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Gabapentinoid
Drug class
Gabapentin, the prototypical gabapentinoid
Class identifiers
Synonyms	α2δ ligands; Ca α2δ ligands
Use	Epilepsy; Neuropathic pain; Postherpetic neuralgia; Diabetic neuropathy; Fibromyalgia, Generalized anxiety disorder; Restless legs syndrome
ATC code	N03AX
Biological target	α2δ subunit-containing VDCCsTooltip voltage-dependent calcium channels
Legal status
In Wikidata

Gabapentinoids, also known as α₂δ ligands, are a class of drugs that are chemically derivatives of the inhibitory neurotransmitter gamma-Aminobutyric acid (GABA) (i.e., GABA analogues) which bind selectively to the α₂δ protein that was first described as an auxiliary subunit of voltage-gated calcium channels (VGCCs).

Clinically used gabapentinoids include gabapentin, pregabalin, and mirogabalin, as well as a gabapentin prodrug, gabapentin enacarbil. Further analogues like imagabalin are in clinical trials but have not yet been approved. Other gabapentinoids which are used in scientific research but have not been approved for medical use include atagabalin, 4-methylpregabalin and PD-217,014.

Additionally, phenibut has been found to act as a very low affinity gabapentinoid in addition to its action as a GABA_B receptor agonist.

Medical uses

Gabapentinoids are approved for the treatment of epilepsy, postherpetic neuralgia, neuropathic pain associated with diabetic neuropathy, fibromyalgia, generalized anxiety disorder, and restless legs syndrome. Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal. 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. The main side-effects include: a feeling of sleepiness and tiredness, decreased blood pressure, nausea, vomiting and also glaucomatous visual hallucinations.

Side effects

Pharmacology

Pharmacodynamics

Gabapentinoids are high affinity ligands of the α₂δ protein that was first described as an auxiliary subunit of certain voltage-gated calcium channels (VGCC). All of the known pharmacological actions of gabapentinoids require binding at this site. There are two drug-binding α₂δ subunits, α₂δ-1 and α₂δ-2, and most gabapentinoids show similar affinity for (and hence lack of selectivity between) these two sites. In most cases, gabapentinoid drugs do not seem to directly alter the action of VGCC and instead reduce the release of certain excitatory neurotransmitters (however, see).

The gabapentinoids do not bind significantly to other known drug receptors and so the α₂δ VGCC subunit has been called the gabapentin receptor. Recently, the same α₂δ-1 protein has been found closely associated not with VGCCs but with other proteins such as presynaptic NMDA-type glutamate receptors, cell adhesion molecules such as thrombospondin and others. Gabapentinoids alter the function of these additional α₂δ binding proteins, and these have been proposed as mediators of drug actions.

Despite the fact that gabapentinoids are GABA analogues, gabapentin and pregabalin do not bind to GABA receptors, do not convert into GABATooltip γ-aminobutyric acid or GABA receptor agonists in vivo, and do not modulate GABA transport or metabolism. Furthermore, gabapentinoids do not act directly as inhibitors of VGCC. Instead, they reduce the release of excitatory neurotransmitters including glutamate and Substance P. Although, gabapentinoids such as gabapentin, but not pregabalin, have been found to activate K_v voltage-gated potassium channels (KCNQ).

The endogenous α-amino acids L-leucine and L-isoleucine, which resemble the gabapentinoids in chemical structure (see figure) are ligands of the α₂δ VDCC subunit with similar affinity as gabapentin and pregabalin (e.g., IC₅₀ = 71 nM for L-isoleucine), and are present in human cerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM for L-leucine, 4.8 μM for L-isoleucine). It has been hypothesized that they may be endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids. In accordance, while gabapentin and pregabalin have nanomolar binding affinities for the α₂δ subunit, their potencies in vivo are in the low micromolar range, and competition for binding by endogenous L-amino acids is likely responsible for this discrepancy.

In one study, the affinity (K_i) 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. Their affinities (K_i) for the GABA_B receptor were >1 mM for gabapentin, 92 μM for (R)-phenibut, >1 mM for (S)-phenibut. Baclofen does not have relevant actions at α₂δ receptors and so it is not regarded as a gabapentinoid.

Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies and mirogabalin is even more potent in vivo.

Pharmacokinetics

Absorption

Gabapentin and pregabalin are absorbed from the intestines by an active transport process mediated via the large neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter for amino acids such as L-leucine and L-phenylalanine. Very few (less than 10 drugs) are known to be transported by this transporter. Unlike gabapentin, which is transported solely by the LAT1, pregabalin seems to be transported not only by the LAT1 but also by other carriers. The LAT1 is easily saturable, so the pharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses. Conversely, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption. Similarly, gabapentin enacarbil is transported not by the LAT1 but by the monocarboxylate transporter 1 (MCT1) and the sodium-dependent multivitamin transporter (SMVT), and no saturation of bioavailability has been observed with the drug up to a dose of 2,800 mg. Similarly to gabapentin and pregabalin, baclofen, a close analogue of phenibut (baclofen specifically being 4-chlorophenibut), is transported by the LAT1, although it is a relatively weak substrate for the transporter.

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. Conversely, the oral bioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 900 mg/day). Food does not significantly influence the oral bioavailability of pregabalin. Conversely, food increases the area-under-curve levels of gabapentin by about 10%. 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 (which slows intestinal peristalsis), the oral bioavailability of a 600 mg dose of gabapentin increased by 50%. 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%. In contrast to the other gabapentinoids, the pharmacokinetics of phenibut have been little-studied, and its oral bioavailability is unknown. 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.

Gabapentin at a low dose of 100 mg has a T_max (time to peak levels) of approximately 1.7 hours, while the T_max increases to 3 to 4 hours at higher doses. The T_max of pregabalin is generally less than or equal to 1 hour at doses of 300 mg or less. However, food has been found to substantially delay the absorption of pregabalin and to significantly reduce peak levels without affecting the bioavailability of the drug; T_max values for pregabalin of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the C_max is reduced by 25–31% in a fed versus fasted state. In contrast to pregabalin, food does not significantly affect the T_max of gabapentin and increases the C_max of gabapentin by approximately 10%. The T_max of the instant-release (IR) formulation of gabapentin enacarbil (as active gabapentin) is about 2.1 to 2.6 hours across all doses (350–2,800 mg) with single administration and 1.6 to 1.9 hours across all doses (350–2,100 mg) with repeated administration. Conversely, the T_max of the 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. The T_max of phenibut has not been reported, 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).

Distribution

Gabapentin, pregabalin, and phenibut all cross the blood–brain barrier and enter the central nervous system. However, due to their low lipophilicity, the gabapentinoids require active transport across the blood–brain barrier. The LAT1 is highly expressed at the blood–brain barrier and transports the gabapentinoids that bind to it across into the brain. As with intestinal absorption of gabapentin mediated by LAT1, 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).

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

Metabolism

Gabapentin, pregabalin, and phenibut all undergo little or no metabolism. Conversely, gabapentin enacarbil, which acts as a prodrug of gabapentin, must undergo enzymatic hydrolysis to become active. This is done via non-specific esterases in the intestines and to a lesser extent in the liver.

Elimination

Gabapentin, pregabalin, and phenibut are all eliminated renally in the urine. They all have relatively short elimination half-lives, with reported values of 5.0 to 7.0 hours, 6.3 hours, and 5.3 hours, respectively. Similarly, the terminal half-life of gabapentin enacarbil IR (as active gabapentin) is short at approximately 4.5 to 6.5 hours. Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels. Similarly, pregabalin has been given 2 to 3 times per day in clinical studies. Phenibut, also, is taken 3 times per day. Conversely, gabapentin enacarbil is taken twice a day and gabapentin XR (brand name Gralise) is taken once a day.

Chemistry

The gabapentinoids are 3-substituted derivatives of GABA; hence, they are GABA analogues, as well as γ-amino acids. Specifically, pregabalin is (S)-(+)-3-isobutyl-GABA, phenibut is 3-phenyl-GABA, and gabapentin is a derivative of GABA with a cyclohexane ring at the 3 position (or, somewhat inappropriately named, 3-cyclohexyl-GABA). The gabapentinoids also closely resemble the α-amino acids L-leucine and L-isoleucine, and this may be of greater relevance in relation to their pharmacodynamics than their structural similarity to GABA.

History

Gabapentin, under the brand name Neurontin, was first approved in May 1993 for the treatment of epilepsy in the United Kingdom, and was marketed in the United States in 1994. Subsequently, gabapentin was approved in the United States for the treatment of postherpetic neuralgia in May 2002. 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 postherpetic neuralgia in January 2011.

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. It was subsequently approved for the treatment of fibromyalgia in the United States in June 2007. 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.

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.

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. It was not discovered to act as a very weak (3.5 orders of magnitude less potent) gabapentinoid until 2015.

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.

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.

Society and culture

Recreational use

Gabapentinoids produce euphoria at high doses, with effects similar to GABAergic central nervous system depressants such as alcohol, γ-hydroxybutyric acid (GHB), and benzodiazepines, and are used as recreational drugs (at 3–20 times typical clinical doses). The overall abuse potential is considered to be low and notably lower than that of other drugs such as alcohol, benzodiazepines, opioids, psychostimulants, and other illicit drugs. In any case, due to its recreational potential, pregabalin is a schedule V controlled substance in the United States. In April 2019, the United Kingdom scheduled gabapentin and pregabalin as Class C drugs under the Misuse of Drugs Act 1971, and as Schedule 3 under the Misuse of Drugs Regulations 2001. However, it is not a controlled substance in Canada, or Australia, and the other gabapentinoids, including phenibut, are not controlled substances either. As such, they are mostly legal intoxicants.

Tolerance to gabapentinoids is reported to develop very rapidly with repeated use, although to also dissipate quickly upon discontinuation, and withdrawal symptoms such as insomnia, nausea, headache, and diarrhea have been reported. More severe withdrawal symptoms, such as severe rebound anxiety, have been reported with phenibut. Because of the rapid tolerance with gabapentinoids, users often escalate their doses, while other users may space out their doses and use sparingly to avoid tolerance.

List of agents

Approved

• Gabapentin (Neurontin, Gabagamma)
  • Gabapentin extended-release (Gralise)
  • Gabapentin enacarbil (Horizant)
• Mirogabalin (Tarlige)
• Phenibut (Anvifen, Fenibut, Noofen)
• Pregabalin (Lyrica)
• Baclofen

Not approved

• 4-Fluorophenibut
• 4-Methylpregabalin
• Atagabalin (PD-200,390)
• Imagabalin
• PD-217,014
• Tolibut

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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. doi:10.1080/14737175.2016.1202764. PMID 27345098. S2CID 33200190.

• Amino acids
• Analgesics
• Anticonvulsants
• Anxiolytics
• Calcium channel blockers
• Euphoriants
• GABA analogues