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REGIONAL ANESTHESIA AND PAIN MANAGEMENT

Preincisional Dextromethorphan Treatment Decreases Postoperative Pain and Opioid Requirement After Laparoscopic Cholecystectomy

Ching-Tang Wu, MD^*, Jyh-Cherng Yu, MD, Chun-Chang Yeh, MD^*, Sy-Tzu Liu, MD^*, Chi-Yuan Li, MD^*, Shung-Tai Ho, MD^*, and Chih-Shung Wong, MD, PhD^*

Departments of *Anesthesiology and Surgery, Tri-Service General Hospital and National Defense Medical Center, Taipei, Taiwan

Address correspondence and reprint requests to Dr. Chih-Shung Wong, Department of Anesthesiology, Tri-Service General Hospital and National Defense Medical Center, #8, Section 3, Tingchow Rd., Taipei, Taiwan 100, Republic of China.

	Abstract

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In the present study, we examined whether preincisional treatment with dextromethorphan (DM) provides preemptive analgesia. Ninety patients scheduled for laparoscopic cholecystectomy were included. Patients receiving chlorpheniramine maleate (CPM) 20 mg via an IM injection 30 min before skin incision were designated as the control group. Patients in Group A received DM 40 mg (containing CPM 20 mg) IM after removal of the gallbladder, whereas in Group B, DM 40 mg (containing CPM 20 mg) was administered IM 30 min before skin incision. Meperidine (1 mg/kg IM) was given for postoperative pain relief as required. Times to first meperidine injection, total meperidine consumption, worst pain score, bed rest time, and side effects were recorded for 48 h after surgery. Times to first meperidine injection were 9.3 ± 15.9, 17.4 ± 3.4, and 28.6 ± 3.9 h for the control group and Groups A and B, respectively. The total meperidine consumption was 90.7 ± 11.9, 77.5 ± 12.7, and 20.0 ± 4.4 mg for the control group and Groups A and B, respectively. The worst visual analog pain scores were 6.0 ± 0.2, 6.0 ± 0.2, and 4.0 ± 0.4 for the control group and Groups A and B, respectively. The bed rest times were 21.0 ± 0.5, 20.0 ± 0.5, and 19.0 ± 0.4 h for the control group and Groups A and B, respectively. The number of patients who required meperidine injection was 26, 22, and 12 for the control group and Groups A and B, respectively. We conclude that DM is more effective in producing postoperative analgesia when it is administered preincision rather than after the gallbladder removal treatment, which suggests a preemptive analgesic effect.

Implications: Preincisional dextromethorphan (40 mg IM) treatment offers a preemptive analgesic effect, thus improving the postoperative pain management.

	Introduction

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Laparoscopic cholecystectomy (LC) is widely used to replace laparotomy cholecystectomy. The benefits of LC, compared with open cholecystectomy, are less postoperative pain and reduced analgesic consumption (1). However, many patients still suffer from moderate or even severe visceral pain after LC, and they sometimes require opioid treatment for pain relief (1). Different treatments have been used to relieve pain, including nonsteroidal antiinflammatory drugs (2), local anesthetic technique (3), and evacuating the insufflated gas (4), but none has been consistently satisfactory.

Preemptive analgesia is an antinociceptive treatment before tissue injury that prevents the establishment of the altered central nociception processing that amplifies postoperative pain. Therefore, adequate prevention of nociceptive neuron sensitization of the spinal cord will improve postoperative pain management (5). N-methyl-D-aspartate (NMDA) antagonists reduce spinal nociceptive neuron hyperexcitability, which has led to renewed interests in NMDA receptor antagonists (e.g., ketamine and dextromethorphan [DM]) in clinical pain management (6–16). DM, an antitussive drug, has been widely used for >40 yr (17). DM and its metabolite, dextrorphan, have a noncompetitive NMDA antagonist property (18–20). Kawamata et al. (6) reported that premedication with DM prevents NMDA receptor-activated central nociceptor sensitization and reduces postoperative pain after tonsillectomy. In the present study, we examined whether preincisional treatment with DM provided better postoperative pain relief after LC.

	Methods

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With institutional approval and written, informed consent, 90 ASA physical status I or II patients scheduled for elective LC were included and randomly divided into three groups. Consistent with our previous study (15), DM 40 mg and chlorpheniramine (CPM) 20 mg were used in the present study. The control group patients received CPM 20 mg via an IM injection 30 min before skin incision; in our domestic market, one ampule of DM (10 mg) contains 5 mg of CPM. Patients in Group A received DM 40 mg (containing CPM 20 mg) IM after removal of the gallbladder, whereas patients in Group B received DM 40 mg (containing CPM 20 mg) IM 30 min before skin incision. Patients who had received opioids or nonsteroidal antiinflammatory drugs within 1 wk of the study were excluded.

Anesthesia was induced with fentanyl (2 µg/kg), atracurium (5 mg), and thiopental (3–5 mg/kg). Endotracheal intubation was facilitated with succinylcholine (1.5 mg/kg). Anesthesia was maintained with desflurane in oxygen (300 mL/min) with a total closed-circuit system; the end-tidal desflurane concentration was maintained at approximately 6.5% ± 0.5%. Atracurium was used for muscle relaxation. No additional opioids were given during the operation. Standard monitors were used. At the end of surgery, residual neuromuscular block was antagonized with edrophonium (0.8 mg/kg) and atropine (0.01 mg/kg), and the endotracheal tube was removed when the patient breathed spontaneously. Meperidine (1 mg/kg IM) was used for postoperative pain relief, if requested. Pain intensity was evaluated by using a visual analog scale (VAS; 0 = no pain to 10 = severe, intolerable pain). The worst pain score was recorded at the first dose of meperidine injection. Side effects related to meperidine (dizziness, drowsiness, nausea and vomiting), CPM (vertigo, drowsiness, headache, nausea, blurred vision, and weakness), and DM (nausea, vomiting, dizziness, hot flashes, drowsiness, heartburn, and headache), as well as total meperidine consumption and bed rest time (the interval between the end of the surgery and end of bed rest) were reported by the patients 48 h after surgery. We recorded the number of patients who suffered any one of these side effects during the 48-h observation. All the assessments were made on a double-blinded basis, and the side effects were treated as necessary.

All data are presented as mean ± SD. Statistical significance was determined by one-way analysis of variance with Dunnett's test. The ² square test was used to evaluate the statistical differences of meperidine requirements and side effects among groups. P < 0.05 was considered statistically significant.

	Results

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There were no demographic data and surgical time differences among the three groups (Table 1). The average time to first meperidine injection was 9.3 ± 15.9 h for the control group, 17.4 ± 18.6 h for Group A (P < 0.05 compared with the control), and 28.6 ± 21.3 h for Group B (P < 0.05 compared with Group A and P < 0.0001 compared with the control). Patients in Group B consumed less meperidine than patients in the control group and in Group A during the 2-day observation period (Table 2). Total meperidine consumption was 90.7 ± 65.2, 77.5 ± 69.6, and 20.0 ± 24.1 mg for the control group and Groups A and B, respectively (P < 0.00001 for Group B versus Group A and P < 0.0000001 for Group B versus the control group). Moreover, higher VAS pain scores were observed in the control group (6.0 ± 1.1) and Group A (6.0 ± 1.1) than in Group B (4.0 ± 2.2; P < 0.0001 compared with Group A and P < 0.000001 compared with the control group) (Table 2). The average bed rest time was significantly shorter in Group B (19.0 ± 0.4 h); P < 0.001 compared with the control group and Group A than in the control group (21.0 ± 0.5 h) and Group A (20.0 ± 0.5 h). Twelve patients required meperidine injection for pain relief in Group B, compared with 26 patients in the control group and 22 patients in Group A). There were no DM and CPM-associated side effects (dizziness, hot flashes, tremor, drowsiness, and heartburn) within the 2-h observation period in the postoperative recovery room. Seven, six, and three patients suffered from either meperidine-associated nausea, vomiting, dizziness, or headache in the control group and Groups A and B, respectively (Table 2).

	Discussion

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DM and other NMDA antagonists have a role in nociceptive responses in the dorsal horn neurons (18–20). Experimental studies have shown that NMDA receptors play a significant role in neuronal wind-up and spinal nociceptor hyperexcitability (21,22). In humans, surgical trauma may cause comparable alterations in sensory processing and may result in amplification and prolongation of postoperative pain, which may result in NMDA receptor activation (23). In our previous studies, we demonstrated that the preoperative epidural NMDA antagonist ketamine (10 mg), in combination with morphine (1 mg) and bupivacaine treatment, provides effective preemptive analgesia (9). Similarly, in the present study, we demonstrated that a single preincisional treatment with DM, an NMDA receptor antagonist, also provides preemptive analgesia.

Using a double-blinded, randomized, placebo-controlled, cross-over study design, Price et al. (10) found that both DM 30 mg and 45 mg effectively reduced slow temporal summation of electrical and thermal-evoked second pain (wind-up) in a dose-dependent manner, in normal volunteers. Ilkjaer et al. (11) also found that DM reduced the magnitude of secondary hyperalgesia to pinprick and prolonged noxious heat stimulation. More recently, Kawamata et al. (6) reported that preincisional treatment with oral DM 45 mg, but not 30 mg, reduces postoperative pain after tonsillectomy. In our previous study, we also found that DM pretreatment before surgical incision provided better postoperative pain relief, in a dose-dependent manner, for upper abdominal surgery (12). All of the above results are consistent with the results of the present study, which show that preincisional treatment with DM provides satisfactory postoperative pain relief by offering a preemptive analgesic effect. DM prevents the induction of central nociceptor sensitization by blocking the NMDA receptor activation.

Some controversial results have been reported. Kauppila et al. (13) found that oral DM 100 mg did not attenuate the pain produced by topical capsaicin application or ischemia; however, pronounced pain relief was observed with a larger dose (200 mg). McQuay et al. (14) failed to demonstrate DM's analgesic effect on neuropathic pain syndromes at doses of either 40.5 mg or 81 mg daily in a 10-day observation. Moreover, Grace et al. (15) failed to demonstrate the preemptive analgesic effect of DM that DM (60 mg) pretreatment did not provide better postlaparotomy pain relief given the night before and repeated 1 h before surgery. McConaghy et al. (16) reported that DM treatment (with a 27-mg capsule, two doses before surgery and three doses in the first 24 h after surgery) did not offer any benefit for postoperative pain relief.

These findings do not necessarily conflict with ours. In Kauppila et al.'s study (13), the effective plasma concentration may not have been achieved when a smaller dosage was assessed. The neuropathic pain syndromes described by McQuay et al. (14) were chronic pain conditions to which the central nociceptors may already have been sensitized before DM administration. Furthermore, the duration of treatment might have been too short for the chronic pain conditions. In our present study, DM was given IM 30 min before surgical incision; postoperative pain is an acute condition of short duration, and IM injection also provides rapid onset that effectively inhibits the central sensitization of the spinal nociceptive neurons. The negative results of the articles described above might be the result of the authors using a dose of DM too small to compare with that used in the present study (13–16). The bioavailability of DM is only 10% after oral administration (24), whereas that after an IM injection is similar to that after an IV injection. The onset of an IM DM injection is almost as rapid as that after IV administration. Compatible with the dose used in the present study (40 mg IM), Nelson et al. (25) found that 381 mg/d DM administered orally also provides satisfactory pain relief from diabetic peripheral neuropathy.

In conclusion, in the present study, we showed that a preincisional IM DM injection, with a rapid onset and reliable blood level, offers a preemptive analgesic effect, thus providing better postoperative pain relief.

	Acknowledgments

 
This work was supported by grants from the National Science Council (NSC 86-2314-B-016-071) and National Health Research Institute (DOH 87-HR-402) of Taiwan, Republic of China.

We thank Mr. Richard Shih-Shien Chou for his editorial assistance.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Joris J, Cigarini I, Legrand M, et al. Metabolic and respiratory changes after cholecystectomy performed via laparotomy or laparoscopy. Br J Anaesth 1992;69:341–5.[Abstract/Free Full Text]
2. Liu J, Ding Y, White PF, et al. Effects of ketorolac on postoperative analgesia and ventilatory function after laparoscopic cholecystectomy. Anesth Analg 1993;76:1061–6.[Abstract/Free Full Text]
3. Joris J, Thirty E, Paris P, et al. Pain after laparoscopic cholecystectomy: characteristics and effect of intraperitoneal bupivacaine. Anesth Analg 1995;81:379–84.[Abstract]
4. Fredman B, Jedeikin R, Olsfanger D, et al. Residual pneumoperitoneum: a cause of postoperative pain after laparoscopic cholecystectomy. Anesth Analg 1994;79:152–4.[Abstract/Free Full Text]
5. Woolf CJ, Chong MS. Preemptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362–79.[Web of Science][Medline]
6. Kawamata T, Omote K, Kawamata M, et al. Premedication with oral dextromethorphan reduces postoperative pain after tonsillectomy. Anesth Analg 1998;86:594–7.[Abstract]
7. Dickenson AH. A cure for wind up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol Sci 1990;11:307–9.[Medline]
8. Dickenson AH, Sullivan AF. Differential effects of excitatory amino-acid antagonists on dorsal horn nociceptive neurons in the rat. Brain Res 1990;506:31–9.[Web of Science][Medline]
9. Wong CS, Lu CC, Cherng CH, Ho ST. Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement. Can J Anaesth 1997;44:31–7.[Web of Science][Medline]
10. Price DD, Mao J, Frenk H, et al. The N-methyl-D-aspartate receptor antagonist dextromethorphan selectively reduce temporal summation of second pain in man. Pain 1994;59:165–74.[Web of Science][Medline]
11. Ilkjaer S, Dirks J, Wernberg W, et al. Effect of systemic N-methyl-aspartate receptor antagonist (dextromethorphan) on primary and secondary hyperalgesia in humans. Br J Anaesth 1997;79:600–5.[Abstract/Free Full Text]
12. Wu CT, Yu JC, Liu ST, et al. Preincisional dextromethorphan treatment provides a better postoperative pain management in upper abdominal surgery. World J Surg. In press.
13. Kauppila T, Gronrooa M, Pertovaara A. An attempt to attenuate experimental pain in humans by dextromethorphan, an NMDA receptor antagonist. Pharmacol Biochem Behav 1995;52:641–4.[Web of Science][Medline]
14. McQuay HJ, Caroll D, Jadad AR, et al. Dextromethorphan for the treatment of neuropathic pain: a double-blind randomized controlled crossover trial with integral n-of-1 design. Pain 1994;59:127–33.[Web of Science][Medline]
15. Grace RF, Power I, Umedaly H, et al. Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparotomy. Anesth Analg 1998;87:1135–8.[Abstract/Free Full Text]
16. McConaghy PM, McSorley P, McCaughey W, Campbell WI. Dextromethorphan and pain after total abdominal hysterectomy. Anaesth 1998;81:731–6.
17. Bem JL, Peck R. Dextromethorphan: an overview of safety issues. Drug Safety 1992;7:190–9.[Web of Science][Medline]
18. Tal M, Bennett GJ. Dextrorphan relieves neuropathic heat-evoked hyperalgesia in the rat. Neurosci Lett 1993;151:107–10.[Web of Science][Medline]
19. Netzer R, Pflimlin P, Trube G. Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. Eur J Pharmacol 1993;238:209–16.[Web of Science][Medline]
20. Elliot KJ, Brodsky M, Hynansky AD, et al. Dextromethorphan suppresses both formalin-induced nociceptive behavior and the formalin-induced increase in spinal cord c-fos mRNA. Pain 1995;61:401–9.[Web of Science][Medline]
21. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurons following C-fibre stimulation. Neuropharmacology 1987;26:1235–8.[Web of Science][Medline]
22. Davies SN, Lodge D. Evidence for involvement of N-methyl-D-aspartate receptors in "wind-up" of class 2 neurones in the dorsal horn of the rat. Brain Res 1987;424:402–6.[Web of Science][Medline]
23. Woolf CJ. Recent advances in the pathophysiology of acute pain. Br J Anaesth 1989;63:139–46.[Free Full Text]
24. Wills RJ, Martin KS. Dextromethorphan/dextrorphan disposition in rat plasma and brain [abstract]. Pharm Res 1988;5:S193.
25. Nelson KA, Park KM, Robinovitz E, et al. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology 1997;48:1212–8.[Abstract]

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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