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 Nine of the 15 studies, accounting for 1492 out of 1884 patients (79%), were unpublished and mainly identified through registry searches and personal communication with the authors.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Third, the authors should be acknowledged for the inclusion of unpublished studies. Non-inclusion of unpublished results may to contribute to publication bias, ie, a selective reporting of positive trials, and thus a reduction of the number of studies available for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.
Conflict of interest statement
The author has no conflicts of interest to declare.
. Borghi B, D'Addabbo M, White PF, Gallerani P, Toccaceli L, Raffaeli W, Tognù A, Fabbri N, Mercuri M. The use of prolonged peripheral neural blockade after lower extremity amputation: the effect on symptoms associated with phantom limb syndrome. Anesth Analg 2010;111:1308–15.
. 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;24:CD008307.
. Chelly JE. Pregabalin effective for the prevention of chronic postsurgical pain: really? Anesth Analg 2013;116:507–8.
. ClinicalTrials.gov. Identifier: NCT00442546. Efficacy and safety of Pregabalin for pain following total knee replacement. Available at ClinicalTrials.gov. Accessed.
. Dahl JB, Kehlet H. Preventive analgesia. Curr Opin Anaesthesiol 2011;24:331–8.
. Haroutinian S, Nikolajsen l, Finnerup NB, Jensen TS. The neuropathic component in postsurgical pain: a systematic review. PAIN 2013;154:95–102.
. Kicinski M. Publication bias in recent meta-analyses. Plos One 2013;8:e81823.
. Lirk P, Stadlbauer KH, Hollmann MW. ESA Clinical Trials Network 2012: PLATA—prevention of phantom limb pain after transtibial amputation: randomised, double-blind, controlled, multicentre trial comparing optimised intravenous pain control versus optimised intravenous pain control plus regional anaesthesia. Eur J Anaesthesiol 2013;30:202–4.
. 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.
. Martinez V, Pichard X, Fletcher D. Perioperative pregabalin administration does not prevent chronic postoperative pain: systematic review with a neta-analysis of randomized trials. PAIN 2017;158:775–83.
. Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J, Jensen TS. A randomized study of the effects of gabapentin on postamputation pain. Anesthesiology 2006;105:1008–15.
. Nikolajsen L. Postamputation pain: studies on mechanisms. Dan Med J 2012;59:B4527.
. Personen 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.
. Sidiropoulou T, Giavasopoulos E, Kostopanagiotou G, Vafeiadou M, Lioulias A, Stamatakis E, Matsota P. Perioperative pregabalin for postoperative pain relief after thoracotomy. J Anesth Surg 2016;3:1–6.
. Treede RD, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand'homme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ. A classification of chronic pain for ICD-11. PAIN 2015;156:1003–7.
. 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.
. Ypsilantis E, Tang TY. Pre-emptive analgesia for chronic limb pain after amputation for peripheral vascular disease: a systematic review. Ann Vasc Surg 2010;24:1139–46.