Gabapentinoid

Source: Wikipedia, the free encyclopedia.
Not to be confused with Gabapentin.

Gabapentinoid
VDCCsTooltip voltage-dependent calcium channels
Legal status
In Wikidata

Gabapentinoids, also known as α2δ ligands, are a

α2δ subunit), as it is the target of the drugs gabapentin and pregabalin.[5]

Clinically used gabapentinoids include gabapentin, pregabalin, and

4-methylpregabalin and PD-217,014.[citation needed
]

Medical uses

Gabapentinoids are approved for the treatment of

alcohol withdrawal.[6][11] Existing evidence on the use of gabapentinoids in chronic lower back pain is limited, and demonstrates significant risk of adverse effects, without any demonstrated benefit.[12] The main side-effects include: a feeling of sleepiness and tiredness, decreased blood pressure, nausea, vomiting and also glaucomatous visual hallucinations.[13]

Side effects

See also: Gabapentin § Side effects, Pregabalin § Side effects, and Phenibut § Side effects

Pharmacology

Pharmacodynamics

Gabapentinoids are

transport or metabolism.[14][16] There is currently no evidence that the relevant actions of gabapentin and pregabalin are mediated by any mechanism other than inhibition of α2δ-containing VDCCs.[17] Although, gabapentinoids such as gabapentin, but not pregabalin, have been found to activate Kv voltage-gated potassium channels (KCNQ).[18]

The

micromolar range, and competition for binding by endogenous L-amino acids has been said to likely be responsible for this discrepancy.[17]

In one study, the affinity (Ki) values of gabapentinoids for the α2δ subunit expressed in rat brain were found to be 0.05 μM for gabapentin, 23 μM for (R)-phenibut, 39 μM for (S)-phenibut, and 156 μM for baclofen.[7] Their affinities (Ki) for the GABAB receptor were >1 mM for gabapentin, 92 μM for (R)-phenibut, >1 mM for (S)-phenibut, and 6 μM for baclofen.[7] Based on the low affinity of baclofen for the α2δ subunit relative to the GABAB (26-fold difference), its affinity for the α2δ subunit is unlikely to be of pharmacological importance.[7]

Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies.[20]

Pharmacokinetics

Absorption

Gabapentin and pregabalin are

substrate for the transporter.[22][25]

The

intestinal peristalsis),[26] the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.[23] The oral bioavailability of gabapentin enacarbil (as gabapentin) is greater than or equal to 68%, across all doses assessed (up to 2,800 mg), with a mean of approximately 75%.[24][1] In contrast to the other gabapentinoids, the pharmacokinetics of phenibut have been little-studied, and its oral bioavailability is unknown.[15] However, it would appear to be at least 63% at a single dose of 250 mg, based on the fact that this fraction of phenibut was recovered from the urine unchanged in healthy volunteers administered this dose.[15]

Gabapentin at a low dose of 100 mg has a

extended-release (XR) formulation of gabapentin enacarbil is about 5.1 hours at a single dose of 1,200 mg in a fasted state and 8.4 hours at a single dose of 1,200 mg in a fed state.[27] The Tmax of phenibut has not been reported,[15] but the onset of action and peak effects have been described as occurring at 2 to 4 hours and 5 to 6 hours, respectively, after oral ingestion in recreational users taking high doses (1–3 g).[28]

Distribution

Gabapentin, pregabalin, and phenibut all cross the

OCTN2 (SLC22A5).[21]

Gabapentin and pregabalin are not significantly bound to plasma proteins (<1%).[23] The phenibut analogue baclofen shows low plasma protein binding of 30%.[32]

Metabolism

Gabapentin, pregabalin, and phenibut all undergo little or no

intestines and to a lesser extent in the liver.[1]

Elimination

Gabapentin, pregabalin, and phenibut are all

elimination half-lives, with reported values of 5.0 to 7.0 hours, 6.3 hours, and 5.3 hours, respectively.[23][15] Similarly, the terminal half-life of gabapentin enacarbil IR (as active gabapentin) is short at approximately 4.5 to 6.5 hours.[27] Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels.[24] Similarly, pregabalin has been given 2 to 3 times per day in clinical studies.[23] Phenibut, also, is taken 3 times per day.[33][34] Conversely, gabapentin enacarbil is taken twice a day and gabapentin XR (brand name Gralise) is taken once a day.[35]

Chemistry

Chemical structures of GABA and some major gabapentinoids

The gabapentinoids are 3-substituted

L-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.[2][19][36]

History

Gabapentin, under the brand name Neurontin, was first approved in May 1993 for the treatment of

generic version of gabapentin first became available in the United States in 2004.[42] 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.[43][44]

Pregabalin, under the brand name Lyrica, was approved in Europe in 2004 and was introduced in the United States in September 2005 for the treatment of epilepsy, postherpetic neuralgia, and neuropathic pain associated with diabetic neuropathy.[38][45][46][47] It was subsequently approved for the treatment of fibromyalgia in the United States in June 2007.[38][45][47] Pregabalin was also approved for the treatment of generalized anxiety disorder in Europe in 2005, though it has not been approved for this indication in the United States.[45][38][48][49]

Gabapentin enacarbil, under the brand name Horizant, was introduced in the United States for the treatment of restless legs syndrome in April 2011 and was approved for the treatment of postherpetic neuralgia in June 2012.[50]

Phenibut, marketed under the brand names Anvifen, Fenibut, and Noofen, was introduced in Russia in the 1960s for the treatment of anxiety, insomnia, and a variety of other conditions.[15][51] It was not discovered to act as a gabapentinoid until 2015.[7]

Baclofen marketed under the brandname of Lioresal was introduced in the United States in 1977 for the treatment of spasticity is chemically similar to phenibut but is usually not considered a gabapentinoid. Mirogabalin, under the brand name Tarlige, was approved for the treatment of neuropathic pain and postherpetic neuralgia in Japan in January 2019.[52]

A longitudinal trend study analyzed multinational sales data, revealing an overall increase in gabapentinoid consumption across 65 countries and regions from 2008 to 2018. This comprehensive analysis underscores the widespread use of gabapentinoids beyond their initial antiseizure applications, reflecting their role in treating a broad spectrum of conditions.[53]

Society and culture

Recreational use

Gabapentinoids produce

Misuse of Drugs Regulations 2001.[56] However, it is not a controlled substance in Canada, or Australia, and the other gabapentinoids, including phenibut, are not controlled substances either.[54] As such, they are mostly legal intoxicants.[54][20][28]

symptoms such as insomnia, nausea, headache, and diarrhea have been reported.[54][20] More severe withdrawal symptoms, such as severe rebound anxiety, have been reported with phenibut.[28] Because of the rapid tolerance with gabapentinoids, users often escalate their doses,[20] while other users may space out their doses and use sparingly to avoid tolerance.[28]

List of agents

Approved

Not approved

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Further reading

  • Calandre EP, Rico-Villademoros F, Slim M (2016). "Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use". Expert Rev Neurother. 16 (11): 1263–1277.
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