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CPSP incidence at 3 months.3,8,16,18,24,27,34,35,39,42 Nine of these 15 studies (60%) presenting data at 3 months were unpublished, and these studies accounted for 1492 of the 1884 (79%) patients included.8,24,34,35, No significant differences were found between the pregabalin and control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]; I2 = 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).
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for CPSNP incidence at 3 months.5,34,42,45 A quarter of the studies in which the incidence of CPSNP was determined were unpublished.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]); I2 = 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).
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.
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
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
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.
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.
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
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.
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