Intravenous magnesium sulfate for post-operative pain in patients undergoing lower limb orthopedic surgery
Institutions of the study: Anesthesiology Department, Anesthesiology Research Center, Shahid Beheshti University, M.C. Tehran, Iran
Anesthesiology Research Center
Shahid Beheshti University
Introduction: This study looks at the effect of supplementary intravenous magnesium sulfate on acute pain when administered in patients undergoing lower limb orthopedic surgery using spinal anesthesia with bupivacaine.
Method and materials: In this double-blind, randomized, placebo-controlled clinical trial, 60 patients were selected and randomly divided into two groups. Efforts were made to place both groups under the same method of anesthesia. One group received 8 mg/kg intravenous magnesium sulfate, started before the incision and continued up to the end of the surgical procedure, using a 50 ml syringe, via a peripheral large bore catheter; the second group received the same volume of placebos using the same method. To present the results, mean (± SD) was used; a P value of <0.05 was considered significant.
Results: There was no difference between the two groups in terms of the basic variables. Pain reported by the first group that received magnesium sulfate was significantly less at the first, third, sixth and 12th hours after the operation in comparison with the group that received placebo. Also, the intravenous morphine requirements in the first 24 h after the surgery were less in the magnesium group (4.2 ± 1.6 mg) than in the control group (9.8 ± 2.1 mg).
Conclusion: Intravenous magnesium sulfate can serve as a supplementary analgesic therapy to suppress the acute post-operative pain, leading to less morphine requirements in the first 24 h.
Post-operative pain control is a major concern for physicians and also the patients. Adverse effects due to acute pain have been described by a number of studies; a multitude of therapeutic modalities (both drugs and non-drug approaches) for pain control have been used because post-operative pain is a great concern in the post-operative period, and has a number of disadvantages in terms of the patient's outcome and the course of treatment.1
Magnesium is an inorganic ion, that is used for the treatment of eclampsia and pre-eclampsia, hypokalemia, premature labor, myocardial protection after ischemia, asthma crisis, post-operative acute pain control and hemodynamic stability during intubation.1–8 There are several products containing magnesium. Magnesium sulfate is a very common product and its usefulness has been assessed in a number of studies in the field of anesthesiology.4–10
This study was planned and executed to assess the effects of intravenous magnesium sulfate on acute post-operative pain in patients undergoing spinal anesthesia for lower limb elective orthopedic surgery after fractures due to trauma.
Method and materials
The protocol of the study was approved by the Institutional Ethics Committee, Deputy of Research Affairs, Anesthesiology Department, Shahid Beheshti University, M.C. Tehran, Iran.
In a double-blind, randomized, placebo-controlled clinical trial, among all the patients admitted in the orthopedic operating room of Taleghani Hospital, Shahid Beheshti University, M.C. Tehran, Iran, during a 12-month period, 60 patients were selected; after obtaining informed written consent, the patients were randomly assigned to two groups. Inclusion criteria were elective lower limb orthopedic surgery due to trauma, having informed written consent and aged 18–65 years. Those who refused to enter the study, abused or illicitly used controlled drugs or substances, had any sign or history indicating existing or previous neuropathy, had a prolonged QTc interval in the pre-operative electrocardiography strip or had any underlying coagulation disorder were excluded from the study.
Then, all the patients were allocated to the two groups randomly, according to a computer table of random numbers, were informed regarding the study the night before the surgery by the same anesthesiologist (among the authors) and were trained regarding their post-operative assessment of the Visual Analog Scale (VAS) pain scoring.
A dose of 0.1 mg/kg morphine was administered intramuscularly 1 h before the surgery as the pre-medication dose. All the patients received nothing per mouth (i.e. Non Per Oss or NPO) for 8 h, pre-operatively.
The anesthesiologist in charge of the patients in the operating room was not a part of either the post-operative process of data collection, or the blinding process (including patients' group allocation). Furthermore, the anesthesiologists and post-operative ward nurses were blinded to the specific group each patient belonged to. In order to prevent any interference in the process of patient blindness, all of them, regardless of their group, received 3 mg of intravenous midazolam before starting anesthesia, accompanied by supplemental nasal oxygen and the standard monitoring (including electrocardiography, pulse oxymetry, non-invasive blood pressure and heart rate). Then each patient received 500 ml of Ringer's solution over 10–15 min. Subarachnoid drug administration was performed with the patient in the lateral decubitus position, under appropriate aseptic conditions, with a guardian nurse. Through the L3/4 intervertebral space, a 25 G Whitacare spinal needle was inserted via a midline approach using a cephalad bevel approach; 20 mg (4 ml) of sterile preservative-free bupivacaine was injected in 10 s and then the patients were placed supine. Using position maneuvers an appropriate sensory block level (T8–T10) was achieved.
After a stable block level and appropriate hemodynamic status, but before the start of the surgery, an intravenous magnesium sulfate infusion was started through a peripheral large-bore catheter with a dose of 8 mg/kg/h of body weight in a 50 ml syringe for magnesium group patients and was continued until the end of the surgical procedure. The control group received the same volume of normal saline (placebo) using exactly the same method. A nurse who allocated the patients to the magnesium or controlled groups (according to the computer table of random numbers) prepared the 50 ml syringes in such a way that no one else was aware of the contents of the syringes. She labelled the syringes and saved the code of each syringe allocated to patient names and groups in a confidential manner.
Patients who had a heart rate below 50/min or a systolic blood pressure value below 90 mmHg were treated accordingly using vasoactive drugs (mainly ephedrine). The patients were operated on and transferred to the post-anesthesia care unit; then they were transferred to the ordinary postoperative ward after meeting the transfer criteria. For post-operative supplementary analgesia the following protocol was used:
- 1the patients were checked at the 1st, 3rd, 6th, 12th, 18th and 24th hours after the operation regarding VAS;
- 2whenever a VAS pain score >3 out of 10 was detected, incremental intravenous morphine sulfate doses were used;
- 3each dose contained 0.05 mg/kg of the drug, which could be increased to 0.1 mg/kg in each injection;
- 4one of the anesthesiologists among the authors trained the ward nurses and supervised them; and
- 5nasal oxygen prong and mask was always available before morphine administration and the patients were monitored.
Pain scores, total morphine consumption and time of operation from incision to skin closure were documented. Throughout the study, the patients' personal data were kept completely confidential, the grouping of the patients was not revealed and the patients could decide to leave the study just by informing one of the researchers.
Data entry and analysis were performed using SPSS software (version 11.5). For data analysis, Student's t-test and χ2-test were used. To present the results, mean ± SD were used and a P value <0.05 was considered significant.
There was no difference between the two groups in terms of the basic variables (Table 1). Pain reported by the first group that received magnesium sulfate was significantly less at the 1st, 3rd, 6th and 12th hours after the operation in comparison with the group that received placebo. At the 18th and 24th hours post-operation, there was no significant difference between the two groups (Table 2). Also, the magnesium group patients needed significantly lower cumulative doses of intravenous morphine sulfate in the first 24-h post-operative period (4.2 ± 1.6 mg) than the control group (9.8 ± 2.1 mg) to attain a VAS score of <3 (P value <0.01).
Age, body weight, duration of surgery and gender in the two groups*.
|Age (years)||33.7 (9.6)||35.1 (7.7)||>0.05 (for t-test)|
|Body weight (kg)||71.7 (6.7)||73.6 (8.3)||>0.05 (for t-test)|
|Duration of surgery (min)||110 (13)||104 (9)||>0.05 (for t-test)|
Pain scores in the two groups (a maximum Visual Analog Scale score of 10).
|1st||1.1 (0.3)||2.5 (0.7)||<0.0001|
|3rd||1.1 (0.4)||2.3 (0.5)||<0.0001|
|6th||1.3 (0.6)||2.6 (0.7)||<0.0001|
|12th||1 (0.5)||2.2 (0.6)||<0.01|
|18th||3.1 (0.8)||3.3 (0.7)||>0.05|
|24th||3.4 (0.6)||3.5 (0.8)||>0.05|
Regarding the adverse effects of magnesium injection, i.e. burning or heat sensations, three cases out of 30 experienced it, but these cases did not have any major complaint or sensation.
This study indicates that intravenous magnesium sulfate administration following orthopedic surgery of the lower extremities in patients undergoing spinal anesthesia with bupivacaine significantly reduces pain and total morphine requirements in the first few hours after the surgery.
In this study, there was a magnesium-related analgesic effect during the early post-operative period (i.e. from the end of surgery until 12 h post-operatively). Although, in this period, there was still some effect from the intrathecal bupivacaine, the additional effects of intravenous magnesium seem to be even more pain relieving than the effects of residual bupivacaine analgesia alone.
Regarding the risk of unblinding the study (and subsequent overestimation of treatment effect) due to the occurrence of typical Mg-related adverse effects, like burning or heat sensations, a number of items were of concern as mentioned in “Method and materials”, including dilution of magnesium, using a large bore catheter and also administration of midazolam before starting the intravenous magnesium administration; hence, these items may have relieved these sensations and it was possibly not a major concern.
The findings of the study demonstrated a beneficial effect for magnesium sulfate in patients undergoing spinal anesthesia with bupivacaine, which had a complementary effect over the analgesic effects of residual intrathecal bupivacaine in the early post-operative period. It has been demonstrated in previous studies that after radical retropubic prostatectomy, administration of MgSO4, concomitant with ropivacaine for post-operative analgesia by the infiltration method, leads to significant reduction in tramadol requirements.11 Also, it has been shown that supplementation of spinal anesthesia with combined intrathecal and epidural MgSO4 significantly reduces patients' post-operative analgesic requirements in patients undergoing orthopedic surgery,7 but another study failed to demonstrate any reduction in the onset time of sensory and motor blockade or prolongation in the duration of spinal anesthesia, in patients undergoing a cesarean section with 0.5% intrathecal bupivacaine and magnesium sulfate.12 Perhaps intravenous administration of magnesium sulfate, combined with intrathecal administration of bupivacaine, could exert the same analgesic effect without the need to administer it intrathecally. It has been mentioned in a systematic review9 that ‘it may be worthwhile to do more studies assessing the role of supplemental magnesium in providing post-operative analgesia.’
It seems that the N-methyl d-aspartate (NMDA) receptor is a major affecting site for the effects of magnesium. Magnesium is an antagonist of the NMDA receptor, acting as a non-competitive antagonist, blocking ion channels in a voltage-dependent fashion. This receptor is found in many parts of the body, including the nerve endings, and plays a well-defined role in modulating pain and a number of inflammatory responses.13–18 NMDA receptor antagonists could prevent central sensitization that occurs due to peripheral nociceptive stimulation.16–21
There are a number of limitations in this study. For example, the blood levels of magnesium sulfate were not determined and compared in the two groups.
However, this study demonstrated that intravenous magnesium sulfate in patients undergoing spinal anesthesia with bupivacaine for orthopedic surgery of the lower extremities significantly reduced pain in the first few hours and total morphine requirements in the first 24 h after the surgery.
Conflict of interest: The authors have no conflict of interest. None of the authors is related to or has financial interests in any of the companies or manufacturers of products related to this study.