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REGIONAL ANESTHESIA AND PAIN MEDICINE

The Effect of the Preemptive Use of the NMDA Receptor Antagonist Dextromethorphan on Postoperative Analgesic Requirements

Anesthesia Department, Faculty of Medicine, Cairo University, Cairo, Egypt

Address correspondence to Dr. Sanaa A. K. Helmy, Assistant Professor, 2 Abdel-Wahab Saleim St., Maadi, Cairo, Egypt.

	Abstract

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Both central sensitization after peripheral tissue injury and the development of opiate tolerance involve activation of N-methyl-D-aspartate receptors. In this double-blinded, randomized study, we investigated the preemptive versus postincisional effects of dextromethorphan, an N-methyl-D-aspartate receptor antagonist, on postoperative pain management. Sixty ASA I and II patients undergoing elective upper abdominal surgery were randomly allocated to three equally sized groups. The Preincisional group patients received dextromethorphan (120 mg) IM 30 min before skin incision and a placebo (isotonic saline) 30 min before the end of surgery. The Postincisional group received the same dose of dextromethorphan 30 min before the end of surgery and a placebo 30 min before skin incision, and the Control group received a placebo both 30 min before skin incision and 30 min before the end of surgery. A standard general anesthetic technique including fentanyl, propofol, isoflurane, and atracurium was used. Postoperative meperidine patient-controlled analgesia (PCA) was used. There were no significant group differences in the median pain scores except in the visual analog scale at 6 h both at rest and on movement; these were significantly lower in the Preincisional group than the other two groups (P < 0.05). The mean time to initiation of PCA was significantly longer in the Preincisional than in the Postincisional and Control groups (mean [SD]: 10.7 [2.2 h], 5.4 [2.1 h], and 3.7 [1.6 h], respectively; P < 0.001]. The 24-h PCA-meperidine consumption was significantly less in the Preincisional than in the Postincisional and Control groups (mean [SD]: 140 [60 mg], 390 [80 mg], and 570 [70 mg], respectively; P < 0.001]. The incidence of postoperative hypoxemia (SpO₂ < 90%) and nausea was significantly less in the Preincisional group (P < 0.05). In conclusion, preincisional IM 120 mg dextromethorphan compared with the same postincisional dose significantly reduced postoperative meperidine consumption.

Implications: IM administration of preincisional dextromethorphan (120 mg), allowing the use of a larger dose sufficient to block the central sensitization caused by activation of the N-methyl-D-aspartate receptors, provides preemptive analgesia and has a supportive role in postoperative pain relief, as shown by a significant decrease in 24-h meperidine consumption.

	Introduction

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Peripheral tissue damage, and the inflammatory response it provokes, initiates a local change in the sensitivity of sensory receptors (i.e., peripheral sensitization) and also triggers an increase in the excitability of neurons in the spinal cord (central sensitization) (1). The pharmacology of central sensitization has revealed that the N-methyl-D-aspartate (NMDA) receptors are involved (2). One direct implication of this fact is that interventions that prevent the establishment of central sensitization may have a therapeutic role: the concept of preemptive analgesia (3). In addition to preventing central sensitization, coadministration of NMDA receptor antagonists with an opioid may enhance opiate-induced antinociception and may prevent tolerance to opioid analgesia (4,5). Perhaps preemptive analgesia with a combination of narcotic analgesic and NMDA receptor antagonist would prevent the central sensitization to reduce postoperative pain.

Dextromethorphan, the d isomer of the codeine analog of levorphanol, has been used clinically as a central antitussive drug for more than 40 yr (6). It has weak affinity for the µ-opioid receptor and has a sedative effect (7). Dextromethorphan and its metabolite, dextrorphan, have noncompetitive NMDA receptor antagonist properties (8). The adult oral antitussive dose of up to 120 mg/day, unlike the l isomer, has no addictive properties, no respiratory depression, and fewer side effects than codeine (9). The bioavailability and the onset of action of IM dextromethorphan is almost the same as that of IV injection. Side effects may be mediated by dextrorphan, the liver metabolite of oral dextromethorphan, and IV administration of large doses leads to hypotension and tachycardia. Therefore, IM administration allowing the use of a larger dose to achieve sufficient antagonistic action at the NMDA receptor, with rapid onset in acute pain states and with fewer side effects, may provide a better alternative than an oral or IV route.

Some studies have demonstrated that a single preincisional treatment with dextromethorphan, an NMDA receptor antagonist, provides preemptive analgesia (10,11). However, other clinical trials have failed to demonstrate this preemptive analgesic effect with the preoperative administration of dextromethorphan (12,13). The aim of this study was to assess the analgesic efficacy and safety of the preemptive versus postincisional administration of IM dextromethorphan on postoperative pain by assessing its effect on analgesic requirements, pain scoring, and side effects after elective upper abdominal surgery.

	Methods

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This prospective, randomized, double-blinded clinical study was conducted after approval by the local ethics committee. Informed consent was obtained from each patient. Sixty adult patients of either sex and ASA grade I–II scheduled for elective upper abdominal surgery were enrolled in the study. Patients with liver, kidney, or endocrine disorders; major diseases of the respiratory system; or marked obesity (50% above the ideal body weight) were not studied. Patients who had received opioids or nonsteroidal antiinflammatory drugs within 1 wk of the study, patients taking regular analgesic medication or monoamine oxidase inhibitors, patients with allergy to opioids, and patients with drug abuse were excluded. On the evening before surgery, patients were taught how to use the patient-controlled analgesia (PCA) pump and how to rate pain with the visual analog scale (VAS).

By use of a table of random numbers, patients were randomly allocated into one of three equally sized groups. The study supervisor, who did not participate in the assessment, prepared a syringe filled with dextromethorphan (120 mg in 5 mL) or isotonic saline (5 mL) as a placebo. The anesthetists who provided the anesthesia and the investigator participating in the pain assessments were unaware of the type of medication given to the patient. Patients were also blinded to their group assignment. Patients in the first group received IM dextromethorphan 120 mg 30 min before skin incision (Preincisional group) and a placebo (IM saline) 30 min before the end of surgery, patients in the second group received a placebo (IM saline) 30 min before skin incision and IM dextromethorphan 120 mg 30 min before the end of surgery (Postincisional group), and patients in the third group received a placebo (IM saline) both 30 min before skin incision and 30 min before the end of surgery (Control group). All patients were premedicated with 0.1 mg/kg of oral midazolam 90 min before surgery. Patients received a standardized anesthetic, with fentanyl (2 µg/kg) and propofol (2.0–2.5 mg/kg) for the induction. Endotracheal intubation was facilitated with atracurium (0.5 mg/kg). The lungs were ventilated to normocapnia, and anesthesia was maintained with isoflurane (1%–2%) in a nitrous oxide (70%) and oxygen mixture and supplemented with increments of 10–15 mg of atracurium. At the end of anesthesia, residual neuromuscular blockade was antagonized with neostigmine (0.05 mg/kg) and atropine (0.01 mg/kg).

On arrival at the recovery room, all patients were given an IV "loading dose" of meperidine (1 mg/kg). PCA was then initiated immediately upon the patient’s request for analgesia with IV medications by using a Graseby PCA pump (Graseby, Watford, Herts, UK). If pain relief was insufficient, patients were encouraged to trigger the next bolus until the achieved satisfactory pain relief. Meperidine demand doses were 20 mg with a 10-min lockout and no background infusion, with a maximum 4-h limit of 300 mg. The total meperidine consumption was recorded. Transcutaneous arterial oxygen saturation (SpO₂) was monitored continuously by pulse oximetry, and naloxone was ordered if SpO₂ decreased to 85%. Noninvasive arterial blood pressure, pulse rate, respiratory rate, and side effects were documented hourly for 24 h. After surgery, assessment of pain intensity was done when the patients were sufficiently awake after surgery. The level of pain relief was assessed at rest and on movement (from supine to sitting in bed) at 6-h intervals by using a 100-mm VAS (0 = no pain to 100 = worst pain imaginable). Sedation level was assessed with the Observer’s Assessment of Alertness/Sedation scale: 5 = responds readily to name spoken in normal tone; 4 = lethargic response to name spoken in normal tone; 3 = responds only after name is called loudly or repeatedly; 2 = responds only after mild prodding or shaking; and 1 = does not respond to mild prodding or shaking (14). After 24 h, a Retrospective Verbal Pain Score was assigned from a six-point scale (0 = no pain at all; 1 = sometimes moderate; 2 = always moderate; 3 = sometimes severe; 4 = always moderate, sometimes severe pain; 5 = discontinuation because of inefficacy) to evaluate the patient’s satisfaction with the quality of postoperative analgesia for the whole treatment period. Assessments of the patients for side effects related to meperidine (drowsiness, respiratory depression, nausea, vomiting) or dextromethorphan (dizziness, ataxia, hot flashes, distorted vision, gastrointestinal upset, and headache) were done by observation and recording throughout the 24-h study period as they occurred or when they were voluntarily mentioned by the patient. Nausea and vomiting were treated as necessary with IV ondansetron 4 mg. IV fluid therapy was maintained with crystalloid 1.5 mL · kg^-1 · h^-1. Assessments were conducted by the resident anesthetists in charge, who were blinded as to the therapy under investigation.

Summary statistics are expressed as means with standard deviations (SD) or medians with ranges. Differences in demographic data and analgesic consumption between groups were analyzed by using Student’s t-test and analysis of variance for parametric data to compare the difference between groups. Differences in the incidence of side effects were analyzed with the ² test. Pain scores and sedation scores were analyzed with the Mann-Whitney U-test with Bonferroni correction. A value of P < 0.05 was considered statistically significant. With an error of 0.05, 16 patients per group were required to achieve a power of 80% for the study.

	Results

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There were no significant differences among the groups in terms of age, weight, sex, ASA physical status, and duration of anesthesia ( Table 1). There were no significant differences in the Observer’s Assessment of Alertness/Sedation scales among the three groups. The mean time between extubation and the first request for analgesia by PCA in the Preincisional group was significantly longer than in the other two groups (P < 0.001). During the 24-h study period, the mean consumption of PCA-meperidine and the average demands per hour recorded per patient in the Preincisional group were significantly fewer (P < 0.001 and P < 0.01, respectively) than in the other two groups ( Table 2).

	Discussion

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Our study shows that the preincisional administration of IM 120 milligrams dextromethorphan, the NMDA receptor antagonist, compared with the same postincisional dose and a control, provides preemptive analgesia and may have a supportive role in postoperative pain relief, as shown by prolonged time to first use of PCA-meperidine and a significant decrease in meperidine consumption over a 24-hour period. IM administration, allowing the use of a larger dose to achieve sufficient antagonistic action at the NMDA receptor with the rapid onset required in acute pain states and with fewer side effects, may provide a better alternative than an oral or IV route.

Peripheral tissue injury provokes peripheral and central sensitization (15). Peripheral sensitization is a reduction in the threshold of nociceptive afferent receptors caused by a local change in the sensitivity of sensory fibers initiated by tissue damage (1). If the peripheral nociceptive afferent input is of sufficient duration and intensity, it sensitizes or increases the excitability of the dorsal horn neurons, resulting in central sensitization (16). Glutamate is the major excitatory amino acid neurotransmitter in the central nervous system. A and C-fiber primary afferent nerve terminals within the substantia gelatinosa of the spinal cord release glutamate and neuroactive peptides in response to noxious stimuli. Glutamate binds to both ionotropic and metabotropic glutamate receptor subtypes. The ionotropic glutamate receptor involves three major subtypes: -amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), NMDA, and kainate receptors (17). The AMPA receptors mediate the fast excitatory transmission involving both innocuous and acute nociceptive input, whereas in normal activity, the NMDA receptors are inactive. However, with prolonged and intense painful stimuli, sufficient amounts of glutamate and peptides are released, resulting in removal of the magnesium block of the NMDA receptor channel. Calcium ions flow through the receptor channel, causing massive neuronal depolarization and increased excitability of the neurons, i.e., central sensitization, which manifests as a decrease in the pain threshold and an enhanced response to noxious stimuli (15).

Thus, central sensitization results mainly from the activation of NMDA receptors in the central nervous system triggered by nociceptive afferent input from the periphery. Hence, one strategy for relieving postoperative pain is to use NMDA receptor antagonists before the occurrence of tissue injury to prevent or minimize the induction of central sensitization (3,15), i.e., preemptive analgesia. Dextromethorphan does not have a direct antinociceptive effect (18), so postoperative analgesia is most likely caused by its antagonistic action at the NMDA receptor.

The results of previous studies that used NMDA receptor antagonists to block or attenuate the central sensitization induced by noxious stimulation are controversial. The present results are compatible with those of Wu et al. (10) and Liu et al. (11), who showed that preoperative dextromethorphan treatment provided a preemptive analgesic effect and may prevent the sensitization of nociceptive neurons in the spinal cord. Kawamata et al. (19) reported that premedication with oral dextromethorphan 45 milligrams, but not 30 milligrams, reduced postoperative pain at rest and on swallowing after tonsillectomy, whereas Price et al. (18) found that both doses effectively reduced wind up. However, McConaghy et al. (12) found no difference in VAS, PCA-morphine consumption, or secondary hyperalgesia with two preoperative doses of dextromethorphan 27 milligrams, followed by three further doses in the first 24 hours after surgery. Grace et al. (13) demonstrated a significant reduction in intraoperative morphine requirement but no difference in postoperative analgesic use or pain scoring when two doses of oral 60 milligrams of dextromethorphan per day were used. Kauppila et al. (20) demonstrated that 100 milligrams of oral dextromethorphan daily did not significantly attenuate pain intensity in response to ischemia or topical capsaicin, whereas 200 milligrams produced marked side effects. The failure of some studies to demonstrate a preemptive analgesic effect of dextromethorphan may be explained by insufficient afferent blockade required to prevent central sensitization because of the use of small doses, oral administration, improper timing of administration in acute pain, and its use in neuropathic pain syndromes after the establishment of central sensitization.

The elimination half-time of oral dextromethorphan is approximately eight hours (21), and the onset of action occurs in 15 to 30 minutes after administration. The bioavailability of oral dextromethorphan is only 10% (22), whereas that after an IM injection is similar to that after an IV injection, with almost the same rapid onset. Side effects may be mediated by dextrorphan, the liver metabolite of oral dextromethorphan, and IV administration of large doses leading to hypotension and tachycardia. Therefore, IM administration may provide a better alternative than an oral or IV route, with the required rapid onset in acute pain states and with fewer side effects. IM administration allowed us to use a dose larger than those used in some previous studies with negative results and less than the doses that can cause side effects. Kissin (23), in his editorial about preemptive analgesia, indicated that one of the reasons for the failure of some clinical trials to demonstrate preemptive analgesia was insufficient afferent blockade. There were no differences in the recorded side effects related to dextromethorphan in the Preincisional or Postincisional groups compared with the Placebo group. This is in agreement with Steinberg et al. (24), who did not find side effects in patients receiving dextromethorphan <2.11 mg/kg every six hours. Also, Henderson et al. (25) did not detect excess sedation with 40 milligrams of oral dextromethorphan every eight hours for 48 hours.

The concept of multimodal analgesia is the current trend for postoperative pain management. This implies that a single antagonist may not be sufficient to prevent postoperative pain if other pathways are not blocked. There is now evidence that both hyperalgesia after tissue injury and the development of opiate tolerance involve activation of the NMDA receptors and subsequent central sensitization (5), which suggests that the blocking of NMDA receptors may substantially potentiate opiate-induced antinociception and reveal the full analgesic potency of opiates. The combination of NMDA receptor antagonists and opiates deserves more consideration. In this respect, dextromethorphan was found to be more effective than ketamine in enhancing the analgesic effects of morphine (26). In our study, the significant reduction in PCA-meperidine requirement with satisfactory pain relief in the Preincisional group may be explained by NMDA receptor blockade by dextromethorphan, preventing central sensitization and increasing the neuronal sensitivity to opioid receptor agonists. The similar low pain scores among the groups implies that postoperative analgesia in the Preincisional group was adequate. The VAS pain intensity value for the Preincisional group was only significantly smaller than the Postincisional and Control groups at the six-hour time point, which may be caused by the preemptive use of dextromethorphan. Thus, the combined administration of proper doses of opioids increasing the threshold of nociceptive neurones and NMDA receptor antagonists blocking the central sensitization results in improved pain relief and reduces the amount of opiates with fewer side effects related to both drugs. Further studies are needed to investigate the added effect of an antiinflammatory drug suppressing any local inflammatory reaction, a local anesthetic preventing an injury discharge, and ₂ agonists enhancing inhibitions and together reducing excitability to produce highly effective antinociception.

In conclusion, preincisional dextromethorphan 120 milligrams IM provides preemptive analgesia and may have a supportive role in postoperative pain relief, as shown by prolonged time to first use of PCA-meperidine and a significant decrease in meperidine consumption over 24 hours after elective upper abdominal surgery. IM administration, allowing the use of a larger dose sufficient to block the central sensitization by its antagonistic action at the NMDA receptor with the rapid onset required in acute pain states and with fewer side effects, may provide a better alternative than an oral or IV route.

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Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999