Fifteen studies, including a total of 1884 patients, reported data for CPSP incidence at 3 months.3,8,16,18,24,27,34,35,39,42 Nine of these 15 studies (60%) presenting data at 3 months were unpublished, and these studies accounted for 1492 of the 1884 (79%) patients included.8,24,34,35, No significant differences were found between the pregabalin and control groups (RR = 0.87 [0.66, 1.14]; I 2 = 57%; Figure 3). Subgroup analysis by publication status, daily dose, type of administration, and type of surgery failed to explain heterogeneity and revealed no differences between subgroups (Table 2). Evidence quality was moderate (Table 3).
Data for CPSNP incidence were less frequently reported, with only 4 studies, including a total of 451 patients, reporting data for CPSNP incidence at 3 months.5,34,42,45 A quarter of the studies in which the incidence of CPSNP was determined were unpublished. The absolute rates of CPSNP were 2/253 (0.7%) in the pregabalin group and 22/198 (11%) in the placebo group. Significant differences were found between the pregabalin and control groups (RR = 0.16 [0.04, 0.73]); I 2 = 15%. However, the quality of evidence was very low (Table 3), and the results were not confirmed at 6 months.5 No data were available concerning CPSNP at 12 months. Two studies showed no difference in the intensity of neuropathic pain symptoms, as assessed by the Neuropathic Pain Scale Inventory, between the pregabalin and control groups. However, neither of these studies reported CPSNP incidence.
Our sensitivity analysis showed no difference in primary outcome when articles with unclear and high risks of bias were removed from the analysis (Table 3).
Our study has several strengths. First, we conducted a rigorous and extensive literature search, including registry searches, making contact with the authors of published studies in this domain, and searches of the abstract proceedings for the 2 main congresses in the field. Second, by collecting a large amount of data, we were able to reach the minimum optimal information size for analysis of the impact of pregabalin on the incidence of CPSP. Third, our systematic review was associated with a rating of evidence quality, providing transparency in the presentation of the evidence available and the extent to which we can be confident that estimates of effect are correct.19 The main weakness of our review is the lack of evaluation of benefit or RR. We chose not to evaluate the incidence of side effects in the studies selected, as this aspect was evaluated in a recent meta-analysis including a larger number of studies in the acute phase.37
Surprisingly, none of the other meta-analyses pooled data from negative and unpublished trials supported by the pharmaceutical industry, despite the availability of the results from the “https://clinicaltrials.gov” registry since 2011 for 3 such trials (NCT00468845, NCT00442546, and NCT00551135). Some of these unpublished trials include in our review have actually been presented—in part—in a collective publication.43 Finally, several unpublished data come directly from the authors who have been contacted. The problem of the selective outcome reporting has already been pointed out in this therapeutic class.44
Trials on postsurgical pain are designed to evaluate early postsurgical pain, with the incidence of CPSP treated as a secondary outcome in most such studies. This raises the possibility of selective reporting bias. GRADE suggests the following: if the total number of patients included in a systematic review is less than the number of patients generated by a conventional sample size calculation for a single adequately powered trial, consider rating down for imprecision. Given an incidence of CPSP of 30%, with a significant clinical effect defined as a 30% decrease, the optimal information size is 1000 patients and 200 CPSP events. This explains why the reported studies did not reach the statistical power required to address the question of long-term benefit. The pooling of data in a meta-analysis increases the statistical power. However, the optimal information size must also be reached in such studies, for meaningful results to be obtained.19 The total number of patients included in the 3 previous meta-analyses (respectively 285, 439, and 549) was far below the optimal information size.6,10,37 The authors of the last meta-analysis concluded that “Data were insufficient to reach conclusions regarding persistent pain.” The inclusion of unpublished data in our meta-analysis made it possible to include a number of patients and CPSP events exceeding the optimal information size, thereby considerably increasing confidence in effect size estimation for CPSP. We can therefore state, with a high degree of confidence, that the available evidence does not support the efficacy of pregabalin for preventing CPSP. The difference in confidence for effect size between CPSP and CPSNP in our meta-analysis was based on GRADE analysis, and helped the clinicians to qualify results.
Reviewers and editors should encourage authors to report the incidence of CPSP in their articles, even when they do not correspond to the primary outcome, and the results obtained were negative. It is also clear that very few data are published concerning the incidence of chronic neuropathic pain. This outcome should be measured in all studies evaluating the prevention of CPSP. Furthermore, none of the studies included in this meta-analysis evaluated the impact of pregabalin in a specific potentially exposed population. The issue of the potential value of pregabalin in populations at risk of postsurgical pain, such as patients with chronic preoperative pain or long-term opioid use, has yet to be evaluated. The benefits of early treatment with pregabalin in patients with postsurgical neuropathic pain also remain unclear.
The available data do not support with a moderate level of evidence the efficacy of pregabalin for systematic prevention of CPSP. There are too few data relating specifically to the prevention of CPSNP to support any particular recommendations.
V. Martinez has received payments and travel funding for lectures from Jansen, Pfizer, and Astellas. D. Fletcher has received payments and travel funding for lectures from Grunenthal, biocodex, and mundipharma. The remaining author has no conflict of interest to declare.
This work used only institutional resources.
Development of the protocol; V. Martinez, X. Pichard, and D. Fletcher; search strategy, searches, and procurement of studies; X. Pichard and V. Martinez. The studies included were selected by X. Pichard and V. Martinez, with D. Fletcher as arbiter, and data were extracted by X. Pichard, V. Martinez. Analyses were conducted by V. Martinez. Data were analyzed and interpreted by V. Martinez, X. Pichard, and D. Fletcher. The final paper was drafted by V. Martinez, with revisions by D. Fletcher.
Supplemental Digital Content
Supplemental Digital Content associated with this article can be found online at http://links.lww.com/PAIN/A382.
Video content associated with this article can be found online at http://links.lww.com/PAIN/A383.
. Acín MP, Bono MC, Rodrigo MD, Martínez R, Faci A, Escartín R. Analgesia preventiva con pregabalina en intervenciones de hernia con malla: revisión al año [in Spanish]. Revista de la Sociedad Española del Dolor 2009;16:215–21.
. Balshem H, Helfand M, Schunemann HJ, Oxman AD, Kunz R, Brozek J, Vist GE, Falck-Ytter Y, Meerpohl J, Norris S, Guyatt GH. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011;64:401–6.
. Brulotte V, Ruel MM, Lafontaine E, Chouinard P, Girard F. Impact of pregabalin
on the occurrence of postthoracotomy pain syndrome: a randomized trial. Reg Anesth Pain Med 2015;40:262–9.
. Burke SM, Shorten GD. Perioperative pregabalin
improves pain and functional outcomes 3 months after lumbar discectomy. Anesth Analg 2010;110:1180–5.
. Buvanendran A, Kroin JS, Della Valle CJ, Kari M, Moric M, Tuman KJ. Perioperative oral pregabalin
reduces chronic pain after total knee arthroplasty: a prospective, randomized, controlled trial. Anesth Analg 2010;110:199–207.
. Chaparro LE, Smith SA, Moore RA, Wiffen PJ, Gilron I. Pharmacotherapy for the prevention
of chronic pain after surgery in adults. Cochrane Database Syst Rev 2013;CD008307.
. Chelly JE. Pregabalin
effective for the prevention
of chronic postsurgical pain: really? Anesth Analg 2013;116:507–8.
. Choi YS, Shim JK, Song JW, Kim JC, Yoo YC, Kwak YL. Combination of pregabalin
and dexamethasone for postoperative pain
and functional outcome in patients undergoing lumbar spinal surgery: a randomized placebo-controlled trial. Clin J Pain 2013;29:9–14.
. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, McCarberg B, Montgomery R, Murphy J, Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL. Management of postoperative pain
: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain 2016;17:131–57.
. Clarke H, Bonin RP, Orser BA, Englesakis M, Wijeysundera DN, Katz J. The prevention
of chronic postsurgical pain using gabapentin and pregabalin
: a combined systematic review
. Anesth Analg 2012;115:428–42.
. Deumens R, Steyaert A, Forget P, Schubert M, Lavand'homme P, Hermans E, De Kock M. Prevention
of chronic postoperative pain
: cellular, molecular, and clinical insights for mechanism-based treatment approaches. Prog Neurobiol 2013;104:1–37.
. Dworkin RH, McDermott MP, Raja SN. Preventing chronic postsurgical pain: how much of a difference makes a difference? Anesthesiology 2010;112:516–18.
. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical research. Lancet 1991;337:867–72.
. Eipe N, Penning J, Yazdi F, Mallick R, Turner L, Ahmadzai N, Ansari MT. The perioperative use of pregabalin
for acute pain- a systematic review
and meta- analysis. PAIN 2015;156:1284–300.
. Eisenberg E. Post-surgical neuralgia. PAIN 2004;111:3–7.
. Fassoulaki A, Melemeni A, Tsaroucha A, Paraskeva A. Perioperative pregabalin
for acute and chronic pain after abdominal hysterectomy or myomectomy: a randomised controlled trial. Eur J Anaesthesiol 2012;29:531–6.
. Fletcher D, Martinez V. Should we use gabapentin for postoperative pain
control? PAIN 2015;156:2402–3.
. Gianesello L, Pavoni V, Barboni E, Galeotti I, Nella A. Perioperative pregabalin
for postoperative pain
control and quality of life after major spinal surgery. J Neurosurg Anesthesiol 2012;24:121–6.
. Guyatt GH, Oxman AD, Kunz R, Brozek J, Alonso-Coello P, Rind D, Devereaux PJ, Montori VM, Freyschuss B, Vist G, Jaeschke R, Williams JW Jr, Murad MH, Sinclair D, Falck-Ytter Y, Meerpohl J, Whittington C, Thorlund K, Andrews J, Schunemann HJ. GRADE guidelines 6. Rating the quality of evidence–imprecision. J Clin Epidemiol 2011;64:1283–93.
. Higgins J, Green S. Guide to the contents of a Cochrane protocol and review. In: Cochrane handbook for systematic reviews of interventions version 5.1.0. Chapter 4. The Cochrane Collaboration, 2011. Available at: http://www.cochrane-handbook.org
. Accessed December 1, 2016.
. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343:d5928.
. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis
. Stat Med 2002;21:1539–58.
. Ho KY, Gan TJ, Habib AS. Gabapentin and postoperative pain
–a systematic review
of randomized controlled trials. PAIN 2006;126:91–101.
. Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin
in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Ann Card Anaesth 2013;16:180–5.
. Kharasch ED, Eisenach JC. Wherefore gabapentinoids? Was there rush too soon to judgment? Anesthesiology 2016;124:10–12.
. Khurana G, Jindal P, Sharma JP, Bansal KK. Postoperative pain
and long-term functional outcome after administration of gabapentin and pregabalin
in patients undergoing spinal surgery. Spine (Phila Pa 1976) 2014;39:E363–8.
. Kim SY, Jeong JJ, Chung WY, Kim HJ, Nam KH, Shim YH. Perioperative administration of pregabalin
for pain after robot-assisted endoscopic thyroidectomy: a randomized clinical trial. Surg Endosc 2010;24:2776–81.
. Lam DM, Choi SW, Wong SS, Irwin MG, Cheung CW. Efficacy of pregabalin
in acute postoperative pain
under different surgical categories: a meta-analysis
. Medicine (Baltimore) 2015;94:e1944.
. Lefebvre C, Manheimer E, Glanville J. Searching for studies. In: Cochrane handbook for systematic reviews of interventions version 5.1.0. Chapter 6.4. The Cochrane Collaboration, 2011. Available at: http://www.cochrane-handbook.org
. Accessed December 1, 2016.
. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009;339:b2700.
. Lunn TH, Husted H, Laursen MB, Hansen LT, Kehlet H. Analgesic and sedative effects of perioperative gabapentin in total knee arthroplasty: a randomized, double-blind, placebo-controlled dose-finding study. PAIN 2015;156:2438–48.
. Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008;101:77–86.
. Martinez V, Baudic S, Fletcher D. Chronic postsurgical pain [in French]. Ann Fr Anesth Reanim 2013;32:422–35.
. Martinez V, Cymerman A, Ben Ammar S, Fiaud JF, Rapon C, Poindessous F, Judet T, Chauvin M, Bouhassira D, Sessler D, Mazoit X, Fletcher D. The analgesic efficiency of combined pregabalin
and ketamine for total hip arthroplasty: a randomised, double-blind, controlled study. Anaesthesia 2014;69:46–52.
. Matsutani N, Dejima H, Takahashi Y, Kawamura M. Pregabalin
reduces post-surgical pain after thoracotomy: a prospective, randomized, controlled trial. Surg Today 2015;45:1411–16.
. Mishra A, Nar AS, Bawa A, Kaur G, Bawa S, Mishra S. Pregabalin
in chronic post-thoracotomy pain. J Clin Diagn Res 2013;7:1659–61.
. Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin
on acute and persistent postoperative pain
: a systematic review
. Br J Anaesth 2015;114:10–31.
. Myhre M, Diep LM, Stubhaug A. Pregabalin
has analgesic, ventilatory, and cognitive effects in combination with remifentanil. Anesthesiology 2016;124:141–9.
. Pesonen A, Suojaranta-Ylinen R, Hammaren E, Kontinen VK, Raivio P, Tarkkila P, Rosenberg PH. Pregabalin
has an opioid-sparing effect in elderly patients after cardiac surgery: a randomized placebo-controlled trial. Br J Anaesth 2011;106:873–81.
. Remerand F, Couvret C, Baud A, Laffon M, Fusciardi J. Benefits and safety of perioperative pregabalin
: a systematic review
[in French]. Ann Fr Anesth Reanim 2011;30:569–77.
. Schünemann HJ, Oxman AD, Higgins JPT, Vist GE, Glasziou P, Guyatt GH. Presenting results and “Summary of findings” tables. In: HJG S, editor. Cochrane handbook for systematic reviews of interventions version 5.1.0. Chapter 11, 2011.
. Sidiropoulou T, Giavasopoulos E, Matsota P, Stamatakis E, Florou P, Kostopanagiotou G. Perioperative pregabalin
and continuouswound infiltration of local anaesthetics in patients following thoracotomy. Reg Anesth Pain Med 2013;38:E231.
. Singla NK, Chelly JE, Lionberger DR, Gimbel J, Sanin L, Sporn J, Yang R, Cheung R, Knapp L, Parsons B. Pregabalin
for the treatment of postoperative pain
: results from three controlled trials using different surgical models. J Pain Res 2015;8:9–20.
. Vedula SS, Bero L, Scherer RW, Dickersin K. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med 2009;361:1963–71.
. YaDeau JT, Lin Y, Mayman DJ, Goytizolo EA, Alexiades MM, Padgett DE, Kahn RL, Jules-Elysee KM, Ranawat AS, Bhagat DD, Fields KG, Goon AK, Curren J, Westrich GH. Pregabalin
and pain after total knee arthroplasty: a double-blind, randomized, placebo-controlled, multidose trial. Br J Anaesth 2015;115:285–93.