Gabapentin

Source: Wikipedia, the free encyclopedia.

Gabapentin
Clinical data
Trade namesNeurontin, others[1]
Other namesCI-945; GOE-3450; DM-1796 (Gralise)
AHFS/Drugs.comMonograph
MedlinePlusa694007
License data
Pregnancy
category
Dependence
liability
Low – Moderate
Addiction
liability
Low
Routes of
administration
By mouth
Drug classGabapentinoid
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability27–60% (inversely proportional to dose; a high fat meal also increases bioavailability)[5][6]
Protein bindingLess than 3%[5][6]
MetabolismNot significantly metabolized[5][6]
Elimination half-life5 to 7 hours[5][6]
ExcretionKidney[5][6]
Identifiers
  • 2-[1-(Aminomethyl)cyclohexyl]acetic acid
JSmol)
  • O=C(O)CC1(CN)CCCCC1
  • InChI=1S/C9H17NO2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10H2,(H,11,12) checkY
  • Key:UGJMXCAKCUNAIE-UHFFFAOYSA-N checkY
  (verify)

Gabapentin, sold under the brand name Neurontin among others, is an

central pain.[8] It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.[9]

respiratory depression, and allergic reactions.[4] Lower doses are recommended in those with kidney disease.[4] Gabapentin acts by decreasing activity of a subset of calcium channels.[10][11][12]

Gabapentin was first approved for use in 1993.

unapproved uses.[17] They have paid out millions of dollars to settle lawsuits regarding these activities.[18]

Medical uses

Gabapentin is recommended for use in

off-label in the US and UK,[19][20] for example, for the treatment of non-neuropathic pain,[19] anxiety disorders and bipolar disorder.[21] There is concern regarding gabapentin's off-label use due to the lack of strong scientific evidence for its efficacy in multiple conditions and its proven side effects.[22][23]

Seizures

Gabapentin is approved for the treatment of

focal seizures;[24] however, it is not effective for generalized epilepsy.[25]

Neuropathic pain

Gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities.[7][8][26][27] This is a general recommendation applicable to all neuropathic pain syndromes except for trigeminal neuralgia, where it may be used as a second- or third-line agent.[8][27]

In regard to the specific diagnoses, a systematic review has found evidence for gabapentin to provide pain relief for some patients with

central pain.[8] A combination of gabapentin with an opioid or nortriptyline may work better than either drug alone.[8][27]

Gabapentin shows substantial benefit (at least 50% pain relief or a patient 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 with placebo.[9]

Evidence finds little or no benefit and significant risk in those with chronic low back pain or sciatica.[28][29] Gabapentin is not effective in HIV-associated sensory neuropathy[30] and neuropathic pain due to cancer.[31]

Anxiety

There is a small amount of research on the use of gabapentin for the treatment of anxiety disorders.[32][33]

Gabapentin is effective for the long-term treatment of social anxiety disorder and in reducing preoperative anxiety.[22][23]

In a controlled trial of breast cancer survivors with anxiety,[33] and in a trial for social phobia,[32] gabapentin significantly reduced anxiety levels.

For panic disorder, gabapentin has produced mixed results.[33][32][23]

Sleep

Gabapentin is effective in treating sleep disorders such as insomnia and restless legs syndrome that are the result of an underlying illness, but comes with some risk of discontinuation and withdrawal symptoms after prolonged use at higher doses.[34]

Gabapentin enhances slow-wave sleep in patients with primary insomnia. It also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal.[35]

Drug dependence

Gabapentin is moderately effective in reducing the symptoms of

alcohol withdrawal and associated craving.[36][37][38] The evidence in favor of gabapentin is weak in the treatment of alcoholism: 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.[39]

Gabapentin is ineffective in cocaine dependence and methamphetamine use,

drug craving.[42][40] There is insufficient evidence for its use in cannabis dependence.[43]

Other

Gabapentin is recommended as a first-line treatment of the acquired pendular nystagmus, torsional nystagmus, and infantile nystagmus; however, it does not work in periodic alternating nystagmus.[44][45][46]

Gabapentin decreases the frequency of hot flashes in both menopausal women and patients with breast cancer. However, antidepressants have similar efficacy, and treatment with estrogen more effectively prevents hot flashes.[47]

Gabapentin reduces

orthostatic tremor.[53][54][55] Although the efficacy of gabapentin for insomnia has not been established, it does alleviate sleep disorder in patients with medical illness.[34]

Gabapentin does not appear to provide benefit for bipolar disorder,[23][37][56] complex regional pain syndrome,[57] post-surgical pain,[58] or tinnitus,[59] or prevent episodic migraine in adults.[60]

Contraindications

Gabapentin should be used carefully and at lower doses in people with

kidney problems due to possible accumulation and toxicity. It is unclear if it is safe during pregnancy or breastfeeding.[4]

Side effects

respiratory depression, and increased suicidal ideation are rare but serious side effects.[65]

Suicide

The gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors.[4] According to an insurance claims database study, gabapentin use is associated with about 40% increased risk of suicide, suicide attempt and violent death as compared with a reference anticonvulsant drug topiramate. The risk is increased for both bipolar disorder and epilepsy patients.[66] Another study has shown an approximately doubled rate of suicide attempts and self-harm in patients with bipolar disorder who are taking gabapentin versus those taking lithium.[67] 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.[68]

Respiratory depression

Serious breathing suppression, potentially fatal, may occur when gabapentin is taken together with

respiratory depression by 30–60%.[69] A Canadian study showed that use of gabapentin and other gabapentinoids, whether for epilepsy, neuropathic pain or other chronic pain was associated with a 35–58% increased risk for severe exacerbation of pre-existing chronic obstructive pulmonary disease.[71]

Withdrawal and dependence

Withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin (almost unambiguously due to extended use and during a very short-term rebound phenomenon) — similar to, albeit less intense than most benzodiazepines.[72] Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia.[72] 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.[73] All these symptoms subside when gabapentin is re-instated[72] or tapered off gradually at an appropriate rate.[citation needed]

On its own, gabapentin appears to not have a substantial addictive power. In human and animal experiments, it shows limited to no

rewarding effects. The vast majority of people abusing gabapentin are current or former abusers of opioids or sedatives.[73] In these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety.[74]

Overdose

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 with alcohol or opioids.[73][75]

Pharmacology

Pharmacodynamics

Gabapentin is a

affinity to two: α2δ-1 and α2δ-2.[77] Most of the pharmacological properties of gabapentin are explained by its binding to just one isoform – α2δ-1.[77][11]

The

micromolar range, and competition for binding by endogenous L-amino acids is likely to be responsible for this discrepancy.[11]

Gabapentin is a potent activator of voltage-gated potassium channels

KCNQ3 and KCNQ5, even at low nanomolar concentrations. However, this activation is unlikely to be the dominant mechanism of gabapentin's therapeutic effects.[80]

Despite the fact that gabapentin is a structural

Pharmacokinetics

Gabapentin is

LAT2.[81] As a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.[77]

The oral 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.[4][82] Drugs that increase the transit time of gabapentin in the small intestine can increase its oral bioavailability; when gabapentin was co-administered with oral morphine, the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.[82]

Gabapentin at a low dose of 100 mg has a

area-under-curve levels of gabapentin by approximately 10%.[82]

Gabapentin can cross the

OCTN2 (SLC22A5).[83] It is not significantly bound to plasma proteins (<1%).[82]

Gabapentin undergoes little or no metabolism.[77][82]

Gabapentin is generally safe in patients with liver cirrhosis.[87]

Gabapentin is

elimination half-life, with the reported average value of 5 to 7 hours.[82] Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels.[88] Gabapentin XR (brand name Gralise) is taken once a day.[89]

Chemistry

Chemical structures of GABA and gabapentin, with commonalities highlighted

Gabapentin is a 3,3-di

carboxylic groups are not in the same relative positions as they are in the GABA;[92] they are more conformationally constrained.[93]

Synthesis

Synthesis of gabapentin.

A process for chemical synthesis and isolation of gabapentin with high yield and purity[94] 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 of sodium hypobromite prepared in situ.

History

Gabapentin was designed by researchers at

generic version of gabapentin first became available in the United States in 2004.[14] An extended-release formulation of gabapentin for once-daily administration, under the brand name Gralise, was approved in the United States for the treatment postherpetic neuralgia in January 2011.[99][100]

Society and culture

Legal status

United Kingdom

Effective April 2019, the United Kingdom reclassified the drug as a class C controlled substance.[101][102][103][104][105]

United States

Effective 1 July 2017, Kentucky classified gabapentin as a schedule V controlled substance statewide.[106] Effective 9 January 2019, Michigan also classified gabapentin as a schedule V controlled substance.[107] Gabapentin is scheduled V drug in other states such as West Virginia,[108] Tennessee,[109] Alabama,[110] and Virginia.[111] Gabapentin is not scheduled or considered a controlled substance (as per the Controlled Substances Act) at the federal level.

Off-label promotion

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,[112] the preponderance of evidence suggests that it is not effective.[113]

Franklin v. Parke-Davis case

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. Parke-Davis case (see below).

While off-label prescriptions are common for a number of drugs, marketing of off-label uses of a drug is not.

one of the largest in U.S. history, and the first off-label promotion case brought successfully under the False Claims Act.[114]

Reuters reported on 25 March 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."[115] 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",[116] and that "the insurer's website also still lists Neurontin as a drug for neuropathic pain."[117] The Wall Street Journal noted that Pfizer spokesman Christopher Loder said, "We are disappointed with the verdict and will pursue post-trial motions and an appeal."[118] He later added that "the verdict and the judge's rulings are not consistent with the facts and the law."[115]

Gabasync

junk bond salesman who has since been indicted for securities fraud relative to another company.[121][119] Hythiam charges up to $15,000 per patient to license its use (of which half goes to the prescribing physician, and half to Hythiam).[122]

In November 2011, the results of a double-blind, placebo-controlled study (financed by Hythiam and carried out at

peer-reviewed journal Addiction. 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."[123]

clinical studies and government approval when bringing to market Prometa; the addiction drug proved to be completely ineffective.[126][127][119][128] Journalist Adam Feuerstein opined: "most of what Peizer says is dubious-sounding hype".[129]

Usage trends

The period from 2008 to 2018 saw a significant increase in the consumption of gabapentinoids. 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 wide range of indications.[130]

Brand names

Gabapentin was originally marketed under the brand name Neurontin. Since it became generic, it has been marketed worldwide using over 300 different brand names.

extended-release formulation of gabapentin for once-daily administration was introduced in 2011, for postherpetic neuralgia under the brand name Gralise.[131]

Related drugs

Parke-Davis developed a drug called pregabalin, which is related in structure to gabapentin, as a successor to gabapentin.[132] Another similar drug atagabalin has been unsuccessfully tried by Pfizer as a treatment for insomnia.[133] A prodrug form (gabapentin enacarbil)[134] was approved by the U.S. Food and Drug Administration (FDA).

Recreational use

Gabapentin when taken in excess, can induce euphoria, a sense of calm, a

marijuana-like high, improved sociability, and reduced alcohol or cocaine cravings.[135][136][137] Also known on the streets as "Gabbies",[138] gabapentin is increasingly abused and misused for these euphoric effects.[139][140] 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.[72][141] Gabapentin misuse, toxicity, and use in suicide attempts among adults in the US increased from 2013 to 2017.[142]

After Kentucky's implementation of stricter legislation regarding opioid prescriptions in 2012, there was an increase in gabapentin-only and multi-drug use in 2012–2015. The majority of these cases were from overdose in suspected suicide attempts. These rates were also accompanied by increases in abuse and recreational use.[143]

Withdrawal symptoms, often resembling those of

CNS depressant drugs, namely opioids, benzodiazepines, and alcohol.[144]

Veterinary use

In cats, gabapentin can be used as an analgesic in multi-modal pain management,[145] anxiety medication to reduce stress in cats for travel or vet visits,[146] and anticonvulsant.[147] Veterinarians may prescribe gabapentin as an anticonvulsant and pain reliever in dogs. It is also used to treat chronic pain-associated nerve inflammation in horses and dogs. Side effects include tiredness and loss of coordination but they generally go away within 24 hours of starting the medication.[148][147]

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External links