Gabapentinoid

{{Short description|Gamma-aminobutyric acid analogs}} {{Distinguish|Gabapentin}} {{cs1 config|name-list-style=vanc}} {{Use mdy dates|date=March 2024}} {{Infobox drug class | Image = GabapentinStructure.svg | ImageClass = skin-invert-image | Alt = | Caption = Gabapentin, the prototypical gabapentinoid | Width = | Synonyms = α2δ ligands; Ca2+ α2δ ligands | Use = Epilepsy, Neuropathic pain, Postherpetic neuralgia, Diabetic neuropathy, Fibromyalgia, Generalized anxiety disorder, Muscle Relaxant, Restless legs syndrome | MeshID = | Consumer_Reports = | ATC_prefix = N03AX | Drugs.com = | Biological_target = α2δ subunit-containing {{abbrlink|VDCCs|voltage-dependent calcium channels}} }}

'''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).<ref name="pmid27345098">{{cite journal | vauthors = Calandre EP, Rico-Villademoros F, Slim M | title = Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use | journal = Expert Rev Neurother | volume = 16 | issue = 11 | pages = 1263–1277 | year = 2016 | pmid = 27345098 | doi = 10.1080/14737175.2016.1202764 | s2cid = 33200190 }}</ref><ref name="pmid17222465">{{cite journal | vauthors = Dooley DJ, Taylor CP, Donevan S, Feltner D | title = Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission | journal = Trends Pharmacol. Sci. | volume = 28 | issue = 2 | pages = 75–82 | year = 2007 | pmid = 17222465 | doi = 10.1016/j.tips.2006.12.006 }}</ref><ref name="WyllieCascino2012">{{cite book | author1 = Elaine Wyllie | author2 = Gregory D. Cascino | author3 = Barry E. Gidal |author4=Howard P. Goodkin | title = Wyllie's Treatment of Epilepsy: Principles and Practice | url = https://books.google.com/books?id=j9t6Qg0kkuUC&pg=RA1-PA423 | date = February 17, 2012 | publisher = Lippincott Williams & Wilkins | isbn = 978-1-4511-5348-4 | page = 423}}</ref><ref name="BenzonRathmell2013">{{cite book | author1 = Honorio Benzon | author2 = James P. Rathmell | author3 = Christopher L. Wu |author4=Dennis C. Turk |author5=Charles E. Argoff |author6=Robert W Hurley | title = Practical Management of Pain | url = https://books.google.com/books?id=kfcDAQAAQBAJ&pg=PA1006 | date = September 11, 2013 | publisher = Elsevier Health Sciences | isbn = 978-0-323-17080-2 | page = 1006}}</ref><ref>{{cite journal |doi=10.1016/j.cell.2009.09.025 |pmid=19818485 |pmc=2791798 |title=Gabapentin Receptor α2δ-1 is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis |journal=Cell |volume=139 |issue=2 |pages=380–92 |year=2009 |last1=Eroglu |first1=Çagla |last2=Allen |first2=Nicola J. |last3=Susman |first3=Michael W. |last4=O'Rourke |first4=Nancy A. |last5=Park |first5=Chan Young |last6=Özkan |first6=Engin |last7=Chakraborty |first7=Chandrani |last8=Mulinyawe |first8=Sara B. |last9=Annis |first9=Douglas S. |last10=Huberman |first10=Andrew D. |last11=Green |first11=Eric M. |last12=Lawler |first12=Jack |last13=Dolmetsch |first13=Ricardo |last14=Garcia |first14=K. Christopher |last15=Smith |first15=Stephen J. |last16=Luo |first16=Z. David |last17=Rosenthal |first17=Arnon |last18=Mosher |first18=Deane F. |last19=Barres |first19=Ben A. |author1-link=Cagla Eroglu }}</ref>

Clinically used gabapentinoids include gabapentin, pregabalin, and mirogabalin,<ref name="WyllieCascino2012" /><ref name="BenzonRathmell2013" /> as well as a gabapentin prodrug, gabapentin enacarbil.<ref name="Kirsch2013">{{cite book | author = Douglas Kirsch | title = Sleep Medicine in Neurology | url = https://books.google.com/books?id=Gf9QAQAAQBAJ&pg=PT241 | date = October 10, 2013 | publisher = John Wiley & Sons | isbn = 978-1-118-76417-6 | page = 241}}</ref> Further analogues like imagabalin and atagabalin have been tested in clinical trials but their development has been halted.<ref>{{cite journal |last1=Vinik |first1=Aaron |last2=Rosenstock |first2=Julio |last3=Sharma |first3=Uma |last4=Feins |first4=Karen |last5=Hsu |first5=Ching |last6=Merante |first6=Domenico |year=2014 |title=Efficacy and Safety of Mirogabalin (DS-5565) for the Treatment of Diabetic Peripheral Neuropathic Pain: A Randomized, Double-Blind, Placebo- and Active Comparator–Controlled, Adaptive Proof-of-Concept Phase 2 Study |journal=Diabetes Care |volume=37 |issue=12 |pages=3253–61 |doi=10.2337/dc14-1044 |pmid=25231896 |doi-access=free}}</ref> Other gabapentinoids which are used in scientific research but have not been approved for medical use include 4-methylpregabalin and PD-217,014.<ref name=":0">{{Cite journal |last=Varadi |first=Gyula |date=2024 |title=Mechanism of Analgesia by Gabapentinoid Drugs: Involvement of Modulation of Synaptogenesis and Trafficking of Glutamate-Gated Ion Channels |journal=Journal of Pharmacology and Experimental Therapeutics |language=en |volume=388 |issue=1 |pages=121–133 |doi=10.1124/jpet.123.001669 |pmid=37918854 |issn=0022-3565|doi-access=free }}</ref>

Additionally, phenibut and baclofen have been found to act as very low affinity gabapentinoid in addition to their action as GABAB receptor agonist.<ref name="pmid26234470" /><ref name="VaversZvejniece2015">{{cite journal|last1=Vavers|first1=Edijs|last2=Zvejniece|first2=Liga|last3=Svalbe|first3=Baiba|last4=Volska|first4=Kristine|last5=Makarova|first5=Elina|last6=Liepinsh|first6=Edgars|last7=Rizhanova|first7=Kristina|last8=Liepins|first8=Vilnis|last9=Dambrova|first9=Maija|title=The neuroprotective effects of R-phenibut after focal cerebral ischemia|journal=Pharmacological Research|volume=113|issue=Pt B|pages=796–801|year=2015|issn=1043-6618|doi=10.1016/j.phrs.2015.11.013|pmid=26621244}}</ref>

==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.<ref name="WyllieCascino2012" /><ref name="Kirsch2013" /><ref name="SchatzbergNemeroff2009">{{cite book |last1=Frye |first1=Mark |last2=Moore |first2=Katherine |year=2009 |chapter=Gabapentin and Pregabalin |pages=767–77 |chapter-url={{Google books|Xx7iNGdV25IC|page=767|plainurl=yes}} |doi=10.1176/appi.books.9781585623860.as38 |editor1-first=Alan F. |editor1-last=Schatzberg |editor2-first=Charles B. |editor2-last=Nemeroff |title=The American Psychiatric Publishing Textbook of Psychopharmacology |isbn=978-1-58562-309-9 }}</ref> Some off-label uses of gabapentinoids include the treatment of insomnia, migraine, social phobia, panic disorder, mania, bipolar disorder, and alcohol withdrawal.<ref name="Kirsch2013"/><ref name="clevelandclinicmeded.com">{{Cite web | url=http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/septoct2005/pregabalin.htm | title=Pharmacotherapy Update | Pregabalin (Lyrica®):Part I}}</ref> 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.<ref>{{cite journal|last1=Shanthanna|first1=Harsha|last2=Gilron|first2=Ian|last3=Rajarathinam|first3=Manikandan|last4=AlAmri|first4=Rizq|last5=Kamath|first5=Sriganesh|last6=Thabane|first6=Lehana|last7=Devereaux|first7=Philip J.|last8=Bhandari|first8=Mohit|last9=Tsai|first9=Alexander C.|title=Benefits and safety of gabapentinoids in chronic low back pain: A systematic review and meta-analysis of randomized controlled trials|journal=PLOS Medicine|date=August 15, 2017|volume=14|issue=8|article-number=e1002369|doi=10.1371/journal.pmed.1002369|pmid=28809936|pmc=5557428 |doi-access=free }}</ref> The main side-effects include: a feeling of sleepiness and tiredness, decreased blood pressure, nausea, vomiting and also glaucomatous visual hallucinations.<ref>{{Cite web |date=September 16, 2021 |title=Side effects of gabapentin |url=https://www.nhs.uk/medicines/gabapentin/side-effects-of-gabapentin/ |access-date=November 21, 2022 |website=nhs.uk |language=en}}</ref>

In a systematic review analysing data from 5 cohort studies having 10,85,488 patients, use of gabapentinoids (pregabalin and gabapentin) was associated with an increased risks 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.<ref>{{cite journal | vauthors = Dutta D, Mohindra R, Kumar M, Banerjee M, Sharma M, Mukhopadhyay S | title = Cardiovascular safety of gabapentinoids gabapentin & pregabalin: A systematic review. | journal = Indian J Med Res | volume = 161 | issue = 4 | date = Apr 2025 | pages = 363–374 | article-number = 363 | pmid = 40536375 | doi = 10.25259/IJMR_1990_2024| pmc = 12178190 | doi-access = free }}</ref>

==Side effects== {{See also|Gabapentin#Side effects|Pregabalin#Side effects|Phenibut#Side effects}}

==Pharmacology== [[File:Gabapentinoids.svg|class=skin-invert-image|thumb|right|350px|Skeletal formulae of GABA and commercially available gabapentinoids—gabapentin, pregabalin, phenibut, baclofen and mirogabalin.]] ===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).<ref name="pmid16376147">{{cite journal | vauthors = Sills GJ | title = The mechanisms of action of gabapentin and pregabalin | journal = Curr Opin Pharmacol | volume = 6 | issue = 1 | pages = 108–13 | year = 2006 | pmid = 16376147 | doi = 10.1016/j.coph.2005.11.003 }}</ref><ref name="pmid27345098" /> 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.<ref name="pmid27345098" /> In most cases, gabapentinoid drugs do not seem to directly alter the action of VGCC and instead reduce the release of certain excitatory neurotransmitters.<ref name="pmid17222465" /> (However, see<ref name="pmid21150315" />).

The gabapentinoid drugs do not bind significantly to other known drug receptors and so the α2δ VGCC subunit has been called the gabapentin receptor.<ref name="pmid16376147" /><ref name="BenzonRathmell2013" /> 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.<ref name=":1">{{Cite journal |last1=Taylor |first1=Charles P. |last2=Harris |first2=Eric W. |date=2020 |title=Analgesia with Gabapentin and Pregabalin May Involve N -Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins |url=http://jpet.aspetjournals.org/lookup/doi/10.1124/jpet.120.266056 |journal=Journal of Pharmacology and Experimental Therapeutics |language=en |volume=374 |issue=1 |pages=161–174 |doi=10.1124/jpet.120.266056 |pmid=32321743 |issn=0022-3565|url-access=subscription }}</ref> Gabapentinoids alter the function of these additional α2δ binding proteins, and these have been proposed as mediators of drug actions.<ref name=":1" /><ref name=":0" />

Despite the fact that gabapentinoids are GABA analogues, gabapentin and pregabalin do not bind to GABA receptors, do not convert into {{abbrlink|GABA|γ-aminobutyric acid}} or GABA receptor agonists ''in vivo'', and do not modulate GABA transport or metabolism.<ref name="pmid16376147" /><ref name="pmid21150315">{{cite journal | vauthors = Uchitel OD, Di Guilmi MN, Urbano FJ, Gonzalez-Inchauspe C | title = Acute modulation of calcium currents and synaptic transmission by gabapentinoids | journal = Channels | volume = 4 | issue = 6 | pages = 490–6 | year = 2010 | pmid = 21150315 | doi = 10.4161/chan.4.6.12864| doi-access = free | hdl = 11336/20897 | hdl-access = free }}</ref> Conversely, GABA does not bind appreciably to the α2δ protein.<ref name=":1" /> Furthermore, gabapentinoids do not act directly as inhibitors or blockers of VGCC.<ref name="pmid17403543" /><ref name=":0" /><ref name=":1" /> Instead, they reduce the release of excitatory neurotransmitters including glutamate, monoamine neurotransmitters and Substance P.<ref name="pmid17222465" /> Although not thought to be a major site of action, gabapentinoids such as gabapentin, but not pregabalin, have been found to activate Kv voltage-gated potassium channels (KCNQ).<ref>{{Cite web|url=http://molpharm.aspetjournals.org/content/molpharm/early/2018/07/18/mol.118.112953.full.pdf|title=Gabapentin is a potent activator of KCNQ3 and KCNQ5 potassium channels.|access-date=March 30, 2020|archive-date=March 19, 2020|archive-url=https://web.archive.org/web/20200319114957/http://molpharm.aspetjournals.org/content/molpharm/early/2018/07/18/mol.118.112953.full.pdf|url-status=dead}}</ref>

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).<ref name="pmid17222465" /> It has been hypothesized that they may be endogenous ligands of the subunit and that they may competitively antagonize the effects of gabapentinoids in brain tissues.<ref name="pmid17222465" /><ref name="pmid17403543">{{cite journal | vauthors = Davies A, Hendrich J, Van Minh AT, Wratten J, Douglas L, Dolphin AC | title = Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels | journal = Trends Pharmacol. Sci. | volume = 28 | issue = 5 | pages = 220–8 | year = 2007 | pmid = 17403543 | doi = 10.1016/j.tips.2007.03.005 }}</ref> 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.<ref name="pmid23642658">{{cite journal |vauthors=Stahl SM, Porreca F, Taylor CP, Cheung R, Thorpe AJ, Clair A |year=2013 |title=The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities? |journal=Trends Pharmacol. Sci. |volume=34 |issue=6 |pages=332–9 |doi=10.1016/j.tips.2013.04.001 |pmid=23642658}}</ref>

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.<ref name="pmid26234470">{{cite journal | vauthors = Zvejniece L, Vavers E, Svalbe B, Veinberg G, Rizhanova K, Liepins V, Kalvinsh I, Dambrova M | title = R-phenibut binds to the α2-δ subunit of voltage-dependent calcium channels and exerts gabapentin-like anti-nociceptive effects | journal = Pharmacol. Biochem. Behav. | volume = 137 | pages = 23–9 | year = 2015 | pmid = 26234470 | doi = 10.1016/j.pbb.2015.07.014 | s2cid = 42606053 }}</ref> Their affinities (Ki) for the GABAB receptor were >1 mM for gabapentin, 92 μM for (''R'')-phenibut, >1 mM for (''S'')-phenibut, 6 μM for Baclofen. Pregabalin has demonstrated significantly greater potency (about 2.5-fold) than gabapentin in clinical studies<ref name="pmid21212719" /> and mirogabalin is even more potent in vivo.

===Pharmacokinetics===

====Absorption==== Gabapentin, Baclofen 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.<ref name="pmid27345098" /><ref name="pmid16376147" /><ref name="pmid23567998">{{cite journal | vauthors = Dickens D, Webb SD, Antonyuk S, Giannoudis A, Owen A, Rädisch S, Hasnain SS, Pirmohamed M | title = Transport of gabapentin by LAT1 (SLC7A5) | journal = Biochem. Pharmacol. | volume = 85 | issue = 11 | pages = 1672–83 | year = 2013 | pmid = 23567998 | doi = 10.1016/j.bcp.2013.03.022 }}</ref> Very few (less than 10 drugs) are known to be transported by this transporter.<ref name="pmid18656534" /> Unlike gabapentin, which is transported solely by the LAT1,<ref name="pmid23567998" /><ref name="pmid20818832" /> pregabalin seems to be transported not only by the LAT1 but also by other carriers.<ref name="pmid27345098" /> The LAT1 is easily saturable, so the pharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.<ref name="pmid27345098" /> Conversely, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption.<ref name="pmid27345098" /> 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.<ref name="pmid20505847">{{cite journal | vauthors = Agarwal P, Griffith A, Costantino HR, Vaish N | title = Gabapentin enacarbil - clinical efficacy in restless legs syndrome | journal = Neuropsychiatr Dis Treat | volume = 6 | pages = 151–8 | year = 2010 | pmid = 20505847 | pmc = 2874339 | doi = 10.2147/NDT.S5712 | doi-access = free }}</ref> Similarly to gabapentin and pregabalin, baclofen, is transported by the LAT1, although it is a relatively weak substrate for the transporter.<ref name="pmid18656534">{{cite journal | vauthors = del Amo EM, Urtti A, Yliperttula M | title = Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2 | journal = Eur J Pharm Sci | volume = 35 | issue = 3 | pages = 161–74 | year = 2008 | pmid = 18656534 | doi = 10.1016/j.ejps.2008.06.015 }}</ref><ref name="pmid11341366">{{cite journal | vauthors = Kido Y, Tamai I, Uchino H, Suzuki F, Sai Y, Tsuji A | title = Molecular and functional identification of large neutral amino acid transporters LAT1 and LAT2 and their pharmacological relevance at the blood-brain barrier | journal = J. Pharm. Pharmacol. | volume = 53 | issue = 4 | pages = 497–503 | year = 2001 | pmid = 11341366 | doi = 10.1211/0022357011775794| s2cid = 38717319 | doi-access = free }}</ref>

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.<ref name="pmid20818832">{{cite journal | vauthors = Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek N, Burger P | title = A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin | journal = Clin Pharmacokinet | volume = 49 | issue = 10 | pages = 661–9 | year = 2010 | pmid = 20818832 | doi = 10.2165/11536200-000000000-00000 | s2cid = 16398062 }}</ref><ref name="pmid20505847" /> 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).<ref name="pmid20818832" /> Food does not significantly influence the oral bioavailability of pregabalin.<ref name="pmid20818832" /> Conversely, food increases the area-under-curve levels of gabapentin by about 10%.<ref name="pmid20818832" /> 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),<ref name="pmid24829664">{{cite journal | vauthors = Khansari M, Sohrabi M, Zamani F | title = The Useage of Opioids and their Adverse Effects in Gastrointestinal Practice: A Review | journal = Middle East J Dig Dis | volume = 5 | issue = 1 | pages = 5–16 | date = January 2013 | pmid = 24829664 | pmc = 3990131 }}</ref> the oral bioavailability of a 600 mg dose of gabapentin increased by 50%.<ref name="pmid20818832" /> 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%.<ref name="pmid20505847" /><ref name="pmid27345098" /> In contrast to the other gabapentinoids, the pharmacokinetics of phenibut have been little-studied, and its oral bioavailability is unknown.<ref name="pmid11830761">{{Cite journal| last1 = Lapin | first1 = I.| title = Phenibut (beta-phenyl-GABA): A tranquilizer and nootropic drug| journal = CNS Drug Reviews| volume = 7| issue = 4| pages = 471–481| year = 2001| pmid = 11830761| doi = 10.1111/j.1527-3458.2001.tb00211.x| pmc = 6494145}}</ref> 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.<ref name="pmid11830761" />

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.<ref name="pmid27345098" /> The Tmax of pregabalin is generally less than or equal to 1 hour at doses of 300 mg or less.<ref name="pmid27345098" /> 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; Tmax values for pregabalin of 0.6 hours in a fasted state and 3.2 hours in a fed state (5-fold difference), and the Cmax is reduced by 25–31% in a fed versus fasted state.<ref name="pmid20818832" /> In contrast to pregabalin, food does not significantly affect the Tmax of gabapentin and increases the Cmax of gabapentin by approximately 10%.<ref name="pmid20818832" /> The Tmax 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.<ref name="pmid18827074">{{cite journal | vauthors = Cundy KC, Sastry S, Luo W, Zou J, Moors TL, Canafax DM | title = Clinical pharmacokinetics of XP13512, a novel transported prodrug of gabapentin | journal = J Clin Pharmacol | volume = 48 | issue = 12 | pages = 1378–88 | year = 2008 | pmid = 18827074 | doi = 10.1177/0091270008322909 | s2cid = 23598218 }}</ref> Conversely, the Tmax 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.<ref name="pmid18827074" /> The Tmax of phenibut has not been reported,<ref name="pmid11830761" /> 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).<ref name="pmid26693960" />

====Distribution==== Gabapentin, pregabalin, and phenibut all cross the blood–brain barrier and enter the central nervous system.<ref name="pmid16376147" /><ref name="pmid11830761" /> However, due to their low lipophilicity,<ref name="pmid20818832" /> the gabapentinoids require active transport across the blood–brain barrier.<ref name="pmid23567998" /><ref name="pmid16376147" /><ref name="pmid26305616">{{cite journal | vauthors = Geldenhuys WJ, Mohammad AS, Adkins CE, Lockman PR | title = Molecular determinants of blood-brain barrier permeation | journal = Ther Deliv | volume = 6 | issue = 8 | pages = 961–71 | year = 2015 | pmid = 26305616 | pmc = 4675962 | doi = 10.4155/tde.15.32 }}</ref><ref name="pmid19937841">{{cite journal | vauthors = Müller CE | title = Prodrug approaches for enhancing the bioavailability of drugs with low solubility | journal = Chemistry & Biodiversity | volume = 6 | issue = 11 | pages = 2071–83 | year = 2009 | pmid = 19937841 | doi = 10.1002/cbdv.200900114 | s2cid = 32513471 }}</ref> The LAT1 is highly expressed at the blood–brain barrier<ref name="pmid10518579">{{cite journal | vauthors = Boado RJ, Li JY, Nagaya M, Zhang C, Pardridge WM | title = Selective expression of the large neutral amino acid transporter at the blood-brain barrier | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 96 | issue = 21 | pages = 12079–84 | year = 1999 | pmid = 10518579 | pmc = 18415 | doi = 10.1073/pnas.96.21.12079| bibcode = 1999PNAS...9612079B | doi-access = free }}</ref> and transports the gabapentinoids that bind to it across into the brain.<ref name="pmid23567998" /><ref name="pmid16376147" /><ref name="pmid26305616" /><ref name="pmid19937841" /> As with intestinal absorption of gabapentin mediated by LAT1, transport of gabapentin across the blood–brain barrier by LAT1 is saturable.<ref name="pmid23567998" /> Gabapentin does not bind to other drug transporters such as P-glycoprotein (ABCB1) or OCTN2 (SLC22A5).<ref name="pmid23567998" />

Gabapentin and pregabalin are not significantly bound to plasma proteins (<1%).<ref name="pmid20818832" /> The phenibut analogue baclofen shows low plasma protein binding of 30%.<ref name="EadieTyrer2012">{{cite book|author1=Mervyn Eadie|author2=J.H. Tyrer|title=Neurological Clinical Pharmacology|url=https://books.google.com/books?id=PXfyCAAAQBAJ&pg=PA73|date=December 6, 2012|publisher=Springer Science & Business Media|isbn=978-94-011-6281-4|pages=73–}}</ref>

====Metabolism==== Gabapentin, pregabalin, and phenibut all undergo little or no metabolism.<ref name="pmid27345098" /><ref name="pmid20818832" /><ref name="pmid11830761" /> Conversely, gabapentin enacarbil, which acts as a prodrug of gabapentin, must undergo enzymatic hydrolysis to become active.<ref name="pmid27345098" /><ref name="pmid20505847" /> This is done via non-specific esterases in the intestines and to a lesser extent in the liver.<ref name="pmid27345098" />

====Elimination==== Gabapentin, pregabalin, and phenibut are all eliminated renally in the urine.<ref name="pmid20818832" /><ref name="pmid11830761" /> 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.<ref name="pmid20818832" /><ref name="pmid11830761" /> Similarly, the terminal half-life of gabapentin enacarbil IR (as active gabapentin) is short at approximately 4.5 to 6.5 hours.<ref name="pmid18827074" /> Because of its short elimination half-life, gabapentin must be administered 3 to 4 times per day to maintain therapeutic levels.<ref name="pmid20505847" /> Similarly, pregabalin has been given 2 to 3 times per day in clinical studies.<ref name="pmid20818832" /> Phenibut, also, is taken 3 times per day.<ref name="Phenibut-Label">{{citation | author = Ozon Pharm | title = Fenibut | access-date = September 15, 2017 | url = http://www.ozonpharm.ru/upload/iblock/608/nmntxzabdzjhlu%20-%20fbdoqpbtdj.ofzsxp%20tkbgeygfzj.pdf | archive-date = September 16, 2017 | archive-url = https://web.archive.org/web/20170916094855/http://www.ozonpharm.ru/upload/iblock/608/nmntxzabdzjhlu%20-%20fbdoqpbtdj.ofzsxp%20tkbgeygfzj.pdf }}</ref><ref name="RLS-Phenibut">{{cite web | author = Регистр лекарственных средств России ([Russian Medicines Register]) | title = Фенибут (Phenybutum) | trans-title = Fenibut (Phenybutum) | access-date = September 15, 2017 | url = https://www.rlsnet.ru/tn_index_id_5320.htm}}</ref> Conversely, gabapentin enacarbil is taken twice a day and gabapentin XR (brand name Gralise) is taken once a day.<ref name="Kaye2017">{{cite book|author=Alan D. Kaye|title=Pharmacology, An Issue of Anesthesiology Clinics E-Book|url=https://books.google.com/books?id=lsUmDwAAQBAJ&pg=PT98|date=June 5, 2017|publisher=Elsevier Health Sciences|isbn=978-0-323-52998-3|pages=98–}}</ref>

==Chemistry== thumb|493x493px|class=skin-invert-image|Major gabapentinoid compound structures compared to GABA and L-leucine.

The gabapentinoids are 3-substituted derivatives of GABA; hence, they are GABA analogues, as well as γ-amino acids.<ref name="WyllieCascino2012" /><ref name="BenzonRathmell2013" /> Specifically, pregabalin is (''S'')-(+)-3-isobutyl-GABA, phenibut is 3-phenyl-GABA,<ref name="pmid11830761" /> and gabapentin is a derivative of GABA with a cyclohexane ring at the 3 position (or, somewhat inappropriately named, 3-cyclohexyl-GABA).<ref name="pmid18221197">{{cite journal | vauthors = Yogeeswari P, Ragavendran JV, Sriram D | title = An update on GABA analogs for CNS drug discovery | journal = Recent Patents on CNS Drug Discovery| volume = 1 | issue = 1 | pages = 113–8 | year = 2006 | pmid = 18221197 | doi = 10.2174/157488906775245291}}</ref><ref name="pmid11966555">{{cite journal | vauthors = Rose MA, Kam PC | title = Gabapentin: pharmacology and its use in pain management | journal = Anaesthesia | volume = 57 | issue = 5 | pages = 451–62 | year = 2002 | pmid = 11966555 | doi = 10.1046/j.0003-2409.2001.02399.x| s2cid = 27431734 | doi-access = free }}</ref><ref name="WhelessWillmore2009">{{cite book|author1=James W. Wheless|author2=James Willmore|author3=Roger A. Brumback|title=Advanced Therapy in Epilepsy|url=https://books.google.com/books?id=4W7UI-FPZmoC&pg=PA302|year=2009|publisher=PMPH-USA|isbn=978-1-60795-004-2|pages=302–}}</ref>

Recently, a detailed three dimensional molecular structure of the α2δ-1 protein with gabapentin and alternatively with L-leucine bound at the gabapentinoid binding site has been published {{PDB|8FD7}}.<ref>{{Cite journal |last1=Chen |first1=Zhou |last2=Mondal |first2=Abhisek |last3=Minor |first3=Daniel L. |date=2023 |title=Structural basis for CaVα2δ:gabapentin binding |journal=Nature Structural & Molecular Biology |language=en |volume=30 |issue=6 |pages=735–739 |doi=10.1038/s41594-023-00951-7 |issn=1545-9993 |pmc=10896480 |pmid=36973510}}</ref> These show that drugs bind to the first calcium channel and chemotaxis (Cache) domain in the α2 part of the α2δ-1. A very similar study shows the structure of α2δ-1 structure with mirogabalin bound.<ref>{{Cite journal |last1=Kozai |first1=Daisuke |last2=Numoto |first2=Nobutaka |last3=Nishikawa |first3=Kouki |last4=Kamegawa |first4=Akiko |last5=Kawasaki |first5=Shohei |last6=Hiroaki |first6=Yoko |last7=Irie |first7=Katsumasa |last8=Oshima |first8=Atsunori |last9=Hanzawa |first9=Hiroyuki |last10=Shimada |first10=Kousei |last11=Kitano |first11=Yutaka |last12=Fujiyoshi |first12=Yoshinori |date=2023 |title=Recognition Mechanism of a Novel Gabapentinoid Drug, Mirogabalin, for Recombinant Human α2δ1, a Voltage-Gated Calcium Channel Subunit |journal=Journal of Molecular Biology |volume=435 |issue=10 |article-number=168049 |doi=10.1016/j.jmb.2023.168049 |issn=0022-2836|doi-access=free |pmid=36933823 }}</ref> These studies also suggests that the L-leucine bound structure is slightly different than the drug bound structure, consistent with L-leucine acting as an antagonist to gabapentinoid drugs.

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.<ref name="pmid17222465" /><ref name="pmid17403543" /><ref name="pmid18221197" />

==History==

alt=Calcium channel alpha-1 and alpha-2-delta subunits with gabapentin|thumb|Structure of the voltage-gated L-type calcium channel CAv1.2 (brown) with the CAva2d-1 auxiliary protein subunit (green) and gabapentin (bright pink) bound at the high affinity site. Light gray horizontal bars represent the cell membrane (intracellular side below). Taken from the RCSB Protein Data Bank: <nowiki>https://www.rcsb.org/structure/8FD7</nowiki>. <nowiki>https://doi.org/10.2210/pdb8FD7/pdb</nowiki> 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.<ref name="AdisInsight-Gabapentin">{{Cite web | url=https://adisinsight.springer.com/drugs/800002421 | title=Gabapentin - Pfizer - AdisInsight}}</ref><ref name="Li2014">{{cite book|author=Jie Jack Li|title=Blockbuster Drugs: The Rise and Fall of the Pharmaceutical Industry|url=https://books.google.com/books?id=7XH1AQAAQBAJ&pg=PA158|year=2014|publisher=OUP USA|isbn=978-0-19-973768-0|pages=158–}}</ref> Subsequently, gabapentin was approved in the United States for the treatment of postherpetic neuralgia in May 2002.<ref name="pmid23342236">{{cite journal | vauthors = Irving G | title = Once-daily gastroretentive gabapentin for the management of postherpetic neuralgia: an update for clinicians | journal = Ther Adv Chronic Dis | volume = 3 | issue = 5 | pages = 211–8 | year = 2012 | pmid = 23342236 | pmc = 3539268 | doi = 10.1177/2040622312452905 }}</ref> A generic version of gabapentin first became available in the United States in 2004.<ref name="Reed2012">{{cite book|author=Diana Reed|title=The Other End of the Stethoscope: The Physician's Perspective on the Health Care Crisis|url=https://books.google.com/books?id=HkICcDDz0qQC&pg=PA63|date=March 2, 2012|publisher=AuthorHouse|isbn=978-1-4685-4410-7|pages=63–}}</ref> 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.<ref name="GoodRx2013">{{Cite web | url=https://www.goodrx.com/blog/yabba-dabba-gabapentin-are-gralise-and-horizant-worth-the-cost/ |title = GoodRx - Error| work=The GoodRx Prescription Savings Blog | date=May 31, 2013 }}</ref><ref name="AdisInsight-Gabapentin-CR">{{Cite web | url=http://adisinsight.springer.com/drugs/800019682 | title=Gabapentin controlled release - Assertio Therapeutics - AdisInsight}}</ref>

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.<ref name="WhelessWillmore2009" /><ref name="AdisInsight-Pregabalin">{{Cite web | url=http://adisinsight.springer.com/drugs/800005758 | title=Pregabalin - Pfizer - AdisInsight}}</ref><ref name="SinatraJahr2010">{{cite book|author1=Raymond S. Sinatra|author2=Jonathan S. Jahr|author3=J. Michael Watkins-Pitchford|title=The Essence of Analgesia and Analgesics|url=https://books.google.com/books?id=ZwPIjKg0XukC&pg=PA298|date=October 14, 2010|publisher=Cambridge University Press|isbn=978-1-139-49198-3|pages=298–}}</ref><ref name="Stolberg2016">{{cite book|author=Victor B. Stolberg|title=Painkillers: History, Science, and Issues|url=https://books.google.com/books?id=plWaCwAAQBAJ&pg=PA76|date=March 14, 2016|publisher=ABC-CLIO|isbn=978-1-4408-3532-2|pages=76–}}</ref> It was subsequently approved for the treatment of fibromyalgia in the United States in June 2007.<ref name="WhelessWillmore2009" /><ref name="AdisInsight-Pregabalin" /><ref name="Stolberg2016" /> 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.<ref name="AdisInsight-Pregabalin" /><ref name="WhelessWillmore2009" /><ref name="Ritsner2010">{{cite book|author=Michael S. Ritsner|title=Brain Protection in Schizophrenia, Mood and Cognitive Disorders|url=https://books.google.com/books?id=KcB8lFjoQHkC&pg=PA490|date=June 16, 2010|publisher=Springer Science & Business Media|isbn=978-90-481-8553-5|pages=490–}}</ref><ref name="SchlaepferNemeroff2012">{{cite book|author1=Thomas E Schlaepfer|author2=Charles B. Nemeroff|title=Neurobiology of Psychiatric Disorders|url=https://books.google.com/books?id=A0NyA5u_N-kC&pg=PA353|date=September 1, 2012|publisher=Elsevier|isbn=978-0-444-53500-9|pages=353–}}</ref>

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.<ref name="Medscape">{{cite web|last1=Jeffrey|first1=Susan|title=FDA Approves Gabapentin Enacarbil for Postherpetic Neuralgia|url=http://www.medscape.com/viewarticle/765233|publisher=Medscape}}</ref>

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.<ref name="pmid11830761" /><ref name="DrobizhevFedotova2016">{{cite journal | last1 = Drobizhev | first1 = M.Yu. | last2 = Fedotova | first2 = A.V. | last3 = Kikta | first3 = S.V. | last4 = Antohin | first4 = E.Yu. | year = 2016 | title = Феномен аминофенилмасляной кислоты | trans-title = [Phenomenon of aminophenylbutyric acid] | url = https://www.rmj.ru/articles/nevrologiya/Fenomen_aminofenilmaslyanoy_kisloty/ | language = ru | journal = Russian Medical Journal | volume = 2017 | issue = 24 | pages = 1657–1663 | issn = 1382-4368}}</ref> It was not discovered to act as a very weak (3.5 orders of magnitude less potent) gabapentinoid until 2015.<ref name="pmid26234470" />

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.<ref name="AdisInsight-Mirogabalin">{{Cite web | url=http://adisinsight.springer.com/drugs/800033181 | title=Mirogabalin - Daiichi Sankyo Company - AdisInsight}}</ref>

Gabapentenoid consumption appears to be increasing; between 2008 and 2018, gabapentenoid use increased by over 17% averaged worldwide, led by growing consumption in the US, Canada, and northern Europe.<ref name="Chan2023">{{Cite journal|last1=Chan|first1=A.Y.L.|last2=Yuen|first2=A.S.C.|last3=Tsai|first3=D.H.T.|date=2023|title=Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study|journal=Nature Communications|volume=14|issue=1 |page=5005|doi=10.1038/s41467-023-40637-8|pmid=37591833 |pmc=10435503 |bibcode=2023NatCo..14.5005C }}</ref>

==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).<ref name="pmid24760436">{{cite journal | vauthors = Schifano F | title = Misuse and abuse of pregabalin and gabapentin: cause for concern? | journal = CNS Drugs | volume = 28 | issue = 6 | pages = 491–6 | year = 2014 | pmid = 24760436 | doi = 10.1007/s40263-014-0164-4 | doi-access = free }}</ref><ref name="pmid21212719">{{cite journal | vauthors = Schifano F, D'Offizi S, Piccione M, Corazza O, Deluca P, Davey Z, Di Melchiorre G, Di Furia L, Farré M, Flesland L, Mannonen M, Majava A, Pagani S, Peltoniemi T, Siemann H, Skutle A, Torrens M, Pezzolesi C, van der Kreeft P, Scherbaum N | title = Is there a recreational misuse potential for pregabalin? Analysis of anecdotal online reports in comparison with related gabapentin and clonazepam data | journal = Psychother Psychosom | volume = 80 | issue = 2 | pages = 118–22 | year = 2011 | pmid = 21212719 | doi = 10.1159/000321079 | hdl = 2299/9328 | s2cid = 11172830 | hdl-access = free }}</ref><ref name="pmid26693960">{{cite journal | vauthors = Owen DR, Wood DM, Archer JR, Dargan PI | title = Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity | journal = Drug Alcohol Rev | volume = 35 | issue = 5 | pages = 591–6 | year = 2016 | pmid = 26693960 | doi = 10.1111/dar.12356 | hdl = 10044/1/30073 | hdl-access = free }}</ref> 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.<ref name="pmid24760436" /><ref name="pmid21212719" /> In any case, due to its recreational potential, pregabalin is a schedule V controlled substance in the United States.<ref name="pmid24760436" /> In April 2019,<ref>{{Cite web|title=Pregabalin and gabapentin to be controlled as class C drugs|url=https://www.gov.uk/government/news/pregabalin-and-gabapentin-to-be-controlled-as-class-c-drugs|access-date=September 29, 2020|website=GOV.UK|language=en}}</ref> 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.<ref>{{Cite web|title=Controlled drugs and drug dependence|url=https://bnf.nice.org.uk/guidance/controlled-drugs-and-drug-dependence.html|website=British National Formulary}}</ref> However, it is not a controlled substance in Canada, or Australia, and the other gabapentinoids, including phenibut, are not controlled substances either.<ref name="pmid24760436" /> As such, they are mostly legal intoxicants.<ref name="pmid24760436" /><ref name="pmid21212719" /><ref name="pmid26693960" />

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.<ref name="pmid24760436" /><ref name="pmid21212719" /> More severe withdrawal symptoms, such as severe rebound anxiety, have been reported with phenibut.<ref name="pmid26693960" /> Because of the rapid tolerance with gabapentinoids, users often escalate their doses,<ref name="pmid21212719" /> while other users may space out their doses and use sparingly to avoid tolerance.<ref name="pmid26693960" />

==List of agents==

===Approved=== * Gabapentin (Neurontin, Gabagamma) ** Gabapentin extended-release (Gralise) ** Gabapentin enacarbil (Horizant) * Mirogabalin (Tarlige) (Japan) * Phenibut (Anvifen, Fenibut, Noofen) * Baclofen (Gablofen, Lioresal) * Pregabalin (Lyrica) * Crisugabalin (HSK16149) (China)

===Not approved=== * 4-Fluorophenibut * 4-Methylpregabalin * Atagabalin (PD-200,390) * Imagabalin * PD-217,014 * Tolibut

==References== {{Reflist|30em}}

==Further reading== * {{cite journal | vauthors = Calandre EP, Rico-Villademoros F, Slim M | title = Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use | journal = Expert Rev Neurother | volume = 16 | issue = 11 | pages = 1263–1277 | year = 2016 | pmid = 27345098 | doi = 10.1080/14737175.2016.1202764 | s2cid = 33200190 }}

{{Navboxes | title = Medical uses | titlestyle = background:#ccccff | list1 = {{Anticonvulsants}} {{Anxiolytics}} {{Neuropathic pain and fibromyalgia pharmacotherapies}} }} {{Navboxes | title = Recreational uses | titlestyle = background:#ccccff | list1 = {{Euphoriants}} {{Recreational drug use}} }} {{Ion channel modulators}} {{Chemical classes of psychoactive drugs}}

Category:Amino acids Category:Analgesics Category:Anticonvulsants Category:Anxiolytics Category:Euphoriants Category:GABA analogues Category:Gabapentinoids