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Additional effect of magnesium sulfate and vitamin C in laparoscopic gynecologic surgery for postoperative pain management: a double-blind randomized controlled trial

Background This clinical trial was conducted to determine whether combined use of magnesium sulfate and vitamin C more significantly reduced postoperative fentanyl consumption and pain than magnesium sulfate or vitamin C alone. Methods The prospective, double-blinded, randomized controlled study enrolled 132 patients scheduled for laparoscopic gynecologic surgery. The patients were randomly allocated to one of the four groups (n = 33 for each group; Group M [magnesium sulfate 40 mg/kg], Group V [vitamin C 50 mg/kg], Group MV [magnesium sulfate 40 mg/kg and vitamin C 50 mg/kg] and Group C [isotonic saline 40 ml]). Cumulative postoperative fentanyl consumption (primary endpoint measure), postoperative pain score by numeric rating scale, and postoperative nausea and vomiting were recorded at 1, 6, 24, and 48 h after discharge from the postanesthesia care unit. Results Cumulative postoperative fentanyl consumption was significantly less in Groups M, V, and MV than in Group C at all time points. Group MV showed significantly less cumulative postoperative fentanyl consumption than Group M at postoperative 24 h (mean ± standard deviation, 156.6 ± 67.5 vs. 235.6 ± 94.6 µg, P = 0.001), as well as significantly less consumption than Groups M and V at postoperative 48 h (190.8 ± 74.6 vs. 301.0 ± 114.8 or 284.1 ± 128.6 µg, P < 0.001, P = 0.003, respectively). Conclusions Combined use of magnesium sulfate and vitamin C provides an additional benefit in postoperative pain management after laparoscopic gynecologic surgery in comparison to single administration of magnesium sulfate or vitamin C.

trointestinal motility, and respiratory depression) [1]. These adverse effects are dose-dependent and have considerable inter-individual variability [3]. To improve the analgesic effect and reduce these adverse effects, several co-analgesic agents and interventions have been introduced [4].
Magnesium is a divalent cation that plays a key role in ATPase activities in physiologic processes. It is an antagonist of N-methyl-D-aspartate (NMDA) receptors in the central nervous system and attenuates central sensitization [5,6].
Vitamin C (ascorbic acid) is a water-soluble vitamin and an antioxidant that is necessary for growth and development.
It is also known for neuroprotective and neuromodulating effects [7,8]. The exact analgesic mechanism of vitamin C is unknown, and multiple functions of the vitamin may be involved in that process.
Several clinical studies have reported that perioperative administration of magnesium or high-dose vitamin C can reduce postoperative opioid requirements [5,9]. Some studies compared the analgesic efficacy of magnesium sulfate with that of other drugs [10][11][12]. Other studies focused on vitamin C also included some comparisons [13]. The authors of the present study were interested in evaluating the combined efficacy of magnesium sulfate and vitamin C in reducing acute pain. To our knowledge, this is the first study that compares magnesium sulfate and vitamin C directly with each other and with the combination of the two.
We investigated the efficacy of the combined use of magnesium sulfate and vitamin C on postoperative pain management by assessing cumulative fentanyl consumption and pain scores for the postoperative 48 h. We hypothesized that a combination of magnesium sulfate and vitamin C would more significantly reduce cumulative fentanyl consumption than either magnesium sulfate or vitamin C alone.

MATERIALS AND METHODS
One hundred thirty-two patients, aged 20 to 60 years, with American Society of Anesthesiologists physical status I or II, who were scheduled for elective laparoscopic gynecologic surgery, were enrolled. This double-blind randomized controlled trial was approved by the Institutional Review Board of our hospital (no. 19-0042), and written, informed consent was obtained for all enrolled patients.
Exclusion criteria were allergy to magnesium sulfate, vita-min C, or any other study drugs; cardiovascular, neuromuscular, renal, or hepatic disease, diabetes, cancer; opioid or analgesic abuse; and treatment with calcium channel blockers. The day before surgery, all enrolled patients were taught how to use the patient-controlled analgesia (PCA) system (AutoMed3400 ® , Ace Medical, Korea).
Patients were randomly (sealed envelope method) allocated to one of four groups: 1) Magnesium sulfate group (Group M, n = 33): 40 ml solution of 40 mg/kg of magnesium sulfate and isotonic saline is injected at a rate of 120 ml/h for 20 min as a bolus immediately prior to anesthesia induction. Subsequently, 40 ml of the same solution is infused at a rate of 10 ml/h by continuous intravenous infusion until the end of the operation (for an infusion of 10 mg/kg/h).
2) Vitamin C group (Group V, n = 33): 40 ml of a solution of 50 mg/kg of vitamin C (Ascorbic Acid Injection ® , Huons Co., Korea) and isotonic saline is injected at a rate of 120 ml/h for 20 min as a bolus immediately prior to anesthesia induction.
Subsequently, 40 ml of isotonic saline is infused at a rate of 10 ml/h by continuous intravenous infusion until the end of the operation.  In the pilot study, including 10 patients, 24 h consumption of fentanyl was mean ± standard deviation (SD) (378.2 ± 153.2 μg) for patients undergoing laparoscopic hysterectomy.
Based on previous studies, we targeted a 30% reduction in postoperative fentanyl consumption, and a minimum sample size of 29 patients was required per group with an alpha value of 0.05 and a power of 80% [5,15,16]. Considering 10% of the rate loss, 33 patients were selected. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc., USA). Differenc-

RESULTS
One hundred thirty-two patients were randomly allocated into groups, and the CONSORT process is illustrated in Fig. 1.
After randomized allocation, seven patients were lost to follow-up. Six patients were lost owing to nausea and vomiting, and one owing to a change of the surgical procedure during the operation (Group MV). There were no signs of residual neuromuscular blockade in any subjects. No significant intergroup differences in demographics or other characteristics were present (Table 1).
Cumulative postoperative fentanyl consumption was significantly less in Group M, Group V, and Group MV than in Group C at all times (Fig. 2). In addition, Group MV showed significantly less cumulative postoperative fentanyl con-  4]; P = 0.001, P = 0.001, P < 0.001, and P = 0.002, respectively).
There was a significant difference in the scores between Group V (4 [3,4]) and Group C (5 [4,6]; P = 0.006) at 1 h postoperatively. In addition, Group MV showed significantly lower NRS than Group M and Group V at 24 h postoperatively (P < 0.001, P = 0.002, respectively) (Fig. 3). There were no significant difference in postoperative pain scores between  Magnesium is an important ion that is involved in the regulation of several ion channels and physiologic processes.
The exact mechanism of its analgesic effect is not yet clear, but possible key functions are NMDA receptor antagonism and inhibition of calcium influx [17,18]. Many studies have reported the analgesic efficacy of perioperative intravenous magnesium administration. These studies have suggested several regimens for bolus and infusion [5]. The doses have spanned a fairly wide range, with a bolus dose from 30-50 mg/kg followed by an infusion of 6-25 mg/kg/h [5,14]. Seyhan et al. [14] reported that magnesium 40 mg/kg as a bolus followed by 10 mg/kg/h by continuous infusion leads to a significant reduction in postoperative morphine consumption, compared to other regimens. We also chose this method in the present study owing to our use of the same surgical model (40 mg/kg as a bolus, 10 mg/kg/h by infusion).
Oxidative stress and inflammation is associated with arthritis, complex regional pain syndrome, infection, cancer, and surgical trauma [9]. Reactive oxygen species (ROS) mediate neuropathic pain, and ROS scavengers are useful in attenuating mechanical discomfort in a rat model [19]. Vitamin C acts as a potent antioxidant, scavenging both ROS and nitrogen species. Vitamin C also has anti-inflammatory properties, decreasing C-reactive protein and pro-inflammatory cytokines, such as tumor necrosis factor, interferon, and interleukins, which are markers of inflammation [20]. In addition to antioxidative and anti-inflammatory properties, vitamin C also has a neuromodulating function that has been shown to modulate dopamine and glutamate mediated neurotransmission [9,21]. Redox change of the NMDA receptor by  www.anesth-pain-med.org vitamin C decreases pain in chemical behavioral models of nociception in mice [21]. Vitamin C also acts as a cofactor for the synthesis of catecholamine neurotransmitters, which are known as the inhibitory pain pathway [22]. Based on these studies, vitamin C has been investigated as a possible adjuvant for postoperative pain management.
Recently, Kanazi et al. [23] used oral vitamin C (2 g) in reducing the postoperative consumption of opioids in patients undergoing laparoscopic cholecystectomy. Jeon et al. [15] used 50 mg/kg vitamin C by intravenous infusion in a similar attempt to reduce the consumption of opiods following surgery in patients undergoing laparoscopic colectomy.
Ayatollahi et al. [24] showed that administration of vitamin C (3 g) by intravenous infusion reduced postoperative pain without increased side effects in patients undergoing uvulopalatopharyngoplasty and tonsillectomy. At a dose of 500 mg, approximately 63% of oral vitamin C is absorbed, compared to absorption of 46% of a dose of 1,250 mg, and steady state plasma vitamin C concentrations rarely exceed 80 μM because of rapid renal clearance [25,26]. In addition, osmotic diarrhea has been reported with administration of oral vitamin C over 5 g [8]. Hence, we chose to administer a dose of 50 mg/ kg vitamin C by intravenous infusion in the present study.
Numerous studies have examined the perioperative use of magnesium sulfate and vitamin C for pain management; these have shown the suppression of neuropathic pain [5,9,13] and the potentiation of opioid analgesia [15,17,23].
According to the previous studies, perioperative magnesium sulfate and vitamin C are relatively safe to use without any reported serious side effects. Moreover, there are many cases of using vitamins with other minerals [27].
As in several previous studies, our study showed that magnesium sulfate and vitamin C were effective in reducing postoperative fentanyl requirements [5,9]. Unlike previous studies, we directly compared all groups and used a combination of both magnesium sulfate and vitamin C as an adjuvant of opioid analgesics. Neither the individual magnesium sulfate nor the vitamin C group showed a significant difference in reduction of fentanyl consumption. Combined use of the two showed a greater reducing effect than not only the control group, but also than the individual magnesium sulfate and vitamin C groups. Moreover, postoperative pain scores were significantly lower in the combined group than in each of the individual magnesium sulfate and vitamin C groups at some time points. These outcomes may have shown that combined use of magnesium sulfate and vitamin C has an additional effect in reducing postoperative fentanyl requirements. In addition, it may be suspected that these two substances act at different NMDA receptor sites, or that they have different sites of analgesic action. The incidence of PONV was slightly higher in Group C than in other groups, especially at 1 and 6 h, but a statistical difference was present only between Group V and Group C.
There are some limitations in the present study. The incidence of PONV was significantly lower in Group V than in Group C in the acute postoperative period (1, 6 h), but further studies are needed in this regard. We did not assess the plasma concentration of all groups. The half-life of intravenous vitamin C (approximately 2 h) is very short and there was time for fasting more than eight hours, so additional research on plasma blood concentration appears to be needed.
Furthermore, we did not apply equianalgesic doses for the comparison of analgesic efficacy. Some clinical studies have compared magnesium sulfate to ketorolac [10] and fentanyl [28]. In addition, rofecoxib, celecoxib, and acetaminophen have been examined in comparison to vitamin C following various surgical procedures [13]. However, because there was limited literature regarding direct comparison of analgesic effects between magnesium sulfate and vitamin C in previous studies, we used doses known to be effective based on the previous studies (magnesium sulfate: 40 mg/kg as a bolus, 10 mg/kg/h of infusion, and vitamin C: 50 mg/kg) [9,14]. As described above, since both magnesium sulfate and vitamin C are relatively safe, further experiments examining additional use after surgery may be considered.
In conclusion, this study reports the analgesic efficacy of