Perioperative intravenous lidocaine for postoperative pain in patients undergoing breast surgery: a meta-analysis with trial sequential analysis of randomized controlled trials

Background The effectiveness of intravenous lidocaine infusion in managing acute and chronic pain following breast surgery has been a topic of debate. This meta-analysis aims to assess the impact of perioperative intravenous lidocaine on the relief of postoperative pain among patients undergoing breast surgery. Methods A systematic search of databases was conducted to identify randomized controlled trials (RCTs) that compared the effects of intravenous lidocaine infusion with placebo or routine care in patients undergoing breast surgery. The primary outcome of interest was the occurrence of chronic post-surgical pain (CPSP) at the longest follow-up. Meta-analyses, incorporating trial sequential analysis, were performed using a random-effects model to assess the overall effect. Results A total of twelve trials, involving 879 patients, were included in the analysis. Perioperative intravenous lidocaine demonstrated a significant reduction in the incidence of CPSP at the longest follow-up (risk ratio [RR] 0.62, 95% confidence interval [CI] 0.48-0.81; P = 0.0005; I2 = 6%). Trial sequential analysis (TSA) indicated that the cumulative z curve crossed the trial sequential monitoring boundary for benefit, providing sufficient and conclusive evidence. Furthermore, intravenous lidocaine was associated with decreased opioid consumption and a shorter length of hospital stay. Conclusion Perioperative intravenous lidocaine is effective in relieving acute and CPSP in patients undergoing breast surgery. Systematic review registration https://inplasy.com/, identifier INPLASY2022100033.


Supplementary Online Content
. GRADE profile Table S2. PRISMA 2020 checklist Figure S1 Forest plot for chronic post-surgical pain at three and six months follow-up after breast surgery     Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.

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Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect.

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10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results. 6-7 Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).

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13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of missing summary statistics, or data conversions.

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13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. 6-7 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.

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13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression). 6-7 13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results.
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

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Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. 5-6

Location where item is reported
Study selection 16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram.

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16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded. 8 Study characteristics 17 Cite each included study and present its characteristics. 8

Risk of bias in studies
18 Present assessments of risk of bias for each included study. 8

Results of individual studies
19 For all outcomes, present, for each study: (a) summary statistics for each group (where appropriate) and (b) an effect estimate and its precision (e.g. confidence/credible interval), ideally using structured tables or plots.

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Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. 8 20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect. 23b Discuss any limitations of the evidence included in the review. 14 23c Discuss any limitations of the review processes used. 14 23d Discuss implications of the results for practice, policy, and future research. 14

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. 3 24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared.
24c Describe and explain any amendments to information provided at registration or in the protocol. Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review. 14-15 Competing interests 26 Declare any competing interests of review authors. 15 Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.

Figure S1
Forest plot for chronic post-surgical pain at three and six months follow-up after breast surgery

Figure S2
Trial sequential analysis for chronic post-surgical pain at the longest follow-up (scaled trial distance). Trial sequential analysis of seven trials (black filled squares) illustrating that the cumulative Z curve crossed the conventional boundary and the trial sequential monitoring boundary for benefit, establishing sufficient and conclusive evidence. A diversity-adjusted required information size of 1724 patients was calculated using α = 0.05 (two-sided), β= 0.20 (power of 80%), an anticipated relative risk reduction of 20%, and an event proportion of 32.75% in the control group.