Magnesium, the fourth most common cation in the body, has numerous physiological activities, including activation of many enzymes involved in energy metabolism and protein synthesis . Magnesium also has antinociceptive effects in animal and human models of chronic pain [2,3]. These effects are primarily based on the regulation of calcium influx into the cell, i.e., "natural physiological calcium antagonism"  and antagonism of the N-methyl-D-aspartate (NMDA) receptor. Results from in vitro studies indicate that NMDA receptor activation increases cytoplasmic calcium concentration in cultured spinal cord neurons . Changes in the intracellular calcium concentration may lead to persistent changes in the excitability of the dorsal horn cells  and therefore have an important role for pain perception
In rats, magnesium suppressed NMDA-induced pain associated with adverse behavioral reactions after deafferentation injury . NMDA receptor antagonists also prevent the induction and maintenance of central sensitization processes and abolish hypersensitivity once it is established . Sensitization is usually manifested as a postinjury reduction of the pain threshold and hypersensitivity of the withdrawal reflex. These data suggest that NMDA receptor antagonists like magnesium have the potential to prevent and treat pain.
In a clinical study , the role of magnesium for postoperative analgesia has been demonstrated. Magnesium administration led to a significant reduction of morphine consumption in the postoperative period in patients after lower abdominal surgery. In addition, there is an inverse relationship between the intensity of pain and the serum magnesium concentration in women during labor and in patients with different medical conditions (e.g., myocardial infarction, pancreatitis, and burns) .
Thus, experimental and clinical data from acute and chronic pain situations demonstrate an effect of magnesium on the pain threshold, which is clinically apparent postoperatively as a reduction of analgesic requirements. The present randomized, double-blind, placebo-controlled study was designed to evaluate whether magnesium supplementation can also affect intraoperative pain.
With approval from our ethics committee and after written, informed consent, 46 patients of either gender undergoing general anesthesia for arthroscopic knee surgery were included in one of two parallel groups. This particular type of surgery was chosen because there is a rather constant level of surgical stimulus and it is not necessary to redose muscle relaxants.
Exclusion criteria included increased serum magnesium levels (>1 mmol/l); known allergy to one of the study medications; major hepatic, renal, or cardiovascular dysfunction, especially atrioventricular block; obesity; and prior treatment with opioids and calcium channel blockers.
The patients were divided randomly (systematic random sample technique) into two groups. Whereas the patients of the magnesium group received 10% MgSO4, the patients of the control group received isotonic sodium chloride solution in a double-blind fashion. An independent anesthesiologist who did not participate in the study prepared the study medication in identical vials.
During the preoperative visit, before the elective surgery, the purpose and protocol of the study and the use of the visual analog scale (VAS) were explained to the patient. Preoperative premedication was midazolam 7.5 mg 1 h before the operation. Usual monitors were used. After the induction of anesthesia with propofol (2 mg/kg) and fentanyl (3 [micro sign]g/kg), the patients received either magnesium sulfate 50 mg/kg IV as a bolus before the start of surgery, and 8 mg [center dot] kg-1 [center dot] h-1 by a continuous IV infusion with a syringe pump over the entire operation period or the same volume of isotonic sodium chloride solution. Lactated Ringer's solution was administered to both groups, 6 mL [center dot] kg (-1) [center dot] h-1 intraoperatively and 4 mL [center dot] kg-1 [center dot] h-1 postoperatively. Preoperative and postoperative serum magnesium concentrations were measured in both groups. Because of the possible enhancement of neuromuscular blockade by magnesium administration , muscle relaxation was monitored by train-of-four stimulation. After orotracheal intubation with the help of vecuronium (0.1 mg/kg), anesthesia was maintained with propofol (6-8 mg [center dot] kg-1 [center dot] h-1). The lungs were mechanically ventilated with oxygen/air (end tidal CO2 35-40 mm Hg) without N2 O. The presence of intraoperative pain was defined solely as an increase of heart rate and mean arterial blood pressure (MAP) of more than 20% from the baseline values after induction and was treated with IV fentanyl (1-2 [micro sign]g/kg) until heart rate and MAP returned to baseline.
Postoperatively, the patients remained in the recovery room for at least 4 h, then were discharged to the ward. When a patient complained of pain, the VAS score was monitored and if the VAS score was >3, fentanyl (0.5 [micro sign]g/kg) was given until an adequate level of analgesia was achieved. The intensity of postoperative pain was assessed by an investigator who was blinded to the patient group. The assessment was made four times for each patient (5, 60, 120, and 240 min after entering the recovery room). Pain was assessed by using a VAS starting from 0 = no pain at all to 10 = worst pain imaginable. Because magnesium is widely regarded as a central nervous system depressant, sedation was monitored by using a 4-point rating scale (1 = patient fully awake, 2 = patient somnolent but responds to verbal commands, 3 = patient somnolent but responds to tactile stimulation, 4 = patient asleep but responds to pain). Oxygen saturation, heart rate, and blood pressure were monitored. Any adverse events or side effects during the postoperative period were monitored and recorded.
We conducted a nonblind pilot study with the result that after preoperative magnesium administration the intra and postoperative analgesic requirement decreased. With regard to this study after power analysis, a sample size of 23 patients per group was considered to be necessary to detect a significant difference in analgesic consumption. The statistical evaluation of variables, such as demographic data and intra- and postoperative fentanyl consumption, was performed using Student's t-test. Other data, like VAS score, were analyzed using the Mann-Whitney U-test. P < 0.05 was considered statistically significant.
Forty-six patients, 23 per group, were included in the study. The patient characteristics in both groups were comparable with respect to age, weight, and duration of surgery (Table 1). All patients underwent the same type of surgery (knee arthroscopy) performed by the same group of surgeons.
The mean intraoperative fentanyl consumption in the control group was significantly higher than that in the magnesium group (P < 0.05) (Figure 1). During the postoperative period, the patients in the control group received a significantly larger mean fentanyl dose than the patients in the magnesium group (P < 0.05) (Figure 1). The postoperative VAS scores were not significantly different between the groups (Figure 2).
Hemodynamic and respiratory variables, such as diastolic and systolic blood pressure, heart rate, and oxygen saturation, were similar in both groups. There were no cases of intra- or postoperative hemodynamic instability during the observation period. Renal function in all the patients was considered normal (normal serum creatinine and serum urea levels). During the observation period, no adverse events could be detected, and there were no cases of respiratory depression.
Patients in the control group had significantly (P < 0.05) lower serum magnesium concentrations postoperatively compared with preoperatively. In the control group, serum magnesium levels decreased from 0.76 +/- 0.11 to 0.69 +/- 0.12 mmol/L. In the magnesium group, serum magnesium concentrations increased from 0.76 +/- 0.07 to 1.4 +/- 0.37 mmol/L (P < 0.01). In 2 of the 46 patients, we found a serum magnesium level >2 mmol/L. Of the 46 patients in the study, there were 2 for whom blood samples were unavailable because of clotting.
The principal finding of this investigation is that the preoperative administration of magnesium reduces not only postoperative, but also intraoperative, analgesic requirements.
The mechanism of this analgesic effect of magnesium is not clear, but interference with calcium channels and NMDA receptors seem to play an important role. The first possibility is based on the observation that calcium channel blockers have an antinociceptive action in algesiometric tests in rats under acute conditions [10,11]. In humans, calcium channel blockers can enhance opiate analgesia in patients with cancer chronically treated with morphine . The analgesic action of calcium channel blockers could be mediated by an increase of the nociceptive threshold resulting from interference with calcium influx because the latter is important for the release of neurotransmitters and other substances implicated in nociception and inflammation.
The second possible explanation for the analgesic action of magnesium is its antagonism of the NMDA receptor. The NMDA receptor, an amino acid receptor responsible for excitatory synaptic transmission, has modulatory sites (NMDA binding sites) positive for excitatory amino acids such as glutamate, and modulatory sites (phenylcyclidine binding site) negative for ketamine or magnesium. Furthermore, this receptor is coupled to an ion channel permeable for K+ and Ca+. Magnesium blocks NMDA-induced currents in a voltage-dependent manner by blocking the receptor channel effects .
In rats, NMDA receptor activation is involved in the induction and maintenance of central sensitization processes that characterize postinjury pain states . Therefore, NMDA receptor antagonists may play a role in the prevention and treatment of perioperative pain. Furthermore, IV magnesium sulfate produced a dose-dependent reduction in halothane minimum alveolar anesthetic concentration (MAC) , as measured by the tail-clamp technique, which could be considered as an anesthetic effect in an acute pain model.
Based on all these data, we conclude that magnesium, which is an antagonist of the NMDA receptor and a physiological calcium channel blocker, has analgesic properties in acute and chronic pain conditions. In addition, a clinical study showed that women undergoing lower abdominal surgery required significantly less postoperative morphine after magnesium sulfate supplementation . In this study, attention was focused on the postoperative period, and no intraoperative antinociceptive effect of magnesium could be measured. In contrast, in our study, we determined that preoperative magnesium administration also reduces intraoperative analgesic requirements. The body weight-related magnesium dose and the absence of halothane and N2 O in our anesthetic procedure may explain the different results.
Additionally, we found a significant decrease in serum magnesium levels intraoperatively in the control group. This decrease in serum magnesium levels may further explain the increase in analgesic requirements in the control group. The reduction of serum magnesium levels takes place not only in major gastrointestinal surgery , but also in minor surgery without large fluid shifts between different body compartments. The reason for the decrease in serum magnesium levels is probably due to a combination of increased urinary loss and a shift into intracellular compartments. With regard to the observation that there is an inverse relationship between the severity of pain  and serum magnesium levels in women during labor and in patients with different medical conditions, such as myocardial infarction or pancreatitis, the control of perioperative serum magnesium levels and the prevention of hypomagnesemia should be addressed carefully.
Limitations of our study involve the detection of intraoperative pain by heart rate and MAP values, because these variables could change for other reasons. Therefore, we included only ASA physical status I or II patients in the study, in whom heart rate and MAP increases are likely caused by pain perception. Five minutes after entering the recovery room, there was no significant difference in VAS scores. This suggests that the quality of analgesia was equivalent in both groups.
Problems that could occur perioperatively after an increase in serum magnesium levels, such as an intensified action of nondepolarizing muscle relaxants, vasodilatation due to direct interaction with calcium ions at vascular membranes , or cardiac conductivity disorders, would have been detected with our perioperative monitoring, but they did not occur in our study.
In conclusion, the administration of magnesium led to a significant reduction of intra- and postoperative analgesic requirements, i.e., fentanyl consumption. This finding complements the known use of magnesium in anesthesia as an antiarrhythmic or anticonvulsant drug. However, before translating the result of this study into clinical anesthesia practice, the possible side effects of magnesium administration, particularly in patients with impaired renal function or atrioventricular conductance disturbance, should be considered carefully.
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