Abstract
Purpose
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Although magnesium sulfate (MgSO4) is widely used as an analgesic adjuvant to peripheral analgesic cocktails, its efficacy in total knee arthroplasty (TKA) is still controversial. Therefore, we systematically reviewed and meta-analyzed the literature to assess the analgesic efficacy of MgSO4 as an adjuvant to the analgesic cocktail in TKA.
Methods
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The PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched. The meta-analysis was performed according to the PRISMA guidelines. Data were qualitatively synthesized or meta-analyzed using a random-effects model.
Results
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Five randomized controlled trials involving 432 patients were included. Meta-analyses detected significant differences between the MgSO4 and control groups in the visual analog scale (VAS) pain scores (rest) at 6, 12, and 24 h postoperatively; VAS pain scores (motion) at 12, 24, and 48 h postoperatively; morphine consumption within 24 h, 24–48 h, and during the total hospitalization period; time to first rescue analgesia after TKA; and length of hospital stay. Regarding the functional recovery, the meta-analysis demonstrated significant differences between groups in terms of knee range of motion on postoperative day 1; daily mobilization distance on postoperative day 1; and daily mobilization distance. There was no significant intergroup difference in surgical complications.
Conclusion
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The findings suggest that MgSO4 is a promising adjunct to the analgesic cocktail, achieving significant improvements in pain scores and total opioid consumption during the early postoperative period after TKA.
Introduction
Total knee arthroplasty (TKA) is an effective surgical intervention aimed at enhancing function and alleviating pain in patients with end-stage knee joint disorders. In the USA, 480 958 TKA procedures were conducted during 2019, and projections suggest a sustained increase in the volume of these procedures in the coming years (1). More than 60% of patients undergoing TKA experience pronounced postoperative pain (2). Pain following TKA is a predominant factor contributing to the extension of the length of hospital stay (LOS) and functional recovery, and frequently serves as a primary cause for patient readmission (3). Therefore, effective postoperative pain management is crucial for early recovery and enhanced patient satisfaction. As a pivotal element within the realm of multimodal analgesia, peripheral analgesia techniques have been extensively used in TKA throughout the past decade (2). These techniques encompass periarticular local anesthetic injection and a range of peripheral nerve blocks.
The standard pharmaceutical approach for peripheral analgesia typically involves combinations of local anesthetics and other adjuvants such as epinephrine and glucocorticoids, which enhance analgesic efficacy (4). The prepared mixed formulations are commonly referred to as ‘cocktails’ by researchers. However, there remains no gold standard for the precise composition and dosing of pharmaceutical components for optimal analgesic cocktails, resulting in divergent efficacy outcomes reported among different medical institutions (5, 6). Consequently, researchers are diligently investigating a more refined composition for analgesic cocktails.
Despite the addition of various adjuvants, including epinephrine, clonidine, morphine, non-steroidal anti-inflammatory drugs, and corticosteroids, to local anesthetics to enhance their analgesic effects (7), the prolongation of postoperative analgesia remains constrained. Magnesium functions as an antagonist of N-methyl-d-aspartate (NMDA) receptors (8) and is an effective analgesic adjuvant for postoperative pain management (9). Magnesium sulfate (MgSO4) has undergone thorough investigation in various orthopedic procedures, and recent studies have evaluated the use of MgSO4 as an additive to the drug cocktail in TKA (10, 11, 12, 13, 14). However, the effectiveness of MgSO4 as an additive to the drug cocktail in TKA is unclear. Studies have reported that incorporating MgSO4 into the peripheral analgesic cocktail after TKA prolongs postoperative analgesia, decreases opioid consumption, and alleviates initial postoperative pain (10, 11, 12, 13), and has the potential to enhance knee joint function (12, 13). However, one study reported that the supplementation of MgSO4 to the peripheral analgesic cocktail had no significant analgesic advantage in patients undergoing TKA (14).
There is a consensus that medical interventions should adhere to an evidence-based approach, which entails drawing conclusions from meticulously conducted randomized controlled trials (RCTs) and meta-analyses that meet the highest contemporary scientific standards. Thus, we performed a systematic review and meta-analysis of RCTs to evaluate the impact of MgSO4 as an additive drug to the peripheral analgesic cocktail in TKA.
Methods
A systematic search was conducted to identify RCTs following the methodologies outlined in the Cochrane Handbook for Systematic Reviews of Interventions (15). This meta-analysis was performed in accordance with the PRISMA statement (16). The review was registered in the PROSPERO, with the registration number CRD42023470356. As all analyses were conducted using data from previously published studies, ethical approval was not required.
Search strategy
We conducted a systematic literature search of major electronic databases, namely PubMed, EMBASE, Web of Science, and the Cochrane Library. The last search date was August 15, 2023. There were no language or publication year restrictions. The search strategy used a combination of medical subject headings and keywords related to ‘Magnesium Sulfate’ and ‘Arthroplasty, Replacement, Knee’. The search terms were ‘Magnesium Sulfate’, ‘Magnesium’, ‘Magnesium Sulfate, Heptahydrate’, ‘Arthroplasty, Replacement, Knee’, ‘Arthroplasty, Knee Replacement’, ‘Knee Replacement Arthroplasty’, ‘Knee Arthroplasty, Total’, ‘Arthroplasty, Total Knee’, ‘Total Knee Arthroplasty’, ‘Replacement, Total Knee’, and ‘Total Knee Replacement’ (Supplemental Table 1, see section on supplementary materials given at the end of this article). Search terms were combined using the Boolean operators ‘AND’ or ‘OR’. The reference lists of relevant articles were meticulously searched to identify additional trials.
Inclusion criteria and study selection
A study was considered eligible for inclusion if: i) it was an RCT comparing TKA patients who received a topical MgSO4 in combination with a peripheral analgesic cocktail to TKA patients who received a peripheral analgesic cocktail alone; and ii) it reported at least one of the following outcomes: pain score, opioid consumption, functional evaluation of the knee joint, length of hospital stay (LOS), or adverse events. A study was excluded if it: i) was based on the use of an intravenous analgesic infusion with added magnesium; ii) compared the effect of MgSO4 with a blank/placebo; iii) involved incomplete data, or the full-text article was not available, or was an animal study; or iv) was published as a review, letter, or conference abstract.
All retrieved studies were imported into EndNote 9 (Thomson Scientific, Stamford, CT, USA). The exclusion of irrelevant studies based on titles and abstracts was independently conducted by the same two authors who had conducted the initial database searches. Subsequently, the full texts of studies that met the predefined inclusion criteria underwent thorough screening, and a final determination on study eligibility was reached. Any discrepancies between the two authors were resolved through discussion with a third author.
Data extraction
The same two authors independently extracted data from selected studies, including the first author(s)’ name, country, publication year, numbers of patients in the intervention and control groups, sample size, dosage of MgSO4 added in the trial group, and composition of the peripheral anesthetic cocktail administered in the control group. Indicators of pain consisted of the visual analog scale (VAS) score at rest or during motion within 72 h after surgery, postoperative morphine consumption for rescue analgesia, and time to first rescue analgesia. Any opioid consumption was converted to the oral morphine equivalent (17). Knee functional recovery was assessed by knee range of motion, daily mobilization distance, and time to first straight leg raising. Additionally, we assessed the LOS and major surgical complications (postoperative nausea or vomiting (PONV), wound complications, deep vein thrombosis, chronic pain, pruritus, and sedation).
Data were independently extracted and inputted into an Excel spreadsheet, and the risk of bias for each eligible article was assessed by two authors. Disagreements were resolved during meetings with all authors.
Quality assessment
The Cochrane risk-of-bias tool was used to assess the quality and risk of bias of the included RCTs (15). We systematically evaluated various aspects of methodological rigor, namely random sequence generation, allocation concealment, blinding of participants and personnel, blind outcome assessment, handling of incomplete outcome data, selective reporting, and potential sources of bias. The overall quality of the included studies was categorized as a low, unclear, or high risk of bias. The quality assessment was conducted independently by two authors, and any discrepancies were resolved through discussions.
The quality of evidence for the outcomes in the current meta-analysis was assessed using the Recommendations Assessment, Development and Evaluation system, which considers the following elements: risk of bias, inconsistency, indirectness, imprecision, and publication bias (18). The level of evidence was categorized as high, moderate, low, and very low.
Statistical analysis
The statistical analysis was performed using RevMan software, version 5.4, provided by the Cochrane Collaboration. All outcomes were meta-analyzed using a random-effects model. Dichotomous data were analyzed using risk ratios (RRs). Continuous data measured on congruent scales were presented as mean differences (MDs) with corresponding 95% CIs, while standardized mean differences (SMDs) were utilized for continuous outcomes assessed on different scales with 95% CIs. Results that were originally presented as the median and interquartile range were transformed into the mean and standard deviation following the guidelines outlined in The Cochrane Handbook (15) when applicable. Statistical significance was set at P < 0.05. Heterogeneity across studies was assessed using the I2 test, with I2 > 50% defined as substantial heterogeneity.
Result
Search results and characteristics of included studies
The systematic searches of the PubMed, Embase, Web of Science, and Cochrane Library databases yielded 24, 54, 27, and 38 citations, respectively. After removing duplicates, 56 articles were subjected to initial screening, wherein the titles and abstracts were independently assessed by two authors. Subsequently, the full text of seven RCTs was read. Two of these RCTs were excluded because they compared the effect of MgSO4 with a blank/placebo (19, 20). Consequently, five RCTs involving 432 patients were included in the meta-analysis. The details of the identification, inclusion, and exclusion of studies are illustrated in Fig. 1.
Search result and study selection procedure.
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
All included RCTs had been published since 2021. Three RCTs were performed in China, one was performed in the USA, and one was performed in Canada. The baseline characteristics of the included RCTs are summarized in Table 1.
Description of studies and participants.
| Reference | Country | Year | Number of patients | Dosage of MgSO4 in IG | Composition of peripheral anesthetic solution cocktail in CG | ||
|---|---|---|---|---|---|---|---|
| IG | CG | Total | |||||
| Zhao et al. (11) | China | 2021 | 30 | 30 | 60 | 250 mg | 20 mL levobupivacaine 50 mg + triamcinolone 25 mg + 0.9% normal saline |
| Zoratto et al. (15) | Canada | 2021 | 41 | 39 | 80 | 2 g of 10% MgSO4 | 10 mL ropivacaine 0.5% + 10 mL normal saline |
| Choi et al. (12) | America | 2022 | 49 | 53 | 102 | 150 mg (0.3 mL) | 30 mL 0.25% bupivacaine and 0.3 mL sterile saline |
| Wang et al. (13) | China | 2023 | 50 | 50 | 100 | 2.5 mg/mL | 100 mL ropivacaine (0.2%), epinephrine (2.0 mg/mL), and dexamethasone (0.1 mg/mL) |
| Zhao et al. (14) | China | 2023 | 45 | 45 | 90 | 2.5 mg/mL | 100 mL 0.2% ropivacaine, dexamethasone (0.1 mg/mL), and epinephrine (2.0 μg/mL) |
CG, control group; IG, intervention group; MgSO4, magnesium sulfate.
All RCTs (10, 11, 12, 13, 14) adhered to clear inclusion and exclusion criteria and thoroughly reported the randomization methodology, with a description of the use of computer-generated randomization. In three RCTs (12, 13, 14), allocation concealment was achieved using sealed envelopes. All RCTs used double-blinding, and two (12, 13) made earnest attempts to blind the assessors. One RCT (14) had a high risk of bias in terms of incomplete outcome data. Two studies (12, 13) had an unclear risk of bias regarding selective reporting. In addition, one RCT (11) had an unclear risk of bias, and one (14) had a high risk of bias. The methodological quality assessment is summarized in Fig. 2. The quality of evidence, as assessed by the GRADE, is presented in Supplementary Table 2.
Risk of bias in included studies. Green indicates a low risk, yellow indicates an unclear risk, and red indicates a high risk of bias.
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
Pain scores
VAS scores (at rest) were investigated in four RCTs involving 320 patients (10, 11, 13, 14). As shown in Fig. 3A, the meta-analysis demonstrated that the VAS scores (at rest) were significantly lower in the MgSO4 group than the control group at 6 h postoperatively (MD: −0.52, 95% CI: −0.77 to −0.26, I2 = 26%, GRADE: MODERATE), 12 h postoperatively (MD: −0.53, 95% CI: −0.74 to −0.31, I2 = 0%, GRADE: LOW), and 24 h postoperatively (MD: −0.58, 95% CI: −1.06 to −0.10, I2 = 72%, GRADE: VERY LOW). However, there was no significant difference between the two groups in the VAS scores (at rest) at 48 h postoperatively (MD: −0.48, 95% CI: −0.96 to 0.00, I2 = 77%, GRADE: VERY LOW) and 72 h postoperatively (MD: −0.18, 95% CI: −0.37 to 0.00, I2 = 0%, GRADE: MODERATE).
Forest plots displaying the mean differences in 6- to 72-h postoperative visual analog scale scores between the magnesium sulfate and control groups A) at rest and B) during motion. Green squares with horizontal lines represent the mean differences and 95% CIs for each trial. Black tiles serve as graphical representations of the mean differences at distinct time intervals (11, 12, 14, 15).
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
VAS scores (motion) were investigated in two RCTs involving 150 patients (10, 13). As shown in Fig. 3B, the meta-analysis demonstrated that the VAS scores (motion) were significantly lower in the MgSO4 group than the control group at 12 h postoperatively (MD: −0.63, 95% CI: −0.85 to −0.40, I2 = 0%, GRADE: LOW), 24 h postoperatively (MD: −0.53, 95% CI: −0.73 to −0.34, I2 = 0%, GRADE: LOW), and 48 h postoperatively (MD: −0.35, 95% CI: −0.54 to −0.16, I2 = 63%, GRADE: VERY LOW). However, there was no significant difference between the two groups in the VAS score (motion) at 48 h postoperatively (MD: −0.17, 95% CI: −0.35–0.01, I2 = 0%, GRADE: MODERATE).
Morphine consumption and time to first rescue analgesia after total knee arthroplasty
Morphine consumption was investigated in four RCTs involving 372 patients (11, 12, 13, 14). As shown in Fig. 4A, the meta-analysis demonstrated that the morphine consumption was significantly lower in the MgSO4 group than the control group within 24 h postoperatively (MD: −11.70, 95% CI: −12.68 to −10.72 mg, I2 = 38%, GRADE: LOW), 24–48 h postoperatively (MD: −7.92, 95% CI: −8.88 to −6.96 mg, I2 = 80%, GRADE: VERY LOW), and during the total hospitalization period (MD −18.14, 95% CI: −19.78 to −16.50 mg, I2 = 91%, GRADE: VERY LOW).
Forest plots displaying the mean differences between the magnesium sulfate and control groups in A) morphine consumption and B) time to first rescue analgesia after total knee arthroplasty. Green squares with horizontal lines represent the mean differences and 95% CIs for each trial. Black tiles serve as graphical representations of the mean differences at distinct time intervals or the indicators (12, 13, 14, 15).
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
The time to first rescue analgesia after TKA was reported in three RCTs involving 269 patients (12, 13, 14). As shown in Fig. 4B, the meta-analysis demonstrated that the time to first rescue analgesia after TKA was significantly shorter in the MgSO4 group than the control group (standardized MD: 0.63, 95% CI: 0.38–0.88, I2 = 84%, GRADE: VERY LOW).
Knee joint function
The knee range of motion was reported in two RCTs involving 190 patients (12, 13). As shown in Fig. 5, the meta-analysis demonstrated that the knee range of motion on postoperative day 1 was significantly greater in the MgSO4 group than the control group (MD: 4.39, 95% CI: 1.65–7.13, I2 = 87%, GRADE: VERY LOW). However, there was no significant difference between the two groups in the knee range of motion on postoperative day 2 (MD: 2.08, 95% CI: −0.01–4.16, I2 = 75%, GRADE: VERY LOW).
Forest plots displaying the mean differences between the magnesium sulfate and control groups on postoperative days 1 and 2 in the A) knee range of motion, B) daily mobilization distance, and C) time to first straight leg raising. Green squares with horizontal lines represent the mean differences and 95% CIs for each trial. Black tiles serve as graphical representations of the mean differences at distinct time intervals or the indicators (11, 13, 14).
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
The daily mobilization distance was reported in two RCTs involving 190 patients (10, 13). As shown in Fig. 5, the meta-analysis demonstrated that the MgSO4 group had a significantly greater daily mobilization distance on postoperative day 1 than the control group (MD: 3.65, 95% CI: 1.93–5.37, I2 = 95%, GRADE: VERY LOW). However, there was no significant difference between the two groups in the daily mobilization distance on postoperative day 2 (MD: 1.78, 95% CI: −0.60–4.16, I2 = 77%, GRADE: VERY LOW).
The time to first straight leg raising after TKA was reported in two RCTs involving 150 patients (10, 13). As shown in Fig. 5, the meta-analysis demonstrated that the MgSO4 group had a significantly shorter daily mobilization distance than the control group (MD −3.79, 95% CI: −5.12 to −2.47, I2 = 95%, GRADE: VERY LOW).
Length of hospital stay
The postoperative LOS was reported in two RCTs involving 190 patients (12, 13). As shown in Fig. 6, the meta-analysis demonstrated that the MgSO4 group had a significantly shorter LOS than the control group (MD: −1.56, 95% CI: −2.79 to −0.32 h, I2 = 91%, GRADE: VERY LOW).
Forest plot displaying the mean difference between the magnesium sulfate and control groups in the length of hospital stay. Green squares with horizontal lines represent the mean differences and 95% CIs for each trial. Black tiles serve as graphical representations of the mean differences of the indicators (13, 14).
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
Surgical complications
The surgical complications are shown in Fig. 7.
Forest plots displaying the mean differences in surgical complications between the magnesium sulfate and control groups. Green squares with horizontal lines represent the mean differences and 95% CIs for each trial. Black tiles serve as graphical representations of the mean differences of the indicators (12, 13, 14, 15).
Citation: EFORT Open Reviews 9, 9; 10.1530/EOR-23-0185
PONV was reported in four RCTs involving 372 patients (11, 12, 13, 14). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of PONV (RR: 0.82, 95% CI: 0.67–1.00, I2 = 0%, GRADE: LOW).
Wound complications were reported in two RCTs involving 190 patients (12, 13). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of wound complications (RR: 0.56, 95% CI: 0.19–1.60, I2 = 0%, GRADE: VERY LOW).
Deep vein thrombosis was reported in one RCT involving 80 patients (13). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of deep vein thrombosis (RR: 0.33, 95% CI: 0.01–7.95, GRADE: VERY LOW).
Chronic pain was reported in one RCT involving 80 patients (13). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of chronic pain (RR: 0.33, 95% CI: 0.07–1.56, GRADE: VERY LOW).
Pruritus was reported in one RCT involving 80 patients (14). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of pruritus (RR: 1.19, 95% CI: 0.52–2.70, GRADE: LOW).
Sedation was reported in one RCT involving 80 patients (14). Meta-analysis demonstrated that there was no significant difference between the MgSO4 and control groups in the incidence of sedation (RR: 0.95, 95% CI: 0.14–6.43, GRADE: VERY LOW).
Discussion
The use of multimodal pain management protocols after TKA has the ability to decrease pain scores, curtail the duration of hospitalization, accelerate recovery, and enhance patient satisfaction (21). Effective perioperative analgesia plays a crucial role in facilitating early return to exercise and rapid recovery after TKA (2). Magnesium causes significant analgesic effects that can decrease the required dose of opioids (22). Nowadays, MgSO4 is used as an effective analgesic adjuvant for various types of postoperative pain (23). In the pursuit of enhancing analgesia and prolonging the duration of peripheral analgesia, researchers began to investigate the addition of MgSO4 to the formulation of peripheral anesthetic cocktails. Recent studies have begun to discuss the addition of MgSO4 to the formulation of peripheral anesthetic cocktails in TKA, but the results are still controversial. Therefore, our meta-analysis and systematic review provide the first comprehensive overview of RCTs evaluating the addition of MgSO4 to the formulation of peripheral anesthetic cocktails used in TKA.
The effectiveness of analgesia for TKA may vary significantly depending on the composition of drugs in the peripheral analgesic cocktail. Presently, peripheral cocktail formulations predominantly comprise amide peripheral anesthetics in combination with glucocorticoids (24). However, commonly used amide peripheral anesthetics, such as ropivacaine and bupivacaine, typically do not offer prolonged analgesia, as their efficacy tends to diminish within approximately 10 h (25). MgSO4 is an NMDA receptor antagonist that can reduce the postoperative requirement for anesthetics and analgesics (26). It is suggested that the antinociceptive effect of magnesium can be harnessed to inhibit NMDA receptors (22). NMDA receptors play an important role in the transmission of central pain information and the regulation of acute hyperalgesia (27). Recent studies have shown that NMDA receptors also exist in peripheral tissues, such as muscles, skin, and joints, and play an important role in the transmission of nociceptive signals (28). Recent research has explored the incorporation of MgSO4 into peripheral anesthetics to enhance and potentially extend the duration of analgesia after various nerve blocks (9, 29). In addition, MgSO4 reportedly has the potential to augment and prolong the effects of ropivacaine-induced brachial plexus blocks (30). MgSO4 may exhibit favorable effects in TKA when used as an adjunct drug within a topical cocktail, but there is currently no evidence-based medicine to support this. Our meta-analysis revealed that the incorporation of MgSO4 into a peripheral analgesic cocktail is associated with a substantial extension of the analgesic duration, lasting for nearly 2 days after TKA. However, the analgesic effect gradually diminishes over time.
A primary objective in TKA is achieving optimal postoperative analgesia while simultaneously minimizing opioid consumption (31). Our meta-analysis suggests that the incorporation of MgSO4 into the peripheral analgesic cocktail has the potential to reduce opioid consumption. This is consistent with the finding that MgSO4 enhances analgesia. In fact, the improvement in pain management and reduction in opioid consumption after the addition of MgSO4 can be attributed to its analgesic properties (32). This finding is consistent with previous studies that have demonstrated the role of MgSO4 in improving pain outcomes after various surgical procedures (33).
The restoration of knee joint function after TKA has great clinical significance. Early functional exercise is essential to minimize joint stiffness, deep vein thrombosis, postoperative infections, and other complications due to inactivity (34). Functional recovery after TKA is influenced by various factors, including age, body mass index, operative factors, and pain. The knee function of the MgSO4 group exhibited a significant improvement compared with the control group within the first day after surgery, aligning with the duration of analgesia. These results suggest that the analgesic effect of MgSO4 may promote early postoperative ambulation and joint function recovery, contributing to enhanced patient mobility and rehabilitation.
Regarding adverse events, our analysis did not find any significant differences between the MgSO4 and control groups in terms of PONV, wound complications, deep vein thrombosis, chronic pain, pruritus, and sedation. Adverse effects of topical magnesium have been very rarely reported, with some studies describing an increased incidence of nausea (35). This is also one of the concerns with intravenous administration of MgSO4. However, our findings did not reveal any significant difference between the MgSO4 and control groups in the occurrence of PONV. There are two possible reasons for this phenomenon. First, the prominent cause of PONV is widely attributed to the administration of opioids. Thus, the potential of MgSO4 to decrease opioid usage may counterbalance the detrimental effects associated with magnesium supplementation. Secondly, adding MgSO4 to the peripheral analgesic cocktail, rather than intravenous MgSO4 administration, may decrease the incidence of adverse reactions. The present findings indicate that adding MgSO4 to the peripheral analgesic cocktail is well tolerated and safe for use in patients undergoing TKA, further supporting its potential as a valuable adjunct in pain management protocols.
LOS is a crucial metric for assessing enhanced recovery after TKA. Interestingly, our meta-analysis suggested that the addition of MgSO4 to the peripheral analgesic cocktail may reduce the LOS. This is possibly due to the analgesic effect of MgSO4 and the related decrease in opioid consumption, leading to faster recovery.
Our study shows that peripheral MgSO4 is effective in achieving analgesia after TKA. Researchers have suggested that the antinociceptive properties of magnesium are linked to its capacity to inhibit NMDA receptors. The function of NMDA receptors is correlated with magnesium levels. In a physiological context, magnesium blocks the ion channel on NMDA receptors, obstructing the entry of extracellular calcium ions into the cell and thereby averting secondary neuronal changes (36). This mechanism has the potential to impede central sensitization associated with nociception (37), which is found in patients with osteoarthritis (38). Therefore, MgSO4 may exert an analgesic effect by modulating central sensitization in patients who have undergone TKA, which may explain the results of our meta-analysis.
The present study represents the first systematic review and meta-analysis of the literature evaluating the impact of incorporating MgSO4 into a peripheral analgesic cocktail. The strengths of this meta-analysis include the extensive literature search, inclusion of updated literature, and comprehensive investigation of the effect of topical MgSO4 for analgesia in TKA. Moreover, we conducted meta-analyses and used the Recommendations Assessment, Development and Evaluation system to assess the evidence. However, our study also has several limitations. First, the numbers of included studies and patients were relatively small, which may have affected the overall statistical power and generalizability of our findings. Secondly, the unavoidable heterogeneity in outcomes requires subgroup analysis and meta-regression. However, owing to the limited number of included studies, the data available for analysis remained inadequate. Thus, a random-effects model was used for all outcomes to enhance the robustness of our findings. Thirdly, owing to the presently restricted data availability, our evaluation exclusively assessed the impact of MgSO4 as a supplementary component within a peripheral analgesic cocktail. However, our study did not evaluate the individual analgesic effects of topical MgSO4 as a standalone medication, nor does it establish the optimal dosage of MgSO4 when used as an adjunct. Future studies with larger sample sizes and standardized protocols are warranted to further validate our results.
Despite these limitations, the present systematic review and meta-analysis provides an up-to-date overview of the impact of topical MgSO4, a strategy that is not widely known, for analgesia in TKA. Our meta-analysis suggests that the addition of MgSO4 to the peripheral analgesic cocktail significantly enhances the analgesic efficacy in the early postoperative period (within 2 days) following TKA and decreases opioid consumption without increasing the incidence of adverse reactions. The use of MgSO4 as an adjunct to traditional analgesic strategies may offer a promising approach for optimizing pain management in TKA. These findings may suggest a new strategy for pain management in the early postoperative period of TKA. However, given the low or very low quality of the studies analyzed for outcomes, there is a need for more high-quality RCTs exploring the long-term addition of MgSO4 to the peripheral analgesic cocktail in order to enhance analgesic efficacy after TKA. Additionally, the dosage of MgSO4 used in the included literature was inconsistent, necessitating further studies to determine the optimal dosage. Given that studies have documented sex-based differences in pain perception (39), further research is also required to address potential confounding factors.
Conclusion
The findings of this meta-analysis suggest that MgSO4 considerably augments the analgesic potency of a peripheral analgesic cocktail during the initial postoperative period (within 2 days) following TKA. Furthermore, the addition of MgSO4 appears to decrease opioid consumption without increasing the incidence of adverse reactions.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/EOR-23-0185.
ICMJE Conflict of Interest Statement
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding Statement
This paper was supported by Traditional Chinese Medicine Inheritance and Innovative Talent Project (Zhongjing Project) Top-notch Chinese Medicine Talents Training Project (Yuwei Chinese Medicine Letter (2021) no. 15).
Acknowledgements
We thank Kelly Zammit, BVSc, from Liwen Bianji (Edanz) (www.liwenbianji.cn/), for editing the English text of a draft of the manuscript.
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