This update reports on an escalating number of randomized controlled trials evaluating perioperative systemic drugs for the prevention of chronic postsurgical pain. The previous review in 2013 included 40 studies and the current one adds 70 new studies in just the last 6 yr. Most studies evaluated drugs that are used to treat acute postoperative pain—namely, ketamine, pregabalin, gabapentin, IV lidocaine, and NSAIDs. Overall, meta-analyses of available studies demonstrated superiority over placebo in 0 of 15 ketamine meta-analyses, 5 of 17 pregabalin meta-analyses, 0 of 4 gabapentin meta-analyses, 2 of 8 IV lidocaine meta-analyses, and 1 of 7 NSAID meta-analyses. Treatment-related adverse effects resulting in study dropouts were reported in only 2 of 27 ketamine studies, 11 of 26 pregabalin studies, 5 of 18 gabapentin studies, 1 of 10 IV lidocaine studies, 1 of 8 NSAID studies, and 0 of 6 corticosteroid studies. Insufficient reporting on the potential harms of each of the pharmacologic interventions was an impediment to conducting quantitative assessments to weigh the benefit–risk trade-offs.
The 110 included studies were of reasonably good quality with mostly low risks of bias related to randomization and blinding. Frequent risks of bias were related to small sample size (fewer than 50 participants).[11,135] Studies which were insufficiently blinded or uncontrolled were excluded as shown in the "Characteristics of Excluded Studies" table (Supplemental Digital Content 2, appendix B, https://links.lww.com/ALN/C629).
The studies included in this review varied with respect to pharmacologic interventions (i.e., 28 different drugs and 16 drug classes); dosage, timing, and duration of drug administration; surgical procedures; participants (e.g., with and without preoperative pain); sample size; outcome measurement tools; and timing of pain assessment (e.g., 3, 6, and/or 12 months). These disparities restrict the amount of data that can be pooled in meta-analysis which presents major challenges in interpretation and applicability of the results. Therefore, caution is advised when generalizing the results beyond the boundaries of the subanalyses conducted in this review. This review should be considered in the setting of several potential limitations. Although 110 randomized controlled trials were included, only 59 studies allowed for direct comparisons in quantitative synthesis. Others were excluded due to variation in drugs evaluated, surgical procedures, pain assessment tools, and timing of pain outcome measurement. Although restriction of this review to double-blind, randomized controlled trials limits the potential for some sources of bias, the relatively small size of most of the studies (i.e., 90% with fewer than 100 participants per arm), and high levels of withdrawals in some studies contribute other sources of bias that potentially overestimate treatment effect. Also, chronic pain was not necessarily the primary outcome for all included studies. Measures of pain at 3 or more months after surgery may have been secondary outcomes which may be a source of selective reporting bias. Furthermore, detailed assessment of pain and its consequences were often not reported beyond "Yes/No" since only a limited number of studies reported relevant moderate/severe pain. However, we believe all available results be considered for inclusion. The heterogeneity with respect to surgical procedures (i.e., nerve vs. other tissue damage), participant populations (preexisting chronic pain, opioid use, and psychiatric morbidities), diverse underlying sources of pain after surgery (e.g., incisional, nerve transection/injury, lymphedema, and deep tissue, among others, occurring after breast cancer surgery), and treatment dose/duration limit interpretation. This includes the question of whether the surgery was done to treat a pain condition, or otherwise, has not been addressed sufficiently in the literature. Other limitations come from heterogeneity regarding the study intervention (e.g., drug dose [small/large], timing with respect to surgery [pre-, intra-, postoperative], and insufficient numbers of trials in each of these categories to conduct relevant subgroup analyses). Although this review did not reveal strong or consistent treatment effects for preventing chronic postsurgical pain, the observation of some statistically significant results points to the concern of multiplicity in systematic reviews where several different meta-analyses are conducted. Although the Cochrane Collaboration and other investigators do not generally recommend adjusting for multiple comparisons and is not generally done in meta-analyses—which seek to estimate intervention effects rather than test for them—this is still an area for future investigation. Finally, lack of access to data from studies that remain unpublished may be an important source of publication bias to consider.
However, strengths of this review should be acknowledged: (1) this is the most up-to-date review of pharmacotherapy for prevention of chronic postsurgical pain with trials published as recently as 2019; (2) we conducted a comprehensive search for eligible randomized controlled trials in any language; (3) procedures throughout the review were conducted in a way that was rigorous, transparent, and replicable; (4) this review follows definitive standard reporting criteria according to the Cochrane Collaboration, Preferred Reporting Items for Systematic Reviews and Meta-analysis, and A Measurement Tool to Assess Systematic Reviews; (5) this is the only known systematic review in the past 5 yr that has considered all perioperative systemic drugs and was not limited by surgical procedure; (6) we reviewed a number of therapeutic agents in the same systematic manner; and (7) we used subgroup analyses according to dose/duration of treatment, surgical procedure, and timing of outcome measurements.
There is a need for better designed, large-scale, high-quality studies with adequate power to detect treatment effects of pharmacologic interventions on chronic pain outcomes 3 or more months after surgery, and focus on patient safety by reporting consistent and reliable data on withdrawals due to treatment-related adverse events. Conducting further trials of gabapentinoids for chronic pain prevention should take into consideration their apparent lack of effect for acute postoperative pain, and the diminishing likelihood of effectiveness for preventing chronic postoperative pain. Researchers should consider using detailed standardized outcome measurement tools (e.g., pain intensity on a 0 to 10 numerical rating scale) that can be summarized using dichotomous outcomes (e.g., any pain [more than 0 out of 10] and moderate to severe pain [greater than or equal to 4 of 10]) assessed at multiple and consistent time points (e.g., 3, 6, and 12 months) postsurgery, along with the specific relation of pain to the operated area, and consider stratification of those with and without preoperative pain and analgesic use, as well as implementing better characterization of surgical procedure (nerve damage) and patient characteristics (high pain responders) where appropriate. Studies should focus on drug dosage and duration within the context of the procedure-specific acute pain trajectory in question. There may be little value to repeat studies on single-shot or short-term drug interventions for this multifactorial problem, with a continuous inflammatory response lasting for several days (or weeks). Finally, considering use of the drugs included in this review to prevent chronic postsurgical pain—in light of their apparently uncertain effectiveness—also requires consideration of their safety in the perioperative setting. Given the potential adverse effects of some of these drugs (e.g., COX-2 inhibitors, gabapentinoids), it should be noted that safety assessment and reporting in perioperative clinical trials is sometimes inadequate.[140,141] Therefore, any future research in this area should incorporate more thorough and comprehensive safety assessment and reporting.
Consistent with our original review, and supported by nearly triple the number of studies, this review suggests again the need for larger-scale, high-quality studies to confirm or refute the effectiveness and safety of pharmacologic interventions for the prevention of chronic postsurgical pain. Based on currently available evidence, none of the drugs studied so far can be recommended for clinical use specifically for the indication of preventing chronic pain after surgery.
The authors wish to thank Joanne Abbott, M.Sc., Cochrane Collaboration, Oxford, United Kingdom, and Amanda Ross-White, B.A., M.L.I.S., Queen's University Library, Kingston, Ontario, Canada, for their valuable assistance with searching the literature.
This review was supported, in part, by the Canadian Institutes of Health Research Strategy for Patient-oriented Research Chronic Pain Network (Hamilton, Ontario, Canada).
The authors declare no competing interests.
Anesthesiology. 2021;135(2):304-325. © 2021 American Society of Anesthesiologists | Lippincott Williams & Wilkins