Pregabalin in Epilepsy: Current Evidence and Clinical Perspectives
DOI:
https://doi.org/10.64960/srimedj.v40i5.268464Keywords:
pregabalin, epilepsy, drug-resistant epilepsy, adjunctive therapyAbstract
Epilepsy is a chronic neurological disorder that significantly impacts quality of life and poses a substantial public health burden, particularly among patients with drug-resistant epilepsy (DRE), which affects up to 30% of cases despite the availability of newer antiepileptic drugs. Pregabalin, a second-generation antiepileptic drug, exerts its therapeutic effects by binding to the α2δ subunit of P/Q-type voltage-gated calcium channels, thereby reducing the release of excitatory neurotransmitters and contributing to seizure control. Additionally, pregabalin possesses anxiolytic and analgesic properties, and is therefore utilized in other clinical indications such as generalized anxiety disorder, neuropathic pain, and fibromyalgia. Clinical evidence from randomized controlled trials and observational studies supports the efficacy and tolerability of pregabalin as an adjunctive therapy for focal-onset seizures, with dose-dependent improvements in seizure response. Common adverse effects include dizziness, somnolence, ataxia, weight gain, and peripheral edema, which are generally dose-related and influenced by renal function. Pregabalin offers additional clinical advantages in patients with comorbidities, the elderly, post-liver transplantation patients, and individuals with alcohol use disorders due to its minimal hepatic metabolism and low potential for drug–drug interactions. However, its safety profile during pregnancy remains uncertain and warrants cautious use. This review article provides a comprehensive overview of the mechanism of action, pharmacokinetic profile, clinical applications, and evidence-based efficacy and safety of pregabalin, with the aim of supporting its appropriate use in the management of epilepsy.
References
World Health Organization. Epilepsy: a public health imperative. Geneva: World Health Organization; 2019.
Trinka E, Kwan P, Lee B, Dash A. Epilepsy in Asia: disease burden, management barriers, and challenges. Epilepsia 2019;60 (Suppl 1):7-21. doi:10.1111/epi.14458.
Espinosa-Jovel C, Toledano R, Aledo-Serrano Á, García-Morales I, Gil-Nagel A. Epidemiological profile of epilepsy in low income populations. Seizure 2018;56:67-72. doi:10.1016/j.seizure.2018.02.002.
Meinardi H, Scott RA, Reis R, Sander JW. The treatment gap in epilepsy: the current situation and ways forward. Epilepsia 2001;42(1):136-49. doi:10.1046/j.1528-1157.2001.32800.x.
Asawavichienjinda T, Sitthi-Amorn C, Tanyanont W. Prevalence of epilepsy in rural Thailand: a population-based study. J Med Assoc Thai 2002;85(10):1066-73.
Neurological Institute of Thailand. Clinical practice guidelines for epilepsy. Bangkok: Tana Press; 2022.
Faught E, Duh MS, Weiner JR, Guérin A, Cunnington MC. Nonadherence to antiepileptic drugs and increased mortality: findings from the RANSOM Study. Neurology 2008;71(20):1572-8. doi:10.1212/01.wnl.0000319693.10338.b9.
O' Rourke G, O' Brien JJ. Identifying the barriers to antiepileptic drug adherence among adults with epilepsy. Seizure 2017;45:160-8. doi:10.1016/j.seizure.2016.12.006.
Calandre EP, Rico-Villademoros F, Slim M. Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use. Expert Rev Neurother 2016;16(11):1263-77. doi:10.1080/14737175.2016.1202764.
Abram M, Jakubiec M, Kamiński K. Chirality as an important factor for the development of new antiepileptic drugs. ChemMedChem 2019;14(20):1744-61. doi:10.1002/cmdc.201900367.
Blommel ML, Blommel AL. Pregabalin: an antiepileptic agent useful for neuropathic pain. Am J Health Syst Pharm 2007;64(14):1475-82. doi:10.2146/ajhp060371.
Schulze-Bonhage A. Pharmacokinetic and pharmacodynamic profile of pregabalin and its role in the treatment of epilepsy. Expert Opin Drug Metab Toxicol 2013;9(1):105-15. doi:10.1517/17425255.2013.749239.
Babu E, Kanai Y, Chairoungdua A, Kim DK, Iribe Y, Tangtrongsup S, et al. Identification of a novel system L amino acid transporter structurally distinct from heterodimeric amino acid transporters. J Biol Chem 2003;278(44):43838-45. doi:10.1074/jbc.M305221200.
Takahashi Y, Nishimura T, Higuchi K, Noguchi S, Tega Y, Kurosawa T, et al. Transport of pregabalin via L-type amino acid transporter 1 (SLC7A5) in human brain capillary endothelial cell line. Pharm Res 2018;35(12):246. doi:10.1007/s11095-018-2532-0.
Feng MR, Turluck D, Burleigh J, Lister R, Fan C, Middlebrook A, et al. Brain microdialysis and PK/PD correlation of pregabalin in rats. Eur J Drug Metab Pharmacokinet 2001;26(1-2):123-8. doi:10.1007/BF03190385.
Pfizer Inc. LYRICA (pregabalin) capsule, solution, and tablet [Internet]. DailyMed 2022 [cited Jul 15, 2025]. Available from: https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=d4734e7d-5079-455e-8ff5-8f4539c998a9&type=display.
Pfizer Inc. LYRICA CR (pregabalin) extended-release tablets, for oral use [Internet]. DailyMed 2020 [cited Jul 15, 2025]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2d832165-3d98-497c-84b0-2d9ae3f838f9.
Asconapé JJ. Use of antiepileptic drugs in hepatic and renal disease. Handb Clin Neurol 2014;119:417-32. doi:10.1016/B978-0-7020-4086-3.00027-8.
Vidaurre J, Gedela S, Yarosz S. Antiepileptic drugs and liver disease. Pediatr Neurol 2017;77:23-36. doi: 10.1016/j.pediatrneurol.2017.09.013.
Shepard PW, St Louis EK. Seizure treatment in transplant patients. Curr Treat Options Neurol 2012;14(4):332-47. doi:10.1007/s11940-012-0180-y.
Hughes JR. Alcohol withdrawal seizures. Epilepsy Behav 2009;15(2):92-7. doi:10.1016/j.yebeh.2009.02.037.
Oulis P, Konstantakopoulos G. Efficacy and safety of pregabalin in the treatment of alcohol and benzodiazepine dependence. Expert Opin Investig Drugs 2012;21(7):1019-29. doi:10.1517/13543784.2012.685651.
Mula M. Pharmacological treatment of anxiety disorders in adults with epilepsy. Expert Opin Pharmacother 2018;19(17):1867-74. doi:10.1080/14656566.2018.1527905.
Brandt C, Mula M. Anxiety disorders in people with epilepsy. Epilepsy Behav 2016;59:87-91. doi:10.1016/j.yebeh.2016.03.020.
Brandt C, Schoendienst M, Trentowska M, Schrecke M, Fueratsch N, Witte-Boelt K, et al. Efficacy and safety of pregabalin in refractory focal epilepsy with and without comorbid anxiety disorders - results of an open-label, parallel group, investigator-initiated, proof-of-concept study. Epilepsy Behav 2013;29(2):298-304. doi:10.1016/j.yebeh.2013.08.004.
French JA, Kugler AR, Robbins JL, Knapp LE, Garofalo EA. Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 2003;60(10):1631-7. doi:10.1212/01.wnl.0000068024.20285.65.
Arroyo S, Anhut H, Kugler AR, Lee CM, Knapp LE, Garofalo EA, et al. Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 2004;45(1):20-7. doi:10.1111/j.0013-9580.2004.31203.x.
Beydoun A, Uthman BM, Kugler AR, Greiner MJ, Knapp LE, Garofalo EA. Safety and efficacy of two pregabalin regimens for add-on treatment of partial epilepsy. Neurology 2005;64(3):475-80. doi:10.1212/01.WNL.0000150932.48688.BE.
Elger CE, Brodie MJ, Anhut H, Lee CM, Barrett JA. Pregabalin add-on treatment in patients with partial seizures: a novel evaluation of flexible-dose and fixed-dose treatment in a double-blind, placebo-controlled study. Epilepsia 2005;46(12):1926-36. doi:10.1111/j.1528-1167.2005.00341.x.
Uthman BM, Bazil CW, Beydoun A, Schulze-Bonhage A, Benabou R, Whalen E, et al. Long-term add-on pregabalin treatment in patients with partial-onset epilepsy: pooled analysis of open-label clinical trials. Epilepsia 2010;51(6):968-78. doi:10.1111/j.1528-1167.2010.02532.x.
Baulac M, Leon T, O'Brien TJ, Whalen E, Barrett J. A comparison of pregabalin, lamotrigine, and placebo as adjunctive therapy in patients with refractory partial-onset seizures. Epilepsy Res 2010;91(1):10-9. doi:10.1016/j.eplepsyres.2010.05.008.
Kwan P, Brodie MJ, Kälviäinen R, Yurkewicz L, Weaver J, Knapp LE. Efficacy and safety of pregabalin versus lamotrigine in patients with newly diagnosed partial seizures: a phase 3, double-blind, randomised, parallel-group trial. Lancet Neurol 2011;10(10):881-90. doi:10.1016/S1474-4422(11)70154-5.
Zaccara G, Almas M, Pitman V, Knapp L, Posner H. Efficacy and safety of pregabalin versus levetiracetam as adjunctive therapy in patients with partial seizures: a randomized, double-blind, noninferiority trial. Epilepsia 2014;55(7):1048-57. doi:10.1111/epi.12679.
French J, Glue P, Friedman D, Almas M, Yardi N, Knapp L, et al. Adjunctive pregabalin vs gabapentin for focal seizures: interpretation of comparative outcomes. Neurology 2016;87(12):1242-9. doi:10.1212/WNL.0000000000003118.
Rheims S, Perucca E, Cucherat M, Ryvlin P. Factors determining response to antiepileptic drugs in randomized controlled trials: a systematic review and meta-analysis. Epilepsia 2011;52(2):219-33. doi:10.1111/j.1528-1167.2010.02915.x.
Carreño M, Maestro I, Molins A, Donaire A, Falip M, Becerra JL, et al. Pregabalin as add-on therapy for refractory partial seizures in every day clinical practice. Seizure 2007;16(8):709-12. doi:10.1016/j.seizure.2007.05.011.
Huber B, Bocchicchio M, Feuerbaum E, May T, Meinert T, Robertson E, et al. Efficacy and tolerability of pregabalin in patients with difficult-to-treat epilepsy and intellectual disability. Epilepsy Behav 2008;13(2):397-401. doi:10.1016/j.yebeh.2008.04.021.
Stephen LJ, Parker P, Kelly K, Wilson EA, Leach V, Brodie MJ. Adjunctive pregabalin for uncontrolled partial-onset seizures: findings from a prospective audit. Acta Neurol Scand 2011;124(2):142-5. doi: 10.1111/j.1600-0404.2011.01507.x.
Brodie MJ, Kelly K, Stephen LJ. Prospective audits with newer antiepileptic drugs in focal epilepsy: insights into population responses? Epilepsy Behav 2014;31:73-6. doi:10.1016/j.yebeh.2013.11.016.
Viteva E, Zahariev Z. Comparative effectiveness of add-on therapy with newer-generation antiepileptic drugs in Bulgarian patients with refractory epilepsy. Epilepsy Behav 2018;87:137-45. doi:10.1016/j.yebeh.2018.07.019.
French J, Kwan P, Fakhoury T, Pitman V, DuBrava S, Knapp L, et al. Pregabalin monotherapy in patients with partial-onset seizures: a historical-controlled trial. Neurology 2014;82(7):590-7. doi:10.1212/WNL.0000000000000119.
Zhou Q, Zheng J, Yu L, Jia X. Pregabalin monotherapy for epilepsy. Cochrane Database Syst Rev 2012;10(10):Cd009429. doi:10.1002/14651858.CD009429.pub2.
Slater J, Chung S, Huynh L, Duh MS, Gorin B, McMicken C, et al. Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: meta-analysis of pivotal trials. Epilepsy Res 2018;143:120-9. doi:10.1016/j.eplepsyres.2017.10.004.
Deng NJ, Li XY, Zhang ZX, Xian-Yu CY, Tao YT, Ma YT, et al. Effectiveness and safety of single anti-seizure medication as adjunctive therapy for drug-resistant focal epilepsy based on network meta-analysis. Front Pharmacol 2025;16:1500475. doi:10.3389/fphar.2025.1500475.
Tian J, Zhu Y, Gui J. Oral adverse events associated with antiseizure medications: an analysis of the FDA adverse event reporting system (FAERS) database. Epilepsy Behav 2025;171:110619. doi:10.1016/j.yebeh.2025.110619.
Zaccara G, Gangemi P, Perucca P, Specchio L. The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011;52(4):826-36. doi:10.1111/j.1528-1167.2010.02966.x.
Stahl SM, Porreca F, Taylor CP, Cheung R, Thorpe AJ, Clair A. The diverse therapeutic actions of pregabalin: is a single mechanism responsible for several pharmacological activities? Trends Pharmacol Sci 2013;34(6):332-9. doi:10.1016/j.tips.2013.04.001.
Roth T, Arnold LM, Garcia-Borreguero D, Resnick M, Clair AG. A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions. Sleep Med Rev 2014;18(3):261-71. doi:10.1016/j.smrv.2013.07.005.
Salinsky M, Storzbach D, Munoz S. Cognitive effects of pregabalin in healthy volunteers: a double-blind, placebo-controlled trial. Neurology 2010;74(9):755-61. doi:10.1212/WNL.0b013e3181d25b34.
Desai A, Kherallah Y, Szabo C, Marawar R. Gabapentin or pregabalin induced myoclonus: a case series and literature review. J Clin Neurosci 2019;61:225-34. doi: 10.1016/j.jocn.2018.09.019.
Ali HT, Khalil SA, Caprara ALF, Rissardo JP. Pregabalin-induced parkinsonism: case report and review of the literature. J Pharm Pract 2024;37(5):1220-4. doi:10.1177/08971900241247119.
Hoppe C, Rademacher M, Hoffmann JM, Schmidt D, Elger CE. Bodyweight gain under pregabalin therapy in epilepsy: mitigation by counseling patients? Seizure 2008;17(4):327-32. doi:10.1016/j.seizure.2007.10.004.
Page RL, 2nd, Cantu M, Lindenfeld J, Hergott LJ, Lowes BD. Possible heart failure exacerbation associated with pregabalin: case discussion and literature review. J Cardiovasc Med (Hagerstown) 2008;9(9):922-5. doi:10.2459/JCM.0b013e3282fb7629.
Rahman AA, Dell'Aniello S, Moodie EEM, Durand M, Coulombe J, Boivin JF, et al. Gabapentinoids and Risk for Severe Exacerbation in Chronic Obstructive Pulmonary Disease : A Population-Based Cohort Study. Ann Intern Med 2024;177(2):144-54. doi:10.7326/M23-0849.
Olaoye O, Dell'Aniello S, Ernst P, Suissa S, Renoux C. Risk of Severe Exacerbation Associated with Gabapentinoid Use in Patients with Chronic Obstructive Pulmonary Disease: A Population-Based Cohort Study. COPD 2025;22(1):2534002. doi: 10.1080/15412555.2025.2534002.
Evoy KE, Sadrameli S, Contreras J, Covvey JR, Peckham AM, Morrison MD. Abuse and misuse of pregabalin and gabapentin: a systematic review update. Drugs 2021;81(1):125-56. doi:10.1007/s40265-020-01432-7.
Winterfeld U, Merlob P, Baud D, Rousson V, Panchaud A, Rothuizen LE, et al. Pregnancy outcome following maternal exposure to pregabalin may call for concern. Neurology 2016;86(24):2251-7. doi:10.1212/WNL.0000000000002767.
Patorno E, Bateman BT, Huybrechts KF, MacDonald SC, Cohen JM, Desai RJ, et al. Pregabalin use early in pregnancy and the risk of major congenital malformations. Neurology 2017;88(21):2020-5. doi:10.1212/WNL.0000000000003959.
Atzenhoffer M, Peron A, Picot C, Cucherat M, Cottin J. The use of pregabalin in early pregnancy and major congenital malformations: a systematic review and meta-analysis. Reprod Toxicol 2025;136:108958. doi:10.1016/j.reprotox.2025.108958.
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