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Anesth Analg 2003;97:35-38
© 2003 International Anesthesia Research Society

PEDIATRIC ANESTHESIA

An Evaluation of the Safety and Efficacy of Administering Rofecoxib for Postoperative Pain Management

Wandana Joshi, DO, Neil Roy Connelly, MD, Scott S. Reuben, MD, Marten Wolckenhaar, MD, and Nikhil Thakkar, MD

Department of Anesthesiology, Baystate Medical Center, Springfield, Massachusetts

Address correspondence and reprint requests to Neil Roy Connelly, MD, Department of Anesthesiology, Baystate Medical Center, 759 Chestnut St., Springfield, MA 01199. Address e-mail to neil.roy.connelly{at}bhs.org


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
The goal of our study was to evaluate the analgesic efficacy and safety of administering rofecoxib (1 mg/kg), a cyclo-oxygenase (COX)-2 selective nonsteroidal antiinflammatory drug, before pediatric tonsillectomy. Sixty-six patients, aged 3–11 yr, scheduled to undergo tonsillectomy received either placebo or rofecoxib (1 mg/kg). There were no significant differences between the two study groups with respect to demographics and blood loss. We found that the pain scores were significantly lower in the rofecoxib group compared with the control group at 2 h (P < 0.05) and 24 h (P < 0.006). The incidence of nausea (P < 0.03) and vomiting (P < 0.004) at home was more frequent in the control group than in the rofecoxib group. We conclude that a single preoperative dose of rofecoxib resulted in less vomiting and lower 24-h pain scores in pediatric patients undergoing an elective tonsillectomy.

IMPLICATIONS: In children undergoing tonsillectomy, a single preoperative dose of rofecoxib decreases 2- and 24-h pain and decreases nausea and vomiting at home.


   Introduction
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 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Tonsillectomy is a common pediatric surgical procedure associated with significant postoperative pain that is a challenge to treat (1–4). Inadequate pain management after tonsillectomy may result in poor oral intake, dehydration, sleep disturbances, behavioral changes, and emesis (2,3). Although opioids may provide sufficient analgesia (5), they are associated with respiratory depression, which can be detrimental to the patient with obstructive airway disease (3). In addition, opioids are associated with an increased incidence of postoperative nausea and vomiting (PONV) in children (5,6). Because nonsteroidal antiinflammatory drugs (NSAIDs) are devoid of these side effects, they may represent an alternative analgesic in the management of pain after pediatric tonsillectomy. NSAIDs are often administered in the management of pain after tonsillectomy (3,4,7). However, nonselective NSAIDs inhibit the synthesis of prostaglandins at both the cyclo-oxygenase (COX)-1 and COX-2 sites, and their use has been associated with bleeding in the tonsillectomy patient (8). In contrast, the perioperative use of COX-2 selective NSAIDs may offer a therapeutic advantage in the management of posttonsillectomy pain.

The objective of our study was to evaluate the analgesic efficacy (improved pain scores) and safety (bleeding episodes) of administering rofecoxib (1 mg/kg) before pediatric tonsillectomy. We hypothesized that the preoperative administration of rofecoxib would decrease pain scores, without increasing the risk of perioperative bleeding, in pediatric tonsillectomy patients.


   Methods
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 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
Before the investigation, IRB approval was obtained. Informed, written consent was obtained from each child’s parent. Eighty healthy ASA physical status I or II patients, aged 3–11 yr, who were scheduled to undergo tonsillectomy, were enrolled in this study.

Patients were assigned to one of two groups (rofecoxib or placebo) according to a predetermined randomization code. The surgeons, anesthesiologists, and recovery room staff members were all blinded with regard to study medications. Approximately 45 min before the induction of anesthesia, the children were administered either placebo or rofecoxib (1 mg/kg) in a strawberry-flavored suspension (0.2 mL/kg). Anesthesia was induced and maintained with sevoflurane and N2O in oxygen. Once IV access was secured, patients received IV fentanyl (2 µg/kg). Intubation was achieved without the use of muscle relaxants. All children received prophylactic IV dolasetron (6.25 mg) and dexamethasone (4 mg). All patients received 20 mL/kg of lactated Ringer’s solution. All operations were performed by one of two surgeons with use of electrocautery to achieve hemostasis. Blood loss was measured in calibrated suction canisters. Patients were kept intubated until they emerged from the anesthetic.

Pain was evaluated with the Wong and Baker faces pain scale score (9), which was recorded by a blinded nurse observer who was unaware of the treatment. Pain scores were bordered, with 0 representing no pain and 6 representing the worst imaginable pain. Pain scores were obtained and recorded at 30 min, 1 h, and 2 h after arrival into the postanesthesia care unit. IV fentanyl (0.5 µg/kg) was administered every 5 min as needed to treat pain. Once the child was able to tolerate oral fluids, pain was treated with a combination of acetaminophen (120 mg) and codeine (5 mg) in a 5-mL dose; dosing was calculated on the acetaminophen content at a 10 mg/kg dose administered every 4 h by mouth as needed. Cumulative fentanyl; acetaminophen and codeine doses; incidence of nausea and vomiting; and antiemetic use were recorded for the first 24 h.

Before this study was instituted, a power analysis was performed with respect to 24-h pain scores. A pilot study determined a 24-h pain score of 4.3 ± 2.8. With an {alpha} of 0.05, a power of 80%, and a reduction of pain of 33%, a 2-sided analysis resulted in 26 patients required per group.

Demographic data were analyzed with ANOVA. Nonparametric testing was used for pain score evaluation and medication dosage. Contingency analysis ({chi}2 testing) was used to evaluate the side effects of nausea and vomiting. P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
Eighty children were enrolled. Fourteen of these were dropped because of various protocol reasons: adenoidectomy only (n = 4), additional diagnostic endoscopy (n = 1), preexisting low-grade fever (n = 1), repeat surgery for hemorrhage (n = 1 patient in the control group), medicine protocol violation (n = 6), and hospitalization for social reasons (n = 1). Thus, 66 patients successfully completed the study (32 in the control group and 34 in the rofecoxib group).

There were no significant differences between the two study groups with respect to age, sex, height, weight, or duration of surgery (Table 1). There was no significant difference in blood loss between the placebo group (1.8 ± 2.3 mL/kg) and the rofecoxib group (0.9 ± 0.7 mL/kg).


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  		Table 1. Demographic and Surgical Data for the Two Groups
 
The pain scores were not different between the groups at 30 min or 1 h. The pain scores were significantly lower in the rofecoxib group than the control group at 2 h (P < 0.05) and 24 h (P < 0.0006) (Table 2).


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  		Table 2. Pain Scores in the Two Groups
 
The total amount of acetaminophen with codeine administered was not different between the 2 groups (29 ± 20 mL in the control group versus 24 ± 16 mL in the rofecoxib group). The incidence of nausea severe enough to require additional antiemetics was not different between the groups (18 of 32 in the control group versus 22 of 34 in the rofecoxib group). The incidence of nausea at home was significantly more frequent (P < 0.03) in the control group (11 patients) than in the rofecoxib group (4 patients). The incidence of vomiting at home was significantly more frequent (P < 0.004) in the control group (11 patients) than in the rofecoxib group (2 patients).


   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
This study revealed that the preoperative oral administration of rofecoxib 1 mg/kg before pediatric tonsillectomy significantly reduced both pain scores and the incidence of PONV after discharge to home. Only one previously published study examined the pediatric use of COX-2-specific NSAIDs in the management of postoperative pain (10). This study revealed no significant analgesic benefit of using rofecoxib (0.0625 mg/kg) before pediatric tonsillectomy. This dose had been chosen on the basis of an adult surgical population study that found equianalgesic results with rofecoxib 50 mg and ibuprofen 400 mg (11). However, pharmacokinetic studies of NSAIDs in children have found weight-normalized clearance and volumes of distribution more than those in adults, but with similar half-lives (12). These pharmacokinetic differences suggest the need for larger initial loading doses of NSAIDs in children. A study examining steady-state concentrations of rofecoxib in children revealed that younger children (aged 2 to 11 years) require a larger (mg · kg-1 · d-1) dose of rofecoxib to obtain levels similar to those achieved in adult historical controls (13). Using a larger dose of rofecoxib, we were able to demonstrate a significant reduction of pain scores at 2 and 24 hours after surgery. There was no significant reduction in pain scores in the postanesthesia care unit at 30 minutes or 1 hour after surgery, which we believe reflects the analgesic duration of fentanyl administered during the surgical procedure. Despite achieving lower pain scores after this time period, we observed no significant reduction in postoperative opioid use. Despite parents recognizing that their children are in pain, most still administer inadequate doses of analgesics (14); this phenomenon may be partially responsible for the fact that opioid dosing was not more frequent in the control group.

Perhaps we might have observed a further reduction in postoperative opioid use if we had administered an even larger dose of rofecoxib. In children aged 2–5 years, it was believed that rofecoxib 0.6 mg · kg-1 · d-1 was approximately equivalent to 25 mg in adults. Therefore, the recommended adult acute pain dose of rofecoxib 50 mg might be equivalent to 1.2 mg/kg in children. Further analgesic and pharmacokinetic studies are necessary to determine the optimal dosing of rofecoxib in children.

Previous data have suggested that celecoxib (15,16), rofecoxib (17), and valdecoxib (18) have analgesic effects similar to conventional NSAIDs when used for acute pain. Rofecoxib and celecoxib have been shown to decrease pain in patients undergoing dental surgery (19,20). Because platelets express only COX-1 and are incapable of expressing COX-2 (21), these selective COX-2 inhibitors do not inhibit platelet function.

The preoperative administration of rofecoxib has a more favorable pharmacokinetic profile than the other COX-2 NSAIDs in the management of pediatric tonsillectomy pain. Rofecoxib provides an onset of clinical analgesia within 27 minutes (22) and has an elimination half-life of 17.5 hours; therefore, rofecoxib can be dosed once daily (17). In addition, this drug is available as a strawberry-flavored oral suspension (containing 12.5 or 25 mg of rofecoxib per 5 mL of solution); this formulation makes pediatric dose titration easy to accomplish.

Although increased bleeding has been demonstrated predominantly with the perioperative use of ketorolac (23–26), other NSAIDs—including aspirin (27), ibuprofen (28), and diclofenac (29,30)—have been implicated as well. In contrast, the COX-2-specific inhibitors do not inhibit platelet function and, therefore, may potentially be safer analgesics in this setting. Rofecoxib has demonstrated analgesic efficacy and safety when administered before a variety of orthopedic (31–34) and abdominal (35) surgeries. Recently, oral premedication with rofecoxib was shown to decrease pain and analgesic use after outpatient otolaryngologic surgery in adults (36).

We observed no significant increase in the incidence of bleeding when rofecoxib was administered before tonsillectomy, similar to other surgeries (31–35). Furthermore, the only patient who required an operation for a tonsil re-bleed was in the control group. Although we are not claiming that rofecoxib decreases surgical bleeding, we found no evidence that it increased the amount of intraoperative bleeding in this population.

The incidence of nausea and vomiting at home was decreased in the rofecoxib group. This may be due to the analgesic efficacy of rofecoxib, because effective prevention of pain can be expected to reduce PONV (37). Further, it has been demonstrated in the animal model that activation of the medullary vomiting center involves prostaglandins and that the preemptive administration of COX inhibitors significantly decreases lipopolysaccharide-induced emesis (38). Perhaps the preemptive administration of rofecoxib in our study contributed to the reduction in PONV through a centrally mediated action.

In conclusion, a single preoperative dose of rofecoxib (1 mg/kg) decreases 2- and 24-hour pain scores and decreases nausea and vomiting at home. This medication does not increase measured intraoperative surgical bleeding, nor does it increase the likelihood of reoperation for bleeding. We thus recommend that clinicians consider using rofecoxib in the management of pediatric patients undergoing tonsillectomy.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 18, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins and Stanford University Libraries' HighWire Press®. Copyright 2003 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press