Benefits and harms of pregabalin in the management of neuropathic pain: a rapid review and meta-analysis of randomised clinical trials

Igho J Onakpoya, Elizabeth T Thomas, Joseph J Lee, Ben Goldacre, Carl J Heneghan, Igho J Onakpoya, Elizabeth T Thomas, Joseph J Lee, Ben Goldacre, Carl J Heneghan

Abstract

Objective: To assess the benefits and harms of pregabalin in the management of neuropathic pain.

Design: Rapid review and meta-analysis of phase III, randomised, placebo-controlled trials.

Participants: Adults aged 18 years and above with neuropathic pain defined according to the International Association for the Study of Pain criteria.

Interventions: Pregabalin or placebo.

Primary and secondary outcome measures: Our primary outcomes were pain (as measured using validated scales) and adverse events. Our secondary outcomes were sleep disturbance, quality of life, Patient Global Impression of Change, Clinician Global Impression scale, anxiety and depression scores, overall discontinuations and discontinuations because of adverse events.

Results: We included 28 trials comprising 6087 participants. The neuropathic pain conditions studied were diabetic peripheral neuropathy, postherpetic neuralgia, herpes zoster, sciatica (radicular pain), poststroke pain and spinal cord injury-related pain. Patients who took pregabalin reported significant reductions in pain (numerical rating scale (NRS)) compared with placebo (standardised mean difference (SMD) -0.49 (95% CI -0.66 to -0.32, p<0.00001), very low quality evidence). Pregabalin significantly reduced sleep interference scores (NRS) compared with placebo (SMD -0.38 (95% CI -0.50 to -0.26, p<0.00001), moderate quality evidence. Pregabalin significantly increased the risk of adverse events compared with placebo (RR 1.33 (95% CI 1.23 to 1.44, p<0.00001, low quality evidence)). The risks of experiencing weight gain, somnolence, dizziness, peripheral oedema, fatigue, visual disturbances, ataxia, non-peripheral oedema, vertigo and euphoria were significantly increased with pregabalin. Pregabalin was significantly more likely than placebo to lead to discontinuation of the drug because of adverse events (RR 1.91 (95% CI 1.54 to 2.37, p<0.00001), low quality evidence).

Conclusion: Pregabalin has beneficial effects on some symptoms of neuropathic pain. However, its use significantly increases the risk of a number of adverse events and discontinuation due to adverse events. The quality of the evidence from journal publications is low.

Keywords: Pregabalin; benefits; harms; meta-analysis; systematic review.

Conflict of interest statement

Competing interests: CJH has received expenses and fees for his media work. He has received expenses from the WHO and FDA and holds grant funding from the NIHR, the NIHR School of Primary Care Research, The Wellcome Trust and the WHO. He has received financial remuneration from an asbestos case. He has also received income from the publication of a series of toolkit books published by Blackwell’s. On occasion, he receives expenses for teaching EBM and is also paid for his general practitioner work in National Health Service out of hours. CEBM jointly runs the EvidenceLive Conference with the BMJ and the Overdiagnosis Conference with some international partners that are based on a non-profit making model. BG receives funding from the Laura and John Arnold Foundation and reports personal fees from intermittent additional personal income from speaking and writing for lay audiences on problems in science and medicine including regulatory shortcomings.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Flow chart showing the process for inclusion of RCTs assessing the effects of pregabalin in the management of neuropathic pain. RCTs, randomised clinical trials.
Figure 2
Figure 2
Graphical representation of the risk of bias in RCTs assessing the effects of pregabalin in the management of neuropathic pain.
Figure 3
Figure 3
Risk of bias summary for RCTs assessing the effects of pregabalin in the management of neuropathic pain.
Figure 4
Figure 4
Effect of pregabalin on pain scores in patients with neuropathic pain.
Figure 5
Figure 5
Effect of pregabalin on the risk of adverse events in patients with neuropathic pain.

References

    1. Verma V, Singh N, Singh Jaggi A. Pregabalin in neuropathic pain: evidences and possible mechanisms. Curr Neuropharmacol 2014;12:44–56. 10.2174/1570159X1201140117162802
    1. Taylor CP, Angelotti T, Fauman E. Pharmacology and mechanism of action of pregabalin: the calcium channel alpha2-delta (alpha2-delta) subunit as a target for antiepileptic drug discovery. Epilepsy Res 2007;73:137–50. 10.1016/j.eplepsyres.2006.09.008
    1. Goodman CW, Brett AS. Gabapentin and Pregabalin for pain - is increased prescribing a cause for concern? N Engl J Med 2017;377:411–4. 10.1056/NEJMp1704633
    1. Spence D. Bad medicine: gabapentin and pregabalin. BMJ 2013;347:f6747 10.1136/bmj.f6747
    1. . High-level prescribing trends for Pregabalin (BNF code 0408010AE) across all GP practices in NHS England. 2010. (accessed 8th Mar 2018).
    1. Wang Y, Yang H, Shen C, et al. . Morphine and pregabalin in the treatment of neuropathic pain. Exp Ther Med 2017;13:1393–7. 10.3892/etm.2017.4102
    1. Lyndon A, Audrey S, Wells C, et al. . Risk to heroin users of polydrug use of pregabalin or gabapentin. Addiction 2017;112:1580–9. 10.1111/add.13843
    1. Morrison EE, Sandilands EA, Webb DJ. Gabapentin and pregabalin: do the benefits outweigh the harms? J R Coll Physicians Edinb 2017;47:310–3. 10.4997/JRCPE.2017.402
    1. Iacobucci G. UK government to reclassify pregabalin and gabapentin after rise in deaths. BMJ 2017;358:j4441 10.1136/bmj.j4441
    1. Ganann R, Ciliska D, Thomas H. Expediting systematic reviews: methods and implications of rapid reviews. Implement Sci 2010;5:56 10.1186/1748-5908-5-56
    1. International Association for the Study of Pain. What is neuropathic pain? (accessed 19th Jan 2018).
    1. Sullivan GM. A primer on the validity of assessment instruments. J Grad Med Educ 2011;3:119–20. 10.4300/JGME-D-11-00075.1
    1. Higgins JP, Altman DG, Gøtzsche PC, et al. . The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928 10.1136/bmj.d5928
    1. Review Manager (RevMan) (Computer program). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2011.
    1. Furukawa TA, Barbui C, Cipriani A, et al. . Imputing missing standard deviations in meta-analyses can provide accurate results. J Clin Epidemiol 2006;59:7–10. 10.1016/j.jclinepi.2005.06.006
    1. GRADEpro. Computer program on . Version 3.6: McMaster University, 2014.
    1. Atkins D, Best D, Briss PA, et al. . Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490 10.1136/bmj.328.7454.1490
    1. Arezzo JC, Rosenstock J, Lamoreaux L, et al. . Efficacy and safety of pregabalin 600 mg/d for treating painful diabetic peripheral neuropathy: a double-blind placebo-controlled trial. BMC Neurol 2008;8:33 10.1186/1471-2377-8-33
    1. Cardenas DD, Nieshoff EC, Suda K, et al. . A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology 2013;80:533–9. 10.1212/WNL.0b013e318281546b
    1. Dworkin RH, Corbin AE, Young JP, et al. . Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 2003;60:1274–83. 10.1212/01.WNL.0000055433.55136.55
    1. Freynhagen R, Strojek K, Griesing T, et al. . Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens. Pain 2005;115:254–63. 10.1016/j.pain.2005.02.032
    1. Guan Y, Ding X, Cheng Y, et al. . Efficacy of pregabalin for peripheral neuropathic pain: results of an 8-week, flexible-dose, double-blind, placebo-controlled study conducted in China. Clin Ther 2011;33:159–66. 10.1016/j.clinthera.2011.02.007
    1. Holbech JV, Bach FW, Finnerup NB, et al. . Imipramine and pregabalin combination for painful polyneuropathy: a randomized controlled trial. Pain 2015;156:958–66. 10.1097/j.pain.0000000000000143
    1. Huffman CL, Goldenberg JN, Weintraub J, et al. . Efficacy and safety of once-daily controlled-release pregabalin for the treatment of patients with postherpetic neuralgia: a double-blind, enriched enrollment randomized withdrawal, placebo-controlled trial. Clin J Pain 2017;33:569–78. 10.1097/AJP.0000000000000445
    1. Kanodia SK, Singhal KC. A study on efficacy of Pregabalin in acute Herpetic Neuralgia. Ann Neurosci 2011;18:148–50. 10.5214/ans.0972.7531.1118405
    1. Kim JS, Bashford G, Murphy TK, et al. . Safety and efficacy of pregabalin in patients with central post-stroke pain. Pain 2011;152:1018–23. 10.1016/j.pain.2010.12.023
    1. Krcevski Skvarc N, Kamenik M. Effects of pregabalin on acute herpetic pain and postherpetic neuralgia incidence. Wien Klin Wochenschr 2010;122(Suppl 2):49–53. 10.1007/s00508-010-1345-x
    1. Lesser H, Sharma U, LaMoreaux L, et al. . Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 2004;63:2104–10. 10.1212/01.WNL.0000145767.36287.A1
    1. Liu Q, Chen H, Xi L, et al. . A randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of pregabalin for postherpetic neuralgia in a population of Chinese patients. Pain Pract 2017;17:62–9. 10.1111/papr.12413
    1. Mathieson S, Maher CG, McLachlan AJ, et al. . Trial of pregabalin for acute and chronic sciatica. N Engl J Med 2017;376:1111–20. 10.1056/NEJMoa1614292
    1. Moon DE, Lee DI, Lee SC, et al. . Efficacy and tolerability of pregabalin using a flexible, optimized dose schedule in Korean patients with peripheral neuropathic pain: a 10-week, randomized, double-blind, placebo-controlled, multicenter study. Clin Ther 2010;32:2370–85. 10.1016/j.clinthera.2011.01.014
    1. Rauck R, Makumi CW, Schwartz S, et al. . A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract 2013;13:485–96. 10.1111/papr.12014
    1. Richter RW, Portenoy R, Sharma U, et al. . Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain 2005;6:253–60. 10.1016/j.jpain.2004.12.007
    1. Rosenstock J, Tuchman M, LaMoreaux L, et al. . Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 2004;110:628–38. 10.1016/j.pain.2004.05.001
    1. Sabatowski R, Gálvez R, Cherry DA, et al. . Pregabalin reduces pain and improves sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109:26–35. 10.1016/j.pain.2004.01.001
    1. Satoh J, Yagihashi S, Baba M, et al. . Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week, randomized, double-blind, placebo-controlled trial. Diabet Med 2011;28:109–16. 10.1111/j.1464-5491.2010.03152.x
    1. Shabbir B, Shafi F, Mahboob F. Amitriptyline Vs Pregabalin in Painful Diabetic Neuropathy A Randomised Placebo-Based Study. P J M H S 2011;5:745–7.
    1. Siddall PJ, Cousins MJ, Otte A, et al. . Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 2006;67:1792–800. 10.1212/01.wnl.0000244422.45278.ff
    1. Simpson DM, Schifitto G, Clifford DB, et al. . Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 2010;74:413–20. 10.1212/WNL.0b013e3181ccc6ef
    1. Simpson DM, Rice AS, Emir B, et al. . A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy. Pain 2014;155:1943–54. 10.1016/j.pain.2014.05.027
    1. Stacey BR, Barrett JA, Whalen E, et al. . Pregabalin for postherpetic neuralgia: placebo-controlled trial of fixed and flexible dosing regimens on allodynia and time to onset of pain relief. J Pain 2008;9:1006–17. 10.1016/j.jpain.2008.05.014
    1. Tölle T, Freynhagen R, Versavel M, et al. . Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain 2008;12:203–13. 10.1016/j.ejpain.2007.05.003
    1. van Seventer R, Feister HA, Young JP, et al. . Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin 2006;22:375–84. 10.1185/030079906X80404
    1. van Seventer R, Bach FW, Toth CC, et al. . Pregabalin in the treatment of post-traumatic peripheral neuropathic pain: a randomized double-blind trial. Eur J Neurol 2010;17:1082–9. 10.1111/j.1468-1331.2010.02979.x
    1. Vranken JH, Dijkgraaf MG, Kruis MR, et al. . Pregabalin in patients with central neuropathic pain: a randomized, double-blind, placebo-controlled trial of a flexible-dose regimen. Pain 2008;136(1-2):150–7. 10.1016/j.pain.2007.06.033
    1. Zhang SS, Wu Z, Zhang LC, et al. . Efficacy and safety of pregabalin for treating painful diabetic peripheral neuropathy: a meta-analysis. Acta Anaesthesiol Scand 2015;59:147–59. 10.1111/aas.12420
    1. Wang SL, Wang H, Nie HY, et al. . The efficacy of pregabalin for acute pain control in herpetic neuralgia patients: A meta-analysis. Medicine 2017;96:e9167 10.1097/MD.0000000000009167
    1. Semel D, Murphy TK, Zlateva G, et al. . 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 10.1186/1471-2296-11-85
    1. Freeman R, Durso-Decruz E, Emir B. Efficacy, safety, and tolerability of pregabalin treatment for painful diabetic peripheral neuropathy: findings from seven randomized, controlled trials across a range of doses. Diabetes Care 2008;31:1448–54. 10.2337/dc07-2105
    1. Finnerup NB, Attal N, Haroutounian S, et al. . Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol 2015;14:162–73. 10.1016/S1474-4422(14)70251-0
    1. Wiffen PJ, Derry S, Moore RA, et al. . Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews. Cochrane Database Syst Rev 2013;11:CD010567 10.1002/14651858.CD010567.pub2
    1. Zaccara G, Gangemi P, Perucca P, et al. . The adverse event profile of pregabalin: a systematic review and meta-analysis of randomized controlled trials. Epilepsia 2011;52:826–36. 10.1111/j.1528-1167.2010.02966.x
    1. Freynhagen R, Serpell M, Emir B, et al. . A comprehensive drug safety evaluation of pregabalin in peripheral neuropathic pain. Pain Pract 2015;15:47–57. 10.1111/papr.12146
    1. Attal N, Cruccu G, Baron R, et al. . EFNS guidelines on the pharmacological treatment of neuropathic pain: 2010 revision. Eur J Neurol 2010;17:1113–e88. 10.1111/j.1468-1331.2010.02999.x
    1. Bril V, England J, Franklin GM, et al. . Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758–65. 10.1212/WNL.0b013e3182166ebe
    1. Moulin D, Boulanger A, Clark AJ, et al. . Pharmacological management of chronic neuropathic pain: revised consensus statement from the Canadian Pain Society. Pain Res Manag 2014;19:328–35. Nov-Dec 10.1155/2014/754693
    1. Gilron I. Methodological issues associated with clinical trials in neuropathic pain. Expert Rev Clin Pharmacol 2016;9:1399–402. 10.1080/17512433.2016.1240029
    1. Taylor-Phillips S, Geppert J, Stinton C, et al. . Comparison of a full systematic review versus rapid review approaches to assess a newborn screening test for tyrosinemia type 1. Res Synth Methods 2017;8:475–84. 10.1002/jrsm.1255
    1. Flacco ME, Manzoli L, Boccia S, et al. . Head-to-head randomized trials are mostly industry sponsored and almost always favor the industry sponsor. J Clin Epidemiol 2015;68:811–20. 10.1016/j.jclinepi.2014.12.016
    1. Lundh A, Lexchin J, Mintzes B, et al. . Industry sponsorship and research outcome. Cochrane Database Syst Rev 2017;2:MR000033 10.1002/14651858.MR000033.pub3
    1. Malik KM, Nelson AM, Avram MJ, et al. . Efficacy of Pregabalin in the Treatment of Radicular Pain: Results of a Controlled Trial. Anesth Pain Med 2015;5:e28110 10.5812/aapm.28110
    1. NHS Gloucestershire. Guidance for Review of Patients taking Pregabalin for Neuropathic Pain. Available at (Last accessed 1st Mar 2018).
    1. Watt A, Cameron A, Sturm L, et al. . Rapid versus full systematic reviews: validity in clinical practice? ANZ J Surg 2008;78:1037–40. 10.1111/j.1445-2197.2008.04730.x

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