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Assad Hasan T, Mohammadi M, Ghorbani S, Nikpayam O, Abd Alnabi Flaifel H, Jabbari A et al . Magnesium's efficacy alone and in combinations in reducing perioperative pain and opioid consumption: A comprehensive narrative review. jcbr 2025; 9 (1) :1-7
URL: http://jcbr.goums.ac.ir/article-1-498-en.html
URL: http://jcbr.goums.ac.ir/article-1-498-en.html
Tahseen Assad Hasan1 
, Mostafa Mohammadi2 , Somayeh Ghorbani3 , Omid Nikpayam4 , Hamed Abd Alnabi Flaifel5 , Ali Jabbari1 , Hassan Mirzaei *6
, Mostafa Mohammadi2 , Somayeh Ghorbani3 , Omid Nikpayam4 , Hamed Abd Alnabi Flaifel5 , Ali Jabbari1 , Hassan Mirzaei *6
1- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran
2- Department of Critical Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
3- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran
4- Department of Nutritional Sciences, School of Health, Golestan University of Medical Sciences, Gorgan, Iran
5- Department of Anesthesia Technologies, Al Farqadain University College, Basra, Iraq
6- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran ,mirzaei22@gmail.com
2- Department of Critical Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
3- Cancer Research Center, Golestan University of Medical Sciences, Gorgan, Iran
4- Department of Nutritional Sciences, School of Health, Golestan University of Medical Sciences, Gorgan, Iran
5- Department of Anesthesia Technologies, Al Farqadain University College, Basra, Iraq
6- Ischemic Disorders Research Center, Golestan University of Medical Sciences, Gorgan, Iran ,
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Acknowledgement
The present study is derived from the author's PhD thesis.
Funding sources
No funding was received.
Ethical statement
This article is ethically approved by Golestan University of Medical Sciences, Gorgan, Iran (IR.GOUMS.REC.1403.004).
Conflicts of interest
The authors declare no conflicts of interest.
Author contributions
Conceptualization, HM and TAH; methodology, MM and SGH; software, TAH; validation, HAF; formal analysis, AJ and HM; resources, ON and MM; data curation, HAF and MM; writing-original draft preparation, TAH and HM; writing-review and editing, AJ and HM; visualization, MM; supervision, AJ; funding acquisition, TAH. All authors have read and agreed to the published version of the manuscript.
Data availability statement
Data sharing is not applicable.
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Introduction
Postoperative pain is a major problem for patients and a challenge for anesthesiologists and surgeons. The frequency of moderate to severe pain varies worldwide (1). In Western countries, the prevalence ranges from 14% to 55%, peaking on the day of surgery. In low- and middle-income countries, the prevalence may be as high as 95% in Kenya and Ethiopia, based on cohort studies (2). Pain encompasses not only sensory features but also cognitive, affective, behavioral, and social dimensions and is associated with multiple comorbidities such as migraine, anxiety, depression, sleep disturbances, and reduced quality of life (3,4).
Magnesium is a safe, cost-effective substance that has been used for over 20 years in anesthetized surgery as a sedative, analgesic, and muscle relaxant, as well as an organ protectant in a variety of conditions (5-7). In the central nervous system, magnesium exerts its inhibitory effects by acting as an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors and an inhibitor of catecholamine release (8). The analgesic effect of magnesium is highly beneficial for managing chronic pain and reducing the duration and intensity of postoperative pain (9). The role of magnesium as an adjunct to local anesthetics in minimizing the need for postoperative analgesics has been demonstrated in various clinical studies involving procedures such as hysterectomy, cesarean section, brachial plexus blocks, and laparoscopic surgery (10). Adequate postoperative pain control is essential for reducing discomfort and achieving a rapid recovery after surgery (4).
Although many clinical studies have been conducted in the literature, not all aspects of magnesium have been covered. This review reports on all forms of magnesium, either alone or in combination, as well as the route of administration, different doses, and toxic magnesium levels. The aim of this review is to conduct a comprehensive search of various studies on the role of magnesium in reducing perioperative pain and opioid consumption.
Methods
This review conducted a comprehensive search up to 2024 through various databases, including PubMed, Google Scholar, and the Cochrane Library. We searched for the following keywords: magnesium sulfate, abdominal surgery, analgesia, and postoperative pain. We included clinical trial studies relevant to magnesium’s role in analgesia, examining magnesium alone and as an additive in combination with other analgesics for postoperative pain management. In addition, this review included patients of all ages undergoing laparoscopic and open abdominal surgeries. Our search was restricted to the English language.
Results
We obtained approximately 70 articles, 41 of which were excluded due to irrelevance or repetition. The remaining 29 articles met the review's aim and were summarized to provide a clear overview of the findings.
Comparison magnesium with analgesics or placebo
Magnesium sulfate is widely used in medicine (11). This study examined the use of magnesium alone as an analgesic in a short-term study, which may help reduce postoperative pain and opioid consumption. A total of 18 randomized clinical trials were summarized to assess the effectiveness of magnesium alone in various surgical procedures. Some articles examined different doses of magnesium sulfate, while others investigated its administration through various routes (Table 1).
Magnesium as additive to combinations
Magnesium compounds have been used in combination with many conventional analgesics. A total of 11 clinical trials were collected to show the effectiveness of magnesium in combination with various conventional anesthetics and analgesics (Table 2).
Discussion
Comparison magnesium with analgesic or placebo
Postoperative pain poses a significant risk of psychological and physical trauma to surgical patients. Thus, anesthesiologists have tried various drugs and techniques to reduce its frequency (4).
Mechanism of magnesium as analgesic
Numerous studies have demonstrated that magnesium has analgesic properties and reduces postoperative pain by blocking somatic and visceral pain fibers (9). However, its mechanism of pain relief is not unequivocal. It is believed that its mechanism as a non-competitive NMDA receptor antagonist may contribute to this analgesic effect (12,13). Magnesium blocks the NMDA receptor channel complex, which is critical for pain transmission (11). Noxious stimulation leads to excessive release of glutamate from presynaptic nociceptive terminals, which reverses magnesium blockade and activates NMDA receptors, leading to upregulation of NMDA currents. Activation of NMDA receptors results in the entry of Na⁺ and Ca²⁺ into the cell, initiating a series of central sensitization processes and leading to long-term enhancement of the responsiveness of spinal cord cells to sustained stimulation (14). Increased intracellular calcium levels seem to play a major role in the initiation of central sensitization, and the build-up of intracellular calcium is associated with various receptors on postsynaptic neurons of the spinal dorsal horn, such as NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, and glutamate receptors (15,16). Central sensitization plays an important role in pain perception and the persistence of postoperative acute and chronic pain, presenting as allodynia (Pain elicited by stimuli that are not normally painful) and hyperalgesia (An amplified response to a painful stimulus) (17,18). Central sensitization leads to pain hypersensitivity, including wind-up or long-term pain potentiation; it causes pain even when peripheral stimuli are not intense and continues to cause pain even after the initiating stimuli have disappeared (14). Magnesium is a physiological inhibitor of calcium channels by controlling calcium influx into cells (9,19). Extracellular magnesium blocks NMDA receptors in a voltage-dependent manner and can thus prevent the establishment of central sensitization and abolish existing hypersensitivity (14). Magnesium boluses and infusions during surgery can prevent central sensitization, reduce allergic reactions, and relieve postoperative pain (14,15,20). NMDA receptor antagonists are best administered before the onset of noxious stimuli to prevent central sensitization (11,12,21). However, regarding shoulder tip pain, it was reported that there was no significant effect on shoulder pain, which especially occurs in laparoscopic surgeries (13). Pain after laparoscopic cholecystectomy is highly variable in intensity and duration and is largely unpredictable (9).
Opioid side effects
Opioids have many side effects; for example, intraoperative infusion of remifentanil may lead to acute opioid tolerance and increase postoperative pain (22). In addition, opioids have adverse side effects, including respiratory depression (Which can worsen postoperative pulmonary complications in more vulnerable obese patients), nausea and vomiting, sedation, confusion, hyperalgesia, chronic postoperative pain, pruritus, and decreased intestinal motility leading to ileus, diarrhea, constipation, and long-term use of opioids can lead to addiction (2,23). Therefore, magnesium can reduce perioperative opioid consumption and help avoid opioid side effects or at least attenuate them.
Multimodal analgesia
Magnesium is among the drugs used in combination with other opioid and non-opioid drugs for the multimodal approach recommended by the American Society of Anesthesiologists Task Force for providing optimal analgesia in acute pain management (24). This approach can provide analgesia while reducing the dose of various medications and their associated side effects. Opioids are often used in combination with other analgesics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), as well as adjunctive analgesics, such as alpha-2 agonists or anti-NMDA receptor agents (e.g., ketamine or magnesium) (23).
Magnesium doses
Magnesium has been administered in various doses. A dose of 50 mg/kg of magnesium sulfate clearly demonstrated an analgesic effect, which may have caused patients to have higher serum magnesium ion concentrations following surgery (23). In contrast, some studies reported that a reduced magnesium dosage had no analgesic effect (6). Some studies examined a dose of 25 mg/kg of magnesium, demonstrating its efficacy in reducing postoperative pain for 3 hours in major abdominal surgery without side effects (19). Magnesium sulfate at a dose of 50 mg/kg, given intravenously within 30 minutes before induction of anesthesia, was considered safe and showed no side effects (12). However, studies emphasized that an initial dose of 30 to 50 mg/kg of magnesium sulfate, followed by a maintenance dose of 6-12 mg/kg/h, was recommended because continuous intravenous infusion may enhance postoperative analgesia and reduce the need for opioids during the postoperative period (20).
Magnesium toxicity
Magnesium toxicity sets in at serum concentrations of 2.5-5 mmol/l. Some studies have used magnesium sulfate boluses of 50 mg/kg and double infusions of 8 mg/kg/h, and serum magnesium levels have been measured well below toxic levels, suggesting that magnesium sulfate is safe for intraoperative analgesia (23).
Routes of magnesium administration
Many trials have examined magnesium administration by intraperitoneal (IP) or intravenous (IV) methods. Some studies demonstrated that the efficacy of the IP method was greater than that of IV in certain situations, especially in laparoscopic surgeries. A study conducted on patients undergoing laparoscopic cholecystectomy with IP MgSO₄ showed that IP was a safer and more effective method for acute postoperative pain compared to IV (15). Another study examined the IP combination of levobupivacaine with MgSO₄ and found that the IP combination was effective for postoperative pain in laparoscopic sleeve gastrectomy (25). MgSO₄ with bupivacaine via IP instillation contributed to prolonging the duration of analgesia and reducing postoperative pain in laparoscopic cholecystectomy (26,27). Therefore, magnesium through intraperitoneal instillation demonstrated its efficacy. IP local anesthetics block visceral afferent signals, potentially altering visceral nociception and providing analgesia. Absorption of local anesthetics from the large peritoneal surface may also be another mechanism of analgesia (28,29). Since high concentrations of drugs can be delivered intraperitoneally to the target site without exposing other parts of the body to excessive amounts of the drug, this method is particularly important in situations where systemic exposure to the drug could lead to harmful side effects (29).
However, some studies emphasized that the use of intravenous magnesium boluses before and during surgery, followed by infusions, can reduce postoperative pain and provide a longer duration of analgesia and reduced analgesic consumption without significant complications (18,30). Some studies reported that MgSO₄ intravenously improved pain after surgery and provided safe, effective, and satisfactory analgesia in major abdominal surgery (20,31). Regarding the use of MgSO₄ by IV over 20 minutes followed by infusion, it demonstrated its anesthetic, analgesic, and muscle relaxant features in plastic surgeries (18). In addition, MgSO₄ administered over 15 minutes followed by infusion intraoperatively was effective as an adjuvant in general anesthesia for abdominal surgeries (21).
Comparison magnesium with analgesics or placebo
Many trials have examined magnesium with a placebo or with other analgesics. In comparison with remifentanil, it showed remarkable efficacy in controlling pain and autonomic response during surgery and reduced fentanyl consumption intraoperatively (28). Its effectiveness in reducing propofol requirements during induction and maintenance of general anesthesia has been demonstrated when compared with propofol (21). In addition, some studies compared magnesium and ketamine separately to identify the best analgesic drug among two different (NMDA) antagonists in laparoscopic cholecystectomy. Using ketamine (0.5 mg/kg) and magnesium (20 mg/kg) boluses, magnesium was found to be more effective than ketamine in postoperative pain management, cumulative morphine consumption, and reduction of fentanyl consumption without adverse effects (32). At the same time, the analgesic effects of intravenous infusion of magnesium sulfate and ketorolac during anesthesia for laparoscopic surgery were compared, and it was found that postoperative morphine consumption and pain intensity were significantly reduced, similar to ketorolac tromethamine. In addition, ketorolac had fewer side effects, but not magnesium (33).
However, in a study that examined the effects of magnesium sulfate, dexmedetomidine, and lidocaine on hemodynamic response and postoperative analgesia in laparoscopic abdominal surgery, dexmedetomidine was superior in maintaining hemodynamic stability and relieving pain, followed by lidocaine, and magnesium was the least effective. In addition, the need for rescue analgesia was minimal with dexmedetomidine compared to lidocaine and magnesium (34). A comparison of intravenous magnesium and diclofenac for postoperative analgesia in patients undergoing total abdominal hysterectomy showed that patients using magnesium sulfate consumed less narcotic medication, especially pethidine, on the first postoperative day than those using diclofenac (35). Magnesium has been reported to be effective as an alternative to non-opioid analgesics like NSAIDs perioperatively through intravenous infusion for anesthesia, especially when NSAIDs are contraindicated (33). When lidocaine, ketamine, and magnesium sulfate were compared regarding their effect on postoperative analgesia and the need for rescue analgesics intraoperatively in laparoscopic cholecystectomy, they also demonstrated efficacy (36). In most trials, magnesium contributed to reducing opioid consumption for recovery, 6 and 24 hours after surgery (37).
Mechanism of magnesium as additive in combination
Many studies with conventional anesthetic analgesic compounds have been used to relieve pain. A combination of drugs was effective in relieving postoperative pain, and they were well-tolerated with no recorded serious adverse events (38). Magnesium is an important ion involved in the regulation of multiple ion channels and physiological processes. Therefore, it is involved in these combinations (39). It does not have analgesic properties on its own, but its NMDA receptor antagonist properties eliminate central mechanisms of pain transmission and modulation, sensitization, and even modulate pain transmission in peripheral tissues. This unique property of magnesium sulfate promotes its use in combination with local anesthetics (40). The mechanism of magnesium as a combination does not differ from that of magnesium and other analgesics or anesthetic drugs separately. For example, since MgSO₄ is a noncompetitive NMDA receptor antagonist and a physiological calcium antagonist, the combination of bupivacaine and magnesium can enhance the analgesic effect of bupivacaine. Therefore, magnesium can be used as an adjunct analgesic both locally and systemically after surgery (41). It increases the number of nerve fibers affected by bupivacaine, thereby increasing its conduction block. Therefore, bupivacaine combined with magnesium is superior to other combinations in relieving postoperative abdominal pain and prolonging the time to first postoperative analgesia. In addition, this combination can effectively reduce postoperative shoulder tip pain during laparoscopic surgery (38,40).
Magnesium plus analgesics or anesthetics as combination
A combination of intravenous magnesium plus ketamine was reported to be effective intraoperatively; morphine consumption was reduced by nearly 50% in the first 12 hours compared with magnesium and ketamine alone in abdominoplasty and liposuction surgeries (7). Furthermore, the addition of a magnesium bolus (50 mg/kg) and continuous infusion (15 mg/kg/h) to ketamine reduced morphine consumption and pain scores at rest, during exercise, and during coughing in obese patients, one of whom underwent open bariatric surgery within 24 hours postoperatively, and reduced perioperative remifentanil requirements (23). Furthermore, the combination of magnesium plus paracetamol plus lidocaine showed a reduction in postoperative pain as indicated by pain scores (20). At 24 and 48 hours after surgery, magnesium plus vitamin C significantly reduced cumulative postoperative fentanyl consumption compared with magnesium and vitamin C alone, suppressed neuropathic pain, enhanced the analgesic effect of opioids, and was safe to use without side effects (39). The addition of dexamethasone or magnesium to bupivacaine during IP instillation: Magnesium was found to have an additive effect over dexamethasone, prolonging the duration of analgesia, reducing postoperative pain scores, and nalbuphine consumption in laparoscopic cholecystectomy (40).
The bupivacaine-magnesium combination was superior to the bupivacaine-tramadol combination in reducing postoperative pain, analgesic consumption, and shoulder pain, particularly during laparoscopic cholecystectomy (9,38). A study on postoperative analgesia in upper abdominal surgery found that regional infiltration of ropivacaine and magnesium sulfate in the first 6 hours provided better postoperative pain control than bupivacaine plus magnesium (40).
In another study, the bupivacaine-magnesium combination had the highest analgesic effect among different combinations, such as bupivacaine plus hydrocortisone and magnesium sulfate plus hydrocortisone, for postoperative abdominal pain in patients undergoing laparoscopic unilateral ovarian cystectomy (38). In a prospective clinical study by Sarenac et al., conducted to evaluate amino acids, lidocaine, and magnesium, it was shown to have both anti-inflammatory and analgesic effects during the first five days after abdominal surgery (41).
Various combinations of intraperitoneal levobupivacaine and/or magnesium sulfate for the relief of postoperative pain in patients undergoing laparoscopic sleeve gastrectomy showed that the addition of magnesium sulfate to levobupivacaine reduced postoperative pain and analgesic consumption within the first 24 hours (25).
This is due to differences in patient populations, types of surgery that may produce varying pain intensities, inconsistent pain ratings, and differences in magnesium doses between surgeries, all of which may affect generalizability. Future studies should aim to address these limitations.
Conclusion
Magnesium has been compared with many anesthetics and analgesics, such as ketamine, propofol, ketorolac, remifentanil, and diclofenac, showing remarkable efficacy in relieving pain during surgery and reducing opioid consumption. Regarding its addition in some combinations, such as magnesium with ketamine, paracetamol, vitamin C, bupivacaine, amino acids, and levobupivacaine, it demonstrated good additive properties in prolonging the duration of anesthesia and reducing perioperative pain and opioid use. Regarding magnesium toxicity, although some studies have used magnesium sulfate boluses of 50 mg/kg and double infusions of 8 mg/kg/h, serum magnesium levels have been measured well below toxic levels. Many studies have found that IP magnesium sulfate was significantly more effective than IV. A dose of 30 to 50 mg/kg of magnesium sulfate, followed by a maintenance dose of 6-12 mg/kg/h, is recommended and has been shown to be effective and safe in many trials.
Postoperative pain is a major problem for patients and a challenge for anesthesiologists and surgeons. The frequency of moderate to severe pain varies worldwide (1). In Western countries, the prevalence ranges from 14% to 55%, peaking on the day of surgery. In low- and middle-income countries, the prevalence may be as high as 95% in Kenya and Ethiopia, based on cohort studies (2). Pain encompasses not only sensory features but also cognitive, affective, behavioral, and social dimensions and is associated with multiple comorbidities such as migraine, anxiety, depression, sleep disturbances, and reduced quality of life (3,4).
Magnesium is a safe, cost-effective substance that has been used for over 20 years in anesthetized surgery as a sedative, analgesic, and muscle relaxant, as well as an organ protectant in a variety of conditions (5-7). In the central nervous system, magnesium exerts its inhibitory effects by acting as an antagonist of N-methyl-D-aspartate (NMDA) glutamate receptors and an inhibitor of catecholamine release (8). The analgesic effect of magnesium is highly beneficial for managing chronic pain and reducing the duration and intensity of postoperative pain (9). The role of magnesium as an adjunct to local anesthetics in minimizing the need for postoperative analgesics has been demonstrated in various clinical studies involving procedures such as hysterectomy, cesarean section, brachial plexus blocks, and laparoscopic surgery (10). Adequate postoperative pain control is essential for reducing discomfort and achieving a rapid recovery after surgery (4).
Although many clinical studies have been conducted in the literature, not all aspects of magnesium have been covered. This review reports on all forms of magnesium, either alone or in combination, as well as the route of administration, different doses, and toxic magnesium levels. The aim of this review is to conduct a comprehensive search of various studies on the role of magnesium in reducing perioperative pain and opioid consumption.
Methods
This review conducted a comprehensive search up to 2024 through various databases, including PubMed, Google Scholar, and the Cochrane Library. We searched for the following keywords: magnesium sulfate, abdominal surgery, analgesia, and postoperative pain. We included clinical trial studies relevant to magnesium’s role in analgesia, examining magnesium alone and as an additive in combination with other analgesics for postoperative pain management. In addition, this review included patients of all ages undergoing laparoscopic and open abdominal surgeries. Our search was restricted to the English language.
Results
We obtained approximately 70 articles, 41 of which were excluded due to irrelevance or repetition. The remaining 29 articles met the review's aim and were summarized to provide a clear overview of the findings.
Comparison magnesium with analgesics or placebo
Magnesium sulfate is widely used in medicine (11). This study examined the use of magnesium alone as an analgesic in a short-term study, which may help reduce postoperative pain and opioid consumption. A total of 18 randomized clinical trials were summarized to assess the effectiveness of magnesium alone in various surgical procedures. Some articles examined different doses of magnesium sulfate, while others investigated its administration through various routes (Table 1).
Magnesium as additive to combinations
Magnesium compounds have been used in combination with many conventional analgesics. A total of 11 clinical trials were collected to show the effectiveness of magnesium in combination with various conventional anesthetics and analgesics (Table 2).
Discussion
Comparison magnesium with analgesic or placebo
Postoperative pain poses a significant risk of psychological and physical trauma to surgical patients. Thus, anesthesiologists have tried various drugs and techniques to reduce its frequency (4).
Mechanism of magnesium as analgesic
Numerous studies have demonstrated that magnesium has analgesic properties and reduces postoperative pain by blocking somatic and visceral pain fibers (9). However, its mechanism of pain relief is not unequivocal. It is believed that its mechanism as a non-competitive NMDA receptor antagonist may contribute to this analgesic effect (12,13). Magnesium blocks the NMDA receptor channel complex, which is critical for pain transmission (11). Noxious stimulation leads to excessive release of glutamate from presynaptic nociceptive terminals, which reverses magnesium blockade and activates NMDA receptors, leading to upregulation of NMDA currents. Activation of NMDA receptors results in the entry of Na⁺ and Ca²⁺ into the cell, initiating a series of central sensitization processes and leading to long-term enhancement of the responsiveness of spinal cord cells to sustained stimulation (14). Increased intracellular calcium levels seem to play a major role in the initiation of central sensitization, and the build-up of intracellular calcium is associated with various receptors on postsynaptic neurons of the spinal dorsal horn, such as NMDA, α-amino-3-hydroxy-5-methyl-4-isoxazole propionate, kainate, and glutamate receptors (15,16). Central sensitization plays an important role in pain perception and the persistence of postoperative acute and chronic pain, presenting as allodynia (Pain elicited by stimuli that are not normally painful) and hyperalgesia (An amplified response to a painful stimulus) (17,18). Central sensitization leads to pain hypersensitivity, including wind-up or long-term pain potentiation; it causes pain even when peripheral stimuli are not intense and continues to cause pain even after the initiating stimuli have disappeared (14). Magnesium is a physiological inhibitor of calcium channels by controlling calcium influx into cells (9,19). Extracellular magnesium blocks NMDA receptors in a voltage-dependent manner and can thus prevent the establishment of central sensitization and abolish existing hypersensitivity (14). Magnesium boluses and infusions during surgery can prevent central sensitization, reduce allergic reactions, and relieve postoperative pain (14,15,20). NMDA receptor antagonists are best administered before the onset of noxious stimuli to prevent central sensitization (11,12,21). However, regarding shoulder tip pain, it was reported that there was no significant effect on shoulder pain, which especially occurs in laparoscopic surgeries (13). Pain after laparoscopic cholecystectomy is highly variable in intensity and duration and is largely unpredictable (9).
Opioid side effects
Opioids have many side effects; for example, intraoperative infusion of remifentanil may lead to acute opioid tolerance and increase postoperative pain (22). In addition, opioids have adverse side effects, including respiratory depression (Which can worsen postoperative pulmonary complications in more vulnerable obese patients), nausea and vomiting, sedation, confusion, hyperalgesia, chronic postoperative pain, pruritus, and decreased intestinal motility leading to ileus, diarrhea, constipation, and long-term use of opioids can lead to addiction (2,23). Therefore, magnesium can reduce perioperative opioid consumption and help avoid opioid side effects or at least attenuate them.
Multimodal analgesia
Magnesium is among the drugs used in combination with other opioid and non-opioid drugs for the multimodal approach recommended by the American Society of Anesthesiologists Task Force for providing optimal analgesia in acute pain management (24). This approach can provide analgesia while reducing the dose of various medications and their associated side effects. Opioids are often used in combination with other analgesics, such as acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), as well as adjunctive analgesics, such as alpha-2 agonists or anti-NMDA receptor agents (e.g., ketamine or magnesium) (23).
Magnesium doses
Magnesium has been administered in various doses. A dose of 50 mg/kg of magnesium sulfate clearly demonstrated an analgesic effect, which may have caused patients to have higher serum magnesium ion concentrations following surgery (23). In contrast, some studies reported that a reduced magnesium dosage had no analgesic effect (6). Some studies examined a dose of 25 mg/kg of magnesium, demonstrating its efficacy in reducing postoperative pain for 3 hours in major abdominal surgery without side effects (19). Magnesium sulfate at a dose of 50 mg/kg, given intravenously within 30 minutes before induction of anesthesia, was considered safe and showed no side effects (12). However, studies emphasized that an initial dose of 30 to 50 mg/kg of magnesium sulfate, followed by a maintenance dose of 6-12 mg/kg/h, was recommended because continuous intravenous infusion may enhance postoperative analgesia and reduce the need for opioids during the postoperative period (20).
Magnesium toxicity
Magnesium toxicity sets in at serum concentrations of 2.5-5 mmol/l. Some studies have used magnesium sulfate boluses of 50 mg/kg and double infusions of 8 mg/kg/h, and serum magnesium levels have been measured well below toxic levels, suggesting that magnesium sulfate is safe for intraoperative analgesia (23).
Routes of magnesium administration
Many trials have examined magnesium administration by intraperitoneal (IP) or intravenous (IV) methods. Some studies demonstrated that the efficacy of the IP method was greater than that of IV in certain situations, especially in laparoscopic surgeries. A study conducted on patients undergoing laparoscopic cholecystectomy with IP MgSO₄ showed that IP was a safer and more effective method for acute postoperative pain compared to IV (15). Another study examined the IP combination of levobupivacaine with MgSO₄ and found that the IP combination was effective for postoperative pain in laparoscopic sleeve gastrectomy (25). MgSO₄ with bupivacaine via IP instillation contributed to prolonging the duration of analgesia and reducing postoperative pain in laparoscopic cholecystectomy (26,27). Therefore, magnesium through intraperitoneal instillation demonstrated its efficacy. IP local anesthetics block visceral afferent signals, potentially altering visceral nociception and providing analgesia. Absorption of local anesthetics from the large peritoneal surface may also be another mechanism of analgesia (28,29). Since high concentrations of drugs can be delivered intraperitoneally to the target site without exposing other parts of the body to excessive amounts of the drug, this method is particularly important in situations where systemic exposure to the drug could lead to harmful side effects (29).
However, some studies emphasized that the use of intravenous magnesium boluses before and during surgery, followed by infusions, can reduce postoperative pain and provide a longer duration of analgesia and reduced analgesic consumption without significant complications (18,30). Some studies reported that MgSO₄ intravenously improved pain after surgery and provided safe, effective, and satisfactory analgesia in major abdominal surgery (20,31). Regarding the use of MgSO₄ by IV over 20 minutes followed by infusion, it demonstrated its anesthetic, analgesic, and muscle relaxant features in plastic surgeries (18). In addition, MgSO₄ administered over 15 minutes followed by infusion intraoperatively was effective as an adjuvant in general anesthesia for abdominal surgeries (21).
Comparison magnesium with analgesics or placebo
Many trials have examined magnesium with a placebo or with other analgesics. In comparison with remifentanil, it showed remarkable efficacy in controlling pain and autonomic response during surgery and reduced fentanyl consumption intraoperatively (28). Its effectiveness in reducing propofol requirements during induction and maintenance of general anesthesia has been demonstrated when compared with propofol (21). In addition, some studies compared magnesium and ketamine separately to identify the best analgesic drug among two different (NMDA) antagonists in laparoscopic cholecystectomy. Using ketamine (0.5 mg/kg) and magnesium (20 mg/kg) boluses, magnesium was found to be more effective than ketamine in postoperative pain management, cumulative morphine consumption, and reduction of fentanyl consumption without adverse effects (32). At the same time, the analgesic effects of intravenous infusion of magnesium sulfate and ketorolac during anesthesia for laparoscopic surgery were compared, and it was found that postoperative morphine consumption and pain intensity were significantly reduced, similar to ketorolac tromethamine. In addition, ketorolac had fewer side effects, but not magnesium (33).
However, in a study that examined the effects of magnesium sulfate, dexmedetomidine, and lidocaine on hemodynamic response and postoperative analgesia in laparoscopic abdominal surgery, dexmedetomidine was superior in maintaining hemodynamic stability and relieving pain, followed by lidocaine, and magnesium was the least effective. In addition, the need for rescue analgesia was minimal with dexmedetomidine compared to lidocaine and magnesium (34). A comparison of intravenous magnesium and diclofenac for postoperative analgesia in patients undergoing total abdominal hysterectomy showed that patients using magnesium sulfate consumed less narcotic medication, especially pethidine, on the first postoperative day than those using diclofenac (35). Magnesium has been reported to be effective as an alternative to non-opioid analgesics like NSAIDs perioperatively through intravenous infusion for anesthesia, especially when NSAIDs are contraindicated (33). When lidocaine, ketamine, and magnesium sulfate were compared regarding their effect on postoperative analgesia and the need for rescue analgesics intraoperatively in laparoscopic cholecystectomy, they also demonstrated efficacy (36). In most trials, magnesium contributed to reducing opioid consumption for recovery, 6 and 24 hours after surgery (37).
Mechanism of magnesium as additive in combination
Many studies with conventional anesthetic analgesic compounds have been used to relieve pain. A combination of drugs was effective in relieving postoperative pain, and they were well-tolerated with no recorded serious adverse events (38). Magnesium is an important ion involved in the regulation of multiple ion channels and physiological processes. Therefore, it is involved in these combinations (39). It does not have analgesic properties on its own, but its NMDA receptor antagonist properties eliminate central mechanisms of pain transmission and modulation, sensitization, and even modulate pain transmission in peripheral tissues. This unique property of magnesium sulfate promotes its use in combination with local anesthetics (40). The mechanism of magnesium as a combination does not differ from that of magnesium and other analgesics or anesthetic drugs separately. For example, since MgSO₄ is a noncompetitive NMDA receptor antagonist and a physiological calcium antagonist, the combination of bupivacaine and magnesium can enhance the analgesic effect of bupivacaine. Therefore, magnesium can be used as an adjunct analgesic both locally and systemically after surgery (41). It increases the number of nerve fibers affected by bupivacaine, thereby increasing its conduction block. Therefore, bupivacaine combined with magnesium is superior to other combinations in relieving postoperative abdominal pain and prolonging the time to first postoperative analgesia. In addition, this combination can effectively reduce postoperative shoulder tip pain during laparoscopic surgery (38,40).
Magnesium plus analgesics or anesthetics as combination
A combination of intravenous magnesium plus ketamine was reported to be effective intraoperatively; morphine consumption was reduced by nearly 50% in the first 12 hours compared with magnesium and ketamine alone in abdominoplasty and liposuction surgeries (7). Furthermore, the addition of a magnesium bolus (50 mg/kg) and continuous infusion (15 mg/kg/h) to ketamine reduced morphine consumption and pain scores at rest, during exercise, and during coughing in obese patients, one of whom underwent open bariatric surgery within 24 hours postoperatively, and reduced perioperative remifentanil requirements (23). Furthermore, the combination of magnesium plus paracetamol plus lidocaine showed a reduction in postoperative pain as indicated by pain scores (20). At 24 and 48 hours after surgery, magnesium plus vitamin C significantly reduced cumulative postoperative fentanyl consumption compared with magnesium and vitamin C alone, suppressed neuropathic pain, enhanced the analgesic effect of opioids, and was safe to use without side effects (39). The addition of dexamethasone or magnesium to bupivacaine during IP instillation: Magnesium was found to have an additive effect over dexamethasone, prolonging the duration of analgesia, reducing postoperative pain scores, and nalbuphine consumption in laparoscopic cholecystectomy (40).
The bupivacaine-magnesium combination was superior to the bupivacaine-tramadol combination in reducing postoperative pain, analgesic consumption, and shoulder pain, particularly during laparoscopic cholecystectomy (9,38). A study on postoperative analgesia in upper abdominal surgery found that regional infiltration of ropivacaine and magnesium sulfate in the first 6 hours provided better postoperative pain control than bupivacaine plus magnesium (40).
In another study, the bupivacaine-magnesium combination had the highest analgesic effect among different combinations, such as bupivacaine plus hydrocortisone and magnesium sulfate plus hydrocortisone, for postoperative abdominal pain in patients undergoing laparoscopic unilateral ovarian cystectomy (38). In a prospective clinical study by Sarenac et al., conducted to evaluate amino acids, lidocaine, and magnesium, it was shown to have both anti-inflammatory and analgesic effects during the first five days after abdominal surgery (41).
Various combinations of intraperitoneal levobupivacaine and/or magnesium sulfate for the relief of postoperative pain in patients undergoing laparoscopic sleeve gastrectomy showed that the addition of magnesium sulfate to levobupivacaine reduced postoperative pain and analgesic consumption within the first 24 hours (25).
This is due to differences in patient populations, types of surgery that may produce varying pain intensities, inconsistent pain ratings, and differences in magnesium doses between surgeries, all of which may affect generalizability. Future studies should aim to address these limitations.
Conclusion
Magnesium has been compared with many anesthetics and analgesics, such as ketamine, propofol, ketorolac, remifentanil, and diclofenac, showing remarkable efficacy in relieving pain during surgery and reducing opioid consumption. Regarding its addition in some combinations, such as magnesium with ketamine, paracetamol, vitamin C, bupivacaine, amino acids, and levobupivacaine, it demonstrated good additive properties in prolonging the duration of anesthesia and reducing perioperative pain and opioid use. Regarding magnesium toxicity, although some studies have used magnesium sulfate boluses of 50 mg/kg and double infusions of 8 mg/kg/h, serum magnesium levels have been measured well below toxic levels. Many studies have found that IP magnesium sulfate was significantly more effective than IV. A dose of 30 to 50 mg/kg of magnesium sulfate, followed by a maintenance dose of 6-12 mg/kg/h, is recommended and has been shown to be effective and safe in many trials.
Table 1. Summary of clinical studies using magnesium sulfate alone.PNG) .PNG) |
Table 2. Summary of clinical studies using magnesium sulfate in combination.PNG) .PNG) |
Acknowledgement
The present study is derived from the author's PhD thesis.
Funding sources
No funding was received.
Ethical statement
This article is ethically approved by Golestan University of Medical Sciences, Gorgan, Iran (IR.GOUMS.REC.1403.004).
Conflicts of interest
The authors declare no conflicts of interest.
Author contributions
Conceptualization, HM and TAH; methodology, MM and SGH; software, TAH; validation, HAF; formal analysis, AJ and HM; resources, ON and MM; data curation, HAF and MM; writing-original draft preparation, TAH and HM; writing-review and editing, AJ and HM; visualization, MM; supervision, AJ; funding acquisition, TAH. All authors have read and agreed to the published version of the manuscript.
Data availability statement
Data sharing is not applicable.
Article Type: Review |
Subject:
Basic medical sciences
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