Pharmacotherapy for the Prevention of Chronic Pain after Surgery in Adults

An Updated Systematic Review and Meta-analysis

Meg E. Carley, B.Sc.; Luis E. Chaparro, M.D., F.R.C.P.C.; Manon Choinière, Ph.D.; Henrik Kehlet, M.D., Ph.D.; R. Andrew Moore, D.Sc.; Elizabeth Van Den Kerkhof, R.N., Dr.PH.; Ian Gilron, M.D., M.Sc.


Anesthesiology. 2021;135(2):304-325. 

In This Article

Materials and Methods

This systematic review was conducted according to the original study protocol,[5] and in a consistent manner with the original review.[4] Procedures were guided by Cochrane Collaboration recommendations[6] and followed the principles of Preferred Reporting Items for Systematic Reviews and Meta-analysis[7] and A Measurement Tool to Assess Systematic Reviews.[8]

Data Sources and Search Strategy

Using the originally published search strategy (Supplemental Digital Content 1, appendix A,,[4] the following databases were searched for trials since the previous review (July 17, 2013, to July 1, 2019): Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. We conducted hand searches of trial registries using each intervention as the key word (e.g., ketamine and pregabalin, among others) and filtered results by interventional studies, age group (18 to 65+ yr), and outcomes (e.g., chronic pain OR persistent pain OR persistent postsurgical pain). No limits were placed regarding date, language, or status of the publications. Backward reference searching was conducted by screening reference lists of included studies and relevant systematic reviews. Authors of included studies and experts were asked about recent or forthcoming studies that fit our eligibility criteria.

Study Selection

We included double-blind, placebo-controlled, randomized controlled trials that involved participants 18 yr and older undergoing a planned surgical procedure, that evaluated one or more drugs administered systemically immediately before, during, or after the procedure by any dose, route, or frequency, and that included data on a patient-reported measure of pain 3 or more months postsurgery. This review only included randomized controlled trials because "randomization is the only way to prevent systematic differences between baseline characteristics of participants in different intervention groups in terms of both known and unknown (or unmeasured) confounders."[6]

Data Extraction and Assessment of Risk of Bias

The following was extracted for each study: drug name; trial methods; trial registration; participant demographics; preoperative pain status and analgesic use; type of surgery; dosing including route, timing, and duration; dropouts due to treatment-emergent adverse effects; concomitant standardized analgesic approach; planned dichotomous outcomes; proportion of patients reporting any pain (more than 0 out of 10) or moderate to severe pain (greater than or equal to 4 out of 10) at 3, 6, and 12 months postsurgery. We reviewed trial registries when available, and in the case of secondary publications, original papers were reviewed. If a study reported parametric measures of pain intensity but not dichotomous measures of proportions of participants reporting pain, we contacted corresponding authors for supplementary data. Extraction was performed by M.E.C. and I.G. by reading each included study and completing the data extraction form.

Eligible studies were evaluated independently by two reviewers (M.E.C., I.G.) for risk of bias using the Cochrane risk of bias tool.[9] Any discrepancies could be resolved by a third coauthor (E.V.); however, this did not occur. Attrition bias was assessed as "low-risk" for studies where the dropout rate was less than 20%.[10] Studies with higher dropout rates that included intention-to-treat analyses were assessed as "unclear" or "high risk of bias." Chronic pain was rarely the prespecified primary outcome and most included trials were underpowered for this outcome; therefore, "other potential sources of bias" were assessed as high-risk in studies that had fewer than 50 participants per arm.[11] While it could be argued that, for pain prevention trials, this number should even be higher than 50 participants per arm, there is currently no consensus for a specific higher threshold for trial size in this setting.[12]

Outcome Measures

The primary outcome for the review was the proportion of participants reporting any pain at the anatomical site of the procedure or pain referred to the surgical site, or both, 3 months or more after the surgery.[2] Secondary outcomes were the number of participants reporting moderate to severe pain at the anatomical site of the procedure or pain referred to the surgical site—or both—6 months or more after surgery, as well as the number of participants who dropped out of the study due to treatment-related adverse effects. All results reported represent aggregate data from the 2013 and current review, unless otherwise specified.

Statistical Analysis

Comparing the study drug(s) with placebo was the primary objective. Studies were grouped if they evaluated the same drug(s) administered in a similar manner (i.e., dosage, route of administration, and treatment duration). Given the potential effect on outcome of surgical procedure and underlying condition, timing of outcome measurement, and duration of the intervention, subgroup analyses were conducted according to these parameters. Given the diverse features of the studies included in the review, not all were necessarily represented in a meta-analysis.

Statistical analyses were conducted using Review Manager v5.3.[13] Dichotomous data were analyzed using Mantel–Haenszel fixed-effects model for risk ratio with 95% CI. Heterogeneity was evaluated by visual examination of forest plots and use of the I2 statistic. In cases of moderate to considerable heterogeneity (i.e., 30 to 100%) the random-effects model was employed.[6] For studies with multiple intervention arms, we split the "shared" (placebo) group into two or more groups with smaller sample size, and included two or more (reasonably independent) comparisons.[6] Sensitivity analyses were conducted to evaluate robustness of a result by omitting studies considered to be outliers with respect to study quality, drug dose and duration, or pain measurement scales.