Postoperative pain continues to have a major impact on the recovery process and patient satisfaction after both ambulatory and inpatient surgery.1–3 Nonsteroidal antiinflammatory drugs (NSAIDs) are becoming increasingly popular as part of a multimodal analgesic regimen for improving the management of pain after ambulatory surgery.4 Previous studies have demonstrated that ibuprofen is useful in decreasing postoperative pain and the need for opioid analgesics after oral, dental, and gynecologic surgical procedures in the ambulatory setting.5–8 Nevertheless, concerns persist regarding the use of nonselective NSAIDs during the perioperative period because of the risk of operative site and gastrointestinal mucosal bleeding due to blockade of prostaglandin synthesis at the cyclooxygenase (COX)-1 enzyme.9,10
The more selective COX-2 inhibitors seem to be as effective as the nonselective NSAIDs for the prevention of postoperative pain and may be associated with a lower risk of operative site bleeding.11–13 However, one study14 failed to demonstrate an advantage of the COX-2 inhibitors when compared with ibuprofen in patients undergoing tonsillectomy procedures. Although the postoperative administration of COX-2 inhibitors as part of a preventative analgesic strategy has been shown to be effective in reducing postoperative pain and facilitating the postdischarge recovery process,15 the benefit of preemptive analgesia using COX-2 inhibitors has been questioned.16 Sun et al.17 failed to find any advantages of perioperative (versus postoperative) administration of celecoxib with respect to improving pain control or accelerating the recovery process after major plastic surgery procedures.
In addition, concerns have been raised regarding the use of COX-2 selective inhibitors in the perioperative period because of the occurrence of cardiovascular complications even after relatively short-term administration (10–14 days) in at-risk surgical populations.18,19 However, clinical studies have demonstrated that postoperative administration of celecoxib, 400 mg/d orally, for up to 4 days decreased postoperative pain and the need for opioid-containing analgesic medication, leading to an improved quality of recovery (QoR) after outpatient laparoscopic procedures and major plastic surgery without either operative site or cardiovascular complications.15,17
One study suggested that a single oral dose of ibuprofen 400 mg has similar analgesic efficacy to celecoxib 400 mg after dental surgery.20 Therefore, the objective of this randomized, double-blind study was to evaluate the efficacy of celecoxib (400 mg/d) and the maximum daily over-the-counter dose of ibuprofen (1200 mg/d) in decreasing postoperative pain and the need for opioid-containing rescue medication, and improving recovery outcomes compared with a placebo treatment when administered for 4 days after common ambulatory surgery procedures. The primary hypothesis was that the postoperative administration of ibuprofen or celecoxib would reduce the time to resumption of daily activities of normal living.
After obtaining IRB approval and written informed consent, 180 patients scheduled for superficial (noncavitary) surgical procedures (e.g., hernia repair, partial mastectomy, or joint arthroscopy) were enrolled in this prospective study. Patients were randomly assigned to 1 of 3 study treatment groups: group 1 = control (placebo); group 2 = celecoxib 400 mg/d; or group 3 = ibuprofen 1200 mg/d according to a computer-generated random numbers table. Patients were excluded if they had difficulty understanding English, had an allergy or contraindication to taking NSAIDs, chronically used NSAIDs, had received an opioid analgesic medication within a 12-hour 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.
Patients were asked to provide a detailed medical history and demographic information, including age, weight, height, alcohol or drug consumption, and history of smoking, postoperative nausea and vomiting, or motion sickness, and ability to perform normal physical activities of daily living. Before entering the operating room, patients completed baseline verbal rating scales (VRS) for pain and nausea, with 0 = none to 10 = severe. Upon arrival in the operating room, standard monitoring devices were applied, as well as the electroencephalographic bispectral index monitor. Hemodynamic and anesthetic variables were recorded before anesthetic administration, at 2-minute intervals from induction of anesthesia until 10 minutes after skin incision, and subsequently at 5-minute intervals until the end of the surgical procedure.
Anesthesia was induced with propofol, 1.5 to 2 mg/kg IV, after 2 mL of 1% lidocaine IV was administered to minimize propofol-induced injection pain. After a laryngeal mask airway was inserted, study patients received propofol, 150 μg/kg/min, and a 50:50 air/oxygen mixture for initial maintenance of anesthesia at a total gas flow rate of 3 L/min. The dose of propofol was subsequently adjusted between 50–200 μg/kg/min to maintain a clinically acceptable depth of anesthesia (i.e., providing good surgical conditions while maintaining a stable spontaneous respiratory rate, mean arterial blood pressure and heart rate values within 20% of the preinduction baseline values). Before the end of surgery, 4 mg IV ondansetron, 4 mg IV dexamethasone, and 10 mg IV metoclopramide were administered to all patients for antiemetic prophylaxis. Preventative analgesia was provided by 50 to 200 μg IV fentanyl and a local anesthetic solution containing a 1:1 mixture of 2% lidocaine and 0.5% bupivacaine injected at the surgical incision site before skin incision and again at the time of closure. The maintenance anesthetic was discontinued after closure of the surgical wound. Upon awakening from anesthesia (i.e., eye opening), the laryngeal mask airway device was removed. Immediately after the application of the surgical dressing, patients were transferred to the day-surgery recovery area.
The study medications (i.e., placebo capsule versus celecoxib 200-mg capsule, and placebo tablet versus ibuprofen 400-mg tablet) were prepared in identical-appearing capsules/tablets. The initial dose of study medication was administered by mouth 20 to 30 minutes after patients arrived in the postanesthesia care unit (PACU). Group 1 (placebo) received either 2 placebo capsules (matching celecoxib) or 1 placebo tablet (matching ibuprofen) in the recovery room and 1 placebo capsule or tablet at bedtime on the day of surgery, followed by 1 placebo capsule or tablet 3 times a day for 3 days after discharge. Group 2 (celecoxib) received celecoxib 400 mg (2 capsules) orally in the recovery room and 1 placebo capsule at bedtime on the day of surgery, followed by celecoxib 200 mg twice a day + placebo every day at bedtime for 3 days after surgery. Group 3 (ibuprofen) received ibuprofen 400 mg (1 tablet) orally in the recovery room and 400 mg orally at bedtime on the day of surgery, followed by 400 mg orally 3 times a day for 3 days after surgery. The patients, observers, and anesthesiologists directly involved in the patients' care were all blinded as to the content of the study medication. Patients were asked to evaluate their pain and nausea on the 11-point VRS at 30-, 60-, 120-, and 240-minute intervals after surgery. Patients complaining of moderate-to-severe pain (VRS score >4) were treated with hydromorphone, 0.1 to 0.2 mg IV. In accordance with the standard hospital PACU nursing practice, the nurses were not required to titrate hydromorphone to achieve a specific VRS pain score. Patients requesting analgesic medication with pain scores of 2 to 3 received oral Vicodin (Qualitest Pharmaceuticals, Huntsville, AL); containing a combination of hydrocodone (5 mg) and acetaminophen (500 mg). If the patient complained of nausea or experienced repeated episodes of retching or vomiting in the PACU, they were treated with ondansetron 4-mg IV boluses. After discharge, all study patients were prescribed Vicodin as rescue analgesic to be used at home.
Anesthesia time (from induction of anesthesia to discontinuation of the propofol infusion) and surgery time (from skin incision to placement of the dressing) were noted. The assessment of recovery times for determining when patients were able to open their eyes, follow commands (e.g., squeeze the investigator's hand), and were oriented to their name and place/date of birth, were assessed by the blinded observer at 1-minute intervals. The times to sitting, tolerating oral fluids, standing, ambulating without assistance, and actual discharge home were assessed at 10-minute intervals in the recovery room. A trained interviewer who was also blinded to the study group contacted each patient by telephone at 24, 48, and 72 hours after discharge to inquire about their maximum VRS pain score, use of oral opioid-containing analgesic medication (i.e., number of pills), occurrence of any emetic symptoms, and use of rescue antiemetic therapy. The patient's QoR scores were also assessed using a standardized 9-item questionnaire.21 Patient satisfaction with postoperative pain management (using a 5-point VRS with 0 = poor, 1 = fair, 2 = good, 3 = very good, 4 = excellent), the times (i.e., number of days after surgery) to tolerate normal fluids and solid food, return to normal bowel movement, and to resume their normal activities of daily living after surgery were recorded at the 72-hour, 7-day and/or 30-day follow-up evaluation. The definition of constipation was as follows: (1) bowel movements occur less often than usual, (2) no bowel movement in the first 3 days after surgery, or (3) unusually hard stools that were painful or difficult to pass. The presence of wound complications (e.g., bleeding, hematomas, and infections) or occurrence of any cardiovascular events was assessed at the time of the initial postsurgical clinic visit, and at the 1-month follow-up telephone interview, respectively.
The study was powered to separate each active treatment from the placebo-treated group. A sample size of 60 patients in each group was determined by power analysis based on the following: (1) time to resumption of daily activities of normal living would be 4 days after surgery in the celecoxib or ibuprofen group compared with 6 days in the placebo group,15,17 with SD = 4; and (2) α = 0.05 and β = 0.2. Analysis of variance was used to compare the continuous variables among the 3 treatment groups, and when significant differences were determined, Tukey's multiple-comparison test was used to determine intergroup differences. Changes in the QoR scores over time in the postoperative period were analyzed using repeated-measures of analysis of variance. The statistical differences in patient satisfaction scores were tested using Mann-Whitney-Wilcoxon testing with the Bonferroni correction. χ2 test (or Fisher exact test) was used to analyze the categorical variables. Data are presented as mean values ± SD, numbers (n), and percentages (%). P values <0.05 were considered statistically significant differences between the treatment groups.
One hundred eighty patients were enrolled in this study and follow-up data were obtained from all enrolled subjects. The 3 treatment groups were similar with respect to age, weight, height, gender, ASA physical status, type of surgical procedures, and durations of surgery and anesthesia. The mean intraoperative doses of propofol, fentanyl, and local anesthetics did not differ among the 3 treatment groups (Table 1). The findings of this study failed to confirm the primary hypothesis that celecoxib or ibuprofen would reduce the time to resumption of normal activities of daily living after ambulatory surgery.
The recovery times were similar with respect to eye opening, orientation and sitting, the first time to oral fluid, walking, and actual discharge from the surgical facility (Table 2). Although the total dose of parenteral analgesic medication (i.e., morphine equivalents) administered in the PACU was numerically less in the celecoxib (versus control) group, this difference failed to achieve statistical significance. The numbers of patients requiring rescue analgesics and pain scores before discharge home were also similar in all 3 treatment groups (Table 3).
During the follow-up period, the maximal pain score and the percentage of patients requiring oral rescue analgesics on the first, second, and third postoperative days were similar among the 3 treatment groups. However, the overall pain scores were lower in the celecoxib and ibuprofen (versus control) groups (Table 3). The amount of opioid-containing analgesics (i.e., Vicodin) required was significantly less in the celecoxib and ibuprofen groups compared with the control group at 24, 48, and 72 hours after discharge (Table 3). More importantly, patient satisfaction with pain management was significantly higher in the celecoxib and ibuprofen (versus control) groups, with P = 0.02 (Table 3). Furthermore, the QoR scores on the first, second, and third postoperative days were significantly higher in the celecoxib and ibuprofen (versus control) groups (P < 0.01) (Fig. 1). Although return of normal bowel function occurred 1 day earlier in patients who received celecoxib and ibuprofen, this difference was not significant compared with the control group (Table 2). Furthermore, the time to tolerate solid food and resumption of normal daily living activities after surgery did not differ among the 3 study groups (Table 2).
Finally, postoperative emetic symptoms were similar among the 3 treatment groups. However, the incidence of postoperative constipation was significantly higher in the control group compared with the celecoxib and ibuprofen groups (P < 0.05) (Table 4). No patients in either of the NSAID groups experienced postoperative unusual bleeding, or wound or cardiovascular complications during the follow-up study period.
The goal in optimizing postoperative pain management is to reduce pain symptoms, improve the patient's QoR, and facilitate resumption of normal activities of daily living.22 Effective pain management has been reported to facilitate the recovery process and enhance patient satisfaction after outpatient surgery.4,15,17 Conversely, inadequately treated acute postoperative pain may lead to chronic pain, even in outpatients undergoing minor surgical procedures (e.g., inguinal hernia repair).23 In the current study involving an adult ambulatory surgery population undergoing outpatient surgery, the postoperative administration of either celecoxib (400 mg/d) or ibuprofen (1200 mg/d) for 4 days immediately after surgery was found to be equi-effective in reducing pain, improving patient satisfaction with their pain management and quality of life, as well as in reducing opioid-related side effects.
We chose to administer the maximum Food and Drug Administration–approved daily dosages of both active drugs on the day of surgery and for 3 days after discharge because the relative potency of celecoxib and ibuprofen remains controversial. This is the first large-scale comparative study involving outpatients undergoing superficial surgical procedures when a selective (e.g., celecoxib) versus nonselective (e.g., ibuprofen) NSAID was administered in the postdischarge period. However, additional comparative studies involving NSAIDs of varying COX-1/COX-2 selectivity are clearly needed in patients undergoing ambulatory surgery procedures.
The primary benefits of celecoxib and ibuprofen administration with respect to improving pain management and facilitating recovery of clinically relevant outcome variables seem to be related to the administration of these NSAIDs over a more extended postoperative period (i.e., postdischarge). These findings are consistent with earlier studies in patients undergoing orthopedic,24 general,25 gynecologic,26 laparoscopic,15,27 and plastic17 surgery procedures. In 2 studies involving patients undergoing major laparoscopic15 and plastic surgery17 procedures, celecoxib 400 mg/d orally for 4 days not only decreased postoperative pain and the need for opioid-containing analgesic medication but more importantly, led to an improvement in the speed and quality of the patient's recovery from surgery. The magnitude of the recovery benefits in the current study was less impressive than in these earlier studies.15,17,27 With respect to the QoR scores and patient satisfaction with their pain management, the mean difference of only 1 point of 18 and 5 points, respectively, would suggest that these statistically significant differences were of limited, if any, clinical significance for ambulatory surgery patients. We speculate that this may be related in part to the use of an outpatient surgical population undergoing a variety of common ambulatory surgery procedures in our current study.
Ibuprofen is a well-known orally administered, nonselective NSAID that has been shown to be effective in pain management after oral, dental, and gynecologic surgical procedures in the outpatient setting.5–8 In one study, patients who had acute musculoskeletal extremity injuries received oral ibuprofen 600 mg or celecoxib 200 or 400 mg in an emergency department.28 Analogous to celecoxib 400 mg/d, these results demonstrate that ibuprofen is an effective analgesic in the postoperative period in a diverse ambulatory surgery population. However, the study was inadequately powered to compare the analgesic efficacy of the 2 active treatment groups. Given the significantly higher cost of celecoxib 400 mg, these investigators questioned the use of celecoxib for pain relief in the emergency department setting.28 Malmstrom et al.29 reported that over an 8-hour evaluation period, a single 400-mg dose of ibuprofen was superior to a single 200-mg dose of celecoxib with respect to overall analgesic efficacy after oral surgery. In a literature review on the use of NSAIDS for patients with acute and chronic arthritis-related pain symptoms, Matheson and Figgitt30 suggested that ibuprofen provided efficacy comparable to rofecoxib, but superior to celecoxib. A 2-center study comparing single doses of celecoxib and ibuprofen after dental surgery found that a 200-mg dose of celecoxib was at least as effective as aspirin 650 mg and acetaminophen 1000 mg for relieving postoperative pain, whereas a 400-mg dose was as effective as ibuprofen 400 mg.20 Our current results demonstrated that short-term administration of celecoxib (400 mg/d) and ibuprofen (1200 mg/d) produced similar analgesic efficacy in preventing postoperative pain after general outpatient surgery procedures.
Although nonselective NSAIDs can produce significant opioid-sparing effects in the perioperative period, they can also produce undesirable side effects (e.g., renal dysfunction, gastrointestinal distress) when administered at high doses over a more extended period of time.9 In women undergoing breast surgery, use of diclofenac was associated with significantly more postoperative bleeding.31 As a result of the occurrence of unexpected postoperative hemorrhages in women receiving ketorolac after plastic surgery, it is generally considered to be contraindicated for this type of surgery.32 Although a systematic review of the risk of operative site bleeding after tonsillectomy with nonselective NSAIDS produced equivocal results,11 Marret et al.12 suggested that these drugs were contraindicated because of an increased risk of reoperation for hemostasis. Of interest, Pickering et al.14 found no difference in intraoperative blood loss when a nonselective NSAID, ibuprofen, was compared with a COX-2 inhibitor, rofecoxib, in this same patient population. However, these authors stated that the study had limited power to demonstrate a difference between the groups because of the large variation in blood loss. Another placebo-controlled study that assessed the subjective frequency of gastrointestinal adverse experiences and measured fecal occult blood loss when ibuprofen 1200 mg/d (versus celecoxib 200 mg/d) was given for 10 consecutive days in >1700 subjects found no significant differences among the 3 treatment groups.33 In a 7-day study evaluating >8600 adults with chronic pain, ibuprofen 1200 mg/d was not different from acetaminophen 3000 mg/d with respect to overall tolerability, and both were superior to aspirin 3000 mg/d.34 There were 6 cases of nonserious gastrointestinal bleeding, none of which occurred in the ibuprofen group.
Although numerous noncardiac surgery studies have confirmed that administration of COX-2 inhibitors before and/or after surgery has beneficial effects with respect to improving postoperative pain management without causing serious complications, the use of COX-2 selective inhibitors has become increasingly controversial after the withdrawal of rofecoxib and valdecoxib, as well as the fraudulent publications on the topic by a leading clinical investigator of the use of COX-2 inhibitors during the perioperative period.35 Even though the current study is clearly underpowered to examine serious cardiovascular complications, our study did not reveal any bleeding or cardiovascular problems, confirming our previous findings.15,17
The concerns about the potential for COX-2 inhibitors to increase prothrombotic complications have led to a search for alternative non-opioid analgesics.4,22 The gabapentinoid compounds are an interesting class of non-opioid analgesics that possess similar benefits to the COX-2 inhibitors in improving patient satisfaction and facilitating the recovery process after elective surgery.36,37 However, their use in the perioperative period may also be associated with an increased incidence of side effects (e.g., sedation, dizziness).38 Other non-opioid compounds (e.g., IV acetaminophen, longer-acting local anesthetics) are also being evaluated as alternatives to the COX-2 inhibitors as part of multimodal analgesic regimens for minimizing the opioid analgesic requirement and improving patient outcomes after elective surgery.39
Despite the opioid-sparing effect of celecoxib and ibuprofen in this outpatient surgery population, the overall incidence of postoperative nausea and vomiting was not significantly reduced in this study. The routine administration of metoclopramide, ondansetron, and dexamethasone for antiemetic prophylaxis in addition to using a propofol infusion for maintenance of general anesthesia and avoiding the use of opioid analgesics during the intraoperative period clearly contributed to a relatively low incidence of postoperative emetic symptoms in all 3 treatment groups. One of the primary deficiencies of this clinical investigation relates to the limited power to detect differences in secondary outcomes (e.g., wound complications, major cardiovascular events).40 Another criticism relates to the varied types of outpatient surgical procedures involved in this study, including operations with small postoperative analgesic requirements. The variety of superficial surgical procedures that were studied may have contributed to our inability to demonstrate differences in the primary and some of the secondary outcome measures. Finally, this study was not adequately powered to evaluate adverse gastrointestinal and/or cardiovascular side effects. As a result of the continuing controversy regarding the perioperative risk of COX-2 inhibitors in patients with preexisting cardiac disease, we excluded all patients with active cardiovascular diseases.
In conclusion, postoperative oral administration of the maximum over-the-counter dose of ibuprofen (1200 mg/d) or the Food and Drug Administration–approved dose of celecoxib (400 mg/d) for 4 days after outpatient surgery decreased postoperative pain and the need for analgesic rescue medication, as well as reduced opioid-related side effects (e.g., constipation), contributing to improved patient satisfaction and their QoR. Given the lower cost of ibuprofen compared with celecoxib, these data suggest that it would be a cost-effective alternative to celecoxib for postdischarge pain control after ambulatory surgery.
Supported in part by a grant from Wyeth Consumer Healthcare, the manufacturer of ibuprofen (Advil®), to Cedars Sinai Medical Center in Los Angeles. Policlinico Abano–Leonardo Foundation has provided support to the White Mountain Institute, a private non-for-profit private foundation that supports nontraditional medical practices and the arts.
Paul White is section Editor of Book, Multimedia, and Meeting Reviews for the journal. This manuscript was handled by Peter S.A. Glass, section Editor of Ambulatory Anesthesiology, and Dr. White was not involved in any way with the editorial process or decision.
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© 2011 International Anesthesia Research Society
40. White PF, Kehlet H. Improving postoperative pain management: what are the unresolved issues? Anesthesiology 2010;112:220–5