Use of the gabapentinoids for pain continues to increase. In 2018, the US Food and Drug Administration (FDA) strengthened the warnings for both gabapentin and pregabalin to emphasize the central nervous system side effects and the risk of respiratory depression, especially when combined with other centrally acting drugs. We reviewed the published comparative effectiveness literature for gabapentinoids for pain as well as all trials (published and unpublished) used by the FDA for the approval of the five pain indications for these agents (one for gabapentin, four for pregabalin). Among the findings of interest are the fact that the FDA rejected the application for gabapentin for diabetic peripheral neuropathy based on the risk versus benefit profile of that drug in the clinical trials that were submitted by the manufacturer. Additionally, both the comparative effectiveness trials as well as the studies used by the FDA tend to be short in duration and show only modest pain benefits for the gabapentinoids. The placebo response in these trials was frequently one-third to one-half as great as the pain benefit demonstrated by the gabapentinoid. Based on the available clinical trial evidence, we feel prescribers should be cautious when using gabapentinoids for pain, particularly when using these agents for a prolonged period or when combined with other, centrally acting agents.
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The United States Food and Drug Administration. FDA warns about serious breathing problems with gabapentin and pregabalin; 2019.
Goodman CW, Brett AS. Gabapentin and pregabalin for pain—is increased prescribing a cause for concern? N Engl J Med. 2017;377(5):411–4.
Throckmorton DC, Gottlieb S, Woodcock J. The FDA and the next wave of drug abuse—proactive pharmacovigilance. N Engl J Med. 2018;379(3):205–7.
Mattson CL, Chowdhury F, Gilson TP. Notes from the field: trends in gabapentin detection and involvement in drug overdose deaths—23 states and the District of Columbia, 2019–2020. MMWR Morb Mortal Wkly Rep. 2022;71(19):664–6.
Kuehn BM. Growing role of gabapentin in opioid-related overdoses highlights misuse potential and off-label prescribing practices. JAMA. 2022;328:1283–5.
Gorfinkel LR, et al. Trends in prescriptions for non-opioid pain medications among U.S. adults with moderate or severe pain, 2014–2018. J Pain. 2022;23(7):1187–95.
(CDC), C.f.D.C., Draft CDC Clinical Practice Guideline for Prescribing Opioids—United States, 2022; 2022.
Vedula SS, et al. Implementation of a publication strategy in the context of reporting biases. A case study based on new documents from Neurontin litigation. Trials. 2012;13:136.
Mathieson S, et al. Trial of pregabalin for acute and chronic sciatica. N Engl J Med. 2017;376(12):1111–20.
Turner EH. How to access and process FDA drug approval packages for use in research. BMJ. 2013;347: f5992.
Rauck R, et al. A randomized, controlled trial of gabapentin enacarbil in subjects with neuropathic pain associated with diabetic peripheral neuropathy. Pain Pract. 2013;13(6):485–96.
Dolgun H, et al. Gabapentin versus pregabalin in relieving early post-surgical neuropathic pain in patients after lumbar disc herniation surgery: a prospective clinical trial. Neurol Res. 2014;36(12):1080–5.
French J, et al. Adjunctive pregabalin vs gabapentin for focal seizures: interpretation of comparative outcomes. Neurology. 2016;87(12):1242–9.
Schmidt P, Rao S. Effects of gabapentin, pregabalin and gastroretentive gabapentin on simulated driving, daytime sedation and cognition. Pain Manag. 2018;8(4):297–306.
Robertson K, et al. Effect of gabapentin vs pregabalin on pain intensity in adults with chronic sciatica (PAGPROS). JAMA Neurol. 2018;76(1):28–34.
Mishra S, et al. A comparative efficacy of amitriptyline, gabapentin, and pregabalin in neuropathic cancer pain: a prospective randomized double-blind placebo-controlled study. Am J Hosp Palliat Care. 2012;29(3):177–82.
Mimenza Alvarado A, Aguilar Navarro S. Clinical trial assessing the efficacy of gabapentin plus B complex (B1/B12) versus pregabalin for treating painful diabetic neuropathy. J Diabetes Res. 2016;2016:4078695.
Atalay H, et al. Cross-over, open-label trial of the effects of gabapentin versus pregabalin on painful peripheral neuropathy and health-related quality of life in haemodialysis patients. Clin Drug Investig. 2013;33(6):401–8.
Biyik Z, et al. Gabapentin versus pregabalin in improving sleep quality and depression in hemodialysis patients with peripheral neuropathy: a randomized prospective crossover trial. Int Urol Nephrol. 2013;45(3):831–7.
Gammoh O, et al. The clinical difference between gabapentin and pregabalin: data from a pilot comparative trial. Rev Recent Clin Trials. 2021;16(3):279–87.
Solak Y, et al. Pregabalin versus gabapentin in the treatment of neuropathic pruritus in maintenance haemodialysis patients: a prospective, crossover study. Nephrology (Carlton). 2012;17(8):710–7.
Khurana G, et al. Postoperative pain and long-term functional outcome after administration of gabapentin and pregabalin in patients undergoing spinal surgery. Spine (Phila Pa 1976). 2014;39(6):E363–8.
Nakhli MS, et al. Effects of gabapentinoids premedication on shoulder pain and rehabilitation quality after laparoscopic cholecystectomy: pregabalin versus gabapentin. Pain Res Manag. 2018;2018:9834059.
Bekawi MS, et al. Clinical study evaluating pregabalin efficacy and tolerability for pain management in patients undergoing laparoscopic cholecystectomy. Clin J Pain. 2014;30(11):944–52.
Ozgencil E, et al. Perioperative administration of gabapentin 1,200 mg day-1 and pregabalin 300 mg day-1 for pain following lumbar laminectomy and discectomy: a randomised, double-blinded, placebo-controlled study. Singapore Med J. 2011;52(12):883–9.
Pakravan M, et al. Pregabalin and gabapentin for post-photorefractive keratectomy pain: a randomized controlled trial. Eur J Ophthalmol. 2012;22(Suppl 7):S106–13.
Pandey CK, et al. Comparative evaluation of prophylactic use of pregabalin, gabapentin and diclofenac sodium for prevention of succinylcholine-induced myalgia: a randomized, double-blinded study. J Postgrad Med. 2014;60(1):16–20.
USFDA, Review and evaluation of clinical data for gabapentin, H.a.H. Services, Editor; 2002, USFDA: Online.
USFDA. Statistical review and evaluation of neurontin, H.a.H. Services, Editor; 2002, Center for Drug Evaluation and Research: Online.
Backonja M, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. JAMA. 1998;280(21):1831–6.
Serpell MG, Neuropathic Pain Study Group. Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain. 2002;99(3):557–66.
Backonja M, Glanzman RL. Gabapentin dosing for neuropathic pain: evidence from randomized, placebo-controlled clinical trials. Clin Ther. 2003;25(1):81–104.
Rice ASC, Maton S, Postherpetic Neuralgia Study Group. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94(2):215–24.
Rowbotham M, et al. Gabapentin for the treatment of postherpetic neuralgia: a randomized controlled trial. JAMA. 1998;280(21):1837–42.
USFDA. Lyrica Prescribing Information; 2020.
USFDA. USFDA review of pregabalin for post-herpetic neuralgia; 2004.
USFDA. USFDA review of pregabalin for diabetic peripheral neuropathy; 2004.
Richter RW, et al. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized, placebo-controlled trial. J Pain. 2005;6(4):253–60.
Lesser H, et al. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology. 2004;63(11):2104–10.
Rosenstock J, et al. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain. 2004;110(3):628–38.
Tolle T, et al. Pregabalin for relief of neuropathic pain associated with diabetic neuropathy: a randomized, double-blind study. Eur J Pain. 2008;12(2):203–13.
Sabatowski R, 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(1–2):26–35.
Dworkin RH, et al. Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology. 2003;60(8):1274–83.
van Seventer R, 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(2):375–84.
Siddall PJ, et al. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology. 2006;67(10):1792–800.
Cardenas DD, et al. A randomized trial of pregabalin in patients with neuropathic pain due to spinal cord injury. Neurology. 2013;80(6):533–9.
USFDA. FDA Review of pregabalin for fibromyalgia; 2007.
Crofford LJ, et al. Pregabalin for the treatment of fibromyalgia syndrome: results of a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2005;52(4):1264–73.
Mease PJ, 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.
Arnold LM, et al. A 14-week, randomized, double-blinded, placebo-controlled monotherapy trial of pregabalin in patients with fibromyalgia. J Pain. 2008;9(9):792–805.
Crofford LJ, et al. Fibromyalgia relapse evaluation and efficacy for durability of meaningful relief (FREEDOM): a 6-month, double-blind, placebo-controlled trial with pregabalin. Pain. 2008;136(3):419–31.
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.
Bockbrader HN, et al. A comparison of the pharmacokinetics and pharmacodynamics of pregabalin and gabapentin. Clin Pharmacokinet. 2010;49(10):661–9.
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.
The authors would like the thank Erick Turner, MD at the VA Portland who provided valuable insight into the processes of obtaining and reviewing FDA drug reviews.
No funding was provided for this project.
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The authors have no conflicts of interest relevant to the content of this article.
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The data that support the findings of this study are available on request from the corresponding author.
All authors conducted an independent review of the FDA review packets and of Pubmed for relevant clinical trials. CDW: conceptualization, supervision, writing, review, and editing. ZAJ and MCH: writing, review, and editing.
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Williams, C.D., Al-Jammali, Z. & Herink, M. Gabapentinoids for Pain: A Review of Published Comparative Effectiveness Trials and Data Submitted to the FDA for Approval. Drugs 83, 37–53 (2023). https://doi.org/10.1007/s40265-022-01810-3