As with all other drugs approved by theFDA for treating epilepsy, the pregabalin labeling warns of an increasedsuicide risk when combined with other drugs.[26][13] When pregabalin is taken at high doses over a long period of time, addiction may occur, but if taken atusual doses the risk is low.[4] Use during pregnancy or breastfeeding is of unclear safety.[27]
Pregabalin was approved for medical use in the United States in 2004.[13] In the US, pregabalin is aSchedule V controlled substance under theControlled Substances Act of 1970,[13] which means that the drug has low abuse potential compared to substances in Schedules I-IV, however, there is still a potential for misuse.[34] It is available as ageneric medication.[24][35][36][37][38] In 2023, it was the 78th most commonly prescribed medication in the United States, with more than 8million prescriptions.[39][40]
For drug-resistant focal epilepsy, pregabalin is useful as an add-on therapy to other treatments.[41] Its use alone is less effective than some other seizure medications.[42] It is unclear how it compares togabapentin for this use.[42]
The European Federation of Neurological Societies recommends pregabalin as a first-line agent for the treatment of pain associated withdiabetic neuropathy,post-herpetic neuralgia, andcentral neuropathic pain.[43] A minority obtain substantial benefit, and a larger number obtain moderate benefit.[44] It is given equal weight asgabapentin andtricyclic antidepressants as a first-line agent, however, the latter are less expensive as of 2010.[45] Pregabalin is as effective at relieving pain asduloxetine andamitriptyline.Combination treatment of pregabalin and amitriptyline or duloxetine offers additional pain relief for people whose pain is not adequately controlled with one medication and is safe.[46][47]
Studies have shown that higher doses of pregabalin are associated with greater efficacy.[48]
Pregabalin's use in cancer-associated neuropathic pain is controversial,[49] though such use is common.[50] It has been examined for the prevention of post-surgical chronic pain, but its utility for this purpose is controversial.[51][52]
Pregabalin is generally not regarded as efficacious in the treatment of acute pain.[44] In trials examining the utility of pregabalin for the treatment of acute post-surgical pain, no effect on overall pain levels was observed, but people did require less morphine and had fewer opioid-related side effects.[51][53] Several possible mechanisms for pain improvement have been discussed.[54]
Pregabalin is effective for treatment ofgeneralized anxiety disorder.[55] It is also effective for the short- and long-term treatment ofsocial anxiety disorder and in reducingpreoperative anxiety.[56][57] However, there is concern regarding pregabalin's off-label use due to the lack of strong scientific evidence for its efficacy in multiple conditions and its proven side effects.[58]
The World Federation of Biological Psychiatry recommends pregabalin as one of several first line agents for the treatment of generalized anxiety disorder, but recommends other agents such as those of theselective serotonin reuptake inhibitor (SSRI) class as first line treatment forobsessive–compulsive disorder (OCD) andpost-traumatic stress disorder (PTSD).[59][60] For PTSD, pregabalin as complementary treatment seems to be effective.[57]
Pregabalin hasanxiolytic effects similar tobenzodiazepines with less risk ofdependence.[61] The effects of pregabalin appear within one week of use,[62] and are similar in effectiveness tolorazepam,alprazolam, andbromazepam, but pregabalin has demonstrated superiority by producing more consistent therapeutic effects forpsychosomatic anxiety symptoms.[63] Long-term trials have shown continued effectiveness without the development oftolerance, and, in addition, unlike benzodiazepines, it has a beneficial effect on sleep andsleep architecture, characterized by the enhancement ofslow-wave sleep.[63] It produces less severe cognitive and psychomotor impairment compared to benzodiazepines.[63][61]
A 2019 review found that pregabalin reduces symptoms, and was generally well tolerated.[55]
In a systematic review analysing data from 5 cohort studies having 1,085,488 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.[71]
A tapered discontinuation is recommended to reduce the chances of withdrawal symptoms. Lyrica's US package insert recommends a taper period of at least one week.[81] Best Practice Advocacy Centre New Zealand[82] and NHS Somerset[83] recommend a much slower withdrawal.
The FDA required new warnings about the risk of respiratory depression to be added to the prescribing information of the gabapentinoids.[85] The FDA also required the drug manufacturers to conduct clinical trials to further evaluate their abuse potential, particularly in combination with opioids, because misuse and abuse of these products together is increasing, and co-use may increase the risk of respiratory depression.[85]
Among 49 case reports submitted to the FDA over the five-year period from 2012 to 2017, twelve people died fromrespiratory depression with gabapentinoids, all of whom had at least one risk factor.[85]
The FDA reviewed the results of two randomized, double-blind, placebo-controlled clinical trials in healthy people, three observational studies, and several studies in animals.[85] One trial showed that using pregabalin alone and using it with an opioid pain reliever can depress breathing function.[85] The other trial showed gabapentin alone increased pauses in breathing during sleep.[85] The three observational studies at one academic medical center showed a relationship between gabapentinoids given before surgery and respiratory depression occurring after different kinds of surgeries.[85] The FDA also reviewed several animal studies that showed pregabalin alone and pregabalin plus opioids can depress respiratory function.[85]
Pregabalin has potential for recreational use and abuse.[citation needed] It possesses a relatively widetherapeutic index and margin of safety compared to other central nervous system (CNS) depressants, and its effects may includeeuphoria,anxiolysis, andsedation.
Although generally considered to have low abuse potential, reports describe pregabalin inducing sensations of euphoria, calmness, excitement, and a "high" comparable to that ofcannabis. These effects may contribute to the development ofsubstance dependence, andwithdrawal symptoms can occur if the medication is stopped abruptly.[87][88]
While pregabalin and cannabis share certain effects, such as CNS depressant andorexigenic (appetite-stimulating) properties, they differ significantly in theirpharmacodynamics. Cannabis is primarily ananxiogenic substance with mildpsychedelic effects, whereas pregabalin is ananxiolytic agent associated with mild euphoria that is prone to rapid tolerance.[89][90]
Anoverdose of pregabalin usually consists of severedrowsiness, severeataxia,blurred vision,slurred speech, uncontrollable jerking motions (myoclonus), and anxiety.[91] In one case study,macular detachment was reported with overdose[92] Despite these symptoms an overdose is not usually fatal unless mixed with another CNSdepressant. Several people withkidney failure developedmyoclonus while receiving pregabalin, apparently as a result of the gradual accumulation of the drug. Acute overdosage may be manifested bydrowsiness,tachycardia, andhypertonia. Plasma, serum, or blood concentrations of pregabalin may be measured to monitor therapy or to confirm a diagnosis of poisoning in hospitalized people.[93][94][95]
No drug interactions have been demonstratedin vivo. However, the manufacturer notes potential pharmacological interactions withopioids,benzodiazepines,barbiturates,ethanol (alcohol), and other central nervous system depressants. Concurrent use ofACE inhibitors and pregabalin may increase the risk ofangioedema. Pregabalin may also enhance the fluid-retaining effects of certain antidiabetic agents, such asthiazolidinediones.[96]
Pregabalin does not directly blockcalcium channels (it is not acalcium channel blocker), as it does not bind to the ion conducting channel protein, called α1. However,in vitro studies show that pregabalin can reduce the normal traffic of calcium channels from intracellular sites (where they do not function) to membrane sites where they are functional.[13][32]
While the mechanism of action of pregabalin is not definitively characterized, its action in animal models of pain, seizures and anxiety requires binding to the α2δ-1 protein.[102] It has been found that this binding inhibits several actions of α2δ-1 and also inhibits the release ofexcitatory neurotransmitters. These excitatory neurotransmitters includeglutamate,norepinephrine (noradrenaline),serotonin,dopamine,substance P, andcalcitonin gene-related peptide.[101] By inhibiting the release of these neurotransmitters, pregabalin reduces excess activity of neuron networks, which helps alleviate symptoms and provides relief for patients experiencing pain, seizures, or other related symptoms.[103]
There are two drug-binding α2δ subunits,α2δ-1 andα2δ-2, and pregabalin shows similaraffinity for (and hence lack ofselectivity between) these two sites.[32] Pregabalin is selective in its binding to the α2δ VGCC subunits and does not bind significantly to other known drug receptors.[104][31]
Recently, the α2δ-1 protein has been found (independent of calcium channels) to associate directly with certainNMDA-type glutamate receptors, someAMPA-type glutamate receptors and also with the extracellular matrix protein,thrombospondin, and to modulate the function of these proteins.[102] This has been proposed to contribute to the analgesic action of pregabalin animal models and in clinical use.
Theendogenousα-amino acidsL-leucine andL-isoleucine, which closely resemble pregabalin and the other gabapentinoids inchemical structure, are apparent ligands of the α2δ VGCC subunit with similar affinity as the gabapentinoids (e.g.,IC50=71 nM forL-isoleucine), and are present in humancerebrospinal fluid at micromolar concentrations (e.g., 12.9 μM forL-leucine, 4.8 μM forL-isoleucine).[29] It has been theorized that they may be the endogenous ligands of the subunit and that they maycompetitively antagonize the effects of gabapentinoids.[29][107] In accordance, while gabapentinoids like pregabalin and gabapentin havenanomolar affinities for the α2δ subunit, their potenciesin vivo are in the lowmicromolar range, and competition for binding by endogenousL-amino acids has been said to likely be responsible for this discrepancy.[106]
Pregabalin was found to possess 6-fold higher affinity than gabapentin for α2δ subunit-containing VGCCs in one study.[108][109] However, another study found that pregabalin and gabapentin had similar affinities for the human recombinant α2δ-1 subunit (Ki=32 nM and 40 nM, respectively).[110] In any case, pregabalin is 2 to 4 times more potent than gabapentin as ananalgesic[105][111] and, in animals, appears to be 3 to 10 times more potent than gabapentin as ananticonvulsant.[105][111]
Pregabalin isabsorbed from theintestines by anactive transport process mediated via thelarge neutral amino acid transporter 1 (LAT1, SLC7A5), a transporter foramino acids such asL-leucine andL-phenylalanine.[32][104][112] Very few (less than 10 drugs) are known to be transported by this transporter.[113] Unlikegabapentin, which is transported solely by the LAT1,[112][12] pregabalin seems to be transported not only by the LAT1 but also by other carriers.[32] The LAT1 is easilysaturable, so thepharmacokinetics of gabapentin are dose-dependent, with diminished bioavailability and delayed peak levels at higher doses.[32] In contrast, this is not the case for pregabalin, which shows linear pharmacokinetics and no saturation of absorption.[32]
Theoralbioavailability of pregabalin is greater than or equal to 90% across and beyond its entire clinical dose range (75 to 600 mg/day).[12] Food does not significantly influence the oral bioavailability of pregabalin.[12] Pregabalin is rapidly absorbed when administered on an empty stomach, with aTmax (time topeak levels) of generally less than or equal to 1 hour at doses of 300 mg or less.[32][11] 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 theCmax is reduced by 25–31% in a fed versus fasted state.[12]
Pregabalin iseliminated by the kidneys in theurine, mainly in its unchanged form.[12][11] It has a relatively shortelimination half-life, with a reported value of 6.3 hours.[12] Because of its short elimination half-life, pregabalin is administered 2 to 3 times per day to maintain therapeutic levels.[12] Thekidney clearance of pregabalin is 73 mL/minute.[9]
Pregabalin was synthesized in 1990 as ananticonvulsant that was developed as a successor to the relatedgabapentin.[124] It was first synthesized bymedicinal chemistRichard Bruce Silverman atNorthwestern University inEvanston, Illinois.[125] During 1988 to 1990, Ryszard Andruszkiewicz, a visiting research fellow, synthesized a series of molecules requested by Silverman.[126] Upon testing in mouse seizure models by collaborators atParke-Davis Pharmaceuticals,[127] one looked particularly promising. In vitro, it activatedL-glutamic acid decarboxylase, an enzyme, but this later proved to be unimportant to prevention of seizures. Silverman had originally hoped that the enzyme would increase the production of the inhibitory neurotransmitter GABA and block convulsions.[128] After extensive development studies and clinical trials by Parke-Davis the drug was approved in the European Union in 2004. The US received FDA approval for use in treatingepilepsy,diabeticneuropathic pain, andpostherpetic neuralgia in December 2004. Pregabalin then appeared on the US market under the brand name Lyrica in the fall of 2005.[129] In 2017, the FDA approved pregabalin extended-release Lyrica CR for the management of neuropathic pain associated with diabetic peripheral neuropathy, and postherpetic neuralgia.[130] However, unlike theimmediate release formulation, Lyrica CR was not approved for the management offibromyalgia or as add-on therapy for adults withpartial onset seizures.[131][9]
Pregabalin is available as ageneric medication in a number of countries, including the United States as of July 2019.[24][35][145] In the United States as of July 2019 the wholesale/pharmacy cost for generic pregabalin is US$0.17–0.22 per 150 mg capsule.[147]
From 2008 until 2018, Pfizer engaged in extensivedirect-to-consumer advertising campaigns to promote its branded product Lyrica forfibromyalgia and diabetic nerve pain indications. In January 2016, the company spent a record amount, $24.6 million for a single drug on TV ads, reaching global revenues of $14 billion, more than half in the United States.[148]
Up until 2009, Pfizer promoted Lyrica for other uses that had not been approved by medical regulators. For Lyrica and three other drugs, Pfizer was fined a record amount of US$2.3billion by the Department of Justice,[149][150][151] after pleading guilty to advertising and branding "with the intent to defraud or mislead". Pfizer illegally promoted the drugs, with doctors "invited to consultant meetings, many in resort locations; attendees expenses were paid; they received a fee just for being there", according to prosecutor Michael Loucks.[149][150]
Northwestern University in the US holds the patent on pregabalin, exclusively licensed to Pfizer.[152][153] That patent, along with others, was challenged by generic manufacturers and was upheld in 2014, giving Pfizer exclusivity for Lyrica in the US until 2018.[154][155]
Pfizer's main patent for Lyrica, for seizure disorders, in the UK expired in 2013. In November 2018, theSupreme Court of the United Kingdom ruled thatPfizer's second patent on the drug, for the treatment of pain, was invalid because there was a lack of evidence for the conditions it covered – central and peripheral neuropathic pain. From October 2015, GPs were forced to change people from generic pregabalin to branded until the second patent ran out in July 2017. This cost the NHS £502 million.[156]
It is marketed as acombination drug withmecobalamin under the brand names Agemax-P, Alphamix-PG, Freenerve-P, Gaben, Macraberin-P, Mecoblend-P, Mecozen-PG, Meex-PG, Methylnuron-P, Nervolin, Nervopreg, Neurica-M, Neuroprime-PG, Neutron-OD, Nuroday-P, Nurodon-PG, Nuwin-P, Pecomin-PG, Prebel-M, Predic-GM, Pregacent-M, Pregamet, Preganerv-M, Pregeb-M OD, Pregmic, Prejunate Plus, Preneurolin Plus, Pretek-GM, Rejusite, Renerve-P, Safyvit-PR, Vitcobin-P, and Voltanerv with Methylcobalamin and ALA by Cogentrix Pharma.[157]
In the US, Lyrica is marketed byViatris after Upjohn was spun off from Pfizer.[158][159][160]
^abcdefghijkBockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey CW, Busch JA, et al. (August 2010). "Clinical pharmacokinetics of pregabalin in healthy volunteers".Journal of Clinical Pharmacology.50 (8):941–950.doi:10.1177/0091270009352087.PMID20147618.S2CID9905501.
^abcdefghijk"Pregabalin". The American Society of Health-System Pharmacists.Archived from the original on December 2, 2019. RetrievedFebruary 3, 2019.
^abExpert Committee on Drug Dependence Forty-first Meeting (November 2018).Critical Review Report: Pregabalin(PDF) (Report). Geneva: World Health Organization. Archived fromthe original(PDF) on October 26, 2020.
^Cross AL, Viswanath O, Sherman AI (July 19, 2022). "Pregabalin".StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing.PMID29261857.Archived from the original on August 3, 2022. RetrievedAugust 27, 2022 – via NCBI Bookshelf.
^Iftikhar IH, Alghothani L, Trotti LM (December 2017). "Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis".European Journal of Neurology.24 (12):1446–1456.doi:10.1111/ene.13449.PMID28888061.S2CID22262972.
^Schmader K, Dworkin RH (January 1, 2018). "Chapter 28 - Herpes Zoster and Postherpetic Neuralgia". In Benzon HT, Raja SN, Liu SS, Fishman SM (eds.).Essentials of Pain Medicine (Fourth ed.). Elsevier. pp. 233–240.e2.doi:10.1016/b978-0-323-40196-8.00028-0.ISBN978-0-323-40196-8.
^abcBritish National Formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 323.ISBN978-0-85711-338-2.
^Oskouei, Z., Moshiri, M., Raouf-Rahmati, A., Nemati, A., Bemani Naeini, M., Jomehpour, H., Roohbakhsh, A., Salmasi, Z., & Etemad, L. (2025). Seizures as an Adverse Effect of Pregabalin Consumption: A Systematic Review. Addiction & Health, 17, 1527.https://doi.org/10.34172/ahj.1527
^abCalandre 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.PMID27345098.S2CID33200190.
^abcdeDooley DJ, Taylor CP, Donevan S, Feltner D (2007). "Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission".Trends Pharmacol. Sci.28 (2):75–82.doi:10.1016/j.tips.2006.12.006.PMID17222465.
^abcdHonorio Benzon, James P. Rathmell, Christopher L. Wu, Dennis C. Turk, Charles E. Argoff, Robert W Hurley (September 11, 2013).Practical Management of Pain. Elsevier Health Sciences. p. 1006.ISBN978-0-323-17080-2.
^abcdefghiCalandre EP, Rico-Villademoros F, Slim M (November 2016). "Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use".Expert Review of Neurotherapeutics.16 (11):1263–1277.doi:10.1080/14737175.2016.1202764.PMID27345098.S2CID33200190.
^Howard P (2017).Palliative care formulary (6 ed.). Pharmaceutical press. p. Chapter 4 Central Nervous System.ISBN978-0-85711-348-1.
^abClarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J (August 2012). "The prevention of chronic postsurgical pain using gabapentin and pregabalin: a combined systematic review and meta-analysis".Anesthesia and Analgesia.115 (2):428–442.doi:10.1213/ANE.0b013e318249d36e.hdl:10315/27968.PMID22415535.S2CID18933131.
^Wensel TM, Powe KW, Cates ME (March 2012). "Pregabalin for the treatment of generalized anxiety disorder".The Annals of Pharmacotherapy.46 (3):424–429.doi:10.1345/aph.1Q405.PMID22395254.S2CID26320851.
^abOwen RT (September 2007). "Pregabalin: its efficacy, safety and tolerability profile in generalized anxiety".Drugs of Today.43 (9):601–610.doi:10.1358/dot.2007.43.9.1133188.PMID17940637.
^abcdBandelow B, Wedekind D, Leon T (July 2007). "Pregabalin for the treatment of generalized anxiety disorder: a novel pharmacologic intervention".Expert Review of Neurotherapeutics.7 (7):769–781.doi:10.1586/14737175.7.7.769.PMID17610384.S2CID6229344.
^Millar J, Sadasivan S, Weatherup N, Lutton S (September 7, 2013). "Lyrica Nights–Recreational Pregabalin Abuse in an Urban Emergency Department".Emergency Medicine Journal.30 (10): 874.2–874.doi:10.1136/emermed-2013-203113.20.S2CID73986091.
^"Lyrica Capsules".medicines.org.uk.Archived from the original on October 20, 2020. RetrievedOctober 19, 2020.
^Schjerning O, Rosenzweig M, Pottegård A, Damkier P, Nielsen J (January 2016). "Abuse Potential of Pregabalin: A Systematic Review".CNS Drugs.30 (1):9–25.doi:10.1007/s40263-015-0303-6.PMID26767525.
^Desai A, Kherallah Y, Szabo C, Marawar R (March 2019). "Gabapentin or pregabalin induced myoclonus: A case series and literature review".Journal of Clinical Neuroscience.61:225–234.doi:10.1016/j.jocn.2018.09.019.PMID30381161.S2CID53165515.
^Baselt RC (2008).Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Biomedical Publications. pp. 1296–1297.ISBN978-0-9626523-7-0.
^"Pregabalin".Lexi-Drugs [database on the Internet. Hudson (OH): Lexi-Comp, Inc. 2007. Archived fromthe original on October 19, 2020. RetrievedOctober 29, 2015..
^abDooley DJ, Taylor CP, Donevan S, Feltner D (February 2007). "Ca2+ channel alpha2delta ligands: novel modulators of neurotransmission".Trends in Pharmacological Sciences.28 (2):75–82.doi:10.1016/j.tips.2006.12.006.PMID17222465.
^abTaylor CP, Harris EW (July 2020). "Analgesia with Gabapentin and Pregabalin May InvolveN-Methyl-d-Aspartate Receptors, Neurexins, and Thrombospondins".The Journal of Pharmacology and Experimental Therapeutics.374 (1):161–174.doi:10.1124/jpet.120.266056.PMID32321743.
^Holsboer-Trachsler E, Prieto R (May 2013). "Effects of pregabalin on sleep in generalized anxiety disorder".The International Journal of Neuropsychopharmacology.16 (4):925–936.doi:10.1017/S1461145712000922.PMID23009881.
^abcStahl SM, Porreca F, Taylor CP, Cheung R, Thorpe AJ, Clair A (June 2013). "The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities?".Trends in Pharmacological Sciences.34 (6):332–339.doi:10.1016/j.tips.2013.04.001.PMID23642658.
^del Amo EM, Urtti A, Yliperttula M (October 2008). "Pharmacokinetic role of L-type amino acid transporters LAT1 and LAT2".European Journal of Pharmaceutical Sciences.35 (3):161–174.doi:10.1016/j.ejps.2008.06.015.PMID18656534.
^abMüller CE (November 2009). "Prodrug approaches for enhancing the bioavailability of drugs with low solubility".Chemistry & Biodiversity.6 (11):2071–2083.doi:10.1002/cbdv.200900114.PMID19937841.S2CID32513471.
^abYogeeswari P, Ragavendran JV, Sriram D (January 2006). "An update on GABA analogs for CNS drug discovery".Recent Patents on CNS Drug Discovery.1 (1):113–118.doi:10.2174/157488906775245291.PMID18221197.
^Silverman RB, Andruszkiewicz R, Nanavati SM, Taylor CP, Vartanian MG (July 1991). "3-Alkyl-4-aminobutyric acids: the first class of anticonvulsant agents that activates L-glutamic acid decarboxylase".Journal of Medicinal Chemistry.34 (7):2295–2298.doi:10.1021/jm00111a053.PMID2067001.
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