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*Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, University of Pennsylvania; and
Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center at Dallas
Address correspondence to P.F. White, PhD, Department of Anesthesiology and Pain Management, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390-9068. Address e-mail to paul.white{at}utsouthwestern.edu
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Abstract |
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IMPLICATIONS: Oral premedication with rofecoxib (50 mg) was more effective than celecoxib (200 mg) and acetaminophen (2 g) in reducing postoperative pain and in improving the quality of recovery and patient satisfaction with pain management after outpatient otolaryngologic surgery with only a small increase in cost of care.
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Introduction |
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COX-2 specific drugs have recently been introduced as alternatives to the nonselective NSAIDs in the management of acute pain, with claims that they produce comparable analgesia without adverse effects on platelet and renal tubular function (6). Whereas preliminary studies with celecoxib (100–200 mg) and rofecoxib (25–50 mg) have shown these drugs to be effective analgesics after dental and orthopedic surgery (6–9) , studies in patients undergoing radical prostatectomy (10) have led to questions regarding the analgesic efficacy of COX-2 inhibitors after other surgical procedures. Recent studies have demonstrated that preoperative rofecoxib (50 mg) and a combination of celecoxib (200 mg) and acetaminophen (2 g) can significantly reduce postoperative pain and improve the quality of recovery after ENT surgery (4,5) . However, there are no direct comparisons of the efficacy of the two COX-2 inhibitors celecoxib and rofecoxib in the ambulatory setting.
We designed this randomized, double-blinded, placebo-controlled study to compare the efficacy of standard analgesic doses of rofecoxib and celecoxib (versus acetaminophen) when administered before outpatient ENT surgery. The hypothesis being tested was that oral premedication with these drugs would reduce postoperative pain and the need for opioid analgesics after ENT surgery and improve patient satisfaction. A pharmacoeconomic analysis was performed to determine the additional expense required to obtain complete satisfaction with pain control in one additional patient compared with a placebo treatment.
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Methods |
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In the preoperative holding area, patients completed baseline verbal rating scales (VRS) for pain and nausea, with 0 = none to 10 = worst imaginable. The patients were randomly assigned to one of four treatment groups: Group 1, placebo (vitamin C 500 mg); Group 2, acetaminophen 2 g; Group 3, celecoxib 200 mg; and Group 4, rofecoxib 50 mg. The drugs were prepared by the operating room (OR) pharmacist according to a computer generated random number schedule and were administered by a day-surgery nurse with 10–20 mL of water 15–45 min before entering the OR. The patients, observers, and those involved in direct patient care were blinded to the contents of the oral premedication.
Patients received midazolam 20 µg/kg IV in the preoperative holding area. On arrival in the OR, anesthesia was induced with propofol 2 mg/kg IV and remifentanil 0.5 µg/kg IV, and tracheal intubation was facilitated with rocuronium 0.6 mg/kg IV. Anesthesia was maintained with desflurane 4% end-tidal concentration in combination with air (0.5 L/min) and oxygen (0.5 L/min). An infusion of remifentanil was administered at an initial rate of 0.1 µg · kg-1 · min-1 and subsequently varied from 0.0625 to 0.125 µg · kg-1 · min-1 to maintain heart rate and blood pressure values within 15% of the baseline values. At the end of the surgical procedure, residual neuromuscular block was antagonized with edrophonium 50–80 mg IV and atropine 0.5–0.8 mg IV, and the maintenance anesthetic drugs were discontinued.
A blinded observer (TI) determined recovery times to awakening (e.g., opening eyes in response to a verbal command) and orientation to person, date, and place at 1-min intervals after discontinuation of the maintenance anesthetics. Patients rated their pain and nausea scores on the 11-point VRS, where 0 = none and 10 = worst possible pain (or nausea). These scores were recorded at 30-min intervals and immediately before receiving any rescue analgesic medication in the postanesthesia care unit (PACU). Patients with pain VRS scores of 6 or higher were considered to have severe pain. Patients complaining of moderate-to-severe pain (VRS >3) were treated with fentanyl 25-µg IV boluses until they no longer complained of pain. Patients with pain scores of 2–3 received a combination of oral hydrocodone (5 mg) and acetaminophen (500 mg). If the patient complained of nausea or experienced repeated episodes of vomiting or retching, they were treated with dolasetron 12.5 mg IV, and if the condition persisted, promethazine was administered in IV boluses of 6.25 mg to a total dose of 25 mg.
Postoperative side effects (e.g., pain, dizziness, nausea, and vomiting) and the requirements for rescue analgesic and antiemetic drugs were recorded along with the duration of stay in the Phase 1 (PACU) and Phase 2 (Day Surgery Unit [DSU]) recovery units, as well as the times until the patient was considered fit for discharge and actually discharged. The criteria used to determine fitness for discharge required the patient to be awake, alert, with stable vital signs on standing, experiencing no intractable postoperative side effects, and able to walk without assistance. All patients received a combination of oral hydrocodone (5 mg) and acetaminophen (500 mg) for treating postdischarge pain. Patient satisfaction with their postoperative pain management and the quality of their recovery was assessed using a verbal analog scale at 24 h after surgery, with 0 = poor to 100 = excellent. Patients who rated their satisfaction with pain management at 100% were considered to have complete satisfaction with the control of their postoperative pain. The number-needed-to-treat (NNT) for complete satisfaction with pain control was calculated as the reciprocal of the absolute difference in the incidence of complete satisfaction between the two groups (11).
Finally, the follow-up telephone evaluations at 24 and 48 h after surgery were used to determine the number of doses (pills) of oral analgesic medications (hydrocodone or acetaminophen) consumed after discharge and the occurrence of postdischarge nausea or vomiting and other side effects. The patient also evaluated their maximum (peak) postdischarge pain using the 11-point VRS.
This study was designed to assess the ability of drugs given before the induction of anesthesia to prevent postoperative pain. Hence, the standard end-points of pain intensity difference, pain relief over time, and time to onset of pain relief were not used. The primary end-point of the study was therefore the dose of fentanyl used for rescue analgesia in the PACU. The secondary end-points for estimating the analgesic efficacy of the study drugs were the maximum (peak) pain score at any time during the study, including the score just before receiving a rescue analgesic in the postoperative period, and the proportion of patients requiring rescue analgesic medications.
An a priori power analysis estimated that 55 patients would be required in each group based on the following assumptions: (a) the mean and SD of the dose of fentanyl for rescue analgesia in the placebo group would be similar to that in previously published studies in this patient population where a similar anesthetic regimen was used (4,5) ; (b) a 40% change in the mean dose of fentanyl used for rescue analgesia from 113 to 68 µg would be of clinical importance; (c) a type I error of 0.05 adjusted for multiple comparisons; and (d) power of 80%. This sample size would have a 90% power at the 0.05 level of significance of detecting a relative reduction of 33% in the peak verbal pain score rating from 6 in the placebo group to 4 in the treatment group after log transformation, assuming the mean and SD (6 and 1.8, respectively) of the peak pain score in the placebo group would be similar to that in these previously published studies (4,5) . This sample size would have an 80% power at the 0.01 level of significance to detect a change in the proportion of patients requiring rescue analgesia in the PACU from 82% in the placebo group to 40% in the treatment group.
Data analyses were performed using StatView for Windows version 5.0.1 (SAS Institute, Cary, NC). Normally distributed continuous data were analyzed using one-way analysis of variance, and if significant differences were noted, a Student-Newman-Keuls test was used for intergroup comparisons. Continuous data not normally distributed (e.g., pain scores) were analyzed by a Kruskal-Wallis analysis of variance, and if significant differences were noted, a Mann-Whitney U-test was used for intergroup differences. Categorical data including the cumulative proportion of patients requiring rescue analgesia at various time points were analyzed using the 
2 test with Yates’ continuity correction or Fisher’s exact test where appropriate.
The cost analysis was incremental and performed from the perspective of the Chief Financial Officer of an outpatient surgical center to determine the additional expense that would be required to achieve complete satisfaction with postoperative analgesia in one patient who would otherwise have been dissatisfied (4,5) . Costs that were common to the four treatment groups, including the costs of all anesthetic drugs that every patient received, were not considered in the cost analysis. The costs of drug preparation and administration were not considered because these costs were assumed to be similar in all four groups. Nursing labor costs were not included because there were no differences in the time spent by a patient in the hospital and consequently no differences in costs to the institution for nursing labor. However, the acquisition costs of the oral study drugs at our institution in the year 2001 were used in the cost analysis, along with the incremental costs of rescue drugs for the management of postoperative pain and emetic symptoms (Table 1). The end point for effectiveness of the study drugs was a patient who was completely satisfied with their postoperative pain management. The product of the NNT for complete satisfaction with pain control and the incremental costs for medication provided the additional expenditure required to achieve complete satisfaction with pain management in one patient who would not have been completely satisfied if treated with another drug (or placebo). The 95% confidence intervals (CI) of these additional costs were calculated using Fieller’s theorem because of the sampling error in both the costs and the NNT (12).
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Results |
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The NNT for complete patient satisfaction with pain control was 1.9 (95% CI, 1.5–3.0), 3.2 (95% CI, 2.2–7.3), and 5.5 (95% CI, 3.1–73.8) for the rofecoxib, celecoxib, and acetaminophen groups, respectively, compared with the placebo group. The NNT for complete patient satisfaction with pain control was 3.0 (95% CI, 2.0–7.2) and 7.5 (95% CI, 3.2–17.8) for the rofecoxib and the celecoxib groups, respectively, compared with the acetaminophen group alone and 5.0 (95% CI, 2.6–166) for rofecoxib compared with celecoxib.
The pharmacoeconomic analysis revealed that the costs of the study drugs were highest in the rofecoxib group (Table 5). However, the costs of other drugs used in the postoperative period were the lowest in this group, and the rate of complete satisfaction with pain management was the largest (Table 5). The costs per completely satisfied patient were the lowest in the rofecoxib group. An incremental expenditure of US $10.35 (95% CI, $3.73–$16.98) and $21.13 (95% CI, $0–$64.68) for two doses of rofecoxib and celecoxib, respectively, would obtain complete satisfaction with postoperative pain management in one additional patient who would not have been completely satisfied if he or she had received the placebo. The incremental expenditure to obtain complete patient satisfaction in one additional patient with rofecoxib and celecoxib compared with acetaminophen would be $23.75 (95% CI, $0–$75.70) and $45.68 ($0–$306), respectively. The incremental cost for additional patient satisfaction with rofecoxib compared with celecoxib would be $6.70 (95% CI, $7.00–$20.68).
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Discussion |
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There have been conflicting reports regarding the efficacy of NSAIDs compared with acetaminophen in the management of postoperative pain. Although some investigators have reported a similar efficacy of acetaminophen and the nonselective NSAIDs (e.g., ketorolac or diclofenac) (3,22,23) , this and others studies (4,5) suggest that the COX-2 inhibitors may be more effective than acetaminophen in preventing pain after ENT surgery. Available data also suggest that the analgesic efficacy of COX-2 inhibitors may be dependent, in part, on the type of surgery (9), with greater efficacy noted when they are used in orthopedic and dental procedures compared with major intraabdominal operations (9,10) . For example, rofecoxib has recently been reported to be opioid sparing in patients undergoing spine fusion surgery, but it failed to reduce pain or the opioid analgesic requirements after radical prostatectomy. However, the failure of rofecoxib in the latter study (10) may have been related to decreased oral absorption because it was encapsulated for "blinding" purposes.
Although all patients were discharged home with similar pain scores, the peak pain scores after discharge were higher in the placebo group compared with the three active treatment groups. This probably reflects the fact that the patients received a second dose of the study drug on the morning after surgery. However, the number of doses of opioid-containing oral analgesic medication after discharge remained significantly smaller in both COX-2 inhibitor treatment groups compared with the placebo and acetaminophen groups. Another possible explanation for this finding is that the COX-2 inhibitors possessed a synergistic action with acetaminophen in the opioid-acetaminophen drug combination used for rescue analgesia, whereas the second dose of acetaminophen had only an additive action.
There are few data in the anesthesia and pain literature regarding the relative efficacy of COX-2 inhibitors in reducing postoperative pain. In our study, the preoperative administration of rofecoxib was superior to both celecoxib and acetaminophen in controlling postoperative pain during the early and late recovery phases. Furthermore, the quality of recovery was judged to be better in the rofecoxib-treated patients. Rofecoxib has also been reported to be superior to celecoxib after dental surgery (6). This apparent prolonged analgesic effect reflects the long duration of action of rofecoxib and is a distinct advantage of this drug when used for outpatient surgery.
The results from the current study suggest that rofecoxib was not only very effective in reducing postoperative pain and the need for opioid-containing analgesic medication, but also led to a better outcome from the patients’ perspective, as reflected by improvement in their satisfaction with postoperative pain management and their quality of recovery. Although many new drugs are more expensive than the older drugs they replace, cost minimization analyses focus on the costs to the institution to acquire a drug without considering the associated costs of managing failure to achieve a desired effect (24). In our opinion, these types of analyses should also consider patient satisfaction with a therapeutic regimen as an important clinical outcome. The incremental costs to achieve complete satisfaction in one additional patient who would not otherwise have been satisfied with alternative therapy may be the most important end-point of an analgesic study.
The current study suggests that the NNT for increased patient satisfaction with the rofecoxib regimen compared with the placebo and acetaminophen regimens were 1.9 and 3.0, respectively. Therefore, it would take an additional expenditure for rofecoxib of US $10.35 and $23.75 to obtain complete satisfaction with the postoperative pain management in one additional patient who would not have been satisfied if he or she had received placebo or acetaminophen, respectively. Similar cost comparisons for celecoxib were US $21.13 and $45.68, respectively. Although the acquisition costs of celecoxib were less than for rofecoxib, its duration of action is shorter, and the total costs of drugs used in the perioperative period were higher in the celecoxib group. Of interest, the estimated cost to increase patient satisfaction in one additional patient when ondansetron is administered for antiemetic prophylaxis exceeds $400 (25).
The costs in our study were sensitive to a number of assumptions including the incidence of PONV and the costs and efficacy of the antiemetic drugs used for prophylaxis and treatment of this condition. This study was completed before the Food and Drug Administration issued its recent warnings and recommendations for a routine screening 12-lead electrocardiogram and a three-hour monitoring interval when droperidol is administered for antiemetic prophylaxis. It is reasonable to expect a decreased use of droperidol in the future with a consequent increase in the cost of therapy for PONV as physicians replace droperidol with the more expensive serotonin antagonists.
This study can be criticized for not comparing the study drugs with traditional NSAIDs such as ketorolac. However, most experts in this field agree that nonselective NSAIDs are relatively contraindicated in ENT patients because of the increased risk of operative site bleeding (2,3,26) . Whereas laboratory studies suggest that the COX-2 inhibitors do not alter platelet function, larger studies need to be performed to determine if their use is associated with fewer hemorrhagic problems. In the current study, there was no evidence of increased bleeding in either of the COX-2 inhibitor groups compared with the placebo or acetaminophen groups. A second criticism of this study may relate to the use of a 200-mg dose of celecoxib. However, this dose was chosen before the Food and Drug Administration revised the celecoxib dosing guidelines for acute pain to 400 mg initially, followed by 200 mg. Of interest, in a subset of outpatients undergoing similar ENT procedures with an identical anesthetic technique, we have found that celecoxib 400 mg orally followed by a 200-mg dose was no more effective than the 200-mg doses of celecoxib used in the current study (27). Finally, the failure to demonstrate a reduction in either postoperative IV or oral opioid analgesic consumption after acetaminophen (24 mg/kg orally) compared with placebo was surprising. However, postdischarge pain scores were in fact lower in the acetaminophen group. In a recent systematic review comparing the analgesic efficacy of acetaminophen and NSAIDs, Hyllested et al. (28) noted that six studies had reported significant differences in pain scores but not in opioid consumption, suggesting that pain scores may be a more sensitive measure of efficacy than the dosage of rescue analgesic medication.
In conclusion, oral premedication with rofecoxib decreases postoperative pain and the need for analgesic rescue medication and improves patient satisfaction with the quality of their recovery after outpatient ENT surgery. Whereas celecoxib is also effective in this patient population, rofecoxib seemed to be superior at the dosages that were studied. Acetaminophen has limited efficacy in the early recovery phase but may be helpful in the postdischarge period as part of a multimodal analgesic regimen.
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Acknowledgments |
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