Efficacy and safety of perioperative intravenous lidocaine infusion for chronic postoperative pain

To the Editor: Chronic postoperative pain (CPSP) is one of the most common complications after surgery. Depending on risk factors, as many as 5–58% of patients experience chronic pain after surgery[1]. The mechanism of CPSP is complex and uncertain; the current understanding suggests that persistent peripheral inflammation and nociceptive hypersensitivity play crucial roles. Lidocaine is a type of sodium channel blocker that is widely used clinically for local anesthesia and antiarrhythmia. Recently, many studies have demonstrated that lidocaine has antinociceptive and antihyperalgesic effects, implying that it may be a promising drug for the prevention of CPSP. Moreover, there is convincing evidence supporting the use of systemic lidocaine for reducing postoperative acute pain, but its protective effect on CPSP remains controversial. Notably, Foo et al[2] reviewed the effectiveness of intravenous (IV) lidocaine negatively and recommended that it should not be started within 4 h of any other local injection. Several meta-analyses, which either included a small number of trials or focused only on breast cancer surgery, have been performed and have yielded inconsistent results. Therefore, we conducted this systematic review and meta-analysis to comprehensively summarize the efficacy and safety of perioperative intravenous lidocaine infusion to prevent CPSP. Our systematic review and meta-analysis were conducted based on the Assessing the Methodological Quality of Systematic Reviews (AMSTAR) guidelines and were registered in PROSPERO (CRD42024505596). Two authors (Zhang and Liang) independently screened and extracted valid data from the included studies. We searched major electronic databases, including PubMed, Embase, Web of Science, the Cochrane Library, and Clinicaltrials.gov, from inception to January 10, 2024. In addition, we meticulously checked the references of all included studies and pertinent review articles to identify additional articles. The specific search strategy is shown in Supplementary Table 1, https://links.lww.com/CM9/C371. The incidence of CPSP at 3 and 6 months after surgery was chosen as the co-primary outcome in this meta-analysis. The secondary outcomes included neuropathic pain at 3 months, 11-point numerical rating scale (NRS) pain scores at 3 months, short-form McGill Pain Questionnaire (SF-MPQ) scores at 3 months after surgery, and the incidence of lidocaine-related adverse effects. We defined neuropathic pain as a Douleur Neuropathique 4 (DN4) questionnaire score ≥4. Furthermore, the threshold for a minimal clinically important difference (MCID) in pain scores at 3 months was defined as a reduction of approximately two points or 30%[3], and lidocaine-related adverse effects refer to local anesthetic systemic toxicity and allergy. RevMan 5.4.1 software (Nordic Cochrane Centre, Cochrane Collaboration) and STATA 14 software (StataCorp LP, College Station, TX, USA) were used to process the data for the meta-analysis. Dichotomous outcomes were reported via risk ratios (RRs) with 95% confidence intervals (CIs), and continuous outcomes were reported via mean differences (MDs) with 95% CIs. Heterogeneity was examined via the I2 index. I2 >50% was considered to indicate significant heterogeneity, and a random-effects model was used. A two-sided P value <0.05 was considered statistically significant. The risk of bias was assessed via the revised Cochrane risk of bias tool (RoB 2) [Figure 1F]. Publication bias was assessed via a visual funnel and the Egger regression test. The overall quality of the evidence was evaluated via the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system [Supplementary Table 2, https://links.lww.com/CM9/C371]. Furthermore, given the high incidence of CPSP in mastectomy, we performed predefined subgroup analyses according to the type of surgery (breast surgery vs. non-breast surgery).Figure 1: Forest plots of the effects of lidocaine vs. placebo on the incidence and intensity of CPSP and the risk of bias of trials. The 14 included RCTs involved a total of 1062 participants. The boxes denote point estimate of the effects, and the error bars denote 95% CI. (A) The incidence of CPSP at 3 months. (B) The incidence of CPSP at 6 months. (C) NRS pain scores at 3 months. (D) The incidence of postoperative neuropathic pain at 3 months. (E) The SF-MPQ scores at 3 months. (F) Assessment of methodological quality of included trials using the revised Cochrane risk of bias 2 tool (RoB 2). CI: Confidence interval; CPSP: Chronic postoperative pain; NRS: 11-point numerical rating scale; SD: Standard deviation; SF-MPQ: Short-form McGill Pain Questionnaire; RCT: Randomized controlled trial.A total of 14 randomized controlled trials (RCTs) were included in the meta-analysis [Supplementary Figure 1, https://links.lww.com/CM9/C371]. The main characteristics of the included studies are summarized in Supplementary Tables 3, 4, https://links.lww.com/CM9/C371. For the primary outcomes, the pooled incidence rates of CPSP at 3 months in the lidocaine and placebo groups were 22.06% and 34.42%, respectively. Lidocaine infusion significantly reduced the risk of CPSP at 3 months (RR: 0.64; 95% CI: 0.50–0.81; P <0.01), and the funnel plot [Supplementary Figure 2, https://links.lww.com/CM9/C371] and Egger test (P = 0.283) did not show significant publication bias. The incidence of CPSP at 6 months was 12.57% in the lidocaine group and 22.72% in the placebo group, indicating that lidocaine also significantly reduced the risk of CPSP at 6 months (RR: 0.56; 95% CI: 0.35–0.88; P = 0.01). In terms of secondary outcomes, lidocaine significantly reduced the risk of neuropathic pain at 3 months (RR: 0.35; 95% CI: 0.17–0.73; P = 0.005). However, our meta-analysis demonstrated that the addition of a lidocaine infusion reduced the pain score at 3 months, with a mean difference of 0.55 (95% CI: –0.70 to –0.41; P <0.01), which did not surpass the MCID. Additionally, no significant difference was observed for the SF-MPQ scores. Lidocaine-related adverse events are listed in Supplementary Table 4, https://links.lww.com/CM9/C371. Two cases of arrhythmia and 13 cases of neurological reactions were reported. The subgroup analysis suggested that lidocaine infusion can only reduce the risk of CPSP at 3 months in nonbreast surgery patients (RR: 0.50, 95% CI: 0.31–0.80, P = 0.004) but not in breast surgery patients (RR: 0.63, 95% CI: 0.39–1.01, P = 0.06). However, the analysis of CPSP at 6 months post-surgery showed the opposite result; that is, lidocaine infusion was beneficial only for breast cancer surgery (RR: 0.41, 95% CI: 0.24–0.70; P = 0.001). Our meta-analysis of 14 RCTs revealed that perioperative lidocaine infusions reduced the incidence of CPSP at 3 and 6 months post-surgery. In addition, our subgroup analyses of CPSP regarding the type of surgery at 3 and 6 months post-surgery yielded opposite results; this is not fully consistent with the meta-analysis by Nasir et al[4], which found that breast cancer surgery does not reduce the rate of chronic pain at 3 and 6 months post-surgery. One possible reason for this inconsistency is that we excluded Toner’s study[5] because it involved lidocaine administered via IV infusions and subcutaneous injections. Another possible reason is that only five included studies reported CPSP incidence at 6 months post-surgery. Therefore, we concluded that lidocaine infusion for breast cancer surgery cannot reduce the risk of CPSP at 3 months. Nevertheless, the effect of lidocaine in different types of surgery on CPSP at 6 months remains a matter of debate. With respect to postoperative neuropathic pain, which is associated with greater pain intensity and duration than CPSP without neuropathic features, the pooled data revealed that lidocaine infusion was associated with a 65% reduction in the risk of neuropathic pain at 3 months after surgery. We further assessed the effects of lidocaine infusions on pain intensity at 3 months post-surgery. We chose the NRS score and the SF-MPQ score as indicators of the intensity of CPSP. Neither indicator was significantly different between the lidocaine infusion group and the placebo group. Therefore, we believe that IV lidocaine can reduce the incidence of CPSP but should has no significant effect on the intensity of pain. An earlier meta-analysis by Martin et al[6] concentrated on a similar issue and came to the same conclusion. However, it is important to note several distinctions between this study and ours. First, our systematic review homogenized the definitions of chronic pain across the different included studies. Second, we examined the incidence of neuropathic pain and pain scores at 3 months. Third, we performed subgroup analyses based on the type of surgery. Finally, because we included nine other recent studies, our meta-analysis met the optimal information size and our conclusions about the primary outcomes are more robust. The strengths of the study include the following: (1) This is a novel systematic review that has analyzed the association between lidocaine infusion and the development of postoperative neuropathic pain. (2) We performed subgroup analyses according to the type of surgery. Several limitations should be mentioned. First, to improve the selectivity of the search, the keyword “lidocaine” was searched using only Medical Subject Headings (MeSH) terms, which may have resulted in the omission of important literature. Second, only four studies were assessed for neuropathic pain at 3 months, so the conclusions regarding this outcome may not be reliable. Third, different interventions such as the dose and duration of lidocaine were not discussed in the subgroup analysis due to the insufficient number of trials in each of these categories. In conclusion, we found that perioperative systemic lidocaine infusion can decrease the incidence of CPSP and neuropathic pain. It is a convenient, affordable, and relatively safe choice that can be used clinically as a component of analgesia in high-risk surgical patients. Considering the small number of included studies, future research should be conducted to confirm the strong preventive effect of perioperative lidocaine infusion on postoperative neuropathic pain. Future studies should also determine the population that would benefit the most from perioperative lidocaine as well as the appropriate infusion method of lidocaine. Funding The work was supported by grants from the National Natural Science Foundation of China (Nos. 82171236 and 82372180), and the Key Research and Development Plan of Hunan Province, China (No. 2021SK2018). Conflicts of interest None.

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