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Featured Clinical Topic: Magnesium for the Treatment of Postoperative Pain

06 Apr 2022 5:08 PM | Anonymous

Magnesium for the Treatment of Postoperative Pain

Author: Brittany Bush, PharmD Candidate 2022, Xavier University of Louisiana College of Pharmacy

Mentor: Rachel C. Wolfe, PharmD, MHA, BCCCP, Barnes-Jewish Hospital – Saint Louis, Missouri

Acute postoperative pain often occurs after surgery with the most severe pain noted within the first 72 hours after intervention.1,2 Systemic opioids are routinely employed to manage postoperative pain. However, they can be associated with significant side effects, including

long-term use and dependence.3-5 The challenge to reduce reliance on opioids for the treatment of postoperative pain has resulted in a growing interest in utilizing non-opioid analgesics. These medications help achieve pain control, while minimizing adverse effects. Since the perception of pain is a complex phenomenon, a multimodal analgesia approach may be utilized to enhance effectiveness.6 This care model lessens opioid use and drug related adverse effects by capitalizing on mechanistic differences between various analgesic medications, such as acetaminophen,

non-steroidal anti-inflammatory drugs, dexamethasone, gabapentinoids, local anesthetics, and NMDA antagonists.6

Literature findings indicate n-methyl-d-aspartate (NMDA) receptor activation is directly associated with pain sensory reception from peripheral tissue and nerve injury. The NMDA receptor is widely located throughout the central nervous system and regulates influx of sodium and calcium and outflow of potassium.7,8 Upon activation, the increased intracellular calcium levels seem to play a role in initiating central sensitization. This is a phenomenon by which repetitive nociceptive inputs eventually results in a prolonged decrease in the pain threshold, leading to hyperalgesia.8 The use of a NMDA receptor antagonist has been shown to significantly decrease pain.7 Magnesium, as an NMDA receptor antagonist, is a pain adjuvant that controls the excitability of the NMDA receptor.8,9

Although there has been recent interest in preoperative oral magnesium as a pre-emptive analgesic agent, the primary perioperative dosing strategies studied utilize intravenous (IV) magnesium sulfate. Studied doses are typically administered by the way of a bolus dose, continuous infusion, or bolus plus infusion. The bolus dose, infusion rates, and infusion durations have also been variable. At this time, most of the literature supports an intraoperative IV bolus dose followed by a continuous infusion.6,8,9,11,12 The most common and well-studied dose of magnesium sulfate for perioperative pain includes an intraoperative IV loading dose of 30-50 mg/kg administered over 15 to 30 minutes at the start of the surgery followed by a continuous infusion at 6-15 mg/kg/hour until surgery completion.6,8,9,11

The effectiveness of magnesium in reducing postoperative pain and opioid consumption has been evaluated in several surgical procedure types such as spine, thoracic, major abdominal, and hysterectomy.8-10 A systematic review performed by Albrecht and colleagues included 25 randomized trials, consisting of a total of 1,461 patients, that received perioperative magnesium for the reduction of postoperative pain. Within this review, the primary endpoint assessed was cumulative IV morphine consumption at 24 hours postoperatively. Statistically significant heterogeneity existed in the wide variety of dosing regimens chosen by various trials analyzed. Despite this limitation, magnesium significantly reduced the 24-hour cumulative consumption of IV morphine by 24.4%. A reduction in the amount of analgesics used was observed regardless of the type of surgery performed. For example, morphine consumption decreased by 12.7% in


gynecological surgery, 37.9% in orthopedic surgeries, and 15% in gastrointestinal surgeries. Time to first analgesic request from patients, however, was not significantly changed with the incorporation of magnesium into the pain regimen. 11

A more recent systematic review performed by Morel and colleagues provided an in-depth analysis of the literature related to magnesium for pain management. This review

contained 81 randomized controlled trials, consisting of 5,447 patients, that explored the efficacy of magnesium for the reduction of pain and/or analgesic consumption, 49 of which focused on postoperative pain. Overall, 29 of 44 studies observed a significant decrease in pain as assessed by the visual analog scale. Contrarily, 16 randomized controlled trials displayed no efficacy in pain reduction. An important limitation among the randomized controlled trials in this review is the heterogeneity in dosing strategies. The most commonly studied method of dosing, seen in 33 of the trials reviewed, was the use of an IV bolus followed by a continuous infusion. Thirty-six of the 45 post-operative randomized controlled trials that analyzed analgesia requirements showed a significant decrease in consumption of analgesic agents such as morphine, tramadol, diclofenac, and fentanyl. Contrarily, 11 randomized controlled trials showed no significant different in analgesic consumption in patients.13

The safety of magnesium in the management of postoperative pain has not been thoroughly evaluated in clinical trials. Side effects of magnesium can be dose or rate related and can present as flushing or hypotension, respectively.14 Monitoring of blood pressure is a useful method to ensure the safety of therapy. 15 Lastly, hypermagnesemia is uncommon in patients with normal renal function; however, due to its significant renal elimination, magnesium doses should be reduced by 50% in patients with renal impairment.12,14

In conclusion, magnesium may play an important role in the evolution of postoperative pain and therefore could be a valuable analgesic adjunct when incorporated into a multimodal regimen within the perioperative arena. Further research is needed to determine the most effective magnesium regimen that reduces pain and opioid consumption in the immediate postoperative period. Furthermore, it is imperative that we gain insight into the patient populations and procedure types that benefit the most from perioperative NMDA antagonism provided by magnesium.

References:

  1. Lynch EP, Lazor MA, Gellis JE, et al. Patient experience of pain after elective noncardiac surgery. Anesth Analg 1997;85(1):117-23.
  2. Svensson I, Sjostrom B, Haljamae H. Assessment of pain experiences after elective surgery. J Pain Symptom Manage 2000;20(3):193-201.
  3. Kessler ER, Shah M, Gruschkus SK, et al. Cost and quality implications of opioid-based postsurgical pain control using administrative claims data from a large health system: opioid-related adverse events and their impact on clinical and economic outcomes. Pharmacotherapy 2013;33(4):383-91.
  4. Hill MV, McMahon ML, Stucke RS, et al. Wide variation and excessive dosage of opioid prescriptions for common general surgical procedures. Ann Surg 2017;265(4):709-14.
  5. Gan TJ. Poorly controlled postoperative pain: prevalence, consequences, and prevention. J Pain Res 2017;10:2287-98.
  6. Beckham, T. Perioperative use of intravenous magnesium sulfate to decrease postoperative pain. J Anest & Inten Care Med. 2020; 10(2): 555788.
  7. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of n-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97(4):1108-1116.
  8. Shin HJ, Na HS, Do SH. Magnesium and Pain. Nutrients. 2020;12(8):2184.
  9. Na HS, Ryu JH, Do SH. The role of magnesium in pain. Adelaide (AU): University of Adelaide Press; 2011.
  10. De Oliveira GS, Jr., Castro-Alves LJ, Khan JH, McCarthy RJ. Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology 2013;119(1):178-90.
  11. Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013 Jan;68(1):79-90.
  12. Do SH. Magnesium: a versatile drug for anesthesiologists. Korean J Anesthesiol. 2013;65(1):4-8.
  13. Morel, Véronique et al. “Magnesium for Pain Treatment in 2021? State of the Art.” Nutrients vol. 13,5 1397. 21 Apr. 2021
  14. Magnesium Sulfate. Lexicomp Online. Hudson, OH: Lexi-Comp.
  15. Cascella M, Vaqar S. Hypermagnesemia. StatPearls Publishing; 2021 Jan.

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