Gabapentin

Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication used to treat neuropathic pain (postherpetic neuralgia) and partial seizures of epilepsy. Gabapentin is a central nervous system (CNS) depressant and derivative of the inhibitory neurotransmitter, GABA. It is used for the treatment of neuropathic pain caused by diabetic neuropathy, postherpetic neuralgia, and central pain.[10] It is moderately effective: about 30–40% of those given gabapentin for diabetic neuropathy or postherpetic neuralgia have a meaningful benefit.

Gabapentin binds to α2δ subunits to modulate calcium channel function and neurotransmitter release, weakly affects glutamate, and does not act on GABA receptors. Sleepiness and dizziness are the most common side effects. Serious side effects include respiratory depression and allergic reactions. On December 16, 2008, the FDA issued gabapentin a class warning for an increased risk of suicide. Approximately two years after this pronouncement, a pharmacoepidemiologic study was conducted that showed there was no outstanding difference in suicide attempt rates between pre- and post- gabapentin prescription groups.

Gabapentin was first approved for use in the United Kingdom in 1993.[11] It has been available as a generic medication in the United States since 2004. It is the first of several other drugs that are similar in structure and mechanism, called gabapentinoids. In 2023, it was the ninth most commonly prescribed medication in the United States, with more than 45million prescriptions.[12][13] During the 1990s, Parke-Davis, a subsidiary of Pfizer, used several illegal techniques to encourage physicians in the United States to prescribe gabapentin for unapproved uses.[14] They have paid out millions of dollars to settle lawsuits regarding these activities.[15]

Medical uses

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 recommended for use in focal seizures and neuropathic pain.[16] Gabapentin is prescribed off-label in the US and the UK,[17][18] for example, for the treatment of non-neuropathic pain,[17] anxiety disorders, sleep problems and bipolar disorder.[19] In recent years, gabapentin has seen increased use, particularly in the elderly.[20]

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.[62]

Dizziness and somnolence are the most frequent side effects. Fatigue, ataxia, peripheral edema (swelling of extremities), and nystagmus are also common. A 2017 meta-analysis found that gabapentin also increased the risk of difficulties in mentation and visual disturbances as compared to a placebo.[27] Gabapentin is associated with a weight gain of 2.2 kg after 1.5 months of use.[63] Case studies indicate that it may cause anorgasmia and erectile dysfunction,[64]

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.[77][85]

Pharmacology

Chemistry

Gabapentin is a 3,3-disubstituted derivative of GABA. Therefore, it is a GABA analog, as well as a γ-amino acid.[108][109] 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;[110] they are more conformationally constrained.[111]

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.

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[114] by Satzinger and Hartenstein.[110][115]

The first pharmacology findings published were sedating properties and prevention of seizures in mice evoked by the GABA antagonist, thiosemicarbazide.[114]

Society and culture

Veterinary use

In cats, gabapentin can be used as an analgesic in multi-modal pain management,[181] anxiety medication to reduce stress during travel or vet visits,[182] and anticonvulsant.[183]

Veterinarians may prescribe gabapentin as an anticonvulsant and pain reliever in dogs.[183] It has beneficial effects for treating epilepsy, different kinds of pain (chronic, neuropathic, and post-operative pain), and anxiety, lip-licking behavior, storm phobia, fear-based aggression.[184][185]

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