The goal in optimizing postoperative pain management should be to reduce pain symptoms, improve the quality of the patient's recovery, and facilitate resumption of normal activities of daily living.1 Nonsteroidal antiinflammatory drugs (NSAIDs) are commonly administered as a part of multimodal analgesic regimens for preventing pain after fast-track surgery.2,3 For example, ketorolac has been found to reduce postoperative pain and the need for opioid analgesics after laparoscopic surgery4 and facilitated an earlier discharge after superficial surgery procedures.5 Nevertheless, concerns persist regarding the use of nonselective NSAIDs (e.g., ketorolac, ibuprofen, and diclofenac) during the perioperative period in patients undergoing major plastic surgery procedures due to the risk of operative site and gastrointestinal mucosal bleeding from blockade of prostaglandin synthesis at the cyclooxygenase (COX)-1 receptor.6–8 The more selective COX-2 inhibitors appear to be as effective as the nonselective NSAIDs for the prevention of postoperative pain with a lower risk of operative site bleeding.9–11
Although preemptive analgesia using COX-2 inhibitors has been recommended for the prevention of postoperative pain,12 the benefit of preemptive versus postoperative analgesia has been questioned.13 Perioperative administration (i.e., before and after surgery) of COX-2 inhibitors reduces pain and opioid-related side effects in the early postoperative period14; however, improvements in clinically relevant recovery outcomes appears to require a more sustained period of drug administration after surgery.15–18 Of concern, studies involving perioperative administration of COX-2 inhibitors for 10–14 days after cardiac surgery demonstrated that these compounds could increase postoperative wound infections19 and cardiovascular complications.20
We designed this randomized, double-blind, placebo- controlled study to test the hypothesis that short-term administration of celecoxib, 400 mg po, would improve pain control and lead to an earlier resumption of normal activities of daily living after major plastic surgery without increasing wound complications. The secondary objective was to compare peri- versus postoperative administration of celecoxib with respect to postoperative pain management, the need for rescue analgesics, and resumption of normal physical activities.
After obtaining IRB approval at UT Southwestern Medical Center, 179 patients with ASA physical status I–III (18–75 yr) undergoing major plastic surgery procedures (e.g., breast augmentation or abdominoplasty with or without liposuction involving abdomen, buttocks, and lower extremities) were screened for participation in this 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; unstable neurologic, cardiovascular, renal, hepatic, or gastrointestinal diseases; or were unwilling to complete the follow-up evaluations.
After obtaining written informed consent, 120 patients were randomly assigned to one of three treatment groups: 1) the control group (n = 40) received two placebo capsules orally 30–90 min before surgery, followed by two placebo capsules 1 h postoperatively in the recovery room; 2) the postoperative group (n = 40) received two placebo capsules orally 30–90 min before surgery and 2 celecoxib 200 mg capsules 1 h after surgery; and 3) the perioperative group (n = 40) received 2 celecoxib 200 mg capsules 30–90 min before surgery and 2 placebo capsules 1 h after surgery. On the first three postoperative days (PODs), patients in the control group received one placebo capsule BID, whereas the postoperative and perioperative groups received celecoxib 200 mg po BID. The study medication was prepared by a hospital pharmacist in identical-appearing capsules according to a computer-generated random number schedule. The patients, nurses, surgeons, and anesthesiologists directly involved in the patients’ care were blinded as to the content of the oral study medication capsules.
In the preoperative holding area, patients completed baseline 11-point verbal rating scales (VRS) for pain, with scores of 0 = no pain to 10 = “worst pain imaginable.” All patients received midazolam, 20 μg/kg IV, immediately before leaving the preoperative holding area. On arrival in the operating room, standard monitoring devices were applied. 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 fentanyl, 100 μg IV. After loss of consciousness, rocuronium (0.6 mg/kg IV) was given for tracheal intubation. Desflurane 4%, in combination with air 50% in oxygen, as well as a sufentanil infusion, 0.005–0.015 μg · kg−1 · min−1, were administered for maintenance of anesthesia. After endotracheal intubation, all patients were mechanically ventilated to maintain the end-expiratory CO2 value between 34 and 36 mm Hg. A local anesthetic solution containing 20 mL of 0.5% bupivacaine was injected at the incision site at the end of surgery in all cases. In addition, ondansetron, 4 mg, and dexamethasone, 4 mg, were administered for routine antiemetic prophylaxis. On completion of surgery, the combination of neostigmine, 2–5 mg IV, and glycopyrrolate, 0.2–0.8 mg IV, was administered for reversal of residual neuromuscular blockade, desflurane was discontinued, and the inspired oxygen flow rate was increased to 5 L/min. Tracheal extubation was performed when the patients could open their eyes or obey simple commands (e.g., squeeze hand). 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 desflurane) and surgery (from incision to placement of the surgical dressing) times were recorded. The discharge criteria from the PACU required that patients be awake and alert with stable vital signs, and not experiencing side effects related to surgery or anesthesia. The hospital discharge criteria required that the patient be able to ambulate without assistance, tolerate oral intake, void, control their pain with oral analgesics, and not be experiencing any drug-related side effects or surgical complications. All patients were asked to assess their quality of recovery using a validated 9-item questionnaire (Appendix 1)21 at 24 h intervals after surgery.
Patients rated their pain and nausea on the 11-point VRS at 30-min intervals and immediately before receiving any rescue analgesic medication in the PACU. Patients with VRS pain scores of 3–6 were considered to be in moderate pain and scores of >6 were considered to have severe pain. Patients complaining of moderate-to-severe pain in the PACU were treated with fentanyl, 25 μg IV boluses. However, the nurses were not required to titrate fentanyl to achieve a specific VRS pain score. Patients with pain scores of 2–3 received a combination of oral hydrocodone (5 mg) and acetaminophen (500 mg). For patients who were being admitted to the hospital, a patient-controlled analgesia (PCA) device was provided and patients were allowed to self-administer morphine 2 mg IV bolus injections with a lockout interval of 10 min and a 4 h limit of 40 mg. The incremental bolus dosage was increased to 3 mg if pain relief was inadequate (VRS pain score >6) after 1 h of PCA use. When the patients were discharged, they were prescribed a combination of oral hydrocodone (5 mg) and acetaminophen (500 mg) po QID, prn for pain control. Patients who complained of nausea or experienced repeated episodes of vomiting after surgery were treated with promethazine, 6.25 mg IV boluses, administered to a total dose of 25 mg.
A trained interviewer who was also blinded to the study medication contacted each patient at 24, 48, and 72 postoperatively to inquire about their maximum VRS pain score. Patients who were still hospitalized were visited by one of the investigators and the opioid medications administered were determined from the medicine administration record. Patients who had been discharged home were contacted by telephone and asked about their use of oral opioid-containing analgesic medication (i.e., number of pills consumed). To compare the opioid consumption of the three groups, morphine equivalents were calculated using a standardized conversion table.22 The patients were only admitted to the hospital if they experienced postsurgical bleeding complications or pain requiring parenteral opioid analgesics for >24 h.
Patient satisfaction with postoperative pain management, the times to tolerate normal fluids and solid food, have a bowel movement, and to resume their normal activities of daily living after surgery were recorded at the 24, 48, 72 h, and at the 7 day follow-up evaluations. The occurrence of any wound complications (e.g., hematoma, infection) was also noted at the time of the first follow-up visit to the plastic surgery clinic, as well as at the long-term follow-up 3 mo postoperatively.
Data were analyzed using analysis of variance (ANOVA) and χ2 analysis as appropriate. Based on the assumption that the control group would self-administer 50 mg of morphine (with a standard deviation of 10 mg), a sample size of 35 patients per group was calculated to detect a difference of 20% or more in PCA morphine consumption (usage) with a power of 80% and a significance level of 0.05 for a two-sided test. Additionally, repeated measure analysis of variance was used to analyze pain scores, early recovery times, and quality of recovery data over time for the three treatment groups. Continuous variables were evaluated using ANOVA. Levene's test for homogeneity of variance was used to determine if ANOVA was appropriate. Welch's ANOVA was applied where heterogeneity of variance was indicated. The Student–Newman–Keuls multiple comparisons test was applied for pairwise comparisons of means among the given treatments. When multiple comparisons of continuous data (e.g., pain scores) were performed among the three treatment groups, a Bonferonni correction was applied. Categorical variables were evaluated using χ2 contingency table analysis. Fisher's exact test was used where cell values were low, therefore not satisfying the assumptions for a valid χ2 contingency table analysis. Statistical partitioning was used to investigate source of variability. For all statistical analyses, P values <0.05 were considered to be statistically significant.
Of the 120 patients entered into the study, 112 patients successfully completed the entire protocol (Fig. 1). The eight patients who did not complete the treatment protocol (e.g., did not take their study medication or refused to complete all the postoperative assessments) had their data included up until the time they withdrew from the study. There were no significant differences among the three 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 sufentanil administered during the operative period were similar in the three treatment groups (Table 1).
Although the total morphine equivalents administered in the PACU were similar in the three groups, the need for opioid analgesics on the first three PODs was significantly less in the postoperative and perioperative groups compared with the control group (18 and 23 mg versus 68 mg, 5 and 13 mg versus 40 mg; and 3 and 3 mg versus 32 mg, respectively, P < 0.05) (Fig. 2). There were no between-group differences in the pain scores at PACU discharge. However, the average pain scores on the first, second, and third PODs were significantly lower in the postoperative and perioperative groups (Fig. 3). There were no statistically significant differences in pain scores or opioid analgesic requirements between the two celecoxib groups at any of the assessment intervals.
Patient satisfaction with pain management was significantly higher in the postoperative and perioperative (versus control) groups (Table 2). In addition, quality of recovery scores on the first, second, and third PODs were significantly higher in the postoperative and perioperative (versus the control) groups. Return of bowel function occurred earlier 1(1–2), 1(1–2) vs 2(1–3) days, respectively, P < 0.05), and more importantly, the time to resumption of normal activities of daily living after surgery was shorter in the perioperative and postoperative groups (versus control) groups 2(1–3), 2(1–3) vs 3(2–5) days, respectively, P < 0.05) (Table 2). Again, there were no statistically significant differences between the peri- versus postoperative groups.
Postoperative emetic symptoms did not differ significantly among the three treatment groups (Table 2). One patient in the postoperative group had a deep venous thrombosis, leading to a prolonged 7 day hospital stay. None of the patients experienced significant wound complications or reported gastrointestinal discomfort at the 7 day and 3 mo follow-up evaluations (Table 3).
Patients undergoing major plastic surgery procedures are at risk of developing opioid-induced side effects (e.g., sedation, postoperative nausea and vomiting, urinary retention, pruritus, ileus, constipation). Rather than emphasizing the use of opioid analgesics for preventing acute postoperative pain, a more balanced view, which uses non-opioid analgesics as the primary drugs for preventing postoperative pain, is recommended.2,3,23 In fact, some authors have suggested that opioid analgesics should only be used when other analgesic techniques have failed to provide adequate pain relief.2,23 After implementing a multimodal analgesic regimen, which includes COX-2 inhibitors in patients undergoing total joint arthroplasty procedures, Peters et al.24 reported earlier mobilization, shortened length of stay, and improved pain control with less opioid analgesic medication. Although nonselective NSAIDs can produce significant opioid-sparing effects, they can also produce side effects (e.g., bleeding complications, renal dysfunction, gastrointestinal distress).6
In plastic surgery patients receiving diclofenac, a reduction in the number of platelets and prolongation of the bleeding time were reported.25 Not surprisingly, in women undergoing breast surgery, use of diclofenac was associated with significantly more postoperative bleeding.26 Because of the occurrence of unexpected postoperative hemorrhages in women receiving ketorolac after plastic surgery, it is considered to be contraindicated for this type of surgery.27 Although a systematic review of the risk of operative site bleeding after tonsillectomy with nonselective NSAIDS reported equivocal results,28 Marret et al.29 suggested that these drugs were contraindicated due to an increased risk of reoperation for hemostasis. Of interest, Pickering et al.30 found no difference in intraoperative blood loss when a nonselective NSAID, ibuprofen, was compared with a COX-2 inhibitor in this same patient population. Placebo-controlled studies evaluating the effects of preoperative administration of a COX-2 inhibitor in patients undergoing spinal fusion surgery reported no significant increase in intraoperative bleeding or in the likelihood of a reoperation due to hematoma formation.9,31
In the current clinical investigation involving adults undergoing major plastic surgery procedures, the preoperative administration of 400 mg oral celecoxib 30–90 min before the start of the operation did not produce an increase in intraoperative blood loss or wound complications. However, the primary benefits of celecoxib administration with respect to improving pain management and facilitating recovery of clinically relevant outcome measures appears to be related to its administration over the 4-day postoperative period. These findings are consistent with earlier studies in patients undergoing orthopedic,15 general,32 gynecologic,17 and laparoscopic16,18 surgery procedures. In the most recent study involving patients undergoing laparoscopic surgery, celecoxib, 400 mg po, for 4 days not only decreased postoperative pain and the need for opioid-containing analgesic medication, but more importantly, led to an improved quality of recovery and earlier resumption of activities of daily living.
In contrast to Reuben et al.,12 we found that preemptive administration of this COX-2 inhibitor was no more effective than giving the same dose after the operation followed by daily use for the first three PODs with respect to pain scores, opioid usage, and resumption of normal activities of daily living. The negative findings in the comparison of perioperative (versus postoperative) drug administration may be related, in part, to inadequate absorption due to the short interval from drug administration to induction of anesthesia (i.e., 30–90 min) and the length of the surgical procedures (i.e., 2–4 h). However, these findings support the conclusions of the meta-analysis by Moiniche et al.13
Perioperative use of COX-2 selective inhibitors has become increasingly controversial after the withdrawal of rofecoxib (Vioxx®) and valdecoxib (Bextra®) from the market due to concerns regarding the occurrence of an increased incidence of cardiovascular and other (e.g., Stevens-Johnson syndrome) complications with long-term administration of these NSAIDs.33 Of even greater concern to anesthesiologists are the reports describing an increase in postoperative complications in patients undergoing cardiac surgery19,20 after relatively short-term (10–14 days) administration of COX-2 inhibitors. In the study by Nussmeier et al.,20 the perioperative use of COX-2 inhibitors parecoxib and valdecoxib was associated with an increased incidence of cardiovascular events within the 30-day follow-up period after cardiac surgery. Despite these reports, many noncardiac surgery studies have confirmed that the administration of COX-2 inhibitors before and for up to 5 days after surgery provides beneficial effects with respect to improving postoperative pain management without producing any serious complications.15–18,34
Of interest, a recent meta-analysis by Zhang et al.35 reported that rofecoxib was associated with an increased risk of renal and cardiac complications, but a COX-2 inhibitor “class” effect was not demonstrated. It has been suggested that the less highly selective COX-2 inhibitors (e.g., celecoxib) may be devoid of significantly increased cardiovascular complications even with more prolonged administration. Despite extensive world-wide use of COX-2 inhibitors in the immediate perioperative period, there have been no reports of serious cardiovascular complications associated with short-term use of COX-2 inhibitors in noncardiac surgery patients.33 The current study is under-powered to examine serious cardiovascular complications. However, one patient in the postoperative group did develop a deep venous thrombosis, a well-known complication after major plastic surgery procedures.36 A recent report by Al-Sukhun et al.37 also suggested that the use of COX-2 inhibitors was associated with early failure of free vascular flaps due to their ability to inhibit production of prostacyclin.
Because of the continuing concerns regarding the potential for nonselective NSAIDs to increase operative site bleeding6 and the COX-2 inhibitors to increase prothrombotic complications after major surgery, non-opioid analgesics, which are devoid of these side effects, are being investigated as alternatives to these compounds as part of multimodal analgesic regimens.38 Preliminary studies using the gabapentinoid compounds, gabapentin39,40 and pregabalin,41 have reported similar beneficial effects to the COX-2 inhibitors with respect to improving patient satisfaction and facilitating the recovery process after elective surgery procedures. These studies also suggest that use of the gabapentinoids in combination with COX-2 inhibitors produce additive (or even synergistic) effects with respect to improving postoperative pain management.41 A recent meta-analysis42 confirmed the analgesic efficacy of the gabapentinoid compounds in the postoperative period. However, their use may also be associated with an increased incidence of side effects (e.g., sedation, dizziness).42,43
The primary deficiencies of this investigation relate to the limited power of this study to detect differences in all secondary outcomes (e.g., wound complications, major cardiovascular events). As a result of the continuing controversy regarding the perioperative risk of COX-2 inhibitors in patients with preexisting cardiac disease,33 we excluded all patients with unstable cardiovascular disease. Additional perceived deficiencies of the study may relate to the celecoxib dosage regimen, the timing of its administration, and the possibility of delayed gastric emptying and drug absorption after induction of anesthesia. Although these operations lasted 2–4 h, it is possible that surgery and anesthesia interfered with the oral uptake of preoperative celecoxib from the gastrointestinal track. The celecoxib dose (400 mg qd)44 and the dosing intervals18 have been reported to be effective in improving postoperative pain control and facilitating recovery after a wide variety of surgical procedures.33 Furthermore, most outpatients undergoing elective surgery procedures typically arrive in the preoperative preparation area only 60–120 min before the start of surgery, precluding earlier administration of the study drug. Clearly, additional large-scale studies are needed to confirm the safety of the perioperative use of COX-2 inhibitors in patients at increased risk of cardiovascular complications.45
In conclusion, postoperative administration of celecoxib (200 mg po BID) for 4 days in patients undergoing major plastic surgery procedures decreased postoperative pain and the need for analgesic rescue medication, contributing to improved patient satisfaction with their quality of recovery. The short-term use of the COX-2 inhibitor in the postoperative period also facilitated the resumption of normal activities of daily living after discharge. Celecoxib administration 30–90 min before surgery offers no significant advantages over simply giving the drug after surgery.
The authors thank Spencer Brown, PhD, for his valuable support of this study.
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