Seizures as an Adverse Effect of Pregabalin Consumption: A Systematic Review

Document Type : Review Article(s)

Authors

1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran,

2 Medical Toxicology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Immunology Department, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Community Medicine Department, Mashhad University of Medical Sciences, Mashhad, Iran

5 Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

6 Psychiatry and Behavioral Sciences Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

7 International UNESCO Center for Health-Related Basic Sciences and Human Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran

10.34172/ahj.1527

Abstract

Background: Pregabalin (PGB), a gabapantinoid drug, which is commonly prescribed by physicians and some patients abuse it,
can lead to seizure. Pregabalin-induced seizures (PGBIS) and their risk factors were systematically reviewed.
Methods: The databases were searched from January 1, 2011, to August 1, 2022. Studies that reported PGBIS were included. The
records were assessed according to the PRISMA-P protocol.
Results: From a total of 224 records, 11 studies were included, comprising four cross-sectional studies and seven case reports. The
data from the cross-sectional studies were notably limited. Seven studies documented nine cases (five females and four males),
with a median age of 51 years (ranging from 16 to 65). PGB was used for therapeutic purposes, abuse, and suicide attempts. One
case had kidney dysfunction. A significant number of cases used PGB with other drugs. There was no difference between the
ingested dose of PGB in men (2700 and 4200 mg) and women (3000, 1200, 3825, and 1200 mg). All cases had normal renal
function, except for one case.
Conclusion: PGBIS is not common. However, it was reported for all purposes of PGB consumption. No specific risk factor for
PGBIS was found. It was more commonly reported in females, patients who consumed high doses of PGB (>1200 mg), patients
who ingested multiple drugs, and patients with renal insufficiency. The dosages used for therapeutic purposes were much lower
than in the other two groups

Keywords


1. Di Guilmi MN, Urbano FJ, Inchauspe CG, Uchitel OD.
Pregabalin modulation of neurotransmitter release is mediated
by change in intrinsic activation/inactivation properties
of ca(v)2.1 calcium channels. J Pharmacol Exp Ther.
2011;336(3):973-82. doi: 10.1124/jpet.110.172171.
2. Etemad L, Moshiri M, Moallem SA. Epilepsy drugs and effects
on fetal development: Potential mechanisms. J Res Med Sci.
2012;17(9):876-81.
3. Bockbrader HN, Radulovic LL, Posvar EL, Strand JC, Alvey
CW, Busch JA, et al. Clinical pharmacokinetics of pregabalin
in healthy volunteers. J Clin Pharmacol. 2010;50(8):941-50.
doi: 10.1177/0091270009352087.
4. Freynhagen R, Grond S, Schüpfer G, Hagebeuker A, Schmelz
M, Ziegler D, et al. Efficacy and safety of pregabalin in
treatment refractory patients with various neuropathic pain
entities in clinical routine. Int J Clin Pract. 2007;61(12):1989-
96. doi: 10.1111/j.1742-1241.2007.01589.x.
5. Sebastian B, Talikoti AT, Nelamangala K, Krishnamurthy D.
Effect of oral pregabalin as preemptive analgesic in patients
undergoing lower limb orthopedic surgeries under spinal
anaesthesia. J Clin Diagn Res. 2016;10(7):UC01-4. doi:
10.7860/jcdr/2016/18854.8081.
6. Rani S, Bhatia MS. Pregabalin dependence - a rising concern.
Ind Psychiatry J. 2024;33(Suppl 1):S299-300. doi: 10.4103/
ipj.ipj_179_23.
7. Vicente J, Wiessing L. European Monitoring Centre for Drugs
and Drug Addiction annual report 2007: positive assessment
of HIV in IDUs though hepatitis C still very high. Euro Surveill.
2007;12(47):3317. doi: 10.2807/esw.12.47.03317-en.
8. Schwan S, Sundström A, Stjernberg E, Hallberg E, Hallberg P.
A signal for an abuse liability for pregabalin--results from the
Swedish spontaneous adverse drug reaction reporting system.
Eur J Clin Pharmacol. 2010;66(9):947-53. doi: 10.1007/
s00228-010-0853-y.
9. Carrus D, Schifano F. Pregabalin misuse-related issues;
intake of large dosages, drug-smoking allegations, and
possible association with myositis: two case reports. J
Clin Psychopharmacol. 2012;32(6):839-40. doi: 10.1097/
JCP.0b013e318272864d.
10. Gahr M, Freudenmann RW, Hiemke C, Kölle MA, SchönfeldtLecuona C. Pregabalin abuse and dependence in Germany:
results from a database query. Eur J Clin Pharmacol.
2013;69(6):1335-42. doi: 10.1007/s00228-012-1464-6.
11. Tambon M, Ponté C, Jouanjus E, Fouilhé N, Micallef J, LapeyreMestre M. Gabapentinoid abuse in France: evidence on health
consequences and new points of vigilance. Front Psychiatry.
2021;12:639780. doi: 10.3389/fpsyt.2021.639780.
12. Mease PJ, Russell IJ, Arnold LM, Florian H, Young JP Jr, Martin
SA, et al. A randomized, double-blind, placebo-controlled,
phase III trial of pregabalin in the treatment of patients with
fibromyalgia. J Rheumatol. 2008;35(3):502-14.
13. Hindmarch I, Trick L, Ridout F. A double-blind, placebo- and
positive-internal-controlled (alprazolam) investigation of the
cognitive and psychomotor profile of pregabalin in healthy
volunteers. Psychopharmacology (Berl). 2005;183(2):133-43.
doi: 10.1007/s00213-005-0172-7.
14. Benassayag Kaduri N, Dressler R, Abu Ahmad W, Rotshild
V. Trends in pregabalin use and prescribing patterns in the
adult population: a 10-year pharmacoepidemiologic study.
CNS Drugs. 2024;38(2):153-62. doi: 10.1007/s40263-024-
01064-5.
15. Nemati A, Dadpour B, Etemad L, Mousavi SR, Alizadeh
Ghomsari A, Mousavi SH, et al. Epidemiological aspects and
pattern of intoxication among elderly in Khorasan-Razavi;
northeast of Iran. J Prev (2022). 2024. doi: 10.1007/s10935-
024-00804-z.
16. Papazisis G, Kouvelas D. The abuse liability of pregabalin:
a pharmacological approach. Research and Advances in
Psychiatry. 2015;2(2):75-80.
17. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann
TC, Mulrow CD, et al. The PRISMA 2020 statement: an
updated guideline for reporting systematic reviews. BMJ.
2021;372:n71. doi: 10.1136/bmj.n71.
18. Isoardi KZ, Polkinghorne G, Harris K, Isbister GK. Pregabalin
poisoning and rising recreational use: a retrospective
observational series. Br J Clin Pharmacol. 2020;86(12):2435-
40. doi: 10.1111/bcp.14348.
19. Dufayet L, Care W, Deheul S, Laborde-Casterot H, Nisse P,
Langrand J, et al. Increase in pregabalin recreational use in
adolescents in France. Clin Toxicol (Phila). 2021;59(11):1027-
30. doi: 10.1080/15563650.2021.1892719.
20. Ryan N, Page C, Isbister G. The Incidence of Pregabalin
Overdose Has Increased but Clinical Effects Are Primarily
Associated with the Coingestants. Brisbane, Australia: TAPNA;
2016 .
21. Ocak M, Uçar C. The effectiveness of hemodialysis in case
of intoxication with pregabalin. J Emerg Med Case Rep.
2019;10(4):112-4. doi: 10.33706/jemcr.535561.
22. Hussain K, Nabil B, Sonia K, Souda AS. Pregabalin induced
absence status epilepticus. J Neurol Sci. 2019;405:68. doi:
10.1016/j.jns.2019.10.897.
23. Slocum GW, Schult RF, Gorodetsky RM, Wiegand TJ, Kamali
M, Acquisto NM. Pregabalin and paradoxical reaction of
seizures in a large overdose. Toxicol Commun. 2018;2(1):19-
20. doi: 10.1080/24734306.2018.1458465.
24. Reedy SJ, Schwartz MD. A case series of recreational
pregabalin overdose resulting in generalized seizures. Clin
Toxicol. 2010;48(6):616-7.
25. Hsiao F, Ma A, Muthukanagaraj P. Pregabalin toxicityinduced posterior reversible encephalopathy syndrome.
Cureus. 2022;14(6):e25656. doi: 10.7759/cureus.25656.
26. Ozturk HM, Morkavuk G. Nasal pregabalin overdose
and myclonus: a new way of misuse. Psychiatry
Clin Psychopharmacol. 2019;29(2):216-9. doi:
10.1080/24750573.2017.1422959.
27. Haji K, Muthu S, Banakh I, Tiruvoipati R. Prolonged encephalopathy and associated nonconvulsive seizures from
suspected pregabalin and tapentadol: two case reports and
review of literature. Clin Case Rep. 2021;9(3):1362-6. doi:
10.1002/ccr3.3772.
28. Etemad L, Mohammad A, Mohammadpour AH, Vahdati
Mashhadi N, Moallem SA. Teratogenic effects of pregabalin
in mice. Iran J Basic Med Sci. 2013;16(10):1065-70.
29. Michelucci R, Pasini E, Riguzzi P, Andermann E, Kälviäinen R,
Genton P. Myoclonus and seizures in progressive myoclonus
epilepsies: pharmacology and therapeutic trials. Epileptic
Disord. 2016;18(S2):145-53. doi: 10.1684/epd.2016.0861.
30. Salem NA, Alsaedi AM, Alasmari BG, Almarghalani RZ, Algobe
SM, Alesawy NH. Neurotoxic assessment of chronic abuse of
pregabalin in Wistar rats. J Pharm Res Int. 2021;33(27B):58-
66. doi: 10.9734/jpri/2021/v33i27B31505.
31. Taha SH, Zaghloul HS, Ali A, Gaballah IF, Rashed LA,
Aboulhoda BE. The neurotoxic effect of long-term use of
high-dose pregabalin and the role of alpha tocopherol in
amelioration: implication of MAPK signaling with oxidative
stress and apoptosis. Naunyn Schmiedebergs Arch Pharmacol.
2020;393(9):1635-48. doi: 10.1007/s00210-020-01875-5.
32. Tai TY, Warner LN, Jones TD, Jung S, Concepcion FA,
Skyrud DW, et al. Antiepileptic action of c-Jun N-terminal
kinase (JNK) inhibition in an animal model of temporal lobe
epilepsy. Neuroscience. 2017;349:35-47. doi: 10.1016/j.
neuroscience.2017.02.024.
33. Jung S, Bullis JB, Lau IH, Jones TD, Warner LN, Poolos NP.
Downregulation of dendritic HCN channel gating in epilepsy
is mediated by altered phosphorylation signaling. J Neurosci.
2010;30(19):6678-88. doi: 10.1523/jneurosci.1290-10.2010.
34. Jeon SH, Kim YS, Bae CD, Park JB. Activation of JNK and p38
in rat hippocampus after kainic acid induced seizure. Exp Mol
Med. 2000;32(4):227-30. doi: 10.1038/emm.2000.37.
35. Zhang W, Wang X, Yu M, Li JA, Meng H. The c-Jun N-terminal
kinase signaling pathway in epilepsy: activation, regulation,
and therapeutics. J Recept Signal Transduct Res. 2018;38(5-
6):492-8. doi: 10.1080/10799893.2019.1590410.
36. Parekh M, Dash GK, Ahamed I. Pregabalin toxicity manifesting
as reversible encephalopathy with continuous triphasic
waves in electroencephalogram. Clin Neuropharmacol.
2017;40(5):226-8. doi: 10.1097/wnf.0000000000000245.
37. Ligtenstein S, Song J, Jin J, Sun H, Paixao L, Zafar S, et al.
Do triphasic waves and nonconvulsive status epilepticus
arise from similar mechanisms? A computational model.
J Clin Neurophysiol. 2021;38(5):366-75. doi: 10.1097/
wnp.0000000000000719.
38. Kim JB, Jung JM, Park MH, Lee EJ, Kwon DY. Negative
myoclonus induced by gabapentin and pregabalin: a
case series and systematic literature review. J Neurol Sci.
2017;382:36-9. doi: 10.1016/j.jns.2017.09.019.
39. Tariq M, Javaid S, Ashraf W, Anjum SM, Rasool MF,
Siddique F, et al. Unveiling the potential of perampanel
and pregabalin in addressing pentylenetetrazole-induced
electrographic alterations and neurobehavioral anomalies.
Biomed Pharmacother. 2024;170:115935. doi: 10.1016/j.
biopha.2023.115935.
40. 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.
41. Prakash S, Rathore C, Rana K, Patel H. Antiepileptic drugs
and serotonin syndrome - a systematic review of case series
and case reports. Seizure. 2021;91:117-31. doi: 10.1016/j.
seizure.2021.06.004.
42. Rissardo JP, Caprara ALF. Pregabalin-associated movement
disorders: a literature review. Brain Circ. 2020;6(2):96-106.
doi: 10.4103/bc.bc_57_19.
43. Bockbrader HN, Wesche D, Miller R, Chapel S, Janiczek
N, Burger P. A comparison of the pharmacokinetics and
pharmacodynamics of pregabalin and gabapentin. Clin
Pharmacokinet. 2010;49(10):661-9. doi: 10.2165/11536200-
000000000-00000.
44. Raouf M, Atkinson TJ, Crumb MW, Fudin J. Rational dosing of
gabapentin and pregabalin in chronic kidney disease. J Pain
Res. 2017;10:275-8. doi: 10.2147/jpr.S130942.
45. Yoo L, Matalon D, Hoffman RS, Goldfarb DS. Treatment of
pregabalin toxicity by hemodialysis in a patient with kidney
failure. Am J Kidney Dis. 2009;54(6):1127-30. doi: 10.1053/j.
ajkd.2009.04.014.
46. Chwedorowicz R, Ɓukawski K, Raszewski G, Czuczwar SJ.
Effect of caffeine on the anticonvulsant action of pregabalin
against electroconvulsions in mice. Pharmacol Rep.
2022;74(2):431-7. doi: 10.1007/s43440-022-00356-1.
47. Bockbrader HN, Burger P, Knapp L, Corrigan BW. Population
pharmacokinetics of pregabalin in healthy subjects and
patients with chronic pain or partial seizures. Epilepsia.
2011;52(2):248-57. doi: 10.1111/j.1528-1167.2010.02933.x.
48. Swartz CM, Michael N. Age-based seizure threshold
determination. J ECT. 2013;29(1):18-20. doi: 10.1097/
YCT.0b013e3182656e5d.
49. Semel D, Murphy TK, Zlateva G, Cheung R, Emir B. Evaluation
of the safety and efficacy of pregabalin in older patients with
neuropathic pain: results from a pooled analysis of 11 clinical
studies. BMC Fam Pract. 2010;11:85. doi: 10.1186/1471-
2296-11-85.