Nonsteroidal antiinflammatory drugs (NSAIDs) are often administered as part of a multimodal analgesic regimen for both treating and preventing pain after ambulatory surgery (1). For example, ketorolac has been reported to be effective in reducing postoperative pain and opioid analgesic requirements, as well as in facilitating an earlier discharge after anorectal surgery (2). However, concern regarding the use of nonselective NSAIDs such as ketorolac during the perioperative period relates to the possibility of increasing the risk of operative site and gastrointestinal mucosal bleeding (3) caused by blockade of prostaglandin synthesis at the cyclooxygenase (COX)-1 site (4).
Preliminary studies with the COX-2 selective inhibitors have suggested that they can improve pain control after dental (5,6), orthopedic (7), and otolaryngologic (ears, nose, and throat [ENT]) surgery (8–11). Recent studies have demonstrated that preoperative rofecoxib (50 mg per os [PO]) significantly decreases postoperative pain and improves patient satisfaction with pain management after outpatient ENT surgery (9,10). However, questions remain regarding the efficacy of perioperative COX-2 inhibitors in decreasing the time to discharge and in improving the later recovery processes and facilitating the resumption of normal activities of daily living (8–14).
Therefore, we designed this randomized, double-blind, placebo-controlled study to test the hypothesis that perioperative administration of rofecoxib (50 mg PO) would lead to an earlier hospital discharge and resumption of normal activities after outpatient inguinal herniorrhaphy procedures.
After obtaining IRB approval at Cedars-Sinai Medical Center and written informed consent, 60 ASA physical status I–III outpatients (18–75 yr) undergoing inguinal hernia repair procedures were studied according to a randomized, double-blind, placebo-controlled protocol. Patients were excluded if they had an allergy or contraindication to NSAIDs, chronically used NSAIDs, had received any analgesic medication within a 12-h period before the operation, were pregnant or breast-feeding, had a history of alcohol or drug abuse, had a bleeding disorder, or had clinically significant neurologic, cardiovascular, renal, hepatic, or gastrointestinal diseases.
In the preoperative holding area, patients completed baseline 11-point verbal rating scales (VRSs) for pain and nausea, with 0 = none to 10 = worst imaginable. The patients were randomly assigned to either the control (vitamin C, 500 mg) or the rofecoxib (rofecoxib, 50 mg) group. The study medication was prepared by an operating room pharmacist according to a computer-generated random number schedule and the first dose was administered with 5–10 mL of water 30–40 min before entering the operating room. A second dose of the same medication was given on the morning of the first postoperative day. The patients, observers, and anesthesiologists directly involved in the patient’s care were blinded as to the content of the oral study medication.
All patients received midazolam, 1–2 mg IV, in the preoperative holding area. Upon arrival in the operating room, standard monitoring devices were applied, including the electroencephalographic bispectral index monitor. The mean arterial blood pressure, heart rate, and hemoglobin oxygen saturation were recorded at 5-min intervals during surgery. Anesthesia was induced with propofol, 1.5–2.5 mg/kg IV, and followed by an initial propofol infusion rate of 100 μg · kg−1 · min−1, in combination with nitrous oxide 67% in oxygen for maintenance of anesthesia. The propofol infusion rate was subsequently adjusted to maintain a bispectral index value between 50 and 60. All patients were allowed to breathe spontaneously via a face mask or laryngeal mask airway, and a local anesthetic solution consisting of a 50:50 mixture of generic lidocaine 2% and bupivacaine 0.5% was injected at the incision site by the surgeon both before the skin incision and before skin closure. No opioid analgesics were administered during the operation. The maintenance anesthetic drugs were discontinued at skin closure. After applying the surgical dressing, all patients were transferred directly to the postanesthesia care unit (PACU).
Anesthesia (from induction of anesthesia to discontinuation of the propofol infusion and nitrous oxide) and surgery (from incision to placement of the surgical dressing) times were recorded. The times at which patients opened their eyes, followed simple commands (e.g., squeeze the investigator’s hand), and were oriented to person, time, and place, were assessed at 1-min intervals. The times to sitting up, standing, ambulating, and tolerating oral fluids, as well as actual discharge times, were assessed at 10-min intervals. All patients were discharged home directly from the PACU (i.e., PACU fast-tracking) (15). “Home readiness” was determined using standardized postanesthetic discharge criteria (16,17). Before discharge, all patients were asked to assess their quality of recovery using a standardized questionnaire (Appendix 1) (18). The discharge criteria from the ambulatory center required that patients be awake and alert with stable vital signs, able to ambulate without assistance, and were not experiencing side effects related to surgery or anesthesia.
The VRSs for pain and nausea were repeated at 30-min intervals after the end of anesthesia, immediately before administering “rescue” analgesic medication, and at the time the patient was discharged home. If patients complained of moderate-to-severe pain (VRS >3), hydromorphone, 0.1–0.2 mg IV, was administered until they no longer complained of pain. However, the PACU nurses were not required to titrate hydromorphone to achieve a specific VRS pain score. Patients with VRS pain scores of 2–3 received a combination of hydrocodone, 5 mg, and acetaminophen, 500 mg PO. If the patient complained of nausea or experienced vomiting or retching, they were treated with metoclopramide, 10 mg IV.
A trained interviewer (RQ) who was also blinded to the study medication contacted each patient by telephone at home 36 h after discharge to inquire about their maximal pain (with none = 0, mild = 1, moderate = 2, and severe = 3), global evaluation of the study medication (with poor = 0, fair = 1, good = 2, very good = 3, and excellent = 4), satisfaction with their postoperative pain management (with poor = 0, fair = 1, good = 2, very good = 3, and excellent = 4), and whether they were able to tolerate normal fluids and solid food. The patients were also contacted on postoperative days 7 and 14 to inquire as to when they were able to resume normal physical activities after surgery. The number of doses of oral analgesic medications used after discharge, and the occurrence of any postdischarge side effects were recorded in the patient’s diary. The surgeon estimated the quantity of intraoperative blood loss at the end of the operation, and the occurrence of any wound complications was noted at the 7-day follow-up evaluation.
An a priori power analysis suggested that group sizes of 30 should be adequate to detect a significant difference in the actual discharge time based on an expected length of stay of 100 min (6) in the control group, and assuming that the rofecoxib would produce a 25% or shorter reduction in the actual discharge time, with an α = 0.05 and β = 0.80 (sd = 26 min). Normally distributed continuous data were analyzed using Student’s t-test. Continuous data not normally distributed (e.g., pain scores) were analyzed by a Mann-Whitney U-test. Categorical data were analyzed using the χ2 test or Fisher’s exact test where appropriate. A P value < 0.05 was considered statistically significant. Data were presented as mean values ± sd, median values (with interquartile ranges), numbers (n), or percentages (%).
Sixty patients (n = 30 in each group) successfully completed the study. There were no significant differences between the two study groups with respect to age, ASA physical status, weight, height, gender, or durations of surgery and anesthesia. In addition, the total dosages of propofol and local anesthetics administered during the operative period were similar in the two treatment groups (Table 1).
Although the emergence times including eye opening, responding to verbal commands, and orientation did not differ between the two study groups, the times to sitting up, tolerating oral fluids, standing, ambulating, “home readiness,” and actual discharge were significantly decreased in the rofecoxib group (Table 2). More importantly, the patients’ quality of recovery score was significantly higher in the rofecoxib group at the time of discharge (Table 2). Although there was no difference in the pain score at 30 min after surgery, the pain score at 1 h was significantly lower in the rofecoxib group (Table 3). The pain scores were similar at the time patients received rescue analgesic medication; however, significantly fewer patients in the rofecoxib group required rescue analgesics (Table 3). During the 36-h follow-up period, rofecoxib-treated patients required significantly less oral analgesic medication. In addition, patients receiving rofecoxib reported a significantly lower maximal pain score and a higher global evaluation of the study medication (Table 4). The rofecoxib group also reported a significantly higher level of satisfaction with their postoperative pain management. However, the percentage of patients resuming normal activities within 36 h after surgery was similar in both groups (Table 4). Although the average times to resumption of normal activities at the follow-up evaluations were slightly shorter in the rofecoxib group, these differences failed to achieve statistical significance (Table 5).
Finally, the overall incidences of postoperative nausea and vomiting were similar in the two study groups before and after discharge (Tables 3 and 4). The average blood loss was 6 ± 2 and 6 ± 2 mL in the control and rofecoxib groups, respectively. None of the patients experienced wound complications (e.g., hematoma formation, infections) after discharge from the hospital.
Pain has been alleged to exert a major impact on the recovery process and patient satisfaction after outpatient surgery (19–21). It has been reported that acute postoperative pain can actually lead to chronic pain in 12%–47% of patients undergoing hernia surgery (22). In this study involving an adult ambulatory surgery population, the perioperative administration of rofecoxib (50 mg) was effective in reducing pain after hernia repair surgery and led to improved patient satisfaction with their pain management and quality of recovery. The time to discharge from the ambulatory surgical center was reduced by 30% in the rofecoxib group. However, later outcomes were not significantly affected by perioperative use of rofecoxib. Perhaps later outcomes would have been improved if rofecoxib had been administered 1–2 days before and/or continued for an additional 1–2 days after surgery. To exert a more profound effect on recovery of normal activities of daily living, a more aggressive multimodal approach to controlling postoperative pathophysiologic changes may also be required (23).
The COX-2 selective inhibitors have become increasingly popular in the ambulatory setting because of their analgesic efficacy (1) and absence of adverse effects on the body’s homeostatic mechanisms (24). Recent studies have reported that preoperative administration of rofecoxib has a significant opioid-sparing effect in patients undergoing both ENT (9,10) and orthopedic procedures (12–14). Rofecoxib has also been used after ambulatory surgery for treating dental (5,6) and orthopedic (7,13) surgery-related pain. The present study demonstrated that perioperative administration of rofecoxib was effective in improving postoperative pain management, and facilitating the early recovery process after outpatient inguinal herniorrhaphy procedures. Although the time to resumption of normal physical activities was achieved an average of one day earlier, this difference failed to achieve statistical significance. The inability to demonstrate differences in the later recovery end points despite the improvement in pain control suggests that other factors (e.g., surgical instructions) may have influenced outcome variables (e.g., resumption of normal diet and physical activities) after discharge home after hernia surgery.
Rofecoxib was chosen for this study because its pharmacokinetic and dynamic profile may be more suitable for perioperative use than the other available COX-2 selective drugs (5,10,13,25). In a study involving volunteers (26), rofecoxib also produced more prolonged analgesic effects than the nonselective NSAIDs ibuprofen and naproxen. Similarly, in studies involving patients undergoing dental, ENT, and orthopedic procedures, rofecoxib has consistently demonstrated clinical advantages over celecoxib in the postoperative period (5,10,13). However, a recent study involving ENT procedures suggested that preoperative administration of a larger dosage of celecoxib (400 mg PO) can improve its analgesic efficacy in the postoperative period (11).
The anesthetic technique used in this study was different from the previously published studies involving the use of rofecoxib for preventing postsurgical pain because no opioid analgesics were administered during the intraoperative period (8–10,12,14). The combination of rofecoxib (a long-acting NSAID) with bupivacaine (a long-acting local anesthetic) produced significant analgesic effects during the postdischarge period. This beneficial effect was evident in the improved pain control (e.g., lower pain scores, reduced oral analgesic requirements) and higher global satisfaction scores during the 36-hour follow-up period after the patients were discharged home. Although the overall incidence of postoperative nausea and vomiting was nonsignificantly reduced in the rofecoxib group (3% vs 13%), the use of a propofol-based anesthetic technique and the avoidance of opioid analgesics during the intraoperative period contributed to the infrequent incidence of postoperative nausea and vomiting in both treatment groups (27).
Because COX-2 inhibitors seem to lack antiplatelet activity (23,26,28), it has been suggested that rofecoxib may be associated with an improved safety profile in the perioperative period (13,29). Although we did not detect an increase in surgical blood loss or wound complications in the rofecoxib group during the perioperative period, the group sizes (n = 30) and average blood loss (6 ± 2 mL) were both too small to draw meaningful conclusions regarding the effects of the COX-2 inhibitor on bleeding diatheses during or after this surgical procedure. Of interest, Joshi et al. (30) have also recently reported that preoperative rofecoxib failed to increase blood loss in children undergoing tonsillectomy procedures.
To justify the additional cost associated with routinely administering the COX-2 inhibitor during the perioperative period, we thought it was necessary to perform a placebo-controlled study that examined both early and late (postdischarge) outcome variables. This study can also be criticized for failing to include a nonselective NSAID comparator (e.g., ketorolac or ibuprofen) or other non-opioid analgesic (e.g., acetaminophen). Recent studies (8–10) have demonstrated that oral premedication with rofecoxib (50 mg) is more effective than celecoxib (200 mg) or acetaminophen (2 g) in reducing pain after outpatient ENT surgery. However, further clinical studies are needed to compare the analgesic efficacy and safety of rofecoxib with nonselective NSAIDs (e.g., ibuprofen) in this and other elective surgical populations when administered for a more extended period before and after surgery.
In conclusion, perioperative administration of rofecoxib decreased postoperative pain and the need for analgesic rescue medication, contributing to improved patient satisfaction with the quality of recovery after outpatient hernia surgery without increasing intraoperative blood loss or postoperative wound complications. However, perioperative rofecoxib failed to facilitate the resumption of normal activities after discharge.
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