Comparative evaluation of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia: a meta-analysis of randomized controlled trials

Background The comparative efficacy of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia remains controversial. Methods We searched Mediline (OvidSP), EMBASE (OvidSP) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify trials that compared epidural bupivacaine and magnesium sulfate combination (intervention) with bupivacaine alone (control). Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to assess the quality of evidence. Results Eleven studies fulfilled our inclusion criteria after screening. We found that epidural bupivacaine combined with magnesium sulfate could prolong the time for first rescue analgesics (SMD 4.96; 95% CI [2.75, 7.17], P < 0.00001, I2 = 98%), reduce the number of patients who need rescue analgesics (RR 0.38; 95% CI [0.20, 0.74], P = 0.004, I2 = 75%) and requirement for rescue analgesics (SMD -2.65; 95% CI [− 4.23, − 1.06], P = 0.001, I2 = 96%). Conclusions Magnesium suifate as an adjuvant of epidural bupivacaine improved postoperative analgesia. However, we rated the quality of evidence to be very low because of high heterogeneity, imprecise of results and small sample sizes. Furthermore, further large high-quality trials are still needed to confirm the effects of magnesium sulfate on postoperative analgesia.


Background
Alleviation of postoperative pain is an important objective for the anesthesiologists. Inadequaten postoperative pain control is associated with deep vein thrombosis and pulmonary embolism, quality-of-life impairment, delayed recovery time and higher health-care costs [1,2]. Epidural anaesthesia is an effective technique, with the advantage of safety, efficiency and prolonged postoperative pain relief [3]. A number of adjuvants have been used with bupivacaine via epidural route over the years with the purpose of prolonging the duration of postoperative analgesia and minimising the side effects. Nevertheless researchers continue to find the optimum adjuvants, as the currently researched adjuvants (e.g. opioids, tramadol, dexmedetomidine) still have some adverse effects such as nausea and vomiting, pruritus, bradycardia, and hypotension [4][5][6].
Magnesium is the fourth most plentiful cation in the body and possess certain analgesic property in both animal and human models of pain [7,8]. Magnesium ion (Mg2+) is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that blocks inward current flow through ion channels linked to NMDA receptors in a voltage-dependent fashion, has the potential to prevent central sensitization induced by peripheral nociceptive stimulation. For these reasons, it seems plausible that magnesium as an adjuvant of epidural bupivacaine can prolong postoperative analgesia and reduce side effects. Therefore we conducted this meta-analysis to test our hypothesis.

Materials and methods
For this meta-analysis, we followed the recommendation with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [9], and the quality of the evidence was assessed using the GRADE approach and recommendations from the Cochrane Collaboration [10].

Eligibility and exclusion criteria
The purpose of this meta-analysis was to evaluate the safety and efficacy of magnesium sulfate as an adjuvant of epidural bupivacaine. Studies will be included if they meet the following criteria: (1) randomized controlled trials (RCTs); (2) adults (≥18 years old); (3) comparing the analgesic efficacy of epidural bupivacaine and magnesium sulfate combination (intervention), with bupivacaine alone (control) for anesthesia or postoperative pain management; (4) study provided data at least on one of the outcomes (time to the first rescue analgesia, number of patients required rescue analgesia, requirement for rescue analgesia, duration of motor block, and side effects); (5) full text published in English. We excluded studies in which another drug (eg.fentanyl, morphine) was added in the intervention or control group, and magnesium sulfate was administered by another route (e.g. intrathecal, intravenous or intramuscular).

Endpoints
Primary outcomes: (1) the time to the first request for rescue analgesics; (2) the number of patients required postoperative rescue analgesics; (3) requirement for rescue analgesics. Secondary outcomes: (1) duration of motor block; (2) adverse events related to postoperative analgesia protocols (the incidence of hypotension, bradycardia, nausea and vomiting, pruritus, shivering).

Search strategy and study selection
We searched Mediline (OvidSP), EMBASE (OvidSP) and Cochrane Central Register of Controlled Trials (CENTRAL) on october 24, 2019 in order to identify trials that compared epidural bupivacaine and magnesium sulfate combination (intervention) with bupivacaine alone (control). The exact search strategies are shown in Appendix 1. After importing the search results into EndNote X9, duplicated studies were excluded. Two investigators (Li and Wang) independently determined eligibility on the basis of the title, abstract and full text according to the inclusion and exclusion criteria, with disagreements resolved by discussion and consensus with a third agent (Fang).

Data extraction and quality assessment
Two review authors (Li and Wang), independently extracted data using a predesigned form and verified for consensus before entry into Review Manager 5.0. Li and Wang independently assessed the risk of bias for each included study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions [11]. We rated the overall risk of bias of a study as low if ≦1 domain were 'high risk' or 'unclear', high if two or more of the domains were identified as 'high risk' or 'unclear'. Resolving any disagreements by discussion and consensus with a third reviewer (Fang).

Statistical analysis
We used the software Review Manager 5.0 for statistical analysis. Only primary and secondary outcomes defined previously were included in our analysis. For continuous data (e.g. the time to the first request for rescue analgesics, requirement for rescue analgesics and duration of motor block), considering the different modes of postoperative pain management and species of rescue analgesics, we calculated standardized mean differences (SMDs) with corresponding 95% confidence intervals (95% CI). We rated the effect size of SMDs as small effect (0.2-0.5), medium effect (0.5-0.8) and large effect (≥0.8). For those studies that did not report a mean and standard deviation (SD), we did not hand and transformate the date, because we did not know if it was normally distributed. We calculated risk ratios (RR) with corresponding 95% CI for dichotomous outcomes (e.g. the number of patients required postoperative rescue analgesics, adverse events related to postoperative analgesia protocols).

Assessment of heterogeneity and subgroup analysis
We assessed statistical heterogeneity using the I 2 statistic, as described in the Cochrane Handbook for Systematic Reviews of Interventions [11], and an I 2 value > 50% is considered to indicate substantial heterogeneity. To explore the sources of clinical heterogeneity, we planned to perform subgroup analyses of bolus injection versus bolus followed a continuous injection according to the administration of magnesium sulfate. We used a randomized-effect model if there was significant heterogeneity among studies (I 2 > 50%), otherwise the fixed effects model was used. A P-value < 0.05 and the 95% CI did not cross the equivalent line were considered statistically significant differences from control.

Sensitivity analysis and assessment of publication bias
We decided to perform sensitivity analyses for the primary outcomes by removing studies with high risk of of bias or using two different models (the randomized effect model and the fixed effect model). If sufficient studies (10 or more) were included for the primary or second outcomes, we had intended to use a funnel plot to explore the possibility of publication bias.

Primary outcome: the time to the first request for rescue analgesics
Nine studies reported the time to the first request for rescue analgesics, in which the data of six studies were reported as mean ± standard deviation (SD) [12-15, 17, 20], while the remaining two studies reported the data in fig [16,19,22].. As a result, only six studies involving 400 patients were included for analysis [12-15, 17, 20]. The meta-analysis showed that the time to the first request for rescue analgesics was prolonged significantly in the magnesium sulfate group compared with the control group (SMD 4.96; 95% CI [2.75, 7.17], P < 0.00001, I 2 = 98%; Fig. 4). We deemed the quality of the evidence to be very low because: (1) four studies had 'high' risk of bias; (2) the     Subgroup analysis was conducted according to the administration of magnesium sulfate. Five studies administrated magnesium sulfate by bolus injection [12][13][14][15]17], and only one study by bolus followed a continuous injection [20]. We noted the time to the first request for rescue analgesics was also prolonged significantly in the magnesium sulfate group compared with the control group when the study by bolus followed a continuous injection was excluded (SMD 3.67; 95% CI [1.75, 5.58], P = 0.0002, I 2 = 97%). We also found significant difference between the subgroups (P < 0.0001) and the bolus followed a continuous injection subgroup had a greater effect on the time to the first rescue analgesics.

Primary outcome: the number of patients required postoperative rescue analgesics
Five studies including 304 patients reported the number of patients required rescue analgesics [12,16,18,19,21]. The merged effect analysis showed that it was significantly less in magnesium group compared with control group (RR 0.38; 95% CI [0.20, 0.74], P = 0.004, I 2 = 75%, Fig. 5). We judged, the quality of the evidence to be very low based on the GRADE framework: (1) three studies had a 'high' risk of bias; (2) there was significant heterogeneity among studies.
Subgroup analysis was conducted according to the administration of magnesium sulfate. Patients required postoperative rescue analgesics was significantly less in magnesium group when magnesium sulfate was administrated by bolus injection (RR 0.49; 95% CI [0.24, 0.97], P = 0.04, I 2 = 70%). No significant difference was shown between the two groups when magnesium sulfate was administrated by bolus followed a continuous injection (RR 0.17; 95% CI [0.01, 1.97], P = 0.16, I 2 = 84%).
We rated the quality of the evidence to be very low: (1) four studies had 'high' risk of bias; (2) the result was imprecise; and (3) there was significant heterogeneity among studies.

Sensitivity analysis and assessment of publication bias
Based on the prior definition, there were only three studies with a low risk of bias [12,13,16], so we did not conduct the sensitivity analysis based on the risk of bias. Sensitivity analyses of primary outcomes using the fixed effect model yielded stable overall results. Consider that each outcome included fewer than 10 studies, there were insufficient data for any publication bias analysis.

Discussion
This meta-analysis aimed to assess the efficacy and safety of magnesium sulfate as an adjuvant in epidural bupivacaine in providing postoperative analgesia. We found that epidural bupivacaine combined with magnesium sulfate could prolong the time for first rescue analgesics. Furthermore, the addition of magnesium sulfate could reduce the number of patients who need rescue analgesics and requirement for rescue analgesics without adverse events. In addition, our metaanalysis showed that the incidence of shivering was lower with bupivacaine-magnesium sulfate than bupivacaine alone. Nevertheless, duration of motor blockade was significantly prolonged in group magnesium sulfate.  We found that many studies did not adequately report randomization methods. Five studies did not describe the generation of random sequences in detail [12,14,15,19,22], two studies did not describe the methods of allocation concealment [17,18], three studies did not describe whether the anaesthetists were blind for this study design [14,15,20] and four studies did not report in detail their blind assessment of the outcomes [14,15,20,21]. Only one studies reported clinical trials registration [12] and we were not clear about the risk of selective outcome reporting bias. We judged evidence for the time to the first request for rescue analgesics, the number of patients required rescue analgesics, requirement for rescue analgesia and duration of motor block to be very low certainty, and evidence for adverse events to be moderate quality. The low quality of evidence for primary outcomes was largely due to significant heterogeneity among studies and imprecision of the result. The significant heterogeneity might be explained by the differences in the types of surgery performed, the doses and manners of magnesium sulfate administered, and the postoperative pain management models. However, results of subgroup analyses on manners of magnesium administered did not appear to explain heterogeneity and we found that high levels of statistical heterogeneity still remained in both subgroups in each analysis. The surgery types varied between studies to include: cesarean section, unilateral thoracic, spinal, abdominal, orthopaedic. These differences may contribute to inconsistency and reduce the overall applicability of the evidence.
Whether the administrative route is intravenous, epidural, or intrathecal, the actual site of action of magnesium sulfate is probably at the spinal cord NMDA receptors. The analgesic effect primarily depends on Mg2+ blocks inward current flow through ion channels linked to NMDA receptors [23]. Although a previous systematic review found that intravenous administration of magnesium sulfate in orthopedic surgery could reduce postoperative requirement for postoperative analgesics and adverse events such as vomiting, nausea, and shivering [24], the role of intravenous magnesium sulfate was controversial. Some studies had found that intravenous magnesium failed to improve postoperative pain in gastrointestinal surgery [25] and in a pediatric population undergoing tonsillectomy [26]. The reason may be the limited ability of magnesium ions to penetrate the blood-brain barrier [27], so it seems plausible that epidural or intrathecia magnesium might be more effective. An earlier meta-analysis focused on cesarean section revealed that the additional neuraxial magnesium sulfate exerted significant effects on prolonging the duration of neuraxial anesthesia, reducing  postoperative pain scores and decreasing requirement for postoperative analgesics, and was therefore in broad similar to our findings [28]. Furthermore, our findings are similar with the findings in a recent published meta-analysis, where the authors reported a reduction of the need for postoperative rescue analgesics in pediatric when magnesium was added to local anesthetics for caudal anesthesia [29].
In addition, magnesium sulfate has been compared with other epidural adjunct analgesic drugs. One study that evaluated the effects of epidural magnesium sulfate versus dexmedetomidine, and found that the time from epidural medication to first rescue analgesics was longer in dexmedetomidine group, duration of sensory and motor blockade was significantly prolonged in group dexmedetomidine, but risk of sedation increased and there was fall in the mean pulse rate in group dexmedetomidine [15]. Radwan et al. compared magnesium sulfate with fentanyl [21] and Mohammad et al. compared magnesium sulfate with clonidine [14] found the effect of magnesium sulfate on postoperative pain to be comparable to that of the other drugs.
In this meta-analysis, the addition of magnesium sulfate significantly prolonged the duration of motor block. The mechanism might be that magnesium inhibits the motor endplate release of acetylcholine due to inhibition of calcium-dependent channels [30,31]. As for adverse effects, our meta-analysis showed that the incidence of shivering was lower in magnesium sulfate group. The reason might be that perioperative magnesium supplementation prevented the postoperative hypomagnesaemia and decreased the incidence of postoperative shivering [32].
There are some limitations to this study. Firstly, our meta-analysis demonstrates efficacy of epidural bupivacaine combined with magnesium sulfate when compared with bupivacaine alone in providing postoperative analgesia. Even if It is possible that our findings cannot be interpreted as truly positive because of the small sample sizes and the low quality of evidence assessed by GRADE framework; Secondly, We found that many studies did not adequately report randomization methods; Third, we didn't assess publication bias due to the limited number of studies; Fourth, our findings showed high heterogeneity among studies, especially the existing clinical heterogeneity, such as types of surgery performed, the doses and manners of magnesium sulfate administered, and the postoperative pain management models.

Conclusion
In conclusion, This meta-analysis revealed that magnesium suifate as an adjuvant of epidural bupivacaine improves postoperative analgesia. However, we rated the quality of evidence to be very low because of high heterogeneity, imprecise of results and small sample sizes. Furthermore, further large high-quality trials are still needed to confirm the effects of magnesium sulfate on postoperative analgesia.