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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

The Preoperative Administration of Intravenous Dextromethorphan Reduces Postoperative Morphine Consumption

Yuan-Yi Chia, MD^*, Kang Liu, MD^*, Lok-Hi Chow, MD^,, and Tak-Yu Lee, MD

*Department of Anesthesia, Veterans General Hospital-Kaohsiung, Taipei; Department of Anesthesiology, School of Medicine, National Yang-Ming University, Taipei; and Graduate Institute of Medical Science, National Defense Medical Center, Taipei, Taiwan, Republic of China

Address correspondence and reprint requests to Yuan-Yi Chia, MD, Department of Anesthesiology, Veterans General Hospital-Kaohsiung, 386, Ta-Chung 1st Rd., Kaohsiung, Taiwan, ROC. Address e-mail to yychia{at}isca.vghks.gov.tw

	Abstract

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We evaluated the effect of dextromethorphan on postoperative pain management. Sixty ASA physical status I–III female patients undergoing major abdominal surgery underwent standardized general anesthesia. Thirty patients received an IV infusion of dextromethorphan 5 mg/kg before anesthetic induction (Pre group), whereas the remaining 30 patients received the same volume of isotonic sodium chloride solution, followed by a postoperative IV infusion of dextromethorphan 5 mg/kg (Post group). Patients in the Pre group received the same volume of isotonic sodium chloride solution postoperatively. All patients were then treated with patient-controlled IV analgesia, which administered a 0.6-mg bolus of morphine on demand (maximal 4 h dose 20 mg). The mean visual analog pain score during cough or movement and at rest were similar in the two groups in the first 3 days postoperatively. However, Post group patients consumed more morphine than Pre group patients during the first 2 days (P < 0.01). The sedation scores, patient satisfaction, and the incidence of morphine-related side effects were similar between the two groups. We conclude that the preoperative administration of dextromethorphan 5 mg/kg reduces postoperative morphine consumption compared with postoperative administration.

Implications: In this double-blinded study, we found that the preoperative administration of IV dextromethorphan 5 mg/kg, compared with postoperative administration, reduces postoperative morphine consumption, which may provide clinical evidence of preemptive or preventive analgesic effects of dextromethorphan.

	Introduction

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Peripheral tissue or nerve injury provokes peripheral and central sensitization. These changes contribute to the postinjury hypersensitivity state found postoperatively, which manifests as an increase in the response to noxious stimuli and a decrease in the pain threshold (1). One strategy for relieving postoperative pain is to prevent or minimize central sensitization (1,2). Central sensitization mainly results from the activation of N-methyl-D-aspartate (NMDA) receptors in the central nervous system triggered by long-lasting nociceptive afferent input. Hence, NMDA antagonist may prevent the induction of central sensitization (3).

Dextromethorphan, a noncompetitive antagonist of NMDA, is the d isomer of the codeine analog of levorphanol. Unlike the l isomer, it has no addictive properties and fewer subjective side effects than codeine (4).

In this double-blinded study, we compared the effect of preoperative versus postoperative administration of IV dextromethorphan on postoperative patient-controlled IV analgesia (PCIA).

	Methods

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We obtained approval from our human investigation committee and written, informed consent from each patient. Sixty ASA physical status I–III female patients undergoing lower abdominal surgery were enrolled. Patients with a history of ischemic heart disease, pulmonary disease, hepatic disease, renal disease, preoperative use of opioids, or allergy to morphine were excluded from the study. Those patients taking monoamine oxidase-inhibiting drugs were also excluded. Before surgery, patients received instructions on how to rate pain using the visual analog scale (VAS; 0 = no pain to 10 = worst possible pain) and how to use the PCIA device. Using a table of random numbers, patients were divided into two groups. Thirty minutes before anesthetic induction, patients in the Pre group (n = 30) received dextromethorphan 5 mg/kg in 300 mL of isotonic sodium chloride solution via an IV infusion for 30 min, whereas the patients in the Post group received a 300-mL isotonic sodium chloride solution infusion. General anesthesia was then induced with fentanyl 3 µg/kg, thiopentone 5 mg/kg, and succinylcholine 2 mg/kg. Endotracheal intubation was performed, and atracurium 0.5 mg · kg^-1 · h^-1 and isoflurane (0.5%–2%) were administered to maintain muscle relaxation and anesthesia. At the end of surgery (during skin closure), the patients in the Post group received dextromethorphan 5 mg/kg dissolved in 300 mL of isotonic sodium chloride solution via an IV infusion for 30 min, whereas patients in the Pre group received a 300-mL isotonic sodium chloride solution infusion. The anesthetic course was managed by an anesthesiologist who was not involved in postoperative evaluation and patient contact. Duration of surgery, total fluids given, and intraoperative blood loss were recorded. Postoperatively, all patients received PCIA, which was initially programmed to administer a 0.6-mg morphine bolus on patient demand for postoperative analgesia. The 4-h limit was 20 mg of morphine. The lockout time between each bolus was 5 min. Pain intensity was evaluated during cough or movement (VASC) and at rest (VASR) on a daily basis for the first 3 days after surgery. On the operative day, assessments of pain intensity were conducted when the patients were sufficiently awake and alert after the surgery. On the following 2 days, the assessments of pain intensity were made at approximately 8 AM by a nurse in our acute pain service. A pain score 3 was considered satisfactory pain relief. If a patient reported a pain score >3 after the initial program setting, we encouraged the patient to trigger the next bolus until he or she experienced satisfactory pain relief. If a patient experienced intolerable nausea or vomiting after a bolus administration, we decreased the bolus dosage by half and treated the side effects with IM metoclopramide 10 mg. Severe pruritus was treated with chlopheniramine maleate 10 mg IV every 8 h as required. Sedation level was assessed by using a 4-point scale (0 = awake and alert; 1 = mildly sedated, easily aroused; 2 = moderately sedated, can be aroused by shaking; 3 = deeply sedated, difficult to arouse, even by shaking). The daily morphine consumption and possible side effects, such as nausea and emesis, pruritus, and respiratory depression (yes/no), were also recorded. Respiratory depression was defined as a respiratory rate of <8 breaths/min. Satisfaction with the quality of pain relief (yes/no) was assessed by the patient and was recorded when the PCA was stopped and the device was disconnected from the patient. Both the evaluator and patient were blinded to the patient's group assignment.

All data are presented as mean ± SD. Differences in demographic data and the daily morphine consumption between groups were analyzed by using Student's t-test. Differences in the types of operations, the incidence of possible side effects, and patient satisfaction were analyzed by using 2 test or Fisher's exact test as appropriate. Pain scores and sedation scores were analyzed by using the Mann-Whitney U-test. A value of P < 0.05 was considered statistically significant. The inclusion of 30 patients in each group was calculated to enable detection of a 20% reduction in morphine requirements with a type I error of 0.05 and a statistical power of approximately 90% (5).

	Results

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The demographic data, types of surgery, duration of surgery, total fluids given, and intraoperative blood loss were similar between the two groups (Table 1). VASC and VASR in the Post group on Days 1–3 (5.2 ± 0.9 and 2.5 ± 0.2; 3.6 ± 0.3 and 1.4 ± 0.2; and 2.5 ± 0.3 and 0.6 ± 0.2, respectively) were higher than those in the Pre group (4.6 ± 0.5 and 2.0 ± 0.3; 3.1 ± 0.3 and 0.9 ± 0.2; and 2.4 ± 0.3 and 0.5 ± 0.2) (Figures 1 and 2). However, those differences were not statistically significant. The first two daily morphine requirements in the Post group (Day 1: 41.6 ± 4.0; Day 2: 21.6 ± 8.9) were significantly higher (P < 0.01) than those in the Pre group (26.1 ± 4.9 and 4.0 ± 5.3, respectively) (Figure 3). All patients could be easily aroused when visited, and there was no significant difference in sedation scores between the two groups. The incidence of adverse effects, such as pruritus and nausea and vomiting, was similar in the two groups (Table 2). Most adverse effects were mild and required no treatment. Only four patients experienced severe vomiting and requested treatment (one in the Post group and three in the Pre group; P = 0.612 by Fisher's exact test). The symptoms improved after the administration of metoclopramide. There was no respiratory depression in either group. Most patients (67% in the Post group, 83% in the Pre group) were satisfied with their postoperative analgesia (Table 2).

View larger version (13K): [in this window] [in a new window]   Figure 1. Postoperative visual analog scale scores during cough or movement (VASC) in patients who received pre- or postoperative administration of dextromethorphan. Data are mean ± SD.

View larger version (11K): [in this window] [in a new window]   Figure 3. Postoperative daily morphine consumption in the patients who received pre- or postoperative administration of dextromethorphan. Data are mean ± SD. *P < 0.01.

View larger version (12K): [in this window] [in a new window]   Figure 2. Postoperative visual analog scale scores at rest (VASR) in patients who received pre- or postoperative administration of dextromethorphan. Data are mean ± SD.

	Discussion

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Previous studies have indicated that the blockade of NMDA receptors before peripheral noxious stimuli enter the central nervous system is effective in attenuating the hypersensitivity state induced by noxious stimulation (6,7). However, there is little clinical evidence supporting a preemptive analgesic effect of dextromethorphan. Most studies address the hyperalgesia induced by neuropathic pain or an opioid-sparing effect in postoperative pain conditions, but the results are controversial. Kauppila et al. (8) demonstrated that a 200 mg of oral dextromethorphan daily does not attenuate pain induced by ischemia or topical capsaicin in healthy human subjects. McQuay et al. (9) also reported that oral dextromethorphan 81 mg daily did not reduce pain in 19 patients with neuropathic pain. However, they concluded that this dose may provide only limited blockade of NMDA receptors and recommended the use of a larger dose for trials. In addition, Grace et al. (10) demonstrated a reduction in intraoperative (but not postoperative) morphine requirement when 120 mg of dextromethorphan was provided orally in two divided doses. However, in a double-blinded, cross-over design using normal volunteers, Price et al. (11) demonstrated that oral doses of 30 and 45 mg of dextromethorphan are effective in attenuating temporal summation of secondary pain by the stimulus. Rogawski (12) and Chen et al. (13) suggested that relatively large doses of low-affinity, noncompetitive channel-blocking NMDA receptor antagonists, such as dextromethorphan, might have a better therapeutic ratio than dissociative, anesthetic-like blockers such as ketamine. Nelson et al. (14) further showed that large doses of oral dextromethorphan (120–960 mg daily) attenuate diabetic neuropathy. In a rabbit model of transient focal brain ischemia, an IV 5-mg/kg loading dose of dextromethorphan, followed by a 2.5-mg · kg^-1 · h^-1 infusion, induced only a slight and transient behavioral effect, whereas plasma dextromethorphan levels of 1000 ng/mL were reached (15). Similar plasma levels of dextromethorphan can be obtained in neurosurgical patients with dextromethorphan at 1440 mg/d without prohibitive adverse effects, and with a promising neuroprotective effect, possibly via inhibition of NMDA receptors (16). Kissin's editorial (17) indicated that one of the reasons some clinical trials failed to demonstrate preemptive analgesia was insufficient afferent blockade. For this reason, we chose a relatively large dose of 5 mg/kg dextromethorphan (approximately 280 mg per patient) for more detailed evaluation. This dose was suggested to be effective for antagonizing NMDA receptors more completely in an animal model (15). The dose is larger than the standard oral antitussive dose of 120 mg/d and larger than the dose used in previous reports without positive findings (8–10). Because dextromethorphan is rapidly metabolized to dextrorphan in the liver (18), it is likely that the side effects produced by the oral administration of dextromethorphan might have been mediated by dextrorphan acting on the phencyclidine site, rather than by dextromethorphan itself (19). In this regard, subcutaneous or IV administration may provide a better alternative than an oral route. Further studies are required to elucidate the dose-response characteristics of dextromethorphan. On administration of the 5-mg/kg dose, 10 patients (6 in the Pre group and 4 in the Post group; P = 0.731 by Fisher's exact test) experienced slight hypotension and tachycardia. However, these hemodynamic variations were within 25% of baseline levels and were reversed in a few minutes by fluid challenge. Patients complained of no other adverse effect that could be attributable to dextromethorphan during the first three postoperative days and a further follow-up at three months. Nausea and vomiting were the only side effects noted in the first three postoperative days (Table 2).

Kawamata et al. (20) showed that premedication with oral dextromethorphan 45 mg markedly reduced spontaneous and swallowing-evoked pain in patients after tonsillectomy. However, they could not conclude that dextromethorphan had a preemptive analgesic effect because the study design lacked comparison with postoperative administration of dextromethorphan. Clinical applications concerning preemptive analgesia have focused on the timing of administration. The effectiveness of these applications has been assessed based on comparisons of postoperative pain intensity or/and analgesic consumption between groups receiving preoperative and postoperative administration of the tested drug (2). Our results support the hypothesis that the preoperative administration of dextromethorphan provides preemptive or preventive analgesia, as evidenced by the significant difference in morphine consumption between the preoperative and postoperative administration groups. The duration of this effect (two days) was longer than the reported antitussive effect of dextromethorphan of five to six hours (4). The results imply that the development of central hyperalgesia in the spinal cord induced by nociceptive stimulation of surgery was blocked or modulated by dextromethorphan acting on NMDA receptors.

The incidence of nausea and vomiting varied (10%–54%) in patients receiving PCIA with morphine for postoperative pain management after general anesthesia (21). Our results are comparable (Table 2). There were no serious adverse effects, such as respiratory depression, from morphine. In addition, reported dextromethorphan-related side effects, such as sedation, distorted vision, feeling drunk, or ataxia (17), were not observed in the present study.

The similar VASC and VASR in the two groups do not exclude the possibility of a preemptive analgesic effect of dextromethorphan. The evidence that the VASR in both groups was <3 from the first to the third postoperative days (Fig. 1) implies that postoperative pain management with morphine provided good analgesia and thus eliminated the small difference in pain intensity between groups. The subjective evaluation also revealed a satisfaction rate of 67% among Post group patients and 83% among Pre group patients.

We conclude that the preoperative IV administration of dextromethorphan 5 mg/kg, compared with postoperative administration, reduced morphine consumption in patients undergoing lower abdominal surgery. The results suggest that preoperatively administered dextromethorphan has a preemptive or preventive analgesic effect on postoperative pain.

	Acknowledgments

 
We thank all members of the Acute Pain Service Team at the Department of Anesthesia, VGHKS, for their assistance in data collection.

	Footnotes

 
Research funding received from VGHKS88–01, Veterans General Hospital-Kaohsiung, Taiwan, ROC.

	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