The Use of Magnesium Sulfate to Prevent Pain on Injection of Propofol (2002)

Propofol is a frequently used IV anesthetic with a rapid onset and a short duration of action. Pain on injection is a common side effect, especially when propofol is given into a small vein on the dorsum of the hand (1). Parenteral magnesium has been used for many years on an empirical basis as an antidysrhythmic for the management of eclampsia and for intra- and postoperative analgesia (2–5). Magnesium has been called “nature’s physiological calcium channel blocker (4).” Calcium channel blockers have antinociceptive effects in animals and potentiate the analgesic effects of morphine in patients with chronic pain (6,7). Magnesium is also an antagonist of the N-methyl-d-aspartate (NMDA) receptor ion channel, and this may explain part of its analgesic activity (8). In view of the analgesic activity of magnesium, we tested the hypothesis that IV magnesium sulfate would be effective in reducing the pain caused by injection of propofol. Methods After obtaining permission from our hospital’s Ethics Committee and written informed consent from the patients, a randomized, double-blinded study was conducted on 100 patients, ASA physical status I-II, who were scheduled to undergo elective arthroscopy or laminectomy operations. Patients with opioid allergy, Parkinson’s disease, and those with thin dorsal hand veins were excluded from the study. Patients were randomly assigned to one of two groups, either receiving magnesium sulfate (Group M) or saline (Group C) before the injection of propofol. The study drugs were prepared in identical syringes by personnel blinded to the study group. No premedication was given. After instituting monitoring (electrocardiogram lead II, noninvasive arterial blood pressure, and pulse oximetry), a 20-gauge cannula was inserted into the brachial vein of both arms. One was used for infusion of IV fluids and the other for drug administration. Patients in Group M (n = 50) were given magnesium sulfate 2.48 mmol (2 mL) diluted in 3 mL of saline IV. Patients in the control group (Group C;n = 50) received 5 mL of saline IV. Twenty seconds later, 50 mg of propofol 1% was injected. No analgesic drug was given before the administration of propofol. The patients were asked a standard question about pain on injection by a second independent anesthesiologist who was unaware of the group to which the patient had been allocated. Any behavioral signs such as facial grimacing, arm withdrawal, or tears were noted. Pain on injection was assessed using a four-point scale (9): 0 = no pain, 1 = mild pain (pain reported only in response to questioning and without any behavioral signs), 2 = moderate pain (pain reported in response to questioning and accompanied by a behavioral sign, or pain reported spontaneously without questioning), and 3 = severe pain (strong vocal response or response accompanied by facial grimacing, arm withdrawal, or tears). The induction of anesthesia was completed with the appropriate amount of propofol. Atracurium 0.5 mg/kg was administered for muscle relaxation. After oral intubation of the trachea, anesthesia was continued with 50% N2O/02 and isoflurane. Within 24 h after the operation, the injection site was checked for pain, edema, or allergic reactions by an anesthesiologist who was unaware which drug had been administered. For the statistical analysis, a student’s t-test was used to compare demographic data. The global association between pain scores and group was determined by log-linear analysis. Fisher’s exact test was used for comparison of side effects. The package SPSS 9.0 (SPSS Inc, Chicago, IL) was used for statistical analysis. A value of P < 0.05 was considered significant. Results The two groups were comparable with respect to demographic characteristics (Table 1). The distribution of pain scores is shown in Table 2. There was a highly significant difference in the pain scores after the injection of propofol between the groups (likelihood ratio, 42.16;P < 0.001).Table 1: Characteristics of the PatientsTable 2: Distribution of Pain Scores in Group M (Magnesium Sulfate) and Group C (Saline)*Nine patients reported mild pain on injection of magnesium sulfate. This did not require treatment and subsided in a few seconds. No complications such as pain, edema, or allergic reactions were observed at the injection site within the first 24 h after the operation. Discussion Propofol causes pain on injection in 45%–75% of patients, particularly when it is administered through the small veins at the back of the hands (10,11). Various ways of minimizing this pain have been proposed, including using larger veins (12), priming with lidocaine, an opioid (e.g., fentanyl, alfentanil, or meperidine), or midazolam before the injection of propofol (10,11,13–15), diluting propofol with 5% glucose or 10% intralipid (13), injecting cold saline with the propofol or discontinuing fluid during the injection (16), or the use of 5-hydroxytryptamine3 antagonists (17). Scott et al. (10) speculated that the injection pain is caused by activation of the kallikrein-kinin system either by propofol or the lipid solvent, thereby generating kinins, probably bradykinin. Bradykinin, by producing local venous vasodilation and hyperpermeability, may increase the contact between the aqueous phase propofol and free nerve endings resulting in pain on injection (18). The mechanism of the analgesic effect of magnesium is not clear, but interference with calcium channels and NMDA receptors may play a role. Magnesium acts as a noncompetitive inhibitor of the inositol 1,4,5-triphosphate (IP3)-gated calcium channel and of IP3 binding. Therefore, it may be considered as an intracellular calcium antagonist acting at IP3 sensitive calcium release channels. It may also have a role as a calcium antagonist at other sites such as the ryanodine subgroup of calcium release channel receptors in the sarcoplasmic reticulum (19). The analgesic action of some 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 is coupled to an ion channel permeable to K+ and Ca+. Magnesium blocks NMDA receptor currents in a voltage-dependent manner by blocking the receptor channel (20). Magnesium also has a vasodilatory effect mediated by endothelium-derived nitric oxide (21,22). Nitric oxide donors protect vascular endothelium from ischemia and reperfusion-mediated endothelial dysfunction. This mechanism might also explain the ability of magnesium to reduce pain on the injection of propofol. Nine of our patients reported mild pain on injection of magnesium sulfate, which subsided in a few seconds without any intervention. The magnesium sulfate solution used in our study has a pH value of 7.0, and the slight acidity may have contributed to the pain on injection. In conclusion, this is the first clinical study showing that magnesium sulfate is effective in the prevention of pain during the injection of propofol. Apart from the minimal pain on the injection of magnesium, other side effects of this drug in the dose used in this study are very unlikely, and thus it is a useful alternative for preventing pain on the injection of propofol.