Gabapentin

In the US, gabapentin is indicated for the treatment of postherpetic neuralgia; and the adjunctive therapy in the treatment of partial onset seizures without secondary generalization, in people with epilepsy. Gabapentin is prescribed off-label in the US and the UK, for example, for the treatment of non-neuropathic pain, In recent years, gabapentin has seen increased use, particularly in the elderly. 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. 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. 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. Gabapentin is approved for the former indication in the US. 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. Gabapentin enhances slow-wave sleep in people 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. While some studies indicate that gabapentin does not significantly reduce the symptoms of opiate 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-induced hyperalgesia and drug craving. 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 people 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. 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. Gabapentin is prescribed off-label as a anxiolytic or anti-anxiety medication, although not as effective as pregabalin in this regard, especially for generalized anxiety disorder, as gabapentin is more effective for social anxiety disorder. ==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==

In a systematic review analysing data from five cohort studies having 1,085,488 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. Dizziness and somnolence are the most frequent side effects. 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. 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 an inflamed pancreas, hallucinations, anaphylaxis, respiratory depression, and increased suicidal ideation are rare but serious side effects. Suicide The gabapentin prescribing information contains a warning of an increased risk of suicidal thoughts and behaviors. The warning is based on a meta-analysis of all approved antiepileptic drugs in 2008, and not with gabapentin alone. Another study has shown an approximately doubled rate of suicide attempts and self-harm in people 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. 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. In addition, a 2010 study published by the Pharmacoepidemiology and Drug Safety journal concluded that although there was no significant suicide rate decrease between the pre-prescription window and the post-prescription window for the non-psychiatric population, significant reductions in suicides rates were observed in psychiatric persons. 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 (almost unambiguously due to extended use and during a very short-term rebound phenomenon) similar to, albeit less intense than most benzodiazepines. Agitation, confusion and disorientation are the most frequently reported, followed by gastrointestinal complaints and sweating, and more rare tremor, tachycardia, hypertension and insomnia. All these symptoms subside when gabapentin is re-instated Psychiatric and behavioral adverse effects Gabapentin is sometimes 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 as aggression, agitation, irritability, mood instability, and suicidal ideation, with some cases noting the emergence of mania, hallucinations, and psychosis, particularly in pediatric populations and individuals with preexisting psychiatric conditions, though such effects have also been reported in adults and in individuals without prior psychiatric history. Large cohort 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. 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. ==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==

and commercially available gabapentinoids—gabapentin, pregabalin, phenibut, baclofen and mirogabalin. Animal models Gabapentin prevents seizures in a dose-related manner in several laboratory animal models. These models include spinal extensor seizures from low-intensity electroshock to the forebrain 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 produce focal seizures by repeated prior electrical stimulation of the hippocampus. Gabapentin slightly increased spontaneous absence-like seizures in a genetically susceptible strain recorded with electroencephalography. All of these effects of gabapentin were seen at dosages at or below the threshold for producing ataxia. Gabapentin has been tested in a variety of animal models that are relevant for analgesic actions. Generally, gabapentin is not active to prevent pain-related behaviors in models of acute nociceptive pain. It prevents pain-related behaviors when animals are made sensitive by prior peripheral inflammation or peripheral nerve damage (inflammatory or neuropathic conditions). Pharmacodynamics Gabapentin is a ligand of the α2δ calcium channel subunit. The α2δ-1 protein is coded by the CACNA2D1 gene. α2δ was first described as 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). The same α2δ protein has more recently been shown to interact directly with some NMDA-type and AMPA-type glutamate receptors at presynaptic sites and also with thrombospondin (an extracellular matrix protein secreted by astroglial cells). Gabapentin is not a direct calcium channel 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 with NMDA receptors, neurexins, and thrombospondin. These proteins are found as mutually interacting parts of the presynaptic active zone, where numerous protein molecules interact with each other to enable and to regulate the release of neurotransmitters from presynaptic vesicles into the synaptic space. Out of the four known isoforms of α2δ protein, gabapentin binds with similar high affinity to two: α2δ-1 and α2δ-2. 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 structurally similar to the neurotransmitter glutamate and competitively inhibits branched-chain amino acid aminotransferase (BCAT), slowing down the synthesis of glutamate. In particular, it inhibits BCAT-1 at high concentrations (Ki = 1 mM), but not BCAT-2. At very high concentrations, gabapentin can suppress the growth of cancer cells, presumably by affecting mitochondrial catabolism; however, the precise mechanism remains elusive. As a result, the pharmacokinetics of gabapentin is dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. 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%. The LAT1 is highly expressed at the blood–brain barrier and transports gabapentin across into the brain. Gabapentin is eliminated renally in the urine. Gabapentin XR (brand name Gralise) is taken once a day. ==Chemistry==

Gabapentin is a 3,3-disubstituted derivative of GABA. Therefore, it is a GABA analog, as well as a γ-amino acid. It is similar to several other compounds that collectively are called gabapentinoids. 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, the amine and carboxylic groups are not in the same relative positions as they are in the GABA; they are more conformationally constrained. 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 by cryo-electron microscopy. A figure of this drug-bound structure is shown in the Chemistry section of the entry on gabapentinoid 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 the voltage gated calcium channel α1 subunit) on the calcium channel and chemotaxis (Cache1) domain of α2δ-1. Synthesis A process for chemical synthesis and isolation of gabapentin with high yield and purity 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==

GABA is the principal inhibitory neurotransmitter in mammalian brains. By the early 1970s, it was appreciated that there are two main classes of GABA receptors, GABAA and GABAB and also that baclofen was an agonist of GABAB receptors. Gabapentin was designed, synthesized, and tested in mice by researchers at the pharmaceutical company Goedecke AG in Freiburg, Germany (a subsidiary of Parke-Davis). It was meant to be a structural analog of the neurotransmitter GABA that could more easily cross the blood–brain barrier. It was first synthesized in 1974/75 and described in 1975 by Satzinger and Hartenstein. The first pharmacology findings published were sedating properties and prevention of seizures in mice evoked by the GABA antagonist, thiosemicarbazide. This study provided evidence that the action of gabapentin, unlike baclofen, did not arise from the GABAB receptor. Initial clinical trials utilizing small numbers of subjects were for treatment of spasticity and migraine 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. Under the brand name Neurontin, it was first approved in the United Kingdom in May 1993, for the treatment of refractory epilepsy. Approval by the US 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. A generic version of gabapentin first became available in the United States in 2004. 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. Gabapentin has been prescribed for a variety of disorders and is one of the more common medications used, particularly in elderly people. ==Society and culture==

Legal status United Kingdom Effective April 2019, the United Kingdom reclassified the drug as a class C controlled substance. United States Gabapentin is not a controlled substance under the federal Controlled Substances Act. Effective in July 2017, Kentucky classified gabapentin as a Schedule V controlled substance statewide. Gabapentin is a schedule V drug in other states such as West Virginia, Tennessee, Alabama, Utah, and Virginia. 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, the preponderance of evidence suggests that it is not effective. Franklin v. Parke-Davis case 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 the Franklin v. Parke-Davis case. While off-label prescriptions are common for many drugs, marketing of off-label uses of a drug is not. Kaiser Foundation Hospitals and Kaiser Foundation Health Plan sued Pfizer Inc., alleging that the pharmaceutical company had misled Kaiser by recommending Neurontin as an off-label treatment for certain conditions (including bipolar disorder, migraines, and neuropathic pain). In 2010, a federal jury in Massachusetts ruled in Kaiser's favor, finding that Pfizer violated the federal Racketeer Influenced and Corrupt Organizations (RICO) Act and was liable for in damages, which was automatically trebled to just under $142.1 million. Pfizer appealed, but the U.S. Court of Appeals for the First Circuit upheld the verdict, Gabasync Gabasync, a treatment consisting of a combination of gabapentin and two other medications (flumazenil and hydroxyzine) as well as therapy, is an ineffective treatment promoted for methamphetamine addiction. It had also been claimed to be effective for dependence on alcohol or cocaine. Gabasync was marketed by Hythiam, Inc., which is owned by Terren Peizer, a former junk bond salesman who has since been convicted of securities fraud relative to another company. Hythiam charges up to $15,000 per patient to license its use (of which half goes to the prescribing physician, and half to Hythiam). 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". 60 Minutes, NBC News, and The Dallas Morning News criticized Peizer after the company bypassed clinical studies and government approval when bringing to market Prometa; the addiction drug proved to be completely ineffective. CBS News journalist Scott Pelley said to Peizer in 2007: "Depending on who you talk to, you're either a revolutionary or a snake oil salesman." In November 2011, the results of a double-blind, placebo-controlled study (financed by Hythiam and carried out at UCLA) were published in the 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." Usage trends The consumption of gabapentinoids rose significantly between 2008 and 2018. A study published 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. Brand names Gabapentin was originally sold under the brand name Neurontin. Since it became generic, it has been sold worldwide using over 300 different brand names. An extended-release formulation of gabapentin for once-daily administration was introduced in 2011 for postherpetic neuralgia under the brand name Gralise. In the US, Neurontin is sold by Viatris after Upjohn was spun off from Pfizer. Related drugs Parke-Davis developed a drug called pregabalin, which is related in structure to gabapentin, as a successor to gabapentin. Another similar drug atagabalin has been unsuccessfully tried by Pfizer as a treatment for insomnia. A prodrug form (gabapentin enacarbil) was approved by the U.S. Food and Drug Administration (FDA). Recreational use When taken in excess, gabapentin can induce euphoria, a sense of calm, improved sociability, and reduced alcohol or cocaine cravings. Also known on the streets as "Gabbies", gabapentin was reported in 2017 to be increasingly abused and misused for these euphoric effects. 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. Gabapentin misuse, toxicity, and use in suicide attempts among adults in the US increased from 2013 to 2017. After the US state of 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. Withdrawal symptoms, often resembling those of benzodiazepine withdrawal, play a role in the physical dependence some users experience. ==Veterinary use==

In cats, gabapentin can be used as an analgesic in multi-modal pain management, anxiety medication to reduce stress during travel or vet visits, and anticonvulsant. 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 these effects generally resolve within 24 hours of starting the medication. == References ==