Chronic postsurgical pain (CPSP) is defined as pain persisting for more than 2 months after surgery.32 Its reported that incidence varies from 10% to 50%.33 A high proportion of CPSP is neuropathic pain (chronic postsurgical neuropathic pain [CPSNP]).15 Surgery provides a unique opportunity to implement pharmacological strategies for preventing the development of CPSP. Central sensitization is a widely documented pathophysiological mechanism in the chronicization of pain after surgery.11 Drugs acting on the central nervous system by inhibiting the release of neurotransmitters or blocking N-methyl-D-aspartate receptors, such as ketamine and gabapentinoids, have, therefore, been evaluated.6 In addition to reducing acute postoperative pain, such drugs would be expected to have an impact on the chronicization of pain.
Pregabalin is one drug of interest in this field, and its perioperative oral use has become widespread. It decreases central sensitization by acting on one subunit (alpha-2-delta) of a calcium channel, thereby inducing neurotransmitter release. However, although pregabalin has marketing authorization for use against “chronic neuropathic pain,” its use for the management of postoperative pain is off-label. Furthermore, previous meta-analyses investigating the efficacy of perioperative pregabalin administration for preventing chronic pain have yielded conflicting results.6,10,37 A first meta-analysis published in 2012 supported the view that perioperative pregabalin administration was effective for reducing the incidence of CPSP.10 A Cochrane systematic review performed 1 year later and including 2 additional trials did not support pregabalin as an effective agent for preventing chronic postoperative pain.6 A pooled analysis of 6 trials concluded, in 2014, that there were insufficient data to draw any firm conclusions concerning the efficacy of pregabalin for reducing persistent pain.37 Finally, extending controversy, limited data from 2 studies in this later publication suggested that pregabalin might be effective for reducing chronic neuropathic pain.37
Unfortunately, none of the 3 meta-analyses included the relevant unpublished studies for which results were available from www.clinicaltrials, despite a commentary pointing out this publication bias published shortly after the first meta-analysis.7 Further studies addressing the efficacy of pregabalin against persistent pain have been published since 2014.
We therefore performed this systematic review to provide an updated meta-analysis of the impact of pregabalin in the prevention of chronic pain. We collected all the available published and unpublished evidence.
The objective was to perform a meta-analysis evaluating the efficacy of pregabalin for preventing both chronic pain and chronic neuropathic pain after surgery, by examining the proportion of patients reporting pain 2 months after surgery. The confidence in our result was rated with the GRADE method.
2.1. Data sources and search strategy
The study was registered at PROSPERO (CRD42016046910). This systematic review of randomized controlled trials (RCTs) was performed in accordance with the criteria of the PRISMA statement and the current recommendations of the Cochrane Collaboration.20,30 We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and LILACS databases for reports of RCTs included from the inception of each database to July 1, 2016, with no limits on publication language, date, or status, using the terms “surgery, mastectomy, thoracotomy, knee arthroplasty, hip arthroplasty, pregabalin, Lyrica.” We identified randomized trials with the highly sensitive search strategy of the Cochrane Collaboration.29 The search equation is available in Supplementary Data 1 (available online at http://links.lww.com/PAIN/A382). We also searched the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects for previous relevant systematic reviews. We searched the annual conference proceedings of the American Society of Anesthesiology and the European Society of Anaesthesiology from 2010 to April 2016, by hand. We searched ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform for completed trials. Reference lists of identified published review articles on the perioperative use of pregabalin were also searched for eligible clinical trials, as were the reference lists of any included studies. We systematically contacted primary authors and manufacturers if the study contained incomplete data or reported only pain intensity but not the proportion of patients with pain. We also contacted, by e-mail, the corresponding authors of the studies exploring pregabalin in the acute postoperative phase cited in the most recent previous review, with a view to obtaining unpublished data relating to chronic pain.
2.2. Study selection
We included all RCTs including adults undergoing surgery and measuring the incidence of chronic pain, defined as a pain 2 months after surgery. The intervention of interest was the administration of pregabalin before, during, or after surgery, at any dose or frequency and for any duration. Two pairs of authors independently screened titles, abstracts, and full manuscripts according to the selection criteria. Any disagreement was discussed with a third author until a consensus was reached.
2.3. Data extraction and assessment of the risk of bias
We developed a data extraction form, and tested it on 5 of the studies included. The form was then refined according to the results obtained. Pairs of reviewers independently extracted data from each study. Disagreements were resolved by consensus with a third author. We extracted information about the trial setting (country), participants (age, sex, and weight), (first author, number of arms in the study, country, and sponsorship), participants (age, American Society of Anesthesiologists, characteristics of the population, and number of patients randomized and analyzed), experimental intervention (timing of administration, duration, and doses). Two independent reviewers assessed the quality of the trial methodology with the Cochrane Risk of Bias tool, with any discrepancies resolved by consensus.21
2.4. Outcome measures
The primary outcome was the proportion of patients reporting CPSP at 3 months. Chronic postsurgical pain was defined as in the initial articles. The secondary outcomes were the proportion of patients reporting CPSP at 6 or 12 months and CPSNP at 3, 6, or 12 months after surgery. A validated tool was used for the diagnosis of neuropathic pain.
2.5. Data synthesis and analysis
For the proportion of patients with CPSP, the treatment effect was the risk ratio (RR), with 95% confidence intervals, for dichotomous data. We expected there to be heterogeneity and we, therefore, used the Dersimonian and Lairs random-effect meta-analysis modules. We assessed statistical heterogeneity by the visual inspection of graphs and use of the I 2 statistic, which describes the proportion of variability in effect estimates due to heterogeneity rather than sampling error. We interpreted the value of the I 2 statistic according to the following thresholds: 0% to 40%, might not be important; 30% to 60%, may represent moderate heterogeneity; 50% to 90%, may represent substantial heterogeneity; and 75% to 100%, considerable heterogeneity.22 We explored heterogeneity in the estimation of the effect of intensity, by performing subgroup analysis for (1) published and unpublished studies, (2) administration for less than 24 hours vs administration for more than 24 hours, (3) doses above and below 150 mg, (4) types of surgery: orthopedic surgery vs cardiac surgery, and thoracic surgery vs visceral surgery. We planned a sensitivity analysis to assess the effect of heterogeneity on the meta-analysis results, excluding studies with a high or unclear risk of bias.
2.6. Rating evidence quality
We present the primary outcomes of the review in “Summary of findings” tables, as recommended in the Cochrane Handbook for Systematic Reviews of Interventions.41 The quality of evidence for each outcome was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) Working Group system,2 for 5 points: risk of bias, inconsistency, indirectness, imprecision, and publication bias. Each point was rated independently by 2 authors (V.M. and D.F.), with discussion to reach a consensus if necessary.
3.1. Characteristics of trials and patients
For the 835 reports identified as potentially eligible, we examined 21 full-text articles and selected 18 reports of trials including a total of 2485 patients (Fig. 1). Four of the 18 (22%) trials included in our meta-analysis came from clinicaltrial.gov (NCT00442546, NCT00468845, NCT00551135, NCT00663962, NCT01391858). We contacted 9 authors by e-mail to obtain additional data: one author said that they did not have the data requested; 2 authors provided unpublished CPSP incidence data for 1 and 3 months, whereas they had published only CPSNP incidence data at 3 months5,35; 3 authors provided the incidence of CPSP at 1 and/or 3 months, whereas they had published data only for the intensity of CPSP pain;4,8,24 and 3 authors who had reported only CPSP intensity did not reply.26,36,43 We contacted 45 authors who had published results only for the acute period: 9 authors replied that they had not evaluated CPSP, and one author provided data for the incidence of CPSP and CPSNP at 3 months.34
All the trials included in the meta-analysis were performed between 2009 and 2016, and 10 of the 18 (55%) trials were supported by Pfizer. The median target sample size was 92 (15-501) (median [min-max]) patients. The studies investigated patients undergoing surgery in various specialties: gynecology,16 visceral surgery,1,27 thoracic surgery,3,35,42 cardiac surgery,24,39 orthopedic surgery,5,34,45 and spinal surgery.4,8,18 General anesthesia was used in 14 trials;3,4,8,16,18,24,27,34,35,39,42 locoregional anesthesia was used in 3 trials;5,45 and the type of anesthesia was not reported in one trial.1 Pregabalin treatment was initiated preoperatively in all the studies considered. Most of the RCTs (N = 12)1,3,5,8,16,35,39,42,45 assessed the use of repeated doses of pregabalin (over periods of more than 2 days). The median duration of treatment was 5 (1-16) days. In most studies, pregabalin was compared with placebo (N = 17). In one trial, the control was loxoprofen.35 The total daily dose of pregabalin administered was 50 to 300 mg, with a median value of 150 mg (Table 1). The overall risk of bias was low for 7 of the 18 (39%) trials, high for 6/18 (33%), and unclear for 5/18 (28%). In the 6 trials with a high risk of bias, this bias resulted principally from the consideration of incomplete outcome data (33%) (Fig. 2).
3.2. Primary outcome: chronic postsurgical pain at 3 months
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).
3.3. Secondary outcomes
No significant differences were found between the pregabalin and control groups for the incidence of CPSP at 6 and 12 months (Table 3). These results are consistent with those for the primary outcome, with a low-to-moderate quality of evidence (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.
3.4. Sensitivity analysis according to risk of bias
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).
This systematic review summarizes the available evidence concerning the impact of pregabalin on the prevention of chronic postoperative pain. Our review, based on moderate-quality evidence, showed no preventive effect of pregabalin on CPSP clearly supporting no benefit to use it systematically. Concerning the prevention of postoperative neuropathic pain, the quality of evidence was very low, the estimate of the effect was highly uncertain, and we cannot make any firm recommendations for clinicians.
4.1. Strengths and weaknesses of our methodology
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
4.2. No impact of pregabalin on the incidence of chronic postsurgical pain
Our review strongly indicates that pregabalin has no impact on the incidence of CPSP. A similar lack of effect was observed 3, 6, and 12 months after surgery. The absence of a preventive effect of pregabalin on CPSP at 3 months was confirmed in our subgroup analysis, regardless of the type of publication, the risk of bias, the type of surgery, and the mode of pregabalin administration. This meta-analysis was justified, as it included 7 more trials and 1257 additional patients than the most recently published previous meta-analysis.37 These figures correspond to 54% more trials and 70% more patients included, thereby considerably increasing the available evidence. Contrary to the conclusions of this meta-analysis, the first published systematic review10 concluded that gabapentin and pregabalin “are effective in reducing the incidence of CPSP.” Our study extends the results obtained by Chaparro and Mishriky, suggesting a lack of effect of pregabalin on CPSP and insufficient data to reach a firm conclusion regarding the impact on persistent pain, respectively. One major difference between our review and the 3 previously published reviews, potentially explaining the divergent conclusions reached, is that we included several unpublished trials. The proportions of unpublished data for the incidence of CPSP at 3 and 6 months reach respectively 60% and 80% of trials and 78% and 89% of included patients. Interestingly, almost all the overall effect comes from unpublished data in our meta-analysis. It was the reverse of what one may expect and what has been published on the publication bias.13 The unpublished data were mostly obtained from registries. None of unpublished trials reported pregabalin to be effective for preventing CPSP or CPSNP at any time (3, 6, and 12 months). This finding highlights the necessity of including unpublished trials in all systematic reviews. This has been greatly facilitated by the registration requirement for all clinical studies since 2006. Reviewers, editors, and clinicians should be aware that this is a crucial issue when evaluating the quality of a systematic review.
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
4.3. First quantitative analysis of the impact of pregabalin on the incidence of chronic postsurgical neuropathic pain
This systematic review is the first to provide a meta-analysis of pooled results for the CPSNP incidence. Clarke and Chaparro did not specifically analyze CPSNP. Mishriki et al., in the most recent meta-analysis wrote “limited data available from 2 studies suggested that pregabalin might be effective for the reduction of neuropathic pain.” We have added data from 2 other trials and our pooled analysis confirms a large effect size in favor of pregabalin efficacy, with a large confidence interval 0.16 (0.04, 0.73) and a very low quality level of evidence. A meta-analysis based on the results of only 4 randomized trials including a total of only 451 patients, 50% of which were in a single study, is likely to be unreliable. In a sensitive analysis excluding this study, totally different results were obtained, with a nonsignificant RR of 0.24 (0.04, 1.39). We also suspect that this analysis is subject to publication bias. Indeed, 2 unpublished trials (NCT00442546, NCT00551135) including a total of 717 patients reported no difference in the intensity of neuropathic symptoms in patients with CPSP. Unfortunately, these trials did not report the proportion of patients with chronic neuropathic pain.
4.4. Confidence in evidence depending on the minimum optimal information size
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.
4.5. Clinical implications
The perioperative use of pregabalin reduces morphine consumption for pain, pain intensity during the first 24 hours, and the risk of nausea and vomiting.37 The evidence indicated that the efficacy of pregabalin was largely restricted to surgical procedures associated with pronociceptive mechanisms, such as spine surgery, arthroplasty, and amputations.14,28 The American Pain Society recommends the use of pregabalin for surgical procedures associated with a high risk of pain.9 However, adverse effects are common and specific to this therapeutic drug class. Previous systematic reviews reported a 2- to 3-fold increase in sedation, 30% higher frequencies of dizziness, and a 3- to 6-fold increase in visual disturbance.14,23,37,45 Recent studies have also questioned the benefits of including gabapentinoids in multimodal analgesic approaches and the risk to benefit ratio associated with their use. Indeed, the addition of gabapentin to multimodal analgesic treatments combining intra-articular infiltration with nonopioid analgesics after knee replacement seemed to be both ineffective for relieving pain and decreasing morphine use and problematic in terms of its adverse effects, including sedation, dizziness, and severe adverse events.31 In volunteers, pregabalin potentiated respiratory depression due to remifentanil, and the combination of these 2 drugs had an adverse effect on cognition.38 The true value of multimodal opioid–gabapentinoid regimens therefore remains unknown.17,25 Based on risk to benefit ratios, gabapentinoids should not be administered systematically for perioperative pain control,17 and their use should be abandoned in minor surgery. Concerning their use for CPSP prevention, this review demonstrates an absence of effect on CPSP incidence and a questionable impact on CPSNP. This preventive use would therefore expose a large number of people to a small risk of side effects, and the harm done by the treatment might well outweigh its benefits, as such benefits are observed in only a few patients.12
4.6. Future research
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.
Conflict of interest statement
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.
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Keywords:© 2017 International Association for the Study of Pain
Pregabalin; Lyrica; Neuropathic pain; Postoperative pain; Prevention; Randomized controlled trial; Systematic review; Meta-analysis