gabapentin gabapentin gabapentin, sold under the brand name neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. it is commonly used medication for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain. it is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit. gabapentinclinical datatrade namesneurontin, othersother namesci-945; goe-3450; dm-1796 (gralise)ahfs/drugs.commonographmedlineplusa694007license data us dailymed: gabapentin us fda: gabapentin pregnancycategory au: b1 dependenceliabilitylow - moderateaddictionliabilitylowroutes ofadministrationby mouthdrug classgabapentinoidatc coden02bf01 (who) legal statuslegal status au: s4 (prescription only) ca: ℞-only uk: class c us: ℞-only pharmacokinetic databioavailability27–60% (inversely proportional to dose; a high fat meal also increases bioavailability)protein bindingless than 3%metabolismnot significantly metabolizedelimination half-life5 to 7 hoursexcretionrenalidentifiers iupac name 2-acetic acid cas number60142-96-3 ypubchem cid3446iuphar/bps5483drugbankdb00996 ychemspider3328 yunii6cw7f3g59xkeggd00332 ychebichebi:42797 ychemblchembl940 ypdb ligandgbn (pdbe, rcsb pdb)comptox dashboard (epa)dtxsid0020074 echa infocard100.056.415 chemical and physical dataformulac9h17no2molar mass171.240 g·mol−13d model (jsmol)interactive image smiles o=c(o)cc1(cn)ccccc1 inchi inchi=1s/c9h17no2/c10-7-9(6-8(11)12)4-2-1-3-5-9/h1-7,10h2,(h,11,12) ykey:ugjmxcakcunaie-uhfffaoysa-n y (verify) sleepiness and dizziness are the most common side effects. serious side effects include an increased risk of suicide, respiratory depression, and allergic reactions. lower doses are recommended in those with kidney disease. gabapentin acts by decreasing activity of a subset of calcium channels. gabapentin was first approved for use in 1993. it has been available as a generic medication in the united states since 2004. in 2020, it was the tenth most commonly prescribed medication in the united states, with more than 49 million prescriptions. during the 1990s, parke-davis, a subsidiary of pfizer, used a number of illegal techniques to encourage physicians in the united states to prescribe gabapentin for unapproved uses. they have paid out millions of dollars to settle lawsuits regarding these activities. medical uses gabapentin is recommended for use in focal seizures and neuropathic pain. gabapentin is widely prescribed off-label in the us and uk, for example, for the treatment of non-neuropathic pain, anxiety disorders and bipolar disorder. 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. seizures gabapentin is approved for the treatment of focal seizures; however, it is not effective for generalized epilepsy. neuropathic pain gabapentin is recommended as a first-line treatment for chronic neuropathic pain by various medical authorities. 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. in regard to the specific diagnoses, a systematic review has found evidence for gabapentin to provide pain relief for some patients with postherpetic neuralgia and diabetic neuropathy. gabapentin is approved for the former indication in the us. in addition to these two neuropathies, european federation of neurological societies guideline notes gabapentin effectiveness for central pain. a combination of gabapentin with an opioid or nortriptyline may work better than either drug alone. 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. evidence finds little or no benefit and significant risk in those with chronic low back pain or sciatica. gabapentin is not effective in hiv-associated sensory neuropathy and neuropathic pain due to cancer. anxiety there is a small amount of research on the use of gabapentin for the treatment of anxiety disorders. gabapentin is effective for the long-term treatment of social anxiety disorder and in reducing preoperative anxiety. in a controlled trial of breast cancer survivors with anxiety, and in a trial for social phobia, gabapentin significantly reduced anxiety levels. for panic disorder, gabapentin has produced mixed results. sleep gabapentin is effective in treating sleep disorders such as insomnia and restless legs syndrome that are the result of an underlying illness. at the same time it comes with a high risk of discontinuation and withdrawal symptoms. gabapentin enhances slow-wave sleep in patients with primary insomnia. it also improves sleep quality by elevating sleep efficiency and decreasing spontaneous arousal. drug dependence gabapentin is moderately effective in reducing the symptoms of alcohol withdrawal and associated craving. 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. gabapentin is ineffective in cocaine dependence and methamphetamine use, and it does not increase the rate of smoking cessation. gabapentin does not significantly reduce the symptoms of opiate withdrawal. there is insufficient evidence for its use in cannabis dependence. 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. 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. gabapentin reduces spasticity in multiple sclerosis and is prescribed as one of the first-line options. it is an established treatment of restless legs syndrome. gabapentin alleviates itching in kidney failure (uremic pruritus) and itching of other causes. it may be an option in essential or orthostatic tremor. although the efficacy of gabapentin for insomnia has not been established, it does alleviate sleep disorder in patients with medical illness. gabapentin does not appear to provide benefit for bipolar disorder, complex regional pain syndrome, post-surgical pain, or tinnitus, or prevent episodic migraine in adults. 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. side effects dizziness and somnolence are the most frequent side effects. fatigue, ataxia, peripheral edema (swelling of extremities), and nystagmus are also common. gabapentin is associated with a weight gain of 2.2 kg after 1.5 months of use. case studies indicate that it may cause anorgasmia and erectile dysfunction, as well as myoclonus that disappear after discontinuing gabapentin or replacing it with other medication. dress, anaphylaxis, respiratory depression, and increased suicide behavior are the rare but serious side effects. suicide the gabapentin label contains a warning of an increased risk of suicidal thoughts and behaviors. 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. 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. 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. respiratory depression serious breathing suppression, potentially fatal, may occur when gabapentin is taken together with opioids, benzodiazepines, or other depressants, or by people with underlying lung problems such as copd. gabapentin and opioids are commonly prescribed or abused together, and research indicates that the breathing suppression they cause is additive. for example, gabapentin use before joint replacement or laparoscopic surgery increased the risk of respiratory depression by 30–60%. withdrawal and dependence withdrawal symptoms typically occur 1–2 days after abruptly stopping gabapentin. agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia. in some cases, users experience withdrawal seizures. all these symptoms subside when gabapentin is re-instated. 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. in these persons, gabapentin can boost the opioid "high" as well as decrease commonly experienced opioid-withdrawal symptoms such as anxiety. 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. pharmacology pharmacodynamics gabapentin is a ligand of the α2δ calcium channel subunit. α2δ is an auxiliary protein connected to the main α1 subunit (the channel-forming protein) of high voltage activated voltage-dependent calcium channels (l-type, n-type, p/q type, and r-type). gabapentin is not a direct channel blocker: it exerts its actions by disrupting the regulatory function of α2δ and its interactions with other proteins. gabapentin prevents delivery of the calcium channels to the cell membrane, reduces the activation of the channels by the α2δ subunit, decreases signaling leading to neurotransmitters release, and disrupts interactions of α2δ with nmda receptors, neurexins, and thrombospondins. out of the four known isoforms of α2δ protein, gabapentin binds with similar high affinity to two: α2δ-1 and α2δ-2. most of the pharmacological properties of gabapentin are explained by its binding to just one isoform – α2δ-1. the endogenous α-amino acids l-leucine and l-isoleucine, which resemble gabapentin in chemical structure, bind α2δ with similar affinity to gabapentin and are present in human cerebrospinal fluid at micromolar concentrations. they may be the endogenous ligands of the α2δ subunit, and they competitively antagonize the effects of gabapentin. accordingly, while gabapentin has nanomolar affinity for the α2δ subunit, its potency in vivo is in the low micromolar range, and competition for binding by endogenous l-amino acids is likely to be responsible for this discrepancy. 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. despite the fact that gabapentin is a structural gaba analogue, and in spite of its name, it does not bind to the gaba receptors, does not convert into gaba or another gaba receptor agonist in vivo, and does not modulate gaba transport or metabolism. pharmacokinetics gabapentin is absorbed from the intestines by an active transport process mediated via an amino acid transporter, presumably, lat2. as a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. 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. 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%. gabapentin at a low dose of 100 mg has a tmax (time to peak levels) of approximately 1.7 hours, while the tmax increases to 3 to 4 hours at higher doses. food does not significantly affect the tmax of gabapentin and increases the cmax and area-under-curve levels of gabapentin by approximately 10%. gabapentin can cross the blood–brain barrier and enter the central nervous system. gabapentin concentration in cerebrospinal fluid is approximately 9–14% of its blood plasma concentration. due to its low lipophilicity, gabapentin requires active transport across the blood–brain barrier. the lat1 is highly expressed at the blood–brain barrier and transports gabapentin across into the brain. as with intestinal absorption mediated by an amino acid transporter, the transport of gabapentin across the blood–brain barrier by lat1 is saturable. gabapentin does not bind to other drug transporters such as p-glycoprotein (abcb1) or octn2 (slc22a5). it is not significantly bound to plasma proteins (<1%). gabapentin undergoes little or no metabolism. gabapentin is eliminated renally in the urine. it has a relatively short elimination half-life, with the reported average value of 5 to 7 hours. this value changes with increasing doses, from 5.4 hours for a 200 mg single dose, to 8.3 hours for a 1,400 mg dose. because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels. gabapentin xr (brand name gralise) is taken once a day. chemistry chemical structures of gaba and gabapentin, with commonalities highlighted