Advertisement

Cardiovascular Safety of Gabapentinoids

  • Leo F. BuckleyEmail author
  • Emad Alsarraf
Pharmacology Care (J Fanikos, Section Editor)
  • 8 Downloads
Part of the following topical collections:
  1. Topical Collection on Pharmacology Care

Abstract

Purpose of Review

The objective of this manuscript is to describe the cardiovascular effects of the gabapentinoids gabapentin and pregabalin.

Recent Findings

The most frequent adverse effects of gabapentin and pregabalin affect the central nervous system, such as somnolence and fatigue. Additionally, pregabalin, and a much lesser extent, gabapentin, may adversely affect the cardiovascular system. Pregabalin induces peripheral edema and may cause or exacerbate heart failure. Pregabalin use has been associated with QTc prolongation in patients taking other QTc–prolonging agents, although the relative contributions of pregabalin to QTc prolongation may be minimal. Pregabalin and gabapentin have been associated with a dose-related increased risk of atrial fibrillation. Most evidence for adverse cardiovascular effects of gabapentinoids derives from case reports and observational studies.

Summary

Clinicians should be aware of the potential for pregabalin and possibly gabapentin to contribute to cardiovascular dysfunction.

Keywords

Gabapentin Pregabalin Cardiovascular Adverse drug effects 

Notes

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Ramsay RE. Clinical efficacy and safety of gabapentin. Neurology [Internet]. 1994 [cited 2019 Jan 27];44:S23–30; discussion S31–2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8022537
  2. 2.
    Gee NS, Brown JP, Dissanayake VU, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J Biol Chem [Internet]. 1996 [cited 2019 Jan 28];271:5768–76. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8621444
  3. 3.
    Walters AS, Ondo WG, Kushida CA, Becker PM, Ellenbogen AL, Canafax DM, Barrett RW, XP045 Study Group. gabapentin enacarbil in restless legs syndrome. Clin Neuropharmacol [Internet]. 2009 [cited 2019 Feb 28];32:311–320. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19667976
  4. 4.
    Harden RN, Freeman R, Rainka M, Zhang L, Bell C, Berges A, Chen C, Graff O, Harding K, Hunter S, Kavanagh S, Schwartzbach C, Warren S, McClung C. A Phase 2a, randomized, crossover trial of gabapentin enacarbil for the treatment of postherpetic neuralgia in gabapentin inadequate responders. Pain Med [Internet]. 2013 [cited 2019 Mar 1];14:1918–1932. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24102928
  5. 5.
    Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia [Internet]. 2004 [cited 2019 Jan 27];45:13–18. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15315511
  6. 6.
    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 [Internet]. 2011 [cited 2019 Jan 28];52:826–836. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21320112
  7. 7.
    Carbone S, Dixon DL, Buckley LF, Abbate A. Glucose-lowering therapies for cardiovascular risk reduction in Type 2 diabetes mellitus: state-of-the-art Review [Internet]. Mayo Clin. Proc. 2018 [cited 2019 Feb 28];93:1629–1647. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30392544
  8. 8.
    • Murphy N, Mockler M, Ryder M, Ledwidge M, McDonald K. Decompensation of chronic heart failure associated with pregabalin in patients with neuropathic pain. J Card Fail [Internet]. 2007 [cited 2018 Dec 15];13:227–229. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17448421. This was one of the first case reports that described worsening heart failure associated with pregabalin use.
  9. 9.
    De Smedt RHE, Jaarsma T, van den Broek SAJ, Haaijer-Ruskamp FM. Decompensation of chronic heart failure associated with pregabalin in a 73-year-old patient with postherpetic neuralgia: a case report. Br J Clin Pharmacol [Internet]. 2008 [cited 2018 Dec 15];66:327–328. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18507657
  10. 10.
    Page RL, Cantu M, Lindenfeld J, Hergott LJ, Lowes BD. Possible heart failure exacerbation associated with pregabalin: case discussion and literature review. J Cardiovasc Med [Internet]. 2008 [cited 2018 Dec 15];9:922–925. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18695430
  11. 11.
    Erdoğan G, Ceyhan D, Güleç S. Possible heart failure associated with pregabalin use: case report. Agri [Internet]. 2011 [cited 2018 Dec 15];23:80–3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21644108
  12. 12.
    Matsuki Y, Morikawa M, Nishimoto T, Yasuda Y, Shigemi K. Heart failure assocated with pregabalin. Pain Physician [Internet]. [cited 2018 Dec 15];15:E536–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22828703
  13. 13.
    Fong T, Lee AJ. Pregabalin-associated heart failure decompensation in a patient with a history of stage I heart failure. Ann Pharmacother [Internet]. 2014 [cited 2019 Jan 28];48:1077–1081. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24769529
  14. 14.
    Guzelkucuk U, Duman I, Yılmaz B, Tan AK. Reversible post-pregabalin peripheral edema in a spinal cord injury patient. Spinal Cord [Internet]. 2012 [cited 2018 Dec 15];50:472–473. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21747401
  15. 15.
    Gallagher R, Apostle N. Peripheral edema with pregabalin. Can Med Assoc J [Internet]. 2013 [cited 2018 Dec 15];185:E506–E506. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23128284
  16. 16.
    Alp R, Citil M, Uzun M, Alp S, Topcu B, Uzlu E, Erdogan HM. Effects of therapeutic doses of Pregabalin on QTc interval in conscious rabbits. Eur Rev Med Pharmacol Sci [Internet]. [cited 2018 Dec 15];12:223–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18727453
  17. 17.
    •• Chen D, Lal R, Zomorodi K, Atluri H, Ho J, Luo W, Tovera J, Bonzo D, Cundy K. Evaluation of gabapentin enacarbil on cardiac repolarization: a randomized, double-blind, placebo- and active-controlled, crossover thorough QT/QTc study in healthy adults. Clin Ther [Internet]. 2012 [cited 2019 Feb 28];34:351–362.e3. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22325733. This study demonstrates a lack of effect on QTc interval for the enacarbil formulation of gabapentin.
  18. 18.
    Rasimas JJ, Burkhart KK. Cardiac conduction disturbances after an overdose of nefazodone and gabapentin. Am J Emerg Med [Internet]. 2006 [cited 2018 Dec 15];24:886–888. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17098120
  19. 19.
    Hill CM, Mostafa P, Stuart AG, Thomas DW, Walker R V. ECG variations in patients pre- and post-local anaesthesia and analgesia. Br Dent J [Internet]. 2009 [cited 2018 Dec 15];207:E23–E23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19893562
  20. 20.
    Schiavo A, Stagnaro FM, Salzano A, Marra AM, Bobbio E, Valente P, Grassi S, Miniero M, Arcopinto M, Matarazzo M, Napoli R, Cittadini A. Pregabalin-induced first degree atrioventricular block in a young patient treated for pain from extrapulmonary tuberculosis. Monaldi Arch Chest Dis [Internet] 2017 [cited 2019 Jan 28];87:838. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29424197, 87
  21. 21.
    Aksakal E, Bakirci EM, Emet M, Uzkeser M. Complete atrioventricular block due to overdose of pregabalin. Am J Emerg Med [Internet]. 2012 [cited 2019 Jan 29];30:2101.e1–4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0735675712000897
  22. 22.
    • Ortiz de Landaluce L, Carbonell P, Asensio C, Escoda N, López P, Laporte JR Gapentin and pregabalin and risk of atrial fibrillation in the elderly: a population-based cohort study in an electronic prescription database. Drug Saf [Internet]. 2018 [cited 2019 Feb 28];41:1325–1331. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29956217. This article reports a significant association of gabapentin and pregabalin to risk of atrial fibrillation. While further research should validate this association and elucidate its mechanism, clinicians should remain cognizant of the potential for these agents to contribute to the development of atrial fibrillation in older adults.
  23. 23.
    Diaper A, Rich AS, Wilson SJ, Craig K, Dourish CT, Dawson GR, Nutt DJ, Bailey JE. Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double-blind, placebo-controlled study of orthostatic challenge, blood pressure and heart rate. Hum Psychopharmacol Clin Exp [Internet]. 2013 [cited 2019 Jan 29];28:562–575. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23955418
  24. 24.
    White AT, Light KC, Bateman L, Hughen RW, Vanhaitsma TA, Light AR. Effect of pregabalin on cardiovascular responses to exercise and postexercise pain and fatigue in fibromyalgia: a randomized, double-blind, crossover pilot study. Pain Res Treat [Internet]. 2015 [cited 2019 Jan 28];2015:1–10. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27026828
  25. 25.
    Spiller HA, Dunaway MD, Cutino L. Massive gabapentin and presumptive quetiapine overdose. Vet Hum Toxicol [Internet]. 2002 [cited 2018 Dec 15];44:243–4. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12136976
  26. 26.
    Singewald N, Pfitscher A, Philippu A. Effects of gamma-vinyl GABA (vigabatrin) on blood pressure and body weight of hypertensive and normotensive rats. Naunyn Schmiedebergs Arch Pharmacol [Internet] 1992 [cited 2018 Dec 15];345:181–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1570022
  27. 27.
    Behuliak M, Bencze M, Polgárová K, Kuneš J, Vaněčková I, Zicha J. Hemodynamic response to gabapentin in conscious spontaneously hypertensive rats. Hypertension [Internet]. 2018 [cited 2019 Jan 28];72:676–685. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30354755

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacy ServicesBrigham and Women’s HospitalBostonUSA

Personalised recommendations