kinds of pain (chronic,neuropathic, and post-operative pain), and anxiety, lip-licking behavior, storm phobia, fear-based aggression.[181][182]
It is also used to treat chronic pain-associated nerve inflammation in horses and dogs. Side effects include tiredness and loss of coordination, but these effects generally resolve within 24 hours of starting the medication.[180][179]
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