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TECHNOLOGY, COMPUTING, AND SIMULATION

Dextromethorphan Reduces Immediate and Late Postoperative Analgesic Requirements and Improves Patients’ Subjective Scorings After Epidural Lidocaine and General Anesthesia

Post-Anesthesia Care Unit, Tel Aviv Sourasky Medical Center, and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

	Abstract

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Central N-methyl-D-aspartate receptors modulate postoperative pain. We compared the effects of preincision oral dextromethorphan (DM), an N-methyl-D-aspartate receptor antagonist, on postoperative IV patient-controlled analgesia morphine demand and on subjective variables in 80 patients undergoing lower-body procedures who were randomly assigned to epidural lidocaine (LA; 16 mL, 1.6%) or general anesthesia (GA). The patients were premedicated 90 min before surgery with placebo or DM 90 mg (20 patients per group) in a double-blinded manner. Postoperative IV patient-controlled analgesia morphine administration started when subjective pain intensity was 4 of 10 (visual analog scale) and lasted 2 h. Observation continued up to 3 days, during which patients could use diclofenac. LA-DM and GA-DM patients required 45%–50% less morphine and diclofenac compared with their placebo counterparts (P < 0.001). However, GA-DM patients made twice as many attempts to self-administer morphine as LA-DM patients (P = 0.005). Eight LA-DM versus two GA-DM patients (P < 0.01) used no morphine or diclofenac. All DM patients experienced significantly (P < 0.001) less pain, were less sedated, and felt better than their placebo counterparts; however, compared with placebo, DM improved subjective scorings in the GA patients more significantly (P < 0.05) than in the LA patients. We conclude that oral DM 90 mg in patients undergoing surgery under LA or GA reduces morphine and diclofenac use by 50% in the immediate and late postoperative period compared with placebo. Subjectively scored levels of pain, sedation, and well-being were better as well.

	Introduction

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The traditional pharmacological management of postoperative pain uses various regimens of opioids and their congeners, which may induce important side effects, of which the most hazardous are deep sedation and respiratory depression. Recent years have witnessed the emergence of new non-opioid strategies of pain control during the postoperative period.

N-methyl-D-aspartate (NMDA) receptor antagonists are credited as having a role in alleviating both acute somatic and visceral pain and are gaining greater clinical acceptance (1–5). They reduce pain perception caused by the activation of the receptors in the spinal cord by periphery-originated nociceptive stimuli (6,7).

Dextromethorphan (DM) is a noncompetitive NMDA receptor antagonist. It is rapidly metabolized in the liver (8), where it is transformed to dextrorphan, its active and more potent derivative, as an NMDA antagonist (9). It was suggested that the side effects documented in clinical studies and attributed to the oral administration of DM might be mediated by this metabolite acting at the phencyclidine receptor site rather than DM itself (10). The neurophysiological activity of DM resembles that of ketamine, although it has a dissimilar action on the receptor neural ion channels (9) and, unlike ketamine, is available in oral form. It has a long history of clinical use in the pediatric population, with an established safety record (11). DM (12) and other NMDA receptor antagonists (13,14) can induce preemptive analgesia when administered before tissue injury occurs, thus reducing the subsequent sensation of pain (2,15,16).

Almost all investigations of the role of DM in the management of postoperative pain were performed on surgical patients undergoing general anesthesia (GA) (1–5,12,15).¹ In this study, we compared the effects of oral DM premedication on immediate (2–6 h) postoperative morphine and late (24 h to 3 days) diclofenac requirements, as well as on several subjective variables, in patients undergoing lower-body surgical procedures under epidural lidocaine anesthesia (LA) and compared them with the drug’s effects when GA was used.

	Methods

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Eighty ASA physical status I–III patients undergoing inguinal herniorrhaphy or diagnostic surgical arthroscopy because of joint instability under LA or GA were enrolled in this double-blinded, placebo-con-trolled, randomized study that was approved by our institutional human investigation committee. All participants signed a Helsinki-approved informed consent and were given full explanation of DM, the IV patient-controlled analgesia (IV-PCA) device, and the linear visual analog score (VAS) from the anesthesiologist 24 h before surgery. Exclusion criteria included allergy to opioids, lidocaine, or nonsteroidal antiinflammatory drugs; the use of these drugs or other analgesics during the 21 days before surgery; a history of chronic pain or psychiatric disorders; and the use of centrally acting drugs of any sort. Patients younger than 18 yr and pregnant women were also excluded from the study. Because significant changes in vital signs (e.g., after epidural placement of the local anesthetic) might affect cognition or pain sensation, >20% variation from those values recorded during the premedication visit, or SpO₂ at any time <90% under 40% oxygen, led to the exclusion of the patient from the study. Finally, individuals in whom the regional block did not succeed and GA was induced in its stead and those in whom the block did not suffice and additional IV drugs had to be administered during surgery were also withdrawn from the study.

All LA patients received a single injection of 1.6% lidocaine 16 mL, always by the same anesthesia team. The same two surgical teams always performed the operations. The level of analgesia was confirmed as being at dermatomes T8 to T10. Propofol 2–2.5 mg/kg injected over 60 s was used for the induction of GA in the appropriate groups, and succinylcholine 1.5 mg/kg was given to enable endotracheal intubation. Anesthesia was maintained with a 50% mixture of oxygen and nitrous oxide fresh gas flow. Intraoperative atracurium infusion was turned off 10 min before surgery was terminated. Fentanyl 2.5 µg/kg was used for maintaining anesthesia. Nitrous oxide was turned off at the end of surgery.

Neuromuscular relaxation was not reversed pharmacologically; complete and normal recovery of neuromuscular activity was based on normal train-of-four and clinical criteria, such as the patient’s ability to perform a sustained head lift for 10 s and estimation of satisfactory hand grasp strength, adequacy of respiratory rate, and normal end-tidal CO₂ concentration, as well as a normal capnographic curve. No additional drugs were administered perioperatively in any of the groups.

At the end of surgery, the patients were taken to the postanesthesia care unit (PACU) for follow-up and the pain control study. When the patients reported feeling pain at an intensity of 4 on the subjective pain VAS (see below), they were connected to an IV-PCA system. The attending anesthesiologist administered the first requested 2-mg morphine dose IV, after which the IV-PCA was initiated. The device was prearranged to deliver similar 2-mg boluses of morphine whenever the patient pushed the button, with a 7-min lockout period. The PCA system was attached to each patient for 2 h after the first bolus. Observation in the PACU continued for another 4 h to exclude late unattended appearance of pain; during this period, the patients could receive diclofenac 75 mg IM to relieve pain. Had there been any side effect in the PACU or later in the ward, it would have been noted by the attending physician and treated accordingly.

The patients were transferred to the ward after a 6-h stay in the PACU and were discharged 24 h after surgery. They and their families were instructed to contact the attending physician at any time should the patient become unwell. The same drug protocol-blinded anesthesiologist contacted each patient on the third postoperative day to obtain the home pain VAS and the number of times oral diclofenac 100 mg was used.

The patients were randomly enrolled into two sets: one LA and one GA (40 patients per set). Each set was further divided into two equal groups—one that received 90 mg of DM orally and the other that received placebo—in a double-blinded manner. DM or placebo (in capsules of similar appearance) was given 90 min before surgery; no other premedication was used. The 90-mg dose was selected because smaller-dose regimens had previously produced inconclusive effects of DM on acute pain and postoperative analgesic consumption (3,4,12). At the same time, we wished to avoid the side effects that were characteristically associated with oral DM doses of >100 mg used for acute pain.¹

The amount of morphine delivered by the IV-PCA was recorded, as was that of diclofenac required later in the PACU, on the ward, and at home. The number of times the requests for morphine self-administrations (PCA use) were made was also recorded, with the intent to distinguish between true small morphine requirement and a high demand for morphine, which might not have been met because some requests could have been made during the lockout period of the device. These and the following variables were recorded (every 15 min within the first 2 h and then every 30 min) by the attending anesthesiologist in the PACU:

1. Subjective pain intensity that was graded on a self-rating VAS from 0 ("no pain") to 10 ("unendurable pain").

2. The patient’s subjective sedation was assessed by a VAS of 1–10 (from fully awake to heavily sedated).

3. Subjective feelings of well-being were recorded by a VAS of 1–10 (from sad and gloomy to happy and content).

Vital signs were recorded in each patient during the premedication visit (baseline values), upon the patient’s arrival in the preanesthesia area, during surgery, and throughout the PACU stay. These measurements included noninvasive blood pressure, a five-lead electrocardiogram, end-tidal CO₂, respiratory rate, and pulse-derived oxygen saturation (Cardiocap^TM; Datex, Helsinki, Finland). All patients were given 10 mL/kg of Hartmann’s solution before anesthesia and during the first hour of surgery, followed by 100 mL/h of Hartmann’s solution during the rest of the perioperative time, unless instructed otherwise by the attending anesthesiologist.

The analyses were performed at the Statistical Laboratory of the School of Mathematics, Tel Aviv University, by using the SPSS Release for Windows, Version 9 (SPSS Inc., Chicago, IL). A prestudy power table in which = 4 (mean difference in morphine consumption recorded in a pilot study), = 0.05, and power = 0.9 resulted in the need for 16 patients in every group. The demographic data (age and weight) and background characteristics (baseline heart and respiratory rates, systolic and diastolic blood pressures, and duration of surgery) of the four study groups were compared by using two-way analysis of variance (ANOVA) (following drug and anesthesia variables). Sex, group distribution of the type of procedure, and the number of times diclofenac was used on the ward were analyzed with the ² test. The effects of DM on the need for morphine and the number of button presses during the 2-h observation in the PACU, as well as patient-evaluated pain, sedation, and feeling VAS scores, were analyzed with two-way ANOVA. Analyses of home pain VAS and the use of diclofenac in the various groups were also performed with two-way ANOVA. All values are expressed as mean ± SD, with significance defined as P 0.05.

	Results

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Of the 80 patients originally enrolled in the study, 5 were excluded from the two LA groups (3 placebo and 2 DM) because of epidural failure and the need to administer GA. The patients’ demographic, diagnostic, and surgery data did not differ statistically among the groups (Table 1); sex distribution within the groups was statistically similar as well (data not shown). The intraoperative thoracic dermatome sensory block upper limits were also statistically similar between the two LA groups: 8.9 ± 0.9 (placebo) versus 9.0 ± 0.8 (DM; not significant). The vital variables were within physiological ranges in all study groups throughout surgery and stay in the PACU and did not differ statistically (data not shown) from the premedication values (Table 1).

View larger version (24K): [in this window] [in a new window]   Figure 1. Patients’ cumulative self-evaluation of pain on a visual analog scale (VAS). "0" time values were those recorded immediately before the administration of the bolus of morphine by the attending anesthesiologist. Data are expressed as mean ± SD, and statistical analyses used repeated-measures analysis of variance. The figure depicts a lower level of pain scores in the dextromethorphan (DM)-treated patients compared with the placebo-administered individuals; this also depended on the type of anesthesia (P = 0.005; drug x anesthesia effect). The magnitude of the differential effect of DM also changed over time (P < 0.001; time x drug x anesthesia interaction). LA = lidocaine anesthesia; GA = general anesthesia.

View larger version (35K): [in this window] [in a new window]   Figure 2. Patients’ cumulative self-evaluation of sedation (upper pane) and feelings of well-being (lower pane) on a visual analog scale (VAS). "0" time values were those recorded immediately before the administration of the bolus of morphine by the attending anesthesiologist. Data are expressed as mean ± SD, and statistical analyses used repeated-measures analysis of variance. The figure depicts lower sedation scores and better feelings of well-being in the dextromethorphan-treated patients compared with those who received placebo, indicating a greater beneficial effect for sedation in the general anesthesia (GA) patients and for feelings of well-being in the lidocaine anesthesia (LA) patients (P < 0.001; drug x anesthesia interaction). Scores pertaining to both variables also demonstrated an effect that changed over time (P < 0.05; time x drug x anesthesia interaction effect), particularly for the feeling scores.

No side effects were registered among the patients during the 3-day home follow-up. The 3-day mean pain VAS and the number of times patients used diclofenac orally were significantly (P < 0.001; main drug effect) less in the DM-treated compared with the placebo patients but were not affected by the type of anesthesia (Table 2). Finally, six LA-DM and two GA-DM patients used no oral diclofenac, and no placebo individual (P < 0.01; drug x anesthesia effect) used oral diclofenac.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of this immediate (six-hour) and late (24-hour and three-day) postoperative study demonstrate that the morphine and diclofenac requirements in patients premedicated with oral DM 90 mg and who later underwent surgery under either LA or GA were less by half than those in the placebo-treated patients. Despite the similarity of the morphine-sparing effect between the two anesthesia sets of patients, the number of requests made by the GA-DM patients was double that of the LA-DM patients, indicating a true smaller morphine requirement in the latter. Also, 47% of the LA-DM patients used neither morphine nor diclofenac, compared with only 11% of the GA-DM patients. At the same time, DM administration was associated with less intense pain or sedation and better feelings of well-being for both anesthesia groups, but the magnitude of DM-associated improvement over time recorded within the GA set was superior to that obtained within the LA set.

The role of the NMDA receptor in modulating acute pain has been clarified over the past few years (5,17) and is of substantial clinical value because it reduces pain perception without the hemodynamic- or respi-ration-depressing consequences that can be evoked by opioids (18). Previous investigations focused mainly on morphine- and pain-related data in patients under GA, and these findings were sometimes contradictory [e.g., Kawamata et al. (12) versus Rose et al. (4) in patients undergoing tonsillectomy]. Our findings clearly demonstrate DM’s effectiveness in sparing analgesic consumption immediately, at 24 hours, and at 3 days after surgery, as well as in improving patients’ subjective conditions independently from the type of anesthesia.

It would seem reasonable to assume that the LA-DM patients made less use of the IV-PCA device compared with their GA counterparts because they were feeling relatively better and experiencing relatively less pain. However, there was less of an improvement over time, as evidenced by the LA-DM compared with the LA-placebo patients’ scores. This could stem from the variable pharmacological interaction between lidocaine and DM at the NMDA receptor level (19), so that DM may have added little to the favorable effect that had been generated by the lidocaine. This consideration could imply a ceiling effect of DM on spinal and cerebral NMDA receptors (as suggested for DM at the µ-opioid receptors) (20). Indeed, when the almost maximally tolerable dose (200 mg) was administered orally every eight hours, DM resulted in a modest reduction in morphine requirements, but no reduction in postoperative pain level was detected compared with the placebo effect (21). Also, 120 mg of DM did not prove to have a better antinociceptive effect on GA patients than a 60-mg dose.¹ The latter two reports thus support a maximal central effect obtainable by DM.

The current literature supports a role of DM as a multimodal analgesic adjutant because, by themselves, NMDA antagonists are not antinociceptive (1,3,5).¹ The total sparing of analgesics in one third of DM-treated patients is, therefore, intriguing. We suggest that lidocaine injected epidurally would act at receptor sites also targeted by DM to attenuate nociception. Support for such an interaction could derive from the findings that ketamine plus morphine under LA provided improved postoperative analgesia compared with ketamine and morphine in GA (22). It was also suggested that glutamate receptor antagonists (e.g., DM) and lidocaine produced synergistic analgesia on somatic and visceral pain at the spinal level (23). Small concentrations of lidocaine were also observed to selectively reduce C fiber-evoked neuronal activity in rats and subsequently the nociceptive transmission in the spinal cord by decreasing NMDA receptor activity (24). Finally, Hirota et al. (25) reported an interaction of local anesthetics with various recombinant opioid receptors. Taken together, these findings suggest that combining NMDA receptor antagonists with both opioid and non-opioid analgesics may increase their analgesic potency (26), which could have enabled some of our patients to refrain from the use of both morphine and diclofenac.

This is the first study that compares the effect of DM on postoperative analgesic requirements, acute pain intensity, and other subjective variables in surgical patients randomized to LA or GA. This protocol also enabled us to report that the untoward somatic, visceral, and behavioral effects that were reported in DM-treated patients after surgery under GA¹ (2) were absent in our patients. These untoward events could be the consequence of an excessive agonistic effect of DM on the central NMDA receptors (19) or of its binding capability at -opioid receptors (27). In line with this contention is the finding that side effects may be mediated by the DM metabolite dextrorphan, which would act at the phencyclidine receptor site, rather than by DM itself (10).

In conclusion, premedication by oral DM 90 mg reduces the postoperative amounts of morphine and diclofenac in patients operated on for lower-body procedures under either LA or GA, both immediately and up to three days afterward. Improvement of subjective feelings and minimization of sedation and pain sensation were more noticeable in the GA-treated patients. However, DM appeared to have an unexplained morphine total sparing effect, mainly among the LA patients: such a possible benefit might have potential importance and warrants additional experimental and clinical investigations.

	Acknowledgments

 
The author thanks Esther Eshkol for editorial assistance.

	Footnotes

 
¹ Minn FL, Nelson SL, Brahim J, Caruso FS. Superior analgesic activity of morphine with dextromethorphan, an NMDA receptor antagonist, in oral surgery pain [abstract]. Clin Pharmacol Ther 1998;63:140.

	References

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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