The objective of treatment of postoperative pain after abdominal surgery is to provide profound analgesia while hastening functional recovery . It has become common practice to employ a polypharmacological approach to the treatment of postoperative pain, because no agent has yet been identified that specifically inhibits nociception without associated side-effects. The use of multiple agents, including opioid plus non-steroidal anti-inflammatory drugs (NSAIDs), N-methyl-D aspartate (NMDA) antagonists, allows additive or synergistic analgesic effects while minimizing side-effects at various points along the nociceptive pathway .
Magnesium is a non-competitive NMDA receptor antagonist and 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 pain [3-6]. These effects are primarily based on the regulation of calcium influx into the cell, i.e., 'natural physiological calcium antagonism' and antagonism of the NMDA receptor [3,7]. An inverse relationship has been demonstrated between the severity of pain with different painful medical and surgical conditions and the serum magnesium concentration [3,6]. Oral magnesium supplementation was more effective in decreasing pain and relieving pre-menstrual mood changes and depression than placebo in women with pre-menstrual syndrome . The aim of this study was to evaluate whether peri- and postoperative infusion of magnesium would reduce postoperative pain, anxiety and analgesic requirements during these periods.
After institutional approval and informed consent, we studied 24 females, who underwent elective abdominal hysterectomy for benign disease, in a prospective, randomized, placebo-controlled study. All patients were American Society of Anesthesiologists' (ASA) physical status I-II, aged 26-65 yr and weighed 54-75 kg. Exclusion criteria included known allergy to one of the study medications; major renal, hepatic, or cardiovascular dysfunction, obesity, prior treatment with opioids and calcium channel blocking drugs and neuromuscular disease. Surgery was performed under general anaesthesia through a Pfannenstiel incision.
During the preoperative visit, the purpose and protocol of the study, the use of the visual analogue scale (VAS) and the use of a patient-controlled analgesia (PCA) device (Abbott Pain Management Provider©; North Chicago, Il, USA) were explained to each patient. Anxiety was assessed using the State-Trait Anxiety Inventory (STAI1-2) three days before surgery .
Patients received midazolam 7.5 mg as a preoperative premedication 1 h before surgery. Standard monitoring equipment was installed: electrocardiography, non-invasive blood pressure monitoring, finger pulse oximetry (Horizon 1000®; Sony Mennen Medical Inc., Thailand) and a neurostimulator (TOF-Guard®; akseleromyelofraf®; Organon Teknika, Belgium) with two electrodes attached on the ulnar side of the wrist. A peripheral venous cannula was inserted.
After the induction of anaesthesia with thiopental 5 mg kg−1 and fentanyl 2 μg kg−1, the patients received either intravenous (i.v.) MgSO4 30 mg kg−1 as a bolus and 500 mg h−1 by a continuous i.v. infusion with a syringe pump for 20 h (Group 1) or the same volume of isotonic sodium chloride solution (Group 2). Vecuronium (0.1 mg kg−1) was given to facilitate orotracheal intubation. The lungs were mechanically ventilated with 50% O2/50% N2O and isoflurane (0.7-1%).
Haemodynamic measurements included mean arterial pressure (MAP), heart rate (HR) and arterial oxygen saturation (SPO2) at the following times; preinduction, post induction, every 15 min and at the end of the operation.
The presence of intraoperative pain was defined solely as an increase of HR and arterial pressure of more than 30% from baseline values after induction and was treated with i.v. fentanyl 1 μg kg−1 until HR and arterial pressure returned to baseline. Adequate muscle relaxation was maintained with supplementary doses of vecuronium until closure of the peritoneum. At the end of the surgery, antagonism of neuromuscular blockade was achieved with i.v. atropine sulphate and neostigmine.
The total amount of fentanyl and the time of the last fentanyl supplement before end of surgery were recorded. In the recovery room, a PCA device, containing morphine 2 mg per dose, with a 20 min lockout interval and no background infusion, was connected to the patient's i.v. catheter at 30 min after VAS assessment. If necessary, morphine 1-2 mg administered in i.v. bolus doses at 5-10 min intervals, were administered until the patient was pain free. Only PCA morphine was used for analgesia during the first 24 h postoperatively. Morphine requirements were assessed 6, 12, 18 and 24 h after surgery.
Because magnesium is widely regarded as a central nervous system depressant, sedation was monitored by using a four 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 somnolent but responds to painful stimulation). Oxygen saturation, HR and non-invasive MAP were monitored continuously and recorded at 30 min and every 6 h during the 24 h postoperatively.
Pain with the patient at rest and in the 30° sitting position and during coughing, was assessed by using a VAS (linear, 100 mm, starting from 0 = no pain to 100 = worst pain imaginable) at the same times. Any adverse events or side-effects during the postoperative period were monitored and recorded. Blood samples for determination of scrum magnesium concentration were obtained before the start of the i.v. study drug treatment and immediately after the end of the infusion. The normal range was 1.3-2.1 mg dL−1.
Insomnia was assessed 24 h postoperatively by asking the patient 'How well did you sleep last night?'. The patient was then asked to rate the quality of her sleep on the VAS (0 = no insomnia, excellent quality of sleep to 10 = absolute insomnia). STAI 1-2 was used to assess postoperative anxiety.
The statistical evaluation of variables, such as demographic data, intra- and postoperative analgesic consumption, was performed using the t-test. Other data, e.g. VAS, sedation and anxiety scores, were analyzed using the U-test. P < 0.05 was considered significant.
The patient characteristics in both groups were comparable with respect to age, weight and duration of surgery (Table 1). The mean intraoperative fentanyl consumption in the control group was significantly higher than in the magnesium group (P < 0.05; Table 2). Intraoperative doses of vecuronium, the time from the last fentanyl administration until the end of surgery, and time of antagonism of neuromuscular blockade at the end of surgery were similar between groups.
After 24 h, in Group 1, postoperative cumulative mean morphine doses decreased significantly (P < 0.05; Table 2). At 30 min and 18 h postoperatively, pain values at rest and during sitting and coughing, were higher in Group 2 than Group 1 (P < 0.05). VAS scores of other times were not significantly different between the groups (Figs 1, 2). Postoperative anxiety scores were significantly better than preoperative scores in all patients but there were no significant differences between groups. In the magnesium group, the quality of sleep was better than in the control group but the difference was statistically insignificant. Mean arterial pressure and HR showed no difference between the groups (Figs 3, 4). Sedation scores and oxygen saturation were similar in both groups during the first 24 h postoperatively.
At the end of the 20 h treatment, patients from the control group had significantly lower magnesium serum concentrations compared to pre-treatment values (P < 0.05). At the end of the infusion, all the concentrations were near to the upper limit of the normal range in Group 1 (Table 3).
Postoperative vomiting was lower in the magnesium group but it was statistically insignificant. Respiratory depression, deep sedation, hypoxia, pruritis and shivering were not observed during the study period in either group.
Minimizing pain is in keeping with the physician's primary goal of relieving suffering. Effective treatment of peri- and postoperative pain also represents an important component of postoperative recovery as it serves to blunt autonomic, somatic and endocrine reflexes with a resultant potential decrease in perioperative morbidity . Various techniques and drugs are available to provide pain relief in surgical patients. Since total postoperative pain relief cannot be achieved by a single agent or method without major expenditure on equipment and surveillance systems, or without significant side-effects, recent efforts have focused on improving pain relief by combinations of agents . Magnesium can block calcium influx and non-competitively antagonize NMDA receptor channels. These effects have prompted the investigation of magnesium as an adjuvant agent for intra- and postoperative analgesia [3,6,11,12].
In rats, NMDA receptor activation is involved in the induction and maintenance of central sensitization processes that characterize post-injury pain states. N-methyl-D aspartate receptor antagonists may play a role in the prevention and treatment of perioperative and postoperative pain . McCarthy showed that the combination of intrathecal magnesium and morphine resulted in a potentiation of antinociception and delay in the development of morphine tolerance in rats .
Tramèr and colleagues showed that intra- and postoperative magnesium infusion decreased postoperative morphine requirements and patients experienced significantly less disturbances in comfort and quality of sleep in the postoperative period compared to control patients . Wilder-Smith and colleagues used magnesium only intraoperatively and suggested that it had a better intraoperative antinociceptive efficacy than fentanyl [11,12]. Koinig and colleagues showed that the administration of magnesium led to a significant reduction of intra- and postoperative analgesic requirements .
Tramèr and colleagues  and Koinig and colleagues  studied bolus doses of magnesium 40-50 mg kg−1 and 50 mg kg−1, and infusion doses of 500 mg h−1 and 8 mg kg−1 h−1, respectively. We used magnesium 30 mg kg−1 as a bolus and 500 mg h−1 as an infusion dose and found that it decreased intraoperative and postoperative analgesic requirements. The mean intraoperative fentanyl consumption in the magnesium group was significantly lower than in the control group and the cumulative morphine consumption was less in magnesium treated patients compared to in control patients. Differences in VAS scores are only significant at 30 min and 18 h. Patient-controlled analgesia devices were connected to the patients just after the 30th min assessments of VAS postoperatively, so at that moment the VAS scores might be different in groups. Magnesium infusion was continuous but there was no background morphine infusion in PCA device. The difference of 18th VAS scores might be as a result of ineffectual PCA device use because of the sleeping period.
In our study, magnesium treatment showed a beneficial but non-significant effect on quality of sleep - similar to the findings in Tramèr and colleagues' study.
There was an inverse relationship between the severity of pain and serum magnesium concentrations in gastrointestinal surgery, in women during labour and in patients with medical conditions, such as myocardial infarction or pancreatitis [3,6]. In two studies, serum magnesium concentrations decreased significantly in control groups. It was suggested that the decrease in serum magnesium concentrations could further explain the increase in analgesic requirements in control group. We found that serum magnesium concentrations were lower than preoperative values in Group 2 at the end of the 20 h postoperatively.
Magnesium supplementation may affect the treatment of pre-menstrual symptoms, with a dose-related improvement in mood changes . In rats, i.v. MgSO4 produced a dose-dependent reduction in halothane minimum alveolar anaesthetic concentration, as measured by the tail-clamp technique, which could be considered as an anaesthetic effect in an acute pain model . Administration of magnesium results in sedation, therefore we evaluated the anxiety scores before and after surgery. There were no significant differences between groups for postoperative anxiety scores because of the low doses of magnesium that we used.
Tramèr and colleagues showed that magnesium had an antiemetic effect, either directly or indirectly, via decreased consumption of morphine in patients . In our study, antiemetic drug requirements were lower in magnesium-treated patients compared to control patients but the difference was not statistically significant.
Haemodynamically, magnesium-treated patients did not show any differences compared to control patients during the study. There was no respiratory depression, deep sedation, hypoxia, pruritis or shivering in any patients.
In conclusion, bolus administration of magnesium during surgery and continuous magnesium infusion in the postoperative period can reduce analgesic requirements during these periods with no adverse events and side-effects. These results demonstrate that magnesium can be an adjuvant for peri- and postoperative analgesic management. However, before applying the results of this study into clinical anaesthesia practice, the possible side-effects of magnesium administration should be considered carefully in patients with renal disease or atrioventricular conduction disturbance.
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