Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist. It is rapidly metabolized in the liver (1), where it is transformed to dextrorphan. As an NMDAR antagonist (2), dextrorphan is an active and more potent derivative. Clinical studies documented that side effects might be mediated by this metabolite acting at the phencyclidine receptor site rather than by DM directly (3). DM has a long history of clinical use with an established safety record (4). In our previous studies, we had found that preincisional IM treatment with 40 mg of DM provided a preemptive analgesic effect in patients who underwent upper abdominal surgery, laparoscopic cholecystectomy, hemorrhoidectomy, and modified radical mastectomy (5–8). Thoracic epidural anesthesia (TEA) and analgesia have been reported to reduce postoperative pain (9,10). Moreover, multimodal analgesia is regarded as the current trend in postoperative pain management (11).
Colonic surgery is associated with severe postoperative pain. In addition, the use of traditional drugs such as opioids for postoperative pain contributes to ileus (12). The purpose of this study was to assess the effect of preoperative administration of DM in combination with intraoperative TEA and postoperative patient-controlled epidural analgesia (PCEA) on postoperative pain and bowel function in patients undergoing elective colonic surgery.
This study was approved by our IRB. Written informed consent was obtained from all patients enrolled in the study. The inclusion criteria were: 1) ASA physical status I or II patients; 2) aged 18–80 yr, scheduled for elective colonic surgery. The exclusion criteria were: 1) patients who had received opioids, corticosteroids, or nonsteroidal antiinflammatory drugs within 1 wk of surgery; 2) patients who were receiving chronic anticoagulation therapy or were contraindicated to receive epidural block; 3) patients with a history of allergic reaction to local anesthetics, opioids, chlorpheniramine maleate (CPM), or DM; 4) patients unable to comprehend the concept of visual analog pain scale (VAS) or use PCEA. All surgical and anesthetic procedures were performed by the same teams. A third party provided a preassigned ballot to randomize patients into three equal-sized treatment groups. Treatment assignment was not revealed to the patient or any clinical personnel involved in the study.
Ninety patients were enrolled and randomized into three equal groups. The CPM-general anesthesia (GA) group (n = 30) received 20 mg of IM CPM 30 min before the incision and received GA. The CPM-TEA group (n = 30) received 20 mg of IM CPM followed by GA and TEA intraoperatively, whereas the DM-TEA group received 40 mg of IM DM (containing 20 mg of CPM) 30 min before the incision, followed by GA and TEA. The commercially available 1 ampule of DM consists of a mixture of 10 mg of DM and 5 mg of CPM. Hence, all patients received 20 mg of CPM as a baseline.
After the preoperative visit by the anesthesiologist, all patients received a thoracic epidural catheter placed at the T6–12 interspaces and advanced 3–4 cm cephalad. A test dose of 1% lidocaine (10 mL) was used to confirm the location of the catheter. Patients were familiarized with the VAS and instructed on the use of the PCEA pump (Pain Management Provider; Abbott, Chicago, IL).
GA was induced with an IV administration of fentanyl (2 μg/kg), atracurium (5 mg), thiopental (3–5 mg/kg), and lidocaine (1.5 mg/kg). Tracheal intubation was facilitated with succinylcholine (1.5 mg/kg). Anesthesia was maintained with desflurane in oxygen (300 mL/min) via a total closed-circuit system. The end-tidal desflurane concentration was controlled to maintain the systolic blood pressure within the range of 20% of the basal systolic pressure. Respiratory rate and tidal volume were adjusted to maintain the end-tidal carbon dioxide level at 35–45 mm Hg. The esophageal temperature was maintained at 35°–37°C with a body warmer.
After induction, the CPM-GA group received 10 mL of normal saline via a thoracic epidural catheter, maintained at 10 mL/h intraoperatively. The CPM-TEA and DM-TEA groups received 8–10 mL of 2% lidocaine bolus with continuous infusion at the rate of 8–10 mL/h (2% lidocaine). The continuous infusion was started 30 min after the bolus dose and terminated at the end of surgery.
For fluid therapy, all patients received balanced salt solution at a rate of 6–10 mL · kg−1 · h−1 perioperatively and 2 mL · kg−1 · h−1 postoperatively. No additional opioids were given during the operation. Standard monitors included pulse oximetry, electrocardiography, and noninvasive arterial blood pressure. At the end of surgery, residual neuromuscular block was reversed with edrophonium (0.8 mg/kg) and atropine (0.01 mg/kg), and the endotracheal tube was removed when the patient started to breathe spontaneously and smoothly.
On arrival to the postanesthesia care unit, all patients were given a PCEA pump and received an initial dose of 10 mL of PCEA solution containing 0.2% ropivacaine and 0.1 mg/mL morphine sulfate with the first trigger. The subsequent PCEA dose was set at 4 mL volume with a lockout time of 15 min without 4-h limit or continuous basal infusion. A 10-cm VAS with end points labeled “no pain” and “worst possible pain” was used to assess pain intensity at rest and with cough at 1, 2, 4, 8, 24, 48, and 72 h postoperatively. Patients were instructed to use the PCEA to achieve a resting VAS ≤ 3. We recorded the time to first PCEA trigger (the patient’s first use of analgesic), total number of PCEA uses and dose delivered, the time to first passage of flatus, and side effects related to morphine (drowsiness, dizziness, nausea, vomiting, and pruritus) for 72 h after the operation. Side effects were treated as necessary. All postoperative observations were made by a study nurse blinded to treatment.
Descriptive data were expressed as mean ± sd or number and percent. Differences in numeric measures among the three groups, including end-tidal desflurane concentration, time to first PCEA use, total PCEA volume, time to first flatus, and length of hospital stay were compared with analysis of variance, followed by post hoc pairwise tests using the Tukey-Kramer adjustment for multiple comparisons. Results were confirmed with the Kruskal-Wallis test to guard against non-normality violations. Pearson’s exact χ2 test was used to compare proportions among groups (gender, rate of side effects). To compare groups’ VAS pain scores over time, a mixed-model repeated-measures analysis of variance (SAS Proc Mixed) was used. Hours were treated categorically to allow post hoc group comparisons at separate times with the Tukey-Kramer adjustment for all multiple comparisons. A follow-up analysis treating hours numerically and nonparametric comparisons using the Kruskal-Wallis test were also conducted to confirm results. All analyses were done with SAS® version 9.1 software (SAS Institute, Cary, NC). An α level of 0.05 after adjustment for multiple comparisons was considered significant.
The groups were similar in age, body weight, height, sex, and duration of surgery. The average end-tidal desflurane concentration was significantly smaller in the TEA groups (3.9% ± 0.2% and 4.1% ± 0.2% versus 6.9% ± 0.3%; P < 0.001, Table 1) likely because of the analgesic effect of the TEA. The DM-TEA group reported coughing VAS pain scores significantly lower than the other 2 groups through the first 24 h postoperatively (all P < 0.001; Fig. 1). The CPM-TEA group patients also experienced lower coughing pain scores than the CPM-GA group during the first 2 h after operation (both P < 0.001; Fig. 1). Although the resting postoperative pain intensity did not differ among groups (data not shown), patients in the DM-TEA and CPM-TEA groups required a significantly smaller amount of PCEA to achieve a similar level of analgesia. The DM-TEA group used a total volume of 47.1 ± 4.4 mL of analgesics during the first 72 h compared with 62.7 ± 7.7 mL in the CPM-TEA group and 87.9 ± 12.1 mL in the CPM-GA group (all P < 0.001; Table 2). The number of PCEA delivered in all three groups was different on the first postoperative day; after that, on days two and three, the two TEA groups were significantly less than the GA group (Fig. 2). There were similar significant differences among all 3 groups in the time to first PCEA demand; 76.5 ± 12.0, 36.0 ± 7.5, and 15.3 ± 5.0 min for the DM-TEA, CPM-TEA, and CPM-GA groups, respectively (all P < 0.001; Table 2). In addition, there were significant differences among groups in the time to first passage of flatus: 40.8 ± 7.8, 55.5 ± 7.2, and 66.5 ± 7.8 h for the DM-TEA, CPM-TEA, and CPM-GA groups, respectively (Table 2). The occurrence of morphine-related side effects (e.g., drowsiness, dizziness, nausea, vomiting, and pruritus) were observed in 10, 10, and 16 patients in the DM-TEA, CPM-TEA, and CPM-GA groups, respectively (not significant; Table 2). There was no significant difference in hospital stay (Table 2) and no DM- or CPM-related side effects were observed during the 72-h observation period.
Our study shows that the preincisional administration of 40 mg of IM DM, the NMDA antagonist, combined with intraoperative administration of 2% lidocaine via thoracic epidural catheter resulted in significantly less postoperative pain, longer time to first PCEA demand, less PCEA consumption over each of the 3 days postoperatively, and facilitated recovery of bowel function. The improved analgesia is consistent with the previous studies (5–7,13–15) that reported a postoperative opioid-sparing effect of the NMDAR antagonist. We further support the use of DM as a multimodal analgesic adjuvant to improve the quality of postoperative pain management, with less opioid and fewer opioid-related side effects (16).
Both pain and opioid can diminish bowel function and cause ileus postoperatively. To some degree, improved analgesia and significant opioid-sparing effects by themselves decrease the risk of postoperative ileus. But the remarkable improvement in bowel function exhibited with the addition of preincisional DM (DM-TEA) over the epidural group (CPM-TEA) was unexpected. Whether this was a result of synergism between local anesthetics and NMDAR antagonist is not clear. The interaction between DM and local anesthetics is yet to be clearly defined. However, the anecdotal clinical evidence does point toward existence of such an effect (15,17). DM has a role in preventing central sensitization by antagonizing NMDARs (5–7). Nagy and Woolf (18) observed that local anesthetics can selectively reduce C fiber-evoked neuronal activity in rats and subsequently the nociceptive transmission in the spinal cord by decreasing NMDAR activity. The local anesthetics administered via intraoperative TEA and postoperative PCEA may have influenced receptors which were targeted by DM to produce synergistic analgesia on both somatic and visceral pain at the spinal level (15,19,20). Furthermore, in previous studies, the preemptive epidural analgesic regimen combining ketamine, morphine, and bupivacaine provided superior analgesia after upper abdominal surgery and total knee replacement (21,22). Thus, it is conceivable that local anesthetics given intraoperatively via TEA and postoperatively via PCEA augmented the NMDAR antagonizing effect of DM. In addition, Hirota et al. (23) reported the possible interaction of local anesthetics with various recombinant opioid receptors. Hence, a synergistic relationship among NMDAR, opioid receptors, and local anesthetics may explain the enhanced postoperative analgesia and prompt return of bowel function as shown in the DM-TEA group. However, these benefits were less apparent on postoperative days two and three evidenced by the VAS score with coughing (Fig. 1) and the frequency of PCEA use (Fig. 2). These smaller group differences may have been caused by the diminishing effect of preincisional DM.
Some of these effects are indeed attributable to intraoperative use of TEA, as the time to first use PCEA was more than double for the CPM-TEA group compared with the CPM-GA group (Table 2); there were corresponding reductions in the amount of PCEA use as well as in the time to first passage of flatus. Local anesthetic infusion via a thoracic epidural catheter is expected to enhance analgesia and promote peristalsis via sympathetic blockade and activation of parasympathetic activity of the gut. Von Dossow et al. (24) demonstrated that the combination of a GA and regional anesthesia technique preempted perioperative pain and temporarily reduced the level of stress hormones, anxiety, and depression compared with GA alone (25,26). In addition to the potentially beneficial effects of blocking nociceptive afferent and sympathetic efferent fibers, the systemic absorption of local anesthetic may also contribute to reducing the duration of postoperative ileus (10). Our results were consistent with these previous reports showing that TEA and analgesia provide good pain relief and improve recovery of bowel function.
Although bowel function was restored significantly earlier in the DM-TEA and CPM-TEA groups, the discharge from hospital was similar for both groups. This is because patients who were ready for their discharge were kept in the hospital by surgical convention for removal of sutures and patient expectation for length of stay.
A potential limitation of our study was that CPM might have provided a sedative effect and delayed the first trigger time for patients in the control group who received CPM 20 mg. However, all patients in the study groups received CPM 20 mg, and the first trigger times were longer than the control group. Therefore, the effect of CPM could not account for our results. Intravenous DM is thought to cause more frequent side effects (such as hypotension and tachycardia) because of rapid formation of dextrorphan, the metabolite of DM (3,27). Therefore, IM administration may provide a more stable hemodynamic profile before patients undergo GA. Based on our previous experience (5–8), the IM administration of DM has minimal side effects.
The aim of this study was to evaluate a single preincisional dose effect of DM on postoperative analgesia and colonic function when combined with TEA. Our study showed that the analgesic benefit of DM was manifested only during the first 24 hours postoperatively. Therefore, further study is necessary to evaluate the optimal continuous IV dosage of DM to sustain analgesia, early recovery of bowel function, and analgesic-sparing effect with minimal side effects.
In conclusion, the combination of preincisional IM DM 40 mg with TEA and postoperative PCEA provides superior postoperative pain control and accelerated recovery of bowel function after colonic surgery. These findings further support the role of DM, an NMDA antagonist, as a part of a multimodal analgesic regimen to enhance postoperative analgesia and to prevent postoperative ileus or obstruction, perhaps in a synergistic manner with local anesthetics and opioids.
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