Archives of Academic Emergency Medicine. 2023; 11(1): e58 REV I EW ART I C L E Intra-Operative Adjunctive Magnesium Sulfate in Pain Management of Total Knee Arthroplasty; a Systematic Re- view and Meta-analysis Amirali Azimi1, Fatemeh-sadat Tabatabaei1∗, Amirfarbod Azimi1, Hamid Mazloom2, Mohammad Mehdi Foruzanfar2, Nastaran Sadat Mahdavi3 1. Department of Medicine, Tehran University of Medical Sciences, Tehran, Iran. 2. Emergency Department, Shohadaye Tajrish Hospital, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 3. Department of Pediatric Anesthesiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Received: June 2023; Accepted: July 2023; Published online: 21 August 2023 Abstract: Introduction: There has been growing interest in the potential role of adjunctive magnesium sulfate in improving pain management. This systematic review and meta-analysis aimed to assess the effect of intra-operative adjunctive magne- sium sulfate on pain management and opioid consumption in total knee arthroplasty (TKA). Methods: A comprehensive search was conducted in Medline, Embase, Scopus, Web of Science, and Cochrane Library databases, covering studies up to April 2023. The extracted data included pain management outcomes, opioid consumption, and adverse effects from the selected studies. Standardized mean differences (SMDs) were calculated for continuous outcomes, while risk ratios (RRs) were calculated for dichotomous outcomes. Meta-analysis was conducted employing random-effects mod- els in STATA 17. Results: In this meta-analysis of 8 randomized controlled trials involving 536 patients, adjunctive mag- nesium sulfate in TKA was found to significantly reduce opioid consumption during the first 24 hours after operation (SMD: -1.88, 95% confidence interval (CI): [-3.66 to -0.10]; p = 0.038). It also resulted in lower pain scores at rest 24 hours after surgery (SMD: -1.53, 95% CI: [-2.70 to -0.37]; p = 0.010). There were no significant differences in time to first rescue analgesic and adverse effects between the groups. The included studies were assessed to have low to high levels of risk of bias. Conclusion: This study presents evidence at low to moderate levels supporting the use of intra-operative ad- junctive magnesium sulfate in TKA for improved pain management and reduced opioid consumption. However, further research is needed to address the heterogeneity and to explore optimal dosing regimens and routes of administration to maximize the benefits of magnesium sulfate in TKA. Keywords: Arthroplasty, replacement, knee; Magnesium sulfate; Pain management; Analgesics, opioid; Meta-analysis Cite this article as: Azimi A, Tabatabaei F, Azimi A, Mazloom H, Foruzanfar MM, Mahdavi NS. Intra-Operative Adjunctive Magnesium Sul- fate in Pain Management of Total Knee Arthroplasty; a Systematic Review and Meta-analysis. Arch Acad Emerg Med. 2023; 11(1): e58. https://doi.org/10.22037/aaem.v11i1.2058. 1. Introduction Total knee arthroplasty (TKA) is a common surgical proce- dure that relieves pain and improves function in patients with end-stage knee osteoarthritis (1). However, effective postoperative pain management remains a challenge, and the excessive use of opioids is often associated with adverse effects, delayed recovery, and increased healthcare costs (2). ∗Corresponding Author: Fatemeh-sadat Tabatabaei; Department of Medicine, Tehran University of Medical Sciences, Poursina St., 16 Azar St., Keshavarz Blvd., Tehran, Iran. Phone: 00989120364374, Email: fatimast1995@gmail.com, Fs-tabatabaei@alumnus.tums.ac.ir, ORCID: https://orcid.org/0000-0003-2975-3543. Therefore, there is a growing interest in identifying adjunc- tive therapies that can enhance pain control and reduce opi- oid requirements following TKA (3-5). Magnesium sulfate, a well-known mineral supplement, has attracted attention for its potential analgesic properties and opioid-sparing effects (6). Magnesium, an essential cofactor in numerous enzymatic reactions, is involved in the modu- lation of N-methyl-D-aspartate (NMDA) receptors, calcium channels, and inflammatory mediators (7, 8). By modulat- ing these pathways, magnesium sulfate has been hypothe- sized to possess analgesic properties, reduce central sensi- tization, and decrease the need for opioid analgesics (9-11). Studies examining the administration of magnesium have re- ported varying outcomes depending on the route of admin- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 2 istration. Intravenous (IV ) administration of magnesium has been extensively studied and has shown consistent reduc- tions in pain and opioid consumption in various surgical pro- cedures (12, 13). In contrast, the evidence regarding other routes, such as intrathecal injection, periarticular injection, and nerve blocks, is more limited and inconclusive (14-17). The potential analgesic benefits of intra-operative adminis- tration of magnesium sulfate have been investigated in sev- eral studies across various surgical procedures. A systematic review conducted in 2018 explored the use of intravenous magnesium sulfate specifically in orthopedic surgery and re- ported a reduction in postoperative analgesic consumption (18). Similarly, a recent systematic review and meta-analysis examining the effect of intravenous magnesium in noncar- diac surgery indicated that magnesium may reduce mor- phine consumption within the first day after the operation and prolong the time to the first analgesia (12). Another systematic review and meta-analysis focused specifically on knee arthroscopic surgeries and found that adding magne- sium sulfate to bupivacaine significantly improved analgesic efficacy (19). However, the specific impact of magnesium sul- fate on pain and opioid consumption following TKA has not been comprehensively evaluated. Recent clinical trials inves- tigating the effect of adjuvant magnesium on postoperative pain and opioid consumption following total knee arthro- plasty have yielded conflicting findings (20-23). In this systematic review and meta-analysis, we aim to evalu- ate the effect of intra-operative administration of magnesium sulfate on postoperative pain, opioid consumption, time to first analgesic in patients undergoing TKA, and its related ad- verse effects. Secondary outcomes, including knee range of motion, patient satisfaction, and length of hospital stay, will also be assessed. By synthesizing the available evidence, we seek to convey an extensive review of the potential benefits of magnesium sulfate as an adjunctive therapy in TKA. 2. Methods The present study adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta- Analyses (PRISMA) (24), ensuring that the systematic review and meta-analysis were conducted and reported in a rigor- ous and transparent manner. The study protocol was not registered by the authors prior to its commencement. The PRISMA checklist 2020 can be find in supplementary table 3 and 4. 2.1. Study design The objective of this review was to evaluate the efficacy of intra-operative magnesium sulfate administration as part of routine analgesic management protocols in TKA. The au- thors framed their study using the PICO framework as fol- lows: Population (P): Individuals of any gender and age who un- derwent TKA. Intervention (I): Treatment with magnesium sulfate via intra- venous, intrathecal, or regional routes, excluding oral admin- istration. Comparison (C): Patients receiving the same medication as the magnesium group, but without magnesium addition. Outcome (O): Postoperative pain, opioid consumption, and adverse effects. 2.2. Search strategy To identify relevant keywords related to TKA and Magnesium Sulfate, a comprehensive approach was employed, includ- ing expert recommendations, MeSH and Emtree databases, as well as screening of titles, abstracts, and subject indexing of relevant articles. Distinct search queries were formulated with relevant tags assigned to each specific database, includ- ing Medline (via PubMed), Embase, Scopus, Web of Science, and Cochrane Library. Searches were performed from the launch of the databases up until January 2023. The supple- mentary file provides an inclusive search strategy employed for each individual database utilized in this study. Addition- ally, a search was conducted on Clinicaltrials.gov and Google Scholar to identify any potentially relevant studies and re- view grey literature. Furthermore, a manual search of the bibliographies of all selected articles during the full-text review was performed, along with forward and backward citation tracking, to iden- tify additional relevant articles. The search was updated in April 2023, leading to the identification of one additional ar- ticle (22), which was subsequently included in the final anal- ysis. 2.3. Eligibility criteria This study included randomized clinical trials (RCTs) and prospective or retrospective observational studies that as- sessed the impact of intra-operative magnesium sulfate ad- ministration on the management of TKA. There were no re- strictions on language or publication date. The following routes of magnesium administration were considered: intra- venous (IV ), epidural, intra-articular injection, peri-articular injection (PAI), adductor canal block (ACB), and femoral nerve block (FNB). Studies evaluating oral magnesium sup- plementation or comparing magnesium in combination with another drug in the control group were excluded. Addition- ally, studies that did not evaluate the main outcomes of in- terest or compared magnesium to other experimental in- terventions (instead of a control group) were also excluded. Case-control studies, animal studies, duplicate reports, let- ters, case reports, case series, and reviews were also excluded. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 3 Archives of Academic Emergency Medicine. 2023; 11(1): e58 2.4. Study selection The initial records retrieved from the search results were ex- ported to Endnote software version 20.0 to remove duplicate records. Two independent authors (AA and FT) conducted a review of titles and abstracts to screen the articles. Sub- sequently, the full texts of potentially eligible studies were obtained, and final studies were selected based on the pre- defined eligibility criteria. Any disagreements were resolved through discussion. 2.5. Outcomes of interest and definitions The primary outcomes of interest in this study were postop- erative pain, opioid consumption, and adverse effects during the first two weeks post operation (PO). Postoperative pain refers to the intensity of pain experienced by patients. Opioid consumption refers to the amount of opioid analgesics con- sumed by patients. The term "time to first analgesic" refers to the duration between the completion of the surgery and the moment when the patient requests the first rescue analgesic for pain relief. Adverse effects encompass any undesired or negative effects resulting from the intra-operative adminis- tration of magnesium sulfate, including nausea, vomiting, hypotension, arrhythmias, respiratory depression, renal dys- function, and allergic reactions. The secondary outcomes of interest included knee range of motion, patient satisfaction, and length of hospital stay. 2.6. Data extraction The data entry process was carried out by two independent authors (AA and FT) using a pre-designed Excel form. Stud- ies that provided data from a single registry were identified by reviewing the registry title, year, setting, and sample char- acteristics. In cases where data for meeting the study objec- tives were missing, we reached out to the corresponding au- thors of the articles and requested the necessary information or original data. For articles that presented data in the form of figures, PlotDigitizer online software was utilized. Data extraction involved gathering study characteristics (au- thors, location, methodology, and anesthesia strategy), pa- tient demographics (population size, age, and gender), in- tervention details (route, and dosage), and control informa- tion (route, and medications used). The recorded outcomes included opioid consumption measured in oral morphine equivalents (OME), postoperative pain assessed using Visual Analog Scale (VAS) or Numeric Rating Scale (NRS), adverse effects documented by frequency or numbers, length of hos- pital stay measured in days or hours, and knee range of mo- tion (ROM) reported in degrees. The "time to first analgesic" data was collected and recorded in minutes or hours follow- ing the surgery. The conversion equivalents employed in this review were as follows: 1 mg of morphine (IV/IM/SC) was considered equivalent to 0.01 mg of fentanyl (IV or Epidu- ral) and 10 mg of pethidine (IV/IM). These conversion fac- tors were utilized to standardize and compare opioid dosages across different administration routes based on the recom- mendations of UpToDate (25). In staged TKA studies, data pertaining to the first knee operated was collected and ana- lyzed. 2.7. Risk of bias assessment Due to the limited number of observational studies included, the meta-analysis in this study focused solely on RCTs. To as- sess the quality of these studies, the second version of the Cochrane risk of bias assessment tool was employed (26). Two independent authors (AA and FT) evaluated all included articles using the criteria outlined in this tool and made de- cisions based on the available data. The assessment of bias in the included studies was conducted based on several do- mains, including randomization, deviations from intended interventions, missing data, outcome measurement, and se- lection of reported outcomes. A classification of "low" was assigned to studies with no risk of bias in any of these do- mains. On the other hand, if "some concerns" or "high" were identified in more than one domain, the overall rating was categorized as "some concerns" or "high" accordingly. 2.8. Certainty of evidence The authors employed the Grading of Recommendations, As- sessment, Development, and Evaluations (GRADE) guideline to determine the level of evidence for each outcome (27). Publication bias, risk of bias assessments, inconsistency, im- precision, and indirectness, were taken into consideration. Based on these assessments, the level of evidence for each investigated outcome was reported as high, moderate, low, or very low. 2.9. Data synthesis and analysis The analysis of data was conducted using STATA software (version 17) for the meta-analysis. The outcomes of postop- erative pain and opioid consumption were assessed using the Standardized Mean Difference (SMD), while the analysis of adverse effects was performed using the risk ratio (RR). For- est plots were employed to visually present the effect sizes of the evaluated outcomes. The subgroup analyses in this study were determined based on the specific follow-up time at which the desired outcome was evaluated. However, due to the limited number of in- cluded articles, subgroup analyses based on the route of magnesium administration could not be conducted. Consid- ering the variations in outcome measurement and interven- tion procedures across the included reports, it was expected that high heterogeneity would be present. To address this po- tential issue, random effects model was employed. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 4 Heterogeneity among the results was assessed using the I2 statistic, following the classification by Higgins (28). Addi- tionally, the Egger’s test (29) was performed to examine the presence of publication bias. Visual inspection of the fun- nel plot by subgroup was also conducted to further evaluate publication bias and assess the symmetry of the data distri- bution. 3. Results 3.1. Search results The initial database search yielded a total of 401 articles based on the specified search strategy. An additional 4 stud- ies were identified from the references of included papers. After removing duplicate records using EndNote, the titles and abstracts of the remaining 195 studies were screened. From this screening, 20 specific studies were selected for a full-text review. Following a thorough evaluation based on the eligibility criteria, 11 studies were excluded for various reasons (30-40), as depicted in Figure 1. Ultimately, 9 articles were deemed suitable for inclusion in the current investiga- tion (20-23, 41-45). However only the 8 RCTs were included in the meta-analysis. The process of study selection, as illus- trated in the PRISMA flow diagram, can be found in Figure 1. 3.2. Study characteristics Table 1 presents the baseline characteristics of the studies in- cluded in this review. The data used for the meta-analysis were derived from 8 RCTs comprising a total of 536 patients. Among these studies, 267 patients were allocated to the treat- ment group, and 269 patients to the control group. The other article had a retrospective observational methodology and was not involved in the meta-analysis. Regarding the ad- ministration route of magnesium, two studies utilized intra- venous administration (23, 41), two studies employed periar- ticular injection (21, 22), two studies utilized adductor canal block (20, 45), one study used femoral nerve block (43), and one study utilized the epidural catheter (44). Due to the lim- ited number of studies available, it was not possible to con- duct subgroup analyses based on the route of magnesium administration. In the studies where magnesium was ad- ministered intravenously, the control group received normal saline as the control (23, 41, 42). However, in the other stud- ies, the control group received local anesthetics, and in the intervention group, magnesium was prescribed in addition to these medications (20-22, 43-45). 3.3. Main outcomes The results of the meta-analysis comparing opioid consump- tion in subgroups with different timing are presented in Fig- ure 2. The standardized mean difference of opioid con- sumption was not statistically significant in the first six hours (SMD: -1.36, 95% confidence interval (CI): [-3.72 to 1.00]; p- value = 0.260), 24 to 48 hours after operation (SMD: -0.61, 95% CI: [-1.32 to 0.10]; p-value = 0.095), and 0 to 48 hours PO (SMD: -0.80, 95% CI: [-1.60 to 0.00]; p-value = 0.050). How- ever, a statistically significant SMD in favor of magnesium was observed in the 0 to 24 hours postoperative period (SMD: -1.88, 95% CI: [-3.66 to -0.10]; p-value = 0.038). The forest plot in Figure 3 illustrates the differences in pain among five subgroups. The pooled analysis revealed a sig- nificant decrease in pain for the intervention group 24 hours after the operation (SMD: -1.53, 95% CI: [-2.70 to -0.37]; p- value = 0.010). Although the Magnesium group showed fa- vorable differences in pain compared to the control group in six hours, 12 hours, 48 hours, and 72 hours after the op- eration, these values were not statistically significant (All P- values > 0.05). Figure 4 displays a forest plot depicting the difference in time to first rescue analgesic based on a pooled analysis. The re- sults indicate that the Magnesium group did not significantly differ in time to first analgesic compared to the control group (SMD: 6.72, 95% CI: [- 5.72 to 19.15]; p-value = 0.290). Figure 5 illustrates the meta-analysis results for the adverse effects reported in the studies. The risk ratio analysis did not show a statistically significant increase in nausea (SMD: -0.14, 95% CI: [-0.34 to 0.05], P-value = 0.156) or pruritus (SMD: 0.26, 95% CI: [-0.40 to 0.91]; p-value = 0.446). 3.4. Secondary outcomes In relation to the secondary outcomes of interest in this re- view, range of motion (ROM) was assessed in only one study (22), which showed insignificant differences amid the inter- vention and control groups. Two studies evaluated the length of hospital stay and found that magnesium had no advantage (20, 22). Patient satisfaction with pain control was investi- gated in three studies (20, 23, 45), revealing no significant superiority in favor of the intervention group. Summary of these outcomes can be found in Supplementary Table S1. 3.5. Heterogeneity Heterogeneity levels for all analyzed outcomes in each sub- group were reported in Figures 2-5. High levels of hetero- geneity were observed for opioid consumption (over 86% in all subgroups), pain (ranging from I2=0% to I2=98%), and time to first analgesic (I2=99%). However, the results indi- cated relatively low heterogeneity among the studies for the adverse effects (I2=0%). 3.6. Publication bias The Egger’s test was performed to assess small-study effects. The regression-based Egger’s test showed a significant asso- ciation between the effect size and the standard error for opi- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 5 Archives of Academic Emergency Medicine. 2023; 11(1): e58 oid consumption (z = -6.25, p-value < 0.001), postoperative pain (z = -4.14, p-value < 0.001), and time to first rescue anal- gesic (z = 8.37, p-value < 0.001) suggesting the presence of small-study effects. Funnel plots for opioid consumption, postoperative pain, and time to first analgesic are presented in supplementary figures S1, S2, and S3, respectively. Over- all, the funnel plots exhibited a symmetrical distribution of studies in each subgroup, suggesting little evidence of publi- cation bias. 3.7. Risk of bias Figure 6 summarizes the assessment of the risk of bias for in- dividual articles via the revised Cochrane Collaboration tool (RoB 2). Among the included studies, three were determined to have a low risk of bias, four were assessed as having a high risk of bias, and one study was deemed to have some con- cerns based on the authors’ judgment. Despite variations in the risk of bias scores, all studies within each subgroup were included in the analysis due to the limited number of avail- able studies. 3.8. Certainty of the evidence The certainty of the evidence for each outcome in this study has been evaluated and reported based on the authors’ judg- ment using the GRADE approach. According to the assess- ment, the evidence for opioid consumption and postopera- tive pain was determined to be of low certainty. There was moderately certain evidence supporting the findings related to the time to first analgesic and adverse effects. Supple- mentary Table S2 contains additional information on the cer- tainty of evidence for each outcome. 4. Discussion This study was a systematic review and meta-analysis of the randomized clinical trials focusing on the effect of intra- operative magnesium sulfate in total knee arthroplasty. The results showed significant improvements in pain manage- ment with the use of adjunctive magnesium sulfate in TKA. The key outcomes included reduced opioid consumption in the first 24 hours after operation and decreased postopera- tive pain 24 hours after operation. However, the effect size of magnesium sulfate varied among the different studies in- cluded in this analysis. There were no significant differences in time to first rescue analgesic and the incidences of postop- erative nausea and pruritus. The use of magnesium in pain management has emerged as a state-of-the-art topic across various medical condi- tions. Despite its recent surge in attention, a substantial number of studies have already been undertaken to explore its effectiveness. A recent systematic review conducted in 2021 examined the use of magnesium in various condi- tions, including post-operative pain, migraine, renal pain, chronic/neuropathic pain, and fibromyalgia. The review found a total of 50 randomized controlled trials specifically focusing on the post-operative setting (46). They concluded that although several studies have demonstrated the pain- relieving and opioid-sparing effects of magnesium, it is im- portant to note that not all studies have reported significant effects (47-50). Studies investigating the effect of magnesium on pain mech- anisms have highlighted the potential influence of the route of administration. Specifically, some articles concentrated on a specific route of magnesium administration in the post- operative setting. For instance, a comprehensive meta- analysis conducted in 2020, encompassing 51 RCTs, exam- ined the impact of IV magnesium on postoperative usage in noncardiac operation. The findings indicated that intra- venous magnesium, when used as part of a multimodal anal- gesia approach, may lead to a reduction in morphine con- sumption within the first 24 hours after surgery and postpone the first rescue analgesia following a noncardiac operation (12). In addition, another meta-analysis on 12 RCTs evalu- ated the application of intrathecal magnesium as an anal- gesic addition for spinal anesthesia. The results indicated that the inclusion of intrathecal magnesium in the spinal anesthetic regimen led to a prolongation of opiate analge- sia duration (17). Another review of 21 studies on the use of magnesium sulfate in peripheral nerve blocks found that it effectively reduced pain scores 6 and 12 hours after surgery, and decreased postoperative analgesic use within the initial 24 hours after surgery (15). Furthermore, it is important to consider that the nature of surgeries can vary, and orthopedic surgeries have been a spe- cific focus in some studies. For instance, a systematic review comprising 11 RCTs examined the efficacy of IV magnesium sulfate for postoperative pain control in the orthopedic set- ting (18). The review concluded that perioperative IV use of magnesium sulfate in orthopedic procedures may lead to a reduction in analgesic usage and mitigate adverse effects. These studies, however, failed to deliver solid proof of favor- able effects on the postoperative level of pain or time to first narcotic need (18). Additionally, another systematic review and meta-analysis involving six RCTs evaluated the impact of combining magnesium with bupivacaine for arthroscopy (51). The findings revealed that the addition of magnesium was associated with a significantly prolonged duration of analgesia, delayed time to analgesic administration, reduced pain scores, and decreased analgesic usage (51). A meta- analysis on intra-articular magnesium for pain management following arthroscopic knee procedures showed that patients who received magnesium experienced lower pain scores at rest and with movement two, four, twelve, and 24h after surgery, and had reduced opioid consumption and longer This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 6 time to the first analgesic requirement (16). To our knowledge, the present study is the first to specifi- cally evaluate the effect of intra-operative magnesium sul- fate administration on total knee replacement. The results of this study demonstrated that magnesium sulfate adminis- tered via various routes, including intravenous, periarticular infiltration, adductor canal block, femoral nerve block, and intrathecal, reduced postoperative pain at rest 24 hours af- ter surgery and opioid consumption within the first 24 hours postoperatively, which is consistent with previous studies (15-17, 46, 51). However, the findings of this study indicated that magnesium administration does not change the time to the first request for analgesics by the patients, which is in contrast with previous studies (16, 51). One possible reason for this controversy is the limited number of included studies in the meta-analysis of time to rescue analgesic in the current study. Also, the effect size of time to first rescue analgesic had a great variation among the included studies ranging from SMD of -0.02 to 26.53, which resulted in the high heterogene- ity observed in the results. Among the findings, the most clinically significant result was the significant reduction in opioid consumption during the first 24 hours, with a standardized mean difference (SMD) of -2.07. This suggests that the use of magnesium has the po- tential to substantially decrease reliance on opioids for pain management in the early postoperative period. The observed effects of adjunctive magnesium sulfate in im- proving pain management in total knee arthroplasty (TKA) may be attributed to several potential mechanisms. Mag- nesium sulfate possesses pharmacological properties that could interact with pain pathways and opioid receptors, thereby modulating the analgesic response. One possible mechanism is the NMDA receptor antagonism activity of magnesium sulfate. NMDA receptors serve a cru- cial role in the formation and maintenance of central sensiti- zation and chronic pain. By blocking NMDA receptors, mag- nesium sulfate may attenuate the amplification of pain sig- nals, resulting in reduced pain perception (52). This mech- anism aligns with the significant reduction in postoperative pain observed in the early follow-up time points of our study. Additionally, magnesium sulfate has been shown to possess calcium channel blocking properties (53). By inhibiting cal- cium influx, magnesium sulfate may reduce neuronal ex- citability and subsequent pain transmission (52). This modu- lation of calcium channels could contribute to the observed decrease in opioid consumption, as calcium signaling is in- volved in opioid receptor desensitization and tolerance de- velopment. Moreover, magnesium sulfate has been reported to exhibit anti-inflammatory effects. Inflammation is a crucial com- ponent of postoperative pain, and the anti-inflammatory properties of magnesium sulfate may help alleviate pain and reduce the need for rescue analgesics (54). These anti- inflammatory effects may contribute to the short-time pain decreasing role of magnesium seen in this study. 5. Strengths and limitations One of the strengths of this study is the inclusion of a com- prehensive search strategy that yielded a substantial number of relevant studies. By employing a systematic approach, we were able to minimize selection bias and ensure a represen- tative sample for our meta-analysis. Another strength is the rigorous assessment of outcomes using standardized mea- sures. The use of standardized protocols for data extraction and analysis increased the reliability and comparability of the results across studies. Furthermore, the inclusion of mul- tiple outcome measures, such as opioid consumption, post- operative pain scores, time to first analgesic, and adverse ef- fects, allowed for a comprehensive evaluation of the effects of magnesium sulfate on various aspects of postoperative pain management. Despite the strengths of this study, there are several limita- tions that should be acknowledged. First, the number of in- cluded studies was relatively small, particularly when sub- group analysis was attempted. The scarce number of stud- ies in subgroups restricted our ability to conduct subgroup analyses based on factors such as route of administration or dosage of magnesium sulfate. Second, the heterogeneity ob- served among the included studies may have influenced the overall findings. Although random effects models were used to account for potential heterogeneity, variations in study de- sign, patient populations, and intervention protocols could have contributed to the observed heterogeneity. Further- more, the risk of bias in the included studies should be con- sidered. While efforts were made to include studies regard- less of their risk of bias score, the presence of studies with high risk of bias or some concerns may have affected the overall reliability and validity of the findings. Finally, based on GRADE, the moderate to low certainty of evidence for cer- tain outcomes, such as opioid consumption and postopera- tive pain, shows that more studies are needed to strengthen the certainty in effect estimates. 6. Future directions This study provides valuable insights into the role of magne- sium sulfate in postoperative pain management following to- tal knee arthroplasty. However, there are several avenues for future research that could further enhance our understand- ing and optimize the use of magnesium sulfate in clinical practice. First, given the limited number of studies available in this re- view, future research should aim to conduct large-scale, mul- ticenter RCTs to provide more robust evidence. Investiga- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 7 Archives of Academic Emergency Medicine. 2023; 11(1): e58 tions comparing different routes and dosages of magnesium sulfate administration could help identify the most effective and well-tolerated regimens, specifically in the TKA setting. In addition to its analgesic properties, the potential impact of magnesium sulfate on other outcomes, such as functional recovery, patient satisfaction, and long-term complications, should be investigated. Long-term follow-up studies assess- ing the durability of pain relief and the effects on joint func- tion and quality of life would provide valuable information for clinical decision-making and patient counseling. More- over, the cost-effectiveness of magnesium sulfate in compar- ison to other analgesic modalities should be assessed. Eco- nomic evaluations, such as cost-effectiveness or cost-utility analyses, could provide insights into the value of incorporat- ing magnesium sulfate into perioperative pain management protocols. Finally, the identification of potential biomark- ers or predictors of response to magnesium sulfate could help personalize pain management strategies. Genetic, pro- teomic, or phenotypic profiling studies could identify patient characteristics or biomarkers associated with a favorable re- sponse to magnesium sulfate, allowing for more targeted and individualized treatment approaches. 7. Conclusion The findings of this study indicate that the addition of mag- nesium sulfate as adjunctive therapy in total knee arthro- plasty improves pain management by reducing opioid con- sumption and alleviating postoperative pain during the early stages of recovery, without causing an increase in the adverse effects. However, considering the limitations of the included studies and the overall low to moderate certainty of the evi- dence, these results should be interpreted with caution. 8. Declarations 8.1. Acknowledgments None to declare. 8.2. Conflict of interest The authors declare that they have no conflict of interest. 8.3. Funding and support No funding or grants were obtained for this study. 8.4. Authors’ contribution All authors made substantial contributions to the production of this work: • Conception and design of the work: Amirali Azimi • Acquisition, analysis, and data interpretation: Amirali Az- imi, Fatemeh-sadat Tabatabaei, Amirfarbod Azimi, Hamid Mazloom • Drafting and work revision: Amirali Azimi, Amirfarbod Az- imi • Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and re- solved: Amirali Azimi, Fatemeh-sadat Tabatabaei, Amirfar- bod Azimi, Hamid Mazloom, Mohammad Mehdi Foruzanfar and Nastaran Sadat Mahdavi. 8.5. Patient and Public Involvement Patients were not involved in this research. 8.6. Data sharing statement All data relevant to the study are included in this article or available in the supplemental file. The authors ensured that no patient-identifiable data are available. 8.7. Ethical approval Resulting from the study design (meta-analysis), an ethical approval is not applicable. 8.8. Informed consent The study was not done on human participants. References 1. Ponnusamy KE, Vasarhelyi EM, Somerville L, McCalden RW, Marsh JD. Cost-Effectiveness of Total Knee Arthro- plasty vs Nonoperative Management in Normal, Over- weight, Obese, Severely Obese, Morbidly Obese, and Super-Obese Patients: A Markov Model. J Arthroplasty. 2018;33(7, Supplement):S32-S8. 2. Christensen TH, Gemayel AC, Bieganowski T, Lawrence KW, Rozell JC, Macaulay W, et al. Opioid Use Dur- ing Hospitalization Following Total Knee Arthroplasty: Trends in Consumption From 2016 to 2021. J Arthro- plasty. 2023;38(6, Supplement):S26-S31. 3. Karam JA, Schwenk ES, Parvizi J. An update on multi- modal pain management after total joint arthroplasty. JBJS. 2021;103(17):1652-62. 4. Suthersan M, Pit S, Gordon L, Loman M, Pezzutti B, Frei- haut R. 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Effectiveness of intravenous magnesium on post- operative pain after abdominal surgery versus placebo: double blind randomized controlled trial. Tunis Med. 2010;88(5):317-23. 51. Xiang WN, Jiang L, Shi LT, Jiang CM, Zhou Y, Yang CH. The effect of magnesium added to bupivacaine for arthroscopy: a meta-analysis of randomized controlled trials. J Orthop Surg Res. 2021;16(1):583. 52. Soleimanpour H, Imani F, Dolati S, Soleimanpour M, Shahsavarinia K. Management of pain using mag- nesium sulphate: a narrative review. Postgrad Med. 2022;134(3):260-6. 53. Franzoni S, Rossi SM, Cassinadri A, Sangaletti R, Benazzo F. Perioperative Pain Management in Total Knee Arthro- This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 10 plasty: A Narrative Review of Current Multimodal Anal- gesia Protocols. Appl. Sci. 2023; 13(6):3798. 54. Lavand’homme PM, Kehlet H, Rawal N, Joshi GP. Pain management after total knee arthroplasty: PROcedure SPEcific Postoperative Pain ManagemenT recommenda- tions. Eur J Anaesthesiol. 2022;39(9):743-57. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 11 Archives of Academic Emergency Medicine. 2023; 11(1): e58 Table 1: Baseline characteristics and method of intervention and control in the included studies Authors ( Year) Country; Study design Sample size (n), General anes- thesia Focal anal- gesics Intervention Intervention route / Magnesium dosage Control route / Control medication Postoperative analgesia Mean age (y), Male (%) MG CG Zhao et al. (2023) (22) China; RCT 45 65.9 20 45 64.2 29 GA PAI MgSO4 + Control Medications PAI / 250 mg MgSO4 PAI / Ropivacaine, Epinephrine Dexametha- sone, Subcutaneous morphine; PO Celecoxib Choi et al. (2022) (45) United states; RCT 49 66.5 43 53 67.4 38 SA ACB MgSO4 + Control Medications ACB / 150 mg (0.3 mL) MgSO4 ACB / Bupivacaine Not defined Zoratto et al. (2021) (20) Canada; RCT 41 67.5 54 39 66.7 54 SA PAI MgSO4 + Control Medications ACB / 2 g MgSO4 ACB / Ropivacaine PCA IV morphine; PO ac- etaminophen; PO Celecoxib Zhao et al. (2021) (21) China; RCT 30 69.6 36 30 69.8 40 SA PAI MgSO4 + Control Medications PAI / 250 mg MgSO4 PAI / Lev- obupivacaine, Triamcinolone PCA IV Sufentanil and Dezocine Park et al. (2020) (42) Sout Korea; ROS 115 72.2 13.9 115 72.2 13 SA FNB MgSO4 IV / Bolus 50 mg/kg Infusion 15 mg/kg.h IV / Normal Saline PCA IV Fentanyl; PO Ac- etaminophen, Celecoxib, Pregabalin; Rescue IV opioids Shin et al. (2016) (41) Sout Korea; RCT 22 74.3 4.8 22 72.3 0 SA FNB PAI MgSO4 IV / Bolus 50 mg/kg Infusion 15 mg/kg.h IV / Normal Saline PCA IV Fentanyl; PO Ac- etaminophen, Celecoxib, Pregabalin; IV Ketoprophen Frassanito et al. (2015) (23) Italy; RCT 20 65.6 40 20 67.4 25 SA - MgSO4 IV / Bolus 40 mg/kg Infusion 10 mg/kg.h IV / Normal Saline PCA IV morphine; IV paracetamol; IV ketorolac Daabiss et al. (2015) (44) Saudi Arabia; RCT 40 61.1 50 40 59.5 57 EA - MgSO4 + Control Medications Epidural catheter / Bolus 50 mg MgSO4 Infusion 10 mg/h Epidural catheter / Bupivacaine PCA epidural Fentanyl; IM Pethidine Elmawgoud et al. (2008) (43) Egypt; RCT 20 55 35 20 55 60 GA FNB MgSO4 + Control Medications FNB / Bolus 1.5 g MgSO4 Infusion 0.3 g/h FNB / Ropivacaine PCA IV morphine RCT: Randomized Clinical Trial; ROS: Retrospective Observational Study; MG: Magnesium Group; CG: Control Group; GA: General Anesthesia; SA: Spinal Anesthesia; PAI: Periarticular infiltration; FNB: Femoral Nerve block; EA: Epidural Anesthesia; IV: Intravenous; ACB: Adductor canal block; PCA: Patient-Controlled Analgesia; MgSO4: Magnesium Sulfate; PO: oral; IM: intramuscular. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 12 Figure 1: Flowchart depicting the study selection process. WOS: Web of Science; TKA: Total Knee Arthroplasty; RCT: Randomized Clinical Trial. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 13 Archives of Academic Emergency Medicine. 2023; 11(1): e58 Figure 2: Forest plot presenting the effect of adjunctive magnesium sulfate on opioid consumption in four subgroups by timing. PO: post operation; SD: Standard Deviation; CI: Confidence Interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 14 Figure 3: Forest plot presenting the effect of adjunctive magnesium sulfate on postoperative pain in five subgroups by timing. PO: post operation; SD: Standard Deviation; CI: Confidence Interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 15 Archives of Academic Emergency Medicine. 2023; 11(1): e58 Figure 4: Forest plot illustrating the effect of adjunctive magnesium sulfate on time to first rescue analgesic. SD: Standard Deviation; CI: Confidence Interval. Figure 5: Forest plot for adverse effects reported in the included studies. This figure presents the risk ratio analysis for the occurrence of nausea and pruritus.CI: Confidence Interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 16 Figure 6: Risk of bias assessment summary using the revised Cochrane Collaboration tool (RoB 2). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 17 Archives of Academic Emergency Medicine. 2023; 11(1): e58 Supplementary figure S 1: Funnel plot for opioid consumption by subgroups. PO: post operation; CI: Confidence Interval. Supplementary table S 1: Secondary outcomes not included in the quantitative analysis Outcome Study ID Magnesium group Control group Reported statistical significance Magnesium compared to control Knee ROM Degree POD 1 Zhao et al. (2023) 89.0 ± 6.3 87.0 ± 9.0 P-value = 0.465 Not superior Degree POD 2 Zhao et al. (2023) 95.8 ± 5.1 95.3 ± 7.3 P-value = 0.834 Not superior Degree POD 3 Zhao et al. (2023) 106.1 ± 5.0 104.7 ± 7.2 P-value = 0.258 Not superior Degree 3 months Zhao et al. (2023) 117.9 ± 4.8 115.7 ± 6.2 P-value = 0.099 Not superior Length of hospital stay Hours Zhao et al. (2023) 68.4 ± 3.2 69.4 ± 3.0 P-value = 0.160 Not superior Days Zoratto et al. (2021) 2.2 [2.0–3.1] 2.1 [1.9–3.9] P-value = 0.550 Not superior Satisfaction with pain control Categorical (Excellent) Zoratto et al. (2021) 13 (38) 12 (38) P-value = 0.320 Not superior Likert scale Choi et al. (2022) 8.8 ±2.0 8.7 ±1.8 P-value = 0.837 Not superior Likert scale Frassanito et al. (2015) 8.9±0.1 8.8±0.2 P-value = 0.060 Not superior POD: post-operative day; ROM: range of motion. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index A. Azimi et al. 18 Supplementary figure S 2: Funnel plot for postoperative pain by subgroups. PO: post operation; CI: Confidence Interval. Supplementary table S 2: Quality of the evidence assessed using GRADE (Grading of Recommendations, Assessment, Development and Eval- uations) scoring system Outcome of interest Risk of bias Imprecision Inconsistency Indirectness Publication bias Quality of the evidence (GRADE) Opioid Consumption Serious limitations No serious limitations Serious limitations No serious limitations No serious limitations • • ◦ ◦ low Postoperative Pain Serious limitations No serious limitations Serious limitations No serious limitations No serious limitations • • ◦ ◦ low Time to first analgesic Serious limitations No serious limitations No serious limitations No serious limitations No serious limitations • • • ◦ Moderate Adverse Effects Serious limitations No serious limitations No serious limitations No serious limitations No serious limitations • • • ◦ Moderate This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index 19 Archives of Academic Emergency Medicine. 2023; 11(1): e58 Supplementary figure S 3: Funnel plot for time to first rescue analgesic. CI: Confidence Interval. Supplements 1: Search strategy Medline (via PubMed) 1. “Arthroplasty, Replacement, Knee”[mh] OR “Hemiarthroplasty”[mh] OR “knee arthroplasties”[tiab] OR “knee arthroplasty”[tiab] OR “knee reconstruction”[tiab] OR “knee joint replacement”[tiab] OR “knee surgery”[tiab] OR “knee surgeries”[tiab] OR “knee re- placement”[tiab] OR “knee replacements”[tiab] OR “total knee arthroplasty”[tiab] 2. “Magnesium”[mh] OR “Magnesium Sulfate”[mh] OR “Magnesium Compounds”[mh] OR “Magnesium Chloride”[mh] OR “Magne- sium Hydroxide”[mh] OR “Magnesium”[tiab] OR “Magnesium Sulfate”[tiab] OR “MgSO4”[tiab] OR “Magnesium Compounds”[tiab] OR “Magnesium Chloride”[tiab] OR “MgCl2”[tiab] OR “Magnesium Hydroxide”[tiab] OR “Mg(OH)4”[tiab] 3. #1 AND #2 Embase: 1. ‘knee surgery’/exp OR ‘knee arthroplasty’/exp OR ‘knee replacement’/exp OR ‘total knee arthroplasty’/exp OR ‘knee arthro- plasty’:ab,ti OR ‘knee reconstruction’:ab,ti OR ‘knee joint replacement’:ab,ti OR ‘knee surgery’:ab,ti OR ‘knee surgeries’:ab,ti OR ‘knee replacement’:ab,ti OR ‘knee replacements’:ab,ti OR ‘total knee arthroplasty’:ab,ti 2. ‘Magnesium’/exp OR ‘Magnesium Sulfate’/exp OR ‘Magnesium Chloride’/exp OR ‘Magnesium’:ab,ti OR ‘Magnesium Sulfate’:ab,ti OR ‘MgSO4’:ab,ti OR ‘Magnesium Compounds’:ab,ti OR ‘Magnesium Chloride’:ab,ti OR ‘MgCl2’:ab,ti OR ‘Magnesium Hydroxide’:ab,ti OR ‘Mg(OH)4’:ab,ti 3. #1 AND #2 Scopus: 1. TITLE-ABS-KEY(“knee arthroplasties” OR “knee arthroplasty” OR “knee reconstruction” OR “knee joint replacement” OR “knee surgery” OR “knee surgeries” OR “knee replacement” OR “knee replacements” OR “total knee arthroplasty”) 2. TITLE-ABS-KEY(“Magnesium” OR “Magnesium Sulfate” OR “MgSO4” OR “Magnesium Compounds” OR “Magnesium Chloride” OR “MgCl2” OR “Magnesium Hydroxide” OR “Mg(OH)4”) 3. #1 AND #2 Web of Science ( WOS): 1. TS=(“knee arthroplasties” OR “knee arthroplasty” OR “knee reconstruction” OR “knee joint replacement” OR “knee surgery” OR “knee surgeries” OR “knee replacement” OR “knee replacements” OR “total knee arthroplasty”) 2. TS=(“Magnesium” OR “Magnesium Sulfate” OR “MgSO4” OR “Magnesium Compounds” OR “Magnesium Chloride” OR “MgCl2” OR “Magnesium Hydroxide” OR “Mg(OH)4”) 3. #1 AND #2 This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: https://journals.sbmu.ac.ir/aaem/index.php/AAEM/index Introduction Methods Results Discussion Strengths and limitations Future directions Conclusion Declarations References