Concern over the opioid epidemic and recognition that perioperative opioid use may increase the risk for long-term opioid dependence has stimulated a growing interest in nonopioid analgesics for perioperative analgesia. Medications such as lidocaine and magnesium are increasingly suggested for use in multimodal analgesia and enhanced recovery programs; reported benefits include reductions in postoperative pain, opioid consumption, and opioid-related side effects.1,2 However, these benefits have been shown to vary by medication and type of surgery. In this issue of Anesthesia & Analgesia, Kim et al3 report the effects of 2 interesting nonopioid analgesics: intravenous lidocaine and intravenous magnesium. They compared these drugs with placebo controls in female patients undergoing total thyroidectomy, using the quality of recovery (QoR) after surgery as the primary outcome. The results provide further evidence for the benefits of lidocaine while raising additional questions about the use of magnesium perioperatively.
Intravenous lidocaine is frequently administered during induction of anesthesia to decrease pain from injection of propofol and to blunt hemodynamic responses to tracheal intubation. Lidocaine is also used as part of total intravenous anesthesia for procedures requiring neurophysiological monitoring because it does not adversely affect stimulation thresholds or signal amplitude. Continuous infusion of the compound also has analgesic effects, and several recent reviews and meta-analyses document the clinical benefits of intravenous lidocaine administered for postoperative analgesia.4–6 In open abdominal surgeries, intravenous lidocaine was shown to reduce visual analog scale pain scores at rest and with activity and to reduce opioid requirements in the first 24 hours after surgery.4,6 Lidocaine was also shown to decrease the incidence of postoperative nausea and vomiting and shorten the duration of postoperative ileus by an average of 8 hours, which may be due in part to an opioid-sparing effect.5
Intravenous lidocaine is typically administered as a bolus of 1–1.5 mg/kg followed by an infusion rate of 1.5–3 mg/kg/h, which achieves plasma concentrations similar to those obtained during epidural administration (~1 μmol/L or 0.23 μg/mL). The mechanism of action is not entirely understood. Preclinical studies suggest a likely mechanism through prevention of polymorphonuclear cell priming and interference with inflammatory signaling. Sodium channel blockade is less likely because polymorphonuclear do not express sodium channels and only a small proportion of neuronal sodium channels are inhibited at the plasma concentrations achieved with typical doses.
In addition to open abdominal procedures, intravenous lidocaine has also been shown to be of benefit for other types of surgery including laparoscopic abdominal procedures, prostatectomy, thoracic surgery, and spine surgery.5 However, it may not provide the same clinical benefit for some other types of surgery, such as total abdominal hysterectomy and total hip arthroplasty.7 The reason for this specificity is poorly understood and adds to the challenge of clinical application.
In this issue of Anesthesia & Analgesia, Kim et al3 demonstrate another type of surgery where intravenous lidocaine may be beneficial. In a randomized controlled trial of 135 female patients undergoing open thyroidectomy, the authors compared the effect of intraoperative intravenous lidocaine (2 mg/kg for 15 minutes followed by 2 mg/kg/h), magnesium (20 mg/kg over 15 minutes followed by 20 mg/kg/h), or saline infusion on postoperative recovery. These doses were chosen based on previous studies with the dose of intravenous lidocaine used here being fairly standard. However, typical doses of magnesium vary widely (bolus dose ranging from 30 to 50 mg/kg and infusion dose ranging from 6 to 25 mg/kg/h) with a low bolus dose but moderately high infusion dose used here.
Unlike previous studies that report postoperative pain scores and opioid consumption, the primary outcome of the present study is the QoR-40 score, which measures functional recovery based on 5 dimensions: physical comfort, emotional state, physical independence, psychological support, and pain. Patients who received lidocaine had higher QoR-40 scores on postoperative days 1 and 2 compared with control, a difference that was both statistically and clinically significant. QoR-40 scores in the dimensions of pain, physical comfort, and physical independence were most significantly affected.
The authors’ results contrast with a recently published study by Choi et al8 in patients undergoing robotic thyroidectomy. In that trial, intravenous lidocaine, compared with placebo control, was not associated with improved QoR-40 scores in the immediate postoperative period. Interestingly, this was despite using a higher rate of infusion (3 vs 2 mg/kg/h in the study by Kim et al3). However, patients who received lidocaine had a lower incidence of chronic postsurgical pain and sensory disturbances 3 months after surgery.
In their study in this issue of the Journal, Kim et al3 further studied the effect of a second nonopioid analgesic, intravenous magnesium, on QoR after thyroidectomy. Magnesium provides analgesia through voltage-dependent blockade of N-methyl-d-aspartate receptors and is used for the treatment of acute and chronic pain. Several meta-analyses have reported the effects of intravenous magnesium for intraoperative and postoperative pain, with mixed results.9 A meta-analysis of 14 randomized trials conducted by Lysakoski et al10 failed to show improved postoperative pain intensity or reduced analgesic requirements with intravenous magnesium; however, this study was over 10 years ago in 2007. Subsequent meta-analyses by Albrecht et al11 (25 trials, 1461 patients), Murphy et al12 (22 trials, 1177 patients), and De Oliveira et al13 (20 trials, 1257 patients) showed reduced postoperative pain scores and opioid requirements with intravenous magnesium infusion (30–50 mg/kg bolus and 6–25 mg/kg/h infusion) compared to placebo. A 2015 study by Guo et al14 examined 27 randomized controlled trials including 1504 patients. Magnesium dosing regimens included bolus doses ranging from 30 to 50 mg/kg and infusion doses ranging from 6 to 15 mg/kg/h. The results suggest that magnesium decreases postoperative pain scores and significantly reduced analgesic consumption in the first 24 hours after urogenital, orthopedic, and cardiovascular surgeries. Magnesium reduced postoperative pain at early time points <2 hours after major abdominal surgery in the 3 trials analyzed by Guo et al14; however, additional studies are necessary to determine whether there is a long-term benefit. As with lidocaine, there may be several possible explanations for these results, including differences in dosages and timing of magnesium administration, patient population, and pain caused by different types of surgery.
The results by Kim et al3 identify total thyroidectomy as another type of surgery without a clear benefit of magnesium for analgesia. The decline in QoR-40 score on postoperative day 1 in patients who received magnesium infusion was not statistically different from that observed in patients receiving placebo. There was no difference between lidocaine and magnesium in the QoR-40 dimension of pain; the authors, therefore, suggest that the difference in overall recovery profile between these 2 medications may result from differential impact on other dimensions of recovery.
The authors’ choice of QoR score as primary outcome is novel and clinically meaningful compared to prior studies focusing on pain scores and opioid consumption. Here the authors compared postanesthesia care unit recovery profiles and observed significantly lower pain scores in the lidocaine and magnesium groups compared to control, but no difference in morphine consumption in the immediate postoperative period. Further comparison of these results to prior studies is limited because the authors did not assess numeric rating scale pain scores or opioid consumption on subsequent postoperative days.
Additional limitations include the generalizability of this study performed in Asian females to other populations. The authors note that sex may affect QoR score, with a greater difference between preoperative and postoperative score observed for females compared to males. Whether intravenous lidocaine would improve postoperative recovery in males is unclear. In addition, the study was powered to detect a difference in QoR score of 10 points compared to control. The authors observed a 6.9 point difference (95% confidence interval, −0.16 to 13.6) between lidocaine and control groups. The study was likely underpowered to detect a significant difference in QoR score between magnesium and control (4.9 point difference; 95% confidence interval, 1.99–11.79), a difference which prove significant if a larger number of patients were enrolled.
In our clinical practice, intravenous lidocaine (1–1.5 mg/kg bolus, 40 μg/kg/h infusion intraoperatively and 0.5–1 mg/min postoperatively for 24 hours) together with magnesium (30 mg/kg bolus over 10 minutes to avoid hypotension) are routinely used as part of enhanced recovery protocols for major abdominal and gynecological procedures at our institution. Previous studies have reported that these medications are relatively safe at these recommended doses.5,14,15 Patients are monitored by the acute pain service postoperatively for signs of lidocaine toxicity, and we have not observed adverse cardiac or neurological effects at the recommended doses, although caution should be exercised in patients with decreased creatinine clearance. Intravenous lidocaine infusion is also frequently used for total intravenous anesthesia and to reduce airway reactivity and provide minimum alveolar concentration-sparing effects for head and neck surgery.
The present study provides further evidence for the benefit of intravenous lidocaine for perioperative analgesia and its ability to reduce postoperative pain and improve functional recovery after surgery for head and neck procedures. The benefits of magnesium, however, remain unclear. With an ever-increasing focus on improved analgesia and faster recovery time, the study highlights that functional recovery may be a more important outcome metric rather than simply pain scores and opioid requirements to assess the benefit of analgesic regimens.
Name: Lauren K. Dunn, MD, PhD.
Contribution: This author helped prepare the manuscript.
Name: Marcel E. Durieux, MD, PhD.
Contribution: This author helped prepare the manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
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