Perioperative interventions for the reduction of chronic postsurgical pain

Nikolajsen, Lone

doi: 10.1097/j.pain.0000000000000852
Global Year 2017

Department of Anesthesiology and Intensive Care, Aarhus University Hospital, Aarhus, Denmark

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Received January 09, 2017

Accepted January 10, 2017

Article Outline

In this issue of PAIN, Martinez and co-workers publish a systemic review with a meta-analysis of randomized trials on the effect of perioperative pregabalin for the prevention of chronic postsurgical pain (CPSP).12 The primary outcome was CPSP after 3 months. Secondary outcomes included CPSP after 6 and 12 months and CPSP with a neuropathic pain component (CPSPNP) after 3, 6, and 12 months. The review comprises 18 studies, of which only 15 studies presented data on the primary outcome. Nine of the 15 studies, accounting for 1492 out of 1884 patients (79%), were unpublished and mainly identified through registry searches and personal communication with the authors. Martinez et al. conclude that there is no evidence to support the use of perioperative pregabalin for the reduction of CPSP. The quality of evidence for reduction of CPSPNP was too low to make any recommendations.

Some methodological issues need to be commented on. First, it can be argued that persistent postoperative pain (PPSP) is a more appropriate term for pain that continues to be present beyond normal healing: chronic postopsurgical pain (CPSP) implies chronicity, which is not always the case.

Second, the diagnostic criteria used for CRPS and CPSPNP are unclear. CPSP was defined “as in the initial articles,” and reported incidence rates varied between 0% and 38% after 3 months.6,15 This variation in reported incidence rates may be ascribed to differences in study populations and research design but could also be explained by the use of different definitions and cut-off levels for CPSP. The interpretation of available data is therefore difficult, and uniform diagnostic criteria for CPSP are called for in order to facilitate interpretation of future studies. In this respect, the work done by the IASP Task Force for the Classification of Chronic Pain in ICD-11 is a step forward.16 The same lack of clear diagnostic criteria applies to the definition of CPSPNP, which was determined by “a validated tool.” According to the systemic review by Martinez et al., only few studies reported incidence rates on CPSPNP after 3 months and rates were quite low (approx. 5%)2,3,11,15,17 compared with those reported in other studies, eg, the comprehensive review by Haroutinian et al.8

Third, the authors should be acknowledged for the inclusion of unpublished studies. Non-inclusion of unpublished results may to contribute to publication bias, ie, a selective reporting of positive trials, and thus a reduction of the number of studies available for meta-analyses.5,9 Interestingly, in the meta-analysis by Martinez et al.—and contrary to the expected—a subgroup analysis by publication status revealed no significant differences on the primary outcome between published and unpublished studies.12

Martinez et al. conclude that the available data do not support the efficacy of pregabalin in the prevention of CPSP, which is consistent with the conclusions in a recent Cochrane review on the use of pharmacological agents for the prevention of CPSP.4 Chaparro et al. identified 40 randomized controlled trials of various interventions, including perioperative systemic administration of N-methyl-D-aspartate (NMDA) blockers (mainly ketamine), gabapentin, pregabalin, NSAIDs, steroids, fentanyl, lidocaine, venlafaxine, and inhaled nitrous oxide. The meta-analysis suggested a modest but statistically significant reduction in the incidence of CPSP following treatment with ketamine but not following treatment with any of the other drugs. The authors advised that the results on ketamine should be interpreted with caution as sample sizes in the included trials were small.4

Other reviews on the prevention of CPSP agree that short-lasting perioperative interventions with single agents are less likely to reduce CPSP.6 The attempt to prevent phantom limb pain after amputation by the use of perioperative blocks is an example of this.19 Early studies with some methodological flaws showed very positive results, but these could not be replicated in larger randomized trials.14,18 It has been suggested that a prolonged perineural infusion of ropivacaine for a median of 30 days following the amputation may reduce phantom pain.1 However, the study was not randomized or blinded. It is hoped that an ongoing multicenter trial on the prevention of phantom limb pain including 400 patients randomized to either a placebo or local anesthetic infused via a sciatic nerve catheter and continued for 1 week after amputation will shed new light on the potential preventive effect of regional blocks.9 No studies exist on the preventive effect of pregabalin on phantom limb pain, but a study on gabapentin administered for 14 days after the amputation showed negative results.13

In conclusion, it is very likely that prevention of the development of CPSP—if at all possible—will require a prolonged postoperative intervention with a combination of drugs with different mechanisms of action which should be continued until the peripheral inflammatory response and afferent input have resolved. Preoperative risk factors for CPSP such as preoperative pain and anxiety must also be taken into consideration and addressed. Such prolonged perioperative interventions may be impossible to achieve for logistic reasons. Although it can be difficult to document a preventive effect of perioperative interventions on CPSP, many of the interventions are beneficial for the treatment of early postoperative pain. Unrelieved postoperative pain is associated with CPSP, although the casual relationship is uncertain. However, regardless of causality, good and efficient analgesia should be provided postoperatively for ethical reasons.

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Conflict of interest statement

The author has no conflicts of interest to declare.

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