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Anesth Analg 2002;94:1188-1193
© 2002 International Anesthesia Research Society


AMBULATORY ANESTHESIA

The Efficacy of Premedication with Celecoxib and Acetaminophen in Preventing Pain After Otolaryngologic Surgery

Tijani Issioui, MD*, Kevin W. Klein, MD*, Paul F. White, PhD MD, FANZCA*, Mehernoor F. Watcha, MD{ddagger}, Margarita Coloma, MD*, Gary D. Skrivanek, MD*, Stephanie B. Jones, MD*, Kevin C. Thornton, BS*, and Bradley F. Marple, MD{dagger}

Departments of *Anesthesiology and Pain Management and {dagger}Otolaryngology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas; and {ddagger}Department of Anesthesiology and Critical Care Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Address correspondence to Dr. P. F. White, 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


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Non-opioid analgesics are often used to supplement opioids for the management of perioperative pain. In this randomized, double-blinded, placebo-controlled study, we examined the effects of acetaminophen and a cyclooxygenase type-2 inhibitor, celecoxib, when administered alone or in combination, before elective otolaryngologic surgery in 112 healthy outpatients. Subjects were assigned to 1 of 4 study groups: Group 1, placebo (vitamin C, 500 mg per os [PO]); Group 2, acetaminophen 2000 mg PO; Group 3, celecoxib 200 mg PO; or Group 4, acetaminophen 2000 mg and celecoxib 200 mg PO. All patients received a standardized anesthetic technique. During the postoperative period, pain was assessed using a 10-point verbal rating scale. Recovery times, the need for rescue analgesics, side effects, and patient satisfaction scores were also recorded. The combination of acetaminophen and celecoxib was significantly more effective than placebo in reducing postoperative pain. Celecoxib, when administered alone or in combination with acetaminophen, improved patients’ satisfaction with their postoperative analgesia. With the combination of acetaminophen and celecoxib, an additional expenditure of $6.16 would be required to obtain complete satisfaction with postoperative pain management in one additional patient who would not have been completely satisfied if he/she had received the placebo. However, oral celecoxib or acetaminophen alone was not significantly more effective than placebo in reducing postoperative pain when administered before surgery. We conclude that oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was highly effective in decreasing pain and improving patient satisfaction after outpatient surgery.

IMPLICATIONS: Oral premedication with a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was effective in decreasing pain and improving patient satisfaction after otolaryngologic surgery. However, acetaminophen (2000 mg) or celecoxib (200 mg) alone was not significantly more effective than placebo in reducing postoperative pain.


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Interest in finding alternatives to opioid analgesics for the treatment and prevention of postoperative pain in the ambulatory setting has led to an increasing use of nonsteroidal antiinflammatory drugs (NSAIDs). However, classical NSAIDs block the synthesis of prostaglandins by inhibiting both cyclooxygenase type-1 (COX-1) and cyclooxygenase type-2 (COX-2), and may produce operative site and gastrointestinal bleeding, as well as renal tubular dysfunction. The COX-2-specific drugs have been recently introduced as alternatives to the classical NSAIDs, allegedly producing comparable analgesia without NSAIDs-like side effects (1,2).

Previous studies have reported that NSAIDs (e.g., ibuprofen, ketorolac) are useful in decreasing pain and/or opioid usage after oral, dental, and gynecologic surgical procedures in the outpatient setting (38). Acetaminophen, another non-opioid analgesic, is also effective when administered rectally before pediatric ambulatory surgery procedures in dosages exceeding 30 mg/kg (912).

Therefore, we designed a randomized, double-blinded, placebo-controlled study to evaluate the analgesic efficacy of celecoxib and acetaminophen when administered alone or in combination before ambulatory surgery. Our hypothesis was that oral premedication with celecoxib alone or in combination with acetaminophen would improve patient satisfaction by reducing pain after otolaryngologic (ears, nose, throat [ENT]) surgical procedures, which are usually performed on an ambulatory basis. A secondary objective was to determine the cost of using celecoxib and/or acetaminophen to improve patients’ satisfaction with their postoperative pain management.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
After obtaining IRB approval and written informed consent, 112 healthy outpatients (aged 18 to 75 yr) undergoing ENT procedures were studied according to a randomized, double-blinded, placebo-controlled protocol. Patients were excluded if they had received any analgesic medication within 12 h before surgery, were pregnant, breast-feeding, were allergic to any of the medications used in the study, had a history of drug abuse, or clinically significant cardiovascular, renal, hepatic, or gastrointestinal disease.

In the preoperative holding area, patients completed verbal rating scales (VRS) for pain and nausea, with 0 = none to 10 = worst imaginable. Patients were randomly assigned to 1 of 4 treatment groups: Group 1, placebo (vitamin C, 500 mg PO); Group 2, acetaminophen 2000 mg PO; Group 3, celecoxib 200 mg PO; and Group 4, acetaminophen 2000 mg and celecoxib 200 mg PO. The doses of study medication were based on previously published data (2,5,12). These drugs were prepared by the operating room pharmacist according to a computer-generated random number schedule, and administered with 15 mL of water 30–60 min before the induction of anesthesia. Patients, observers, and those involved in the postoperative patient care were blinded to the content of the oral premedication.

Patients were also premedicated with midazolam 20 µg/kg IV. Anesthesia was induced with propofol 1.5–2 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%–6% 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 0.125 µg · kg-1 · min-1 IV and subsequently titrated from 0.0625 to 0.25 µg · kg-1 · min-1 IV to maintain heart rate and blood pressure within 15% of the baseline values. At the end of the surgical procedure, residual neuromuscular block was antagonized with edrophonium 50–80 µg/kg IV, and atropine 0.5–0.8 mg IV, and the maintenance anesthetic drugs were discontinued.

Recovery times to awakening (e.g., spontaneous eye opening in response to a verbal command) and orientation to person, date, and place were determined by a blinded observer (TI) at 1-min intervals after discontinuation of the maintenance anesthetics. Patients rated their pain and nausea scores on a 10-point VRS at 30-min intervals and just before receiving any rescue drug in the postanesthesia care unit (PACU). Patients with pain VRS scores of six or higher were considered to have severe pain. Patients complaining of moderate-to-severe pain (VRS > 3) were treated with fentanyl 25 µg IV at 5–10-min intervals until adequate pain relief was achieved. Patients with pain VRS scores of 2–3 received a combination of oral hydrocodone (5 mg) and acetaminophen (500 mg). Nausea and episodes of vomiting were managed with dolasetron 12.5 mg IV, and if the emetic symptoms persisted, promethazine 6.25 mg IV was administered to a total dose of 25 mg.

Postoperative side effects (e.g., pain, nausea, vomiting) and the requirements for "rescue" analgesic and antiemetic drugs were recorded, as well as the durations of stay in the PACU (Phase I) and step-down (Phase II) recovery unit, and the time to be considered fit for discharge ("home ready"). The criteria used to determine fitness for discharge required that the patient be awake, alert, with stable vital signs on standing, experiencing no intractable postoperative side effects, and be able to walk without assistance.

Follow-up evaluations were performed via a telephone interview at 24 h after surgery to determine the number of doses of oral opioid-containing analgesic medications consumed, along with the patient’s evaluation of his or her maximal pain after discharge using the 10-point VRS. Patients’ satisfaction with their postoperative pain management and the quality of their recovery score were assessed by using a 100-point VRS, with 0 = poor to 100 = excellent. Patients who rated their satisfaction with pain management as excellent (VRS = 100) were considered to have complete satisfaction with postoperative pain control. The incidence of complete satisfaction with pain management was calculated separately for each of the study groups, and then subtracted from the incidence of complete satisfaction in the Placebo group to obtain the absolute difference in this outcome variable. The number-needed-to-treat (NNT) was calculated as the reciprocal of the absolute difference between the study and placebo groups in the incidence of complete satisfaction with their pain management.

The cost analysis was an incremental cost analysis performed from the perspective of a chief financial officer, and costs that were common to all four groups were not considered in the analysis. However, the acquisition costs of oral drugs administered in the preoperative phase were used in the cost analysis. The product of the NNT and the costs of the oral premedication drugs provided the additional expenditure required to obtain complete satisfaction with pain management in one patient who would not have been completely satisfied if treated with the placebo.

This study was designed to assess the ability of drugs given before the induction of anesthesia to reduce postoperative pain. Therefore, the standard end-points of pain intensity difference, pain relief over time, and time to onset of pain relief were not used. The analgesic efficacy of the study drugs was assessed by comparing the maximal pain scores before rescue in the postoperative period, the time-related proportion of patients requiring rescue, and the dose of rescue analgesic medications required in each treatment group.

The primary end-point of this study was the percentage of patients with moderate-to-severe postoperative pain. An a priori power analysis estimated that 28 patients would be required in each group. This was based on the following assumptions: 1) the incidence of moderate-to-severe pain in the Placebo group would be similar to that in a previously published study in this patient population in which a similar anesthetic regimen was used (13), 2) a 35% absolute reduction (from 70% to 35%) in the incidence of moderate-to-severe pain was considered of clinical importance, 3) a type I error of 0.05 not adjusted for multiple comparisons, and 4) power = 80%.

Data analysis was performed by using Statview® for Windows® version 5.0.1 (SAS Institute, Cary, NC). Normally distributed continuous data were analyzed by using one-way analysis of variance and if significant differences were noted, a Student-Newman-Keuls test was used for intergroup comparisons. Postoperative pain scores were analyzed by a repeated measures analysis of variance. Data not normally distributed were analyzed by using a Kruskal-Wallis nonparametric analysis of variance, and if significant differences were present, intergroup comparisons were performed with a Mann-Whitney U-test. Categorical data were analyzed by using the {chi}2 test with Yates’ continuity correction or Fisher’s exact test where appropriate. Data were presented as mean values ± SD, median values (interquartile range), numbers, or percentages. A P value < 0.05 was considered statistically significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
There were no significant differences among the four treatment groups with respect to age, weight, sex, type and duration of surgery and anesthesia, and intraoperative opioid analgesic medication (Table 1). Baseline pain and nausea scores were also similar in all four groups. There were no significant differences in the times from discontinuation of maintenance anesthetics to eye opening, response to commands, or orientation (Table 2). In addition, there were no differences in the time spent in the Phase I and II recovery units, or in the times to achieve home readiness ("fit for discharge").


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Table 1. Patient Characteristics, Surgery Type, Anesthesia and Surgery Times, and Intraoperative Analgesic and Anesthetic Dosages in the Four Study Groups
 

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Table 2. Recovery Times, Time to First Analgesic Rescue Medication, and Postoperative Pain and Nausea Scores in the Four Study Groups
 
Repeated measures analysis of variance demonstrated that the Combination group experienced significantly less postoperative pain compared with the Placebo group, whereas the differences between the other groups failed to achieve statistical significance versus placebo before discharge. The proportion of patients with severe pain and the maximal pain scores during the postoperative period were also significantly lower in the Combination group compared with the Placebo group (Table 2). However, there were no significant differences among the study groups in the time to first rescue analgesic or the total dose of fentanyl administered in the PACU (unreported data). Of interest, the time to antiemetic rescue was longer in the Combination group compared with the Placebo and Acetaminophen groups. However, the maximal nausea scores and the incidence of vomiting were comparable in all four groups (Table 2).

The maximal pain scores and the number of doses of oral analgesic medication taken after discharge were significantly higher in the Placebo group compared with the Combination group (Table 3). More important, patients in the Combination group were more highly satisfied with their postoperative pain management (96 ± 5) than the Placebo group (82 ± 12). The percentage of patients who were completely satisfied with their postoperative pain management was also significantly larger in the Combination and Celecoxib groups compared with the Placebo group (61% in the Combination group compared with 46%, 32%, and 11% for the Celecoxib, Acetaminophen, and Placebo groups, respectively) (Table 3). The NNT for complete satisfaction with postoperative analgesia in the Celecoxib alone and in the Combination group were 3 (95% confidence limits 2.0–11.5) and 2 (95% confidence limits 1.4–4.1), respectively. The postdischarge nausea scores were significantly larger in the Placebo group compared with the Celecoxib and Combination groups (1.9 ± 2.3 for the Placebo group versus 0.4 ± 1.2 and 0.2 ± 0.9 for the Celecoxib and Combination groups, respectively). Finally, the overall quality of recovery was significantly improved in the Combination group compared with the Placebo group (90 ± 17 versus 81 ± 13) (Table 3).


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Table 3. Pain, Nausea, and Patient Satisfaction Scores 24 Hours After Surgery in the Four Study Groups
 
The pharmacoeconomic analysis revealed that the administration of a combination of celecoxib 200 mg and acetaminophen 2000 mg at an additional expenditure of $6.16 would obtain complete satisfaction with the postoperative pain management in one additional patient who would not have been completely satisfied if he/she had received the placebo.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Achieving effective pain control after outpatient surgery continues to be a clinically significant issue in facilitating the recovery process and enhancing patient satisfaction after ambulatory surgery (14). Although opioids remain the most effective analgesics, their associated side effects (e.g., nausea, vomiting, drowsiness, and respiratory depression) can delay discharge after ambulatory surgery. NSAIDs are effective in reducing postoperative pain after dental and other minor surgical procedures. However, there is a "ceiling effect" with respect to the analgesia produced by NSAIDs and, therefore, they are optimally used as adjuvants to reduce postoperative opioid requirements (1,1517).

In this study, the preoperative oral administration of a combination of acetaminophen (2000 mg) and celecoxib (200 mg) was effective in reducing pain in the postoperative period and the need for opioid-containing oral analgesic medication after discharge, as well as in improving patient satisfaction after surgery. However, we did not find that these doses of celecoxib or acetaminophen when administered alone were significantly more effective than placebo in reducing pain in this adult population undergoing ambulatory surgery. It is possible that a larger study size or use of larger doses of acetaminophen (3–4 g) and celecoxib (400 mg) would have shown statistically significant differences in postoperative pain scores among the Acetaminophen, Celecoxib, and Placebo groups, and may have also shown differences in other analgesic end-points (e.g., the dose of rescue analgesics and the time to first rescue).

A placebo-controlled study in children undergoing ambulatory surgery procedures confirmed the dose-dependent efficacy of acetaminophen as an analgesic in the postoperative period (12). In a pediatric ENT study, Rusy et al. (18) reported that rectal acetaminophen (35 mg/kg) was as effective as ketorolac (1 mg/kg IV) for postoperative pain control. More recent pharmacokinetic studies suggest that acetaminophen blood levels of 10 mg/mL are required for satisfactory analgesia (10,11). The bioavailability of rectally administered acetaminophen is allegedly less than with oral dosing because the absorption of acetaminophen from suppositories is less predictable (9,19).

Similar pharmacokinetic data on analgesic blood levels of oral acetaminophen in adults are not available, and there are conflicting data on the analgesic efficacy of rectal acetaminophen in adults. Cobby et al. (20) noted that rectal acetaminophen (1300 mg) had a morphine-sparing effect after hysterectomy. However, Hein et al. (19) failed to demonstrate analgesia with rectal doses of 1000 mg after minor gynecologic surgery. In contrast to these data on the rectal route, there is good evidence that oral acetaminophen, 650–1000 mg, has a significant analgesic effect after dental and oral surgery, and in women who had undergone episiotomy procedures (4,5,15,2123). We used a larger oral dose of acetaminophen (2000 mg) in our ENT study and yet, failed to demonstrate a statistically significant analgesic effect. However, in this adult surgical population, the acetaminophen dose was equivalent to "only" 25 mg/kg.

Combinations of NSAIDs with acetaminophen should be more effective than either drug alone, because they possess different sites of analgesic action. It may therefore be possible to provide effective analgesia with smaller doses of acetaminophen and celecoxib than were used in this study if they are administered in combination for oral premedication. Analogous to our findings, combinations of diclofenac and acetaminophen were effective in reducing pain after both gynecologic and oral surgical procedures (16,24). It is a common clinical practice to use fixed dosage combinations of acetaminophen with oral opioids such as codeine, hydrocodone, or oxycodone for pain management after discharge (6,7,25,26).

The classical NSAIDs (e.g., ketorolac, diclofenac, naproxen) are nonselective at the COX-1 and COX-2 receptor sites. As a result, these drugs can produce adverse effects on gastric mucosal function and hemostasis, and are contraindicated in the presence of peptic ulcers and for procedures with an "open" surgical site (e.g., tonsillectomy) (2,17,18). The newer COX-2 inhibitors (e.g., celecoxib, rofecoxib) are more selective and should have a decreased potential for these adverse effects. Although celecoxib is usually used for treating rheumatoid and osteoarthritis, it has recently been recommended for the treatment of acute pain (27). In a comparative study involving celecoxib and rofecoxib, Reuben and Connelly (17) reported that celecoxib produced a shorter-lasting analgesic effect than rofecoxib after spinal fusion surgery. In our study, celecoxib (200 mg PO) did not offer any significant advantage over acetaminophen 2000 mg in the prevention of postoperative pain. The time to maximal plasma concentration of celecoxib is 2–4 hours after oral ingestion (2), and our patients received the study drugs 30–60 min before the induction of anesthesia and 120–180 min before arrival in the PACU. Therefore, this should have been an adequate time interval for therapeutic blood levels to be achieved.

Newer drugs (e.g., celecoxib) may be more expensive than the currently available generic oral analgesics. However, patients receiving celecoxib alone or in combination with acetaminophen were more satisfied with their postoperative pain management and quality of recovery than the Placebo (control) group. In fact, our study suggests that the NNT for increased patient satisfaction with the combination regimen was only two. Therefore, it would require an additional expenditure of $6.16 to obtain complete satisfaction with the postoperative pain management in one additional patient who would not have been satisfied if he/she had received the placebo treatment. By comparison, the costs to improve patient satisfaction in one additional patient when ondansetron is administered prophylactically exceeds $400 (28).

This study can be criticized for the type of surgical procedures chosen for this analgesic study. Although ENT surgery might not be considered an operation that is associated with a frequent incidence of severe postoperative pain, we found that 50% of the patients in the Placebo group experienced moderate-to-severe pain in the early postoperative period. Furthermore, previous studies have demonstrated that pain after ENT surgery is an acceptable model for studying non-opioid analgesics (18).

We conclude that oral premedication with a combination of celecoxib (200 mg) and acetaminophen (2000 mg) was highly effective in decreasing postoperative pain and improving patient satisfaction after ambulatory ENT surgery. Patients’ satisfaction with their postoperative pain management was also improved with celecoxib alone; however, the NNT to achieve this improvement was larger than with the celecoxib-acetaminophen combination. In this outpatient surgery population, celecoxib (200 mg) and acetaminophen (2 g) alone were not significantly more effective than a placebo in reducing postoperative pain when administered orally before surgery.


    Acknowledgments
 
Finanacial support was provided by the White Mountain Institute in Los Altos, CA (this is a non-for-profit private foundation and PFW is the President).


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication December 28, 2001.




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W. Joshi, N. R. Connelly, S. S. Reuben, M. Wolckenhaar, and N. Thakkar
An Evaluation of the Safety and Efficacy of Administering Rofecoxib for Postoperative Pain Management
Anesth. Analg., July 1, 2003; 97(1): 35 - 38.
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M. F. Watcha, T. Issioui, K. W. Klein, and P. F. White
Costs and Effectiveness of Rofecoxib, Celecoxib, and Acetaminophen for Preventing Pain After Ambulatory Otolaryngologic Surgery
Anesth. Analg., April 1, 2003; 96(4): 987 - 994.
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A. Turan, S. Emet, B. Karamanlioglu, D. Memis, N. Turan, and Z. Pamukcu
Analgesic Effects of Rofecoxib in Ear-Nose-Throat Surgery
Anesth. Analg., November 1, 2002; 95(5): 1308 - 1311.
[Abstract] [Full Text] [PDF]


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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press