Postoperative pain is a major factor that affects recovery from anesthesia and surgery. Given the multiplicity of mechanisms involved in postoperative pain, a multimodal analgesia regimen using a combination of opioid and non-opioid analgesics has become the treatment of choice for facilitating the recovery process (1). Before its withdrawal from the market, the long-acting cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, had become a popular adjuvant for reducing postoperative pain and opioid analgesic requirement, as well as for improving the quality of recovery after a wide variety of surgical procedures (2–8).
Gabapentin, an anticonvulsant drug, was initially reported to be effective in treating neuropathic pain (9) and diabetic neuropathy (10). Although postoperative pain is typically regarded as a type of nociceptive pain involving peripheral mechanoreceptor stimulation, it is clear that inflammatory, neurogenic, and visceral mechanisms also contribute to acute pain symptoms. Recently, it has been suggested that postoperative pain can be associated with a transient, reversible type of neuropathic pain (11). An animal study demonstrated that gabapentin could reduce visceral nociception (12). Early clinical studies of surgical patients suggested that preoperative administration of gabapentin decreased postoperative pain scores and opioid analgesic requirements after mastectomy (13,14), spinal surgery (15), and otolaryngologic surgery (16).
Analogous to the COX-2 inhibitors, gabapentin appears to be effective in reducing postoperative pain and opioid analgesic requirement in clinical pain models (2–8,13–16). However, their comparative effects on clinically relevant outcome measures have not been previously investigated. This double-blind, placebo-controlled study was designed to compare the perioperative effect of gabapentin (1.2 g/d PO) with rofecoxib (50 mg/d PO) alone and in combination on postoperative pain scores and opioid analgesic requirements. The secondary objectives of this study were to examine the effect of these drugs on recovery of bowel function, resumption of normal activities, quality of recovery, and patient satisfaction after lower abdominal surgery.
After obtaining approval of the Institutional Ethics Committee at Trakya University in Edirne, Turkey, and written informed consent, 100 patients undergoing elective abdominal hysterectomy with salpingo-oophorectomy were enrolled in this study. Patients were eligible for enrollment in the study if they were at least 18 yr old, willing to comply with the postoperative follow-up evaluations, within 50% of ideal body weight, had no clinically significant cardiovascular or central nervous system disease, and could operate a patient-controlled analgesia (PCA) device. Exclusion criteria were known allergy to any of the study medications, contraindications to the use of PCA morphine or any of the anesthetic drugs, renal insufficiency, peptic ulcer disease, as well as a history of bleeding diathesis or drug abuse.
The patients were randomly assigned to one of four treatment groups using a computer-generated table. Group 1 (control) received oral placebo capsules and pills, Group 2 (rofecoxib) received oral placebo capsules and rofecoxib 50 mg (Vioxx™; Merck Sharp and Dohme Pty Ltd., South Granville, NSW, Australia), Group 3 (gabapentin) received oral gabapentin 1.2 g (Neurontin™; Pfizer, Goedecke GmbH, Germany) and placebo pills, and Group 4 (combination) received oral gabapentin 1.2 g and rofecoxib 50 mg. The initial dose of the study medication was administered 1 h before surgery. The same dosage regimens were administered at 09:00 on the first and second postoperative days (POD). All study drugs were prepared by the hospital pharmacy, and an appropriate code number was assigned to each patient.
All patients were premedicated with midazolam 0.07 mg/kg IM 45 min before the surgical procedure. On arrival in the operating room, a crystalloid IV infusion was started, and baseline mean arterial blood pressure, heart rate, and peripheral oxygen saturation values were obtained using standard monitors. Anesthesia was induced with propofol (2 mg/kg IV) and atracurium (0.5 mg/kg IV) and was initially maintained with sevoflurane 1.5% inspired at a fresh gas flow rate of 2 L/min in combination with nitrous oxide 50% in oxygen. Fentanyl, 2 μg/kg IV, was administered 3–5 min before the surgical incision. The operation was performed via a Pfannenstiel incision. After endotracheal intubation, all patients' lungs were mechanically ventilated to maintain the end-expiratory CO2 values between 34–36 mm Hg. Morphine, 2 mg IV, was administered immediately before discontinuing sevoflurane and nitrous oxide. At the start of skin closure, residual neuromuscular blockade was antagonized with neostigmine, 1.5 mg IV, and atropine, 0.5 mg IV.
After tracheal extubation and on awakening from anesthesia, patients were transferred to the postanesthesia care unit (PACU). Assessment of postoperative pain was performed using an 11-point verbal rating scale (VRS), with 0 = no pain and 10 = worst pain imaginable. After arrival in the PACU, patients were connected to a PCA device and postoperative analgesia was provided using 2 mg IV bolus injections of morphine at a lockout interval of 10 min and with a maximum 4-h limit of 40 mg. The incremental bolus dose of morphine was increased to 3 mg if analgesia was inadequate (VRS pain score >5) after the first hour of PCA use. Sedation was assessed using an 11-point VRS, with 0 = no sleepiness or drowsiness to 10 = almost asleep or extremely drowsy. Assessments of pain, sedation, opioid usage, and side effects were performed at 1, 4, 8, 12, 16, 20, 24, 30, 36, 42, 48, 60, and 72 h intervals after arrival in the PACU by a research assistant blinded as to the group allocation. The PCA device was discontinued when the patient made no demands for the opioid analgesic in the preceding 4-h interval. Oral analgesia was provided using acetaminophen 500 mg in combination with codeine 30 mg PO q 6–8 h, on demand. The occurrence of postoperative side effects (e.g., nausea and vomiting, constipation, dizziness, drowsiness, peripheral edema, diarrhea, headache, and pruritus) were recorded at 24, 48, and 72 h follow-up intervals. Assessment of postoperative pain was made both while resting in bed and with activity (i.e., on assuming the sitting position). If the patient experienced sustained nausea or vomiting lasting longer than 5 min, ondansetron (4 mg IV) was administered.
Before the start of the study, patients were instructed to write down the exact time they first passed flatus and experienced their first bowel movement after surgery. In addition, when the research assistant assessed their pain, they also asked each patient whether they had passed flatus or had experienced a bowel movement. The surgeons oscutated the abdomen for bowel sounds twice daily and documented the presence or absence of bowel sounds in the patient's chart. The times to resumption of oral dietary intake and unassisted ambulation were also evaluated at regular 2-h intervals during the day by the blinded research assistant. At 24-h intervals after the operation, patients were assessed as to their readiness for discharge from the hospital using the following discharge criteria: 1) normal defecation and no urinary retention; 2) ability to mobilize and dress without assistance; 3) pain was adequately controlled with oral analgesics (VRS pain score <5); and 4) lack of any surgical complications. The length of the hospital stay was also recorded.
Patient satisfaction with the postoperative pain management was assessed using a 100-point VRS, with 1 = highly dissatisfied to 100 = completely satisfied. All measurements were recorded by a research assistant who was blinded as to the study medication. At the time of discharge from the hospital, all patients were asked to assess their quality of recovery using a standardized 18-point questionnaire (17). Patients were also contacted by one of the investigators on POD 7 and at 3 mo after discharge to inquire as to when they were able to resume normal activities of daily living (i.e., return to work) and whether they had any residual postoperative (incisional) pain.
A sample size of 25 patients per group was calculated to be required to detect a significant difference of 20% or more in PCA morphine consumption (usage) with a power of 80% and a significance level of 0.05. Using a computer-generated random numbers table, 100 consecutive numbers were assigned to one of the four treatment groups. All variables were tested for normal distribution using the Kolmogorov-Smirnov test. Normal distributed variables are expressed as mean (± sd), or median (IQR: 25th/75th percentile) values. For measured times, differences among the four groups in normal distributed variables were determined by one-way analysis of variance, and for non-normally distributed variables, the Kruskal-Wallis Z-test was used. Multiple comparisons for homogenous variances were performed using the Tukey HSD test and for non-homogenous variances, Tamhane tests were used for post hoc testing. For differences in nominal (or ordinal) variables, χ2 test was used. P values <0.05 were considered statistically significant.
From October 1, 2003 to September 1, 2004, 196 patients were assessed for study eligibility (43 patients failed to meet the inclusion criteria and 53 patients refused to sign the consent form). The remaining 100 consenting patients who fulfilled the entry criteria were enrolled in this study. All patients were able to complete the entire study and their data were included in the final analysis. The four groups were comparable with respect to age, body weight, height, ASA physical status, and duration of surgery (Table 1). The mean arterial blood pressure, heart rate, oxygen saturation, and respiratory rate values did not differ among the groups at any of the measured time intervals (data not reported). Sedation scores were also similar among the four groups at all the measured time intervals (data not reported).
The VRS pain scores at rest were significantly lower in Groups 2, 3, and 4 compared with the control (placebo) at 4 h (P < 0.05, P < 0.01, P < 0.05, respectively), 8 h (P < 0.001), 16 h (P < 0.05, P < 0.001, P < 0.05, respectively), and 20 h (P < 0.05) postoperatively and in Groups 3 and 4 at 12 h (P < 0.001) and 24 h (P < 0.05). The VRS pain scores with movement were also significantly lower in Group 3 at 4 h (P < 0.01), in Groups 2, 3, and 4 at 8 h (P < 0.001, P < 0.001, P < 0.05, respectively) and in Groups 2 and 3 at 20 h (P < 0.05) compared with Group 1. Compared with the control group, PCA morphine requirement was significantly reduced in all 3 analgesic treatment groups at 1, 8, 24, and 30 h after surgery (Fig. 1). In addition, total PCA morphine use was decreased by 43%, 24%, and 50% in Groups 2, 3, and 4, respectively, compared with Group 1 (Fig. 1). During the 36-h follow-up period, patients in Group 4 required IV opioid analgesics for a shorter period of time compared with Group 1 (Table 2). Oral analgesic consumption was also smaller in Groups 2 and 4 compared with Group 1 (Table 2). Return of bowel sounds and passage of flatus occurred earlier in the three analgesic treatment groups (Table 2). Resumption of oral intake occurred earlier in the gabapentin (versus placebo) group. However, ambulation and hospitalization times, as well as the quality of recovery scores, were not significantly different among the four groups (Table 2).
Discharge eligibility scores in Groups 2 and 4 were improved at 24 h compared with Group 1 (Table 2). Although patients in the 3 analgesic treatment groups were discharged an average of 1 day earlier and returned to work 2–3 days sooner than patients in the control group, this difference failed to achieve statistical significance (Table 2). Patient satisfaction with postoperative pain management was significantly higher at 24 h in Groups 2, 3, and 4 compared with the control group. However, at 48 h and 72 h only Group 4 had significantly higher satisfaction scores (Table 3). At the 72-h follow-up, all of the patients in Group 4 were completely satisfied with pain management compared with only 32%, 64%, and 72% in Groups 1, 2, and 3, respectively.
The most common side effects during the postoperative period were nausea and vomiting (Table 3). The incidence of nausea was significantly less frequent in Group 4 compared with Group 1 (Table 3). Not surprisingly, antiemetic usage was also significantly reduced in the combination (versus placebo) group. The incidences of incisional pain (4%–8%) at the 3-mo follow-up evaluation were similar in all four groups.
Perioperative administration of the COX-2 inhibitor, rofecoxib, and the anticonvulsant, gabapentin, as part of a multimodal analgesic regimen with PCA morphine, led to improved pain control and reduced opioid-related side effects. Moreover, the use of the combination of the two non-opioid analgesics was marginally better than either drug alone. Given the recent withdrawal of rofecoxib from the market because of cardiovascular side effects with chronic usage and serious concerns regarding postoperative complications with parecoxib and valdecoxib in patients undergoing cardiac surgery (18,19), these data suggest that gabapentin could prove to be a cost-effective alternative to the COX-2 inhibitors. The acquisition cost for a rofecoxib (25-mg) pill was $3.16, and a gabapentin (400 mg) capsule cost $1.88. Therefore, the total cost of the study medication administered over the 3-day period was $18.96, $16.92, and $35.88 USD in Groups 2, 3, and 4, respectively.
Recent studies reported that perioperative rofecoxib improved early recovery (6) and postdischarge clinical outcomes when it was administered for a more extended period of time after discharge (5). Even a single preoperative dose produced a beneficial effect in the early postoperative period after orthopedic (2), otolaryngologic (3,4), and lower abdominal (7,8) surgery. Although celecoxib, 200 mg PO, was less effective than rofecoxib, 50 mg PO (2,20,21), the use of a larger dose of celecoxib (400 mg/d PO) provided analgesic effects comparable to those of rofecoxib in reducing postoperative pain (22). Using animal models of postoperative pain, Kroin et al. (23) reported that the spinal effects of the COX-2 inhibitors reduced postoperative pain and the need for opioid analgesics.
Gabapentin has been successfully used for treating neuropathic pain syndromes (9,10). Clinical studies involving the use of gabapentin for the prevention of postoperative pain (13–16) suggest that gabapentin (and pregabalin) may also be useful in the perioperative period (11). A recent study comparing gabapentin 1800 mg, rofecoxib 50 mg, or a combination of the two drugs in hysterectomy patients revealed that the drug combination was superior to either drug alone with respect to reducing postoperative pain, opioid-sparing effects, and accelerating pulmonary recovery (24). In the current study, the combination of perioperative rofecoxib (50 mg PO) and gabapentin (1.2 g PO) provided additional improvement in patient satisfaction with pain management. However, there was no significant benefit compared with similar doses of these drugs when administered alone with respect to other outcome measures (e.g., quality of recovery scores, recovery of bowel function, and resumption of normal activities).
Analogous to the COX-2 inhibitors, animal experiments suggest that the antinociceptive effects of gabapentin correlated with the suppression of noxious-evoked release of excitatory amino acids in the spinal cord (12). The current study supports the previous studies suggesting that gabapentin may be a useful adjuvant to parenteral opioid analgesics in the postoperative period (13–16,24). The opioid-sparing effects of gabapentin appear to facilitate recovery of bowel function and may allow patients to more rapidly resume normal activities of daily living. Compared with the control group, hospital discharge and return to work occurred an average of 1 day and 2–3 days earlier, respectively, in the 3 analgesic treatment groups. Unfortunately, these differences failed to achieve statistical significance because the study was not adequately powered to find differences in these important secondary outcome measures. The sudden withdrawal of rofecoxib from the market precluded us from enrolling additional patients in this study. Of interest, the benefit of perioperative use of these non-opioid analgesics in patients undergoing lower abdominal surgery appears to be less impressive for improving clinical outcomes than in patients undergoing major orthopedic procedures (e.g., total knee arthroplasty) (5).
As a result of the recent withdrawal of rofecoxib, parecoxib, and valdecoxib as the result of concerns regarding cardiovascular and wound complications, practitioners are searching for alternatives to the COX-2 inhibitors for minimizing postoperative pain and the need for opioid analgesics (25). It is possible that gabapentin may prove to be a good alternative to the currently available oral and IV COX-2 inhibitors in the perioperative period. Furthermore, administration of gabapentin in divided doses (versus a single daily dose) would be expected to further enhance its analgesic efficacy because the elimination half-life of gabapentin is only 5–7 hours (26).
One deficiency of the current study design relates to the arbitrarily chosen dosages of the study medications. However, the maximum recommended doses of the two study drugs were used. Another possible criticism relates to the fact that the study population involved only female patients undergoing lower abdominal surgery. Further comparative studies are clearly needed in other surgical populations (e.g., orthopedic). Finally, a formal cost-effectiveness analysis is needed to determine if gabapentin would be a useful component of a standard multimodal analgesic regimen for minimizing postoperative pain and facilitating an earlier recovery and improved rehabilitation after elective surgery.
In summary, perioperative administration of gabapentin (1.2 g/d) was similar to the COX-2 inhibitor rofecoxib (50 mg/d) for improving pain control and decreasing opioid consumption in the postoperative period after lower abdominal surgery. The use of a combination of the two drugs provided additional improvement in patient satisfaction with postoperative pain management.
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© 2006 International Anesthesia Research Society
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