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Anesth Analg 2004;98:336-342 © 2004 International Anesthesia Research Society doi: 10.1213/01.ANE.0000093390.94921.4A
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Abstract |
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In this multicenter, double-blinded, randomized, placebo-controlled study we evaluated the analgesic and opioid-sparing efficacy of a preoperative dose of IV parecoxib followed by oral valdecoxib in treating pain associated with elective laparoscopic cholecystectomy. Patients were randomized to receive a single IV dose of parecoxib 40 mg (n = 134) or placebo (n = 129) 30–45 min before induction of anesthesia. Six to 12 h after the IV dose, the parecoxib group received a single oral dose of valdecoxib 40 mg, followed by valdecoxib 40 mg qd on postoperative days 1–4, then 40 mg qd prn days 5–7. The placebo IV group received oral placebo on an identical schedule. All patients were allowed supplemental IV fentanyl as needed during the first 4 h postoperatively (T0–240 min) followed by hydrocodone 5 mg/acetaminophen 500 mg (Vicodin®; 1–2 tablets orally every 4–6 h as needed). Patients taking parecoxib used 21% less fentanyl than those receiving placebo (P = 0.011). The mean area under the curve of pain intensity (PI) scores over time from T0–240 min was 55.2 for parecoxib and 61.2 for placebo (P = 0.083). At T180 and T240 min, mean PI score was 7.0 and 7.6 points lower in the parecoxib group, respectively (P < 0.02). Fewer patients on valdecoxib required supplemental analgesics (P < 0.05) after discharge. At T240 min and at day 7, Patient’s and Physician’s/Nurse’s Global Evaluations were significantly better in the parecoxib/valdecoxib group (P < 0.05). Incidences of adverse events, adverse events causing withdrawal, and serious adverse events were less for parecoxib/valdecoxib than for placebo. The authors conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to the standard of care for treating pain after laparoscopic cholecystectomy, and subsequent treatment with oral valdecoxib extends this clinical benefit.
IMPLICATIONS: Parecoxib 40 mg IV, 30–45 min preoperatively followed by oral valdecoxib 40 mg qd reduced opioid requirements and provided superior pain relief as well as improved patient global evaluation after laparoscopic cholecystectomy.
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Introduction |
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For laparoscopic cholecystectomy (LC), pain is both the most frequent complaint and the most common cause of delayed discharge after the procedure (1,2). Pain associated with outpatient LC is usually managed with opioid analgesics, often in conjunction with acetaminophen and/or nonsteroidal antiinflammatory drugs (NSAIDs). Opioids are effective analgesics, but their usefulness is limited by side effects, such as somnolence, nausea and vomiting, constipation, and respiratory depression (3). Nonopioids (e.g., acetaminophen, NSAIDs, and local anesthetics) have opioid-sparing effects (4–6).
Valdecoxib is a highly specific inhibitor of the cyclooxygenase-2 (COX-2) enzyme, recently approved in the United States for the treatment of arthritis and dysmenorrhea, that is being investigated for use in postsurgical pain (7). Parecoxib is a parenterally administered inactive prodrug that undergoes rapid amide hydrolysis in vivo to the pharmacologically active COX-2 inhibitor, valdecoxib (8). This study was performed to evaluate the analgesic efficacy of a preoperative dose of IV parecoxib, followed by oral valdecoxib, for treating postoperative pain in patients undergoing elective LC. The principal hypothesis was that patients receiving these analgesics would experience less pain and require less supplemental opioid analgesia than patients receiving placebo.
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Methods |
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This multicenter, double-blinded, randomized, placebo-controlled study was conducted in accordance with good clinical practice and the Declaration of Helsinki. An IRB at each of the 24 study sites approved the protocol. Patients aged 18–75 yr requiring elective ambulatory LC were eligible for enrollment in the study. Patients were excluded if they had clinically diagnosed acute pancreatitis, were scheduled to undergo any surgical procedure expected to produce more trauma than LC alone, had acute preoperative pain other than biliary colic, required chronic pain treatment, or had current or recent cancer or any condition that would contraindicate participation in a surgical study of this nature. Patients were assessed for eligibility within 14 days before surgery, provided a full medical history, and underwent complete physical examination and laboratory tests. A written informed consent was obtained from all patients.
On the day of surgery (day 0), eligible patients were randomized to receive parecoxib/valdecoxib or placebo based on the computer generated randomization scheme. After assessing baseline pain score using a visual analog scale (VAS) and establishing IV access, patients received midazolam 1–2 mg IV, followed by either parecoxib 40 mg or placebo IV, 30–45 min before the induction of anesthesia. The hospital pharmacist who was not involved with patient care or data collection prepared the IV study drugs (2 mL solution identical in appearance) and provided them to the investigator. LC was performed according to standard surgical and anesthetic protocols. General anesthesia was induced with propofol 1–2 mg/kg and fentanyl 2–5 µg/kg followed by a nondepolarizing neuromuscular blocking drug to facilitate tracheal intubation. Anesthesia was maintained with sevoflurane 1%–3% end-tidal concentrations. No local anesthetic was administered either IV or at the surgical site. All patients received ondansetron 4 mg IV, 10–20 min before the end of surgery. Neuromuscular blockade was reversed with neostigmine and glycopyrrolate. The tracheal tube was removed after the patient was able to maintain adequate ventilation and followed commands.
The 4-h period beginning at Time T0 was considered the "early postoperative period." T0 was when the patient had been transferred to the postanesthesia care unit and had been awake for 10 min. The time of awakening was defined as the first time after extubation when the patient was able to open eyes to command. At times T0, T15, T30, T45, T60, T90, T120, and T180 min, pain intensity (PI) at rest was assessed using a 100-mm VAS where 0 mm represented "no pain" and 100 mm "worst possible pain." Ambulation and other patient activities were restricted for 10 min before any pain assessments. Patients requiring supplemental analgesics between T0–240 min were titrated to comfort using 25–50 µg IV doses of fentanyl.
At T240 min, Patient’s and Physician’s/Nurse’s Global Evaluations of Study Medication were assessed by the "blinded" investigator using a scale from 1 (very poor) to 6 (excellent), and patients rated their "Maximal PI" by completing the statement: "My maximum pain following surgery is: none (0), mild (1), moderate (2), or severe (3)." Throughout the patient’s stay in the surgical facility, all adverse events experienced and all medications administered were recorded, including times and amounts of fentanyl administration. After a minimum stay of 4 h after awakening, patients considered to be clinically stable could be discharged.
Patients were given a diary and instructions for its completion during the oral dosing period after discharge. The oral dosing period of the study began with a single oral dose of valdecoxib 40 mg or placebo taken on day 0, between 6 and 12 h after the IV dose of study medication. No second randomization was done; patients who received parecoxib during the IV phase received valdecoxib, and those who received IV placebo received oral placebo.
On postoperative days 1–4, patients took 2 valdecoxib 20 mg tablets or 2 matching placebo tablets once per day in the morning. From days 5–7, the oral study medication was taken only as needed. Patients needing additional analgesics could take hydrocodone 5 mg/acetaminophen 500 mg (Vicodin®; 1–2 tablets orally every 4–6 h as needed) to a maximum of 6 on day 0 and 8 on the remaining days.
Throughout days 1–7, patients recorded in the diary any adverse events experienced and all study medication, supplemental analgesia, and concurrent medications taken as well as the "worst" level of pain experienced by the patient in the last 24 h, categorized as none, mild, moderate, or severe. Patients returned for a final visit on postoperative day 7 (or up to 3 days later if necessary), when Patient’s and Physician’s/Nurse’s Global Evaluations were completed, the patient diary was collected and reviewed with the patient, and all adverse symptoms experienced and all medications taken during the course of the study were reviewed. Blood collection for laboratory tests and a complete physical examination were performed, during which the investigator specifically noted the presence and degree of any surgical site infection and the degree of wound healing.
Medications routinely used in surgical settings were permitted to be taken or administered perioperatively at the discretion of the investigator. However, the following medications were specifically prohibited: intrathecal opioids, systemic corticosteroids, analgesics other than those described, nerve or plexus blocks, succinylcholine, NSAIDs, acetaminophen within 12 h of dosing with study medication, sedating antiemetics until at least one dose of ondansetron had been administered for postoperative nausea or vomiting, topical peritoneal anesthetics, and antipsychotic and antiepileptic medications.
The sample size for this study was based on the assumption that compared with placebo, parecoxib would produce a reduction in PI area under the curve (AUC0–240) of at least 20 mm per unit of time, with a common standard deviation of 50 mm per unit of time. To detect this difference with 80% power would require a sample size of 100 patients per treatment group. To allow for a 15% nonevaluable rate, 230 patients (115 per treatment group) were planned to be recruited. In all statistical analyses, the Type I error for hypothesis testing was set at 0.05, and all tests were two sided unless specified. Analyses of pretreatment data included all patients who were randomized and took at least one dose of study medication.
The primary measures of efficacy in this study were the amount of fentanyl consumed and the time-specific PI-VAS AUC0–240 during the early postoperative period performed on the parecoxib evaluable cohort (i.e., all treated patients except those who used any prohibited medication, underwent conversion from LC to open cholecystectomy surgery, had local anesthesia administered at the port site, received postoperative fentanyl before awakening, or did not have the time of awakening recorded).
Efficacy analyses relating to the oral dosing period included all patients in the parecoxib evaluable cohort except those who took supplemental analgesics other than the Vicodin® provided, missed more than 2 days of dosing, or demonstrated <50% study medication compliance for day 0 through day 4. Missing efficacy values were imputed by carrying forward the last observed value.
Categorical variables were assessed using Fisher’s Exact test and continuous variables were assessed using one-way analysis of variance. If the patient received fentanyl for supplemental analgesia, PI scores for all subsequent evaluations were assigned the last score preceding the time of fentanyl administration. Comparisons of safety results between treatment groups included all patients who took at least one dose of study medication and consisted primarily of incidences of adverse events, withdrawals attributable to adverse events, and serious adverse events.
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Results |
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A total of 276 patients were randomized into this study. Thirteen patients did not take IV or oral study medication. Therefore, 263 patients received treatment at 24 centers in the study (134 in the parecoxib group and 129 in the placebo group). The completion status and reasons for termination from the study are shown in Figure 1. The treatment groups were statistically comparable with respect to demographics, anesthesia, and surgical data (Table 1).
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The proportions of patients using fentanyl during the early postoperative period (T0–240 min) were 92% in the parecoxib group and 98% in the placebo group (P = 0.065) (Table 2). However, patients receiving parecoxib used a mean of approximately 21% less fentanyl than those receiving placebo in the T0–240 min period (P = 0.011) (Table 2).
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Although the mean PI-AUC0–240 (standardized to the 100-mm VAS) in the parecoxib group were 10% lower than placebo group, the differences were not statistically significant (P = 0.084–0.092) (Table 2). The large standard deviations seen in the AUC data may be an artifact of the method of analysis. Owing to the large percentages of patients in both groups who took fentanyl, the last observed value carry forward method could result in more variability.
At all postoperative time points, PI was numerically smaller in the parecoxib group than in the placebo group (Fig. 2). At T180 and T240, the difference between treatment groups was significant (P < 0.02). At T240 min, approximately half of patients in both treatment groups described their maximal PI during the preceding 4 h as "moderate" (Table 2). However, in the parecoxib group, more patients (24%) reported "mild" pain and fewer reported "severe" pain (22%) compared with the placebo group (13% "mild" and 36% "severe"; P = 0.031).
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On each of postoperative days 2–5, the proportion of patients in the valdecoxib group who took Vicodin® decreased from the previous day, from 65% on day 1 to 25% on day 5 (Fig. 3). The proportions in the placebo group decreased similarly (86% on day 1 to 40% on day 5). On all 5 days, the proportions taking Vicodin® were significantly larger for placebo than for valdecoxib (P < 0.05).
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P < 0.01 versus placebo.Patients receiving valdecoxib took a mean of 2.4 Vicodin® tablets on day 1 and decreased with each successive day to 0.8 on day 5 with a mean total of 6.2 between days 1–4. In the placebo group, the mean use was 3.6 Vicodin® tablets on day 1 and decreasing to 1.1 on day 5 with the mean total number of 9.7 between days 1–4. These differences were significant for total number of Vicodin® tablets taken between days 1–4 (P = 0.001) as well as for the number on each individual day (P
0.036). Only on day 5, when study medication use was optional, was the difference between groups not significant (P = 0.196). From patient’s assessment of the worst pain in the previous 24 h period, on day 1 the percentage of patients reporting moderate-to-severe pain (71%) was almost double that in the parecoxib group (37%), (P < 0.001). On subsequent days the percentage decreased in both the groups, until on day 5 approximately one-fifth of patients in either group reported moderate-to-severe pain (21% for parecoxib and 18% for placebo). After day 1, the differences in proportions between groups were not statistically significant (P = 0.085).
At T240 min as well as on day 7, Patient’s and Physician’s/Nurse’s Global Evaluations assessments of "excellent" or "very good" were given more frequently in the parecoxib/valdecoxib group (Fig. 4). In both Global Evaluations, the distributions among the categories were significantly different in favor of parecoxib (P < 0.05). On day 7, Global Evaluations of "excellent," "very good," or "good" by patients was 91% for valdecoxib versus 68% for placebo (P < 0.001), and by physicians/nurses it was 89% for valdecoxib versus 62% for placebo (P < 0.001).
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Of the 14 individual events with an incidence of at least 5% in either treatment group, 10 showed more frequent incidences for placebo than for parecoxib/valdecoxib (Table 3). The more frequent adverse event incidence for placebo is principally composed of more frequent incidences of pain-related events (e.g., headache, pain, abdominal pain, and arthralgia) and of laboratory value abnormalities (e.g., increases in
-glutamyl transferase, alanine aminotransferase, and aspartate aminotransferase). The four events with more frequent incidences in the parecoxib/valdecoxib group were nausea, fatigue, vomiting, and dizziness. A total of 18 patients withdrew owing to one or more adverse events: 8 (6%) in the parecoxib group and 10 (8%) in the placebo group. No pattern of effect was evinced by the withdrawal results, with the possible exception of withdrawals attributable to pain being more frequent in the placebo group.
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Ten serious adverse events were reported in 7 patients (5%) in the parecoxib/valdecoxib group, and 14 serious adverse events occurred in 13 patients (10%) receiving placebo. In one parecoxib/valdecoxib patient and two placebo patients, the dermis was separated or the wound was open to the subcutaneous level. No significant difference was seen between the groups in the distribution of the wound healing findings (P = 0.817). Evidence of superficial infection of the surgical site was seen in 2% of parecoxib patients and 4% of placebo patients (P = 0.713).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrated that preoperative parecoxib 40 mg IV reduced fentanyl consumption by 21% in the early postoperative period after LC. A significant number of patients (92% in the parecoxib group and 98% in placebo) received fentanyl, probably as a result of more aggressive prompting by nursing staff after implementation of new guidelines from the Joint Commission for Accreditation of Healthcare Organizations around the time of the study. This may have reduced the power to distinguish differences in PI between the two groups. Nonetheless, mean PI scores at all time points were consistently lower in the parecoxib group with the difference being significant at T180 (22% lower) and T240 min (27% lower). Significant improvements in maximum PI and Global Assessments at T240 min also support the use of parecoxib as part of a "multimodal" analgesic regimen for managing postoperative pain.
On switching to oral dosing, the opioid-sparing properties of valdecoxib were also distinguishable. On all postoperative days, significantly fewer valdecoxib patients required supplemental Vicodin®, and the number of Vicodin® tablets taken was also reduced through the entire period of protocol-mandated valdecoxib dosing. Additionally, the valdecoxib group demonstrated significantly better Patient’s and Physician’s/Nurse’s Global Evaluations of the analgesic experience at day 7. This suggests that the benefits of a multimodal analgesic regimen incorporating COX-2 specific inhibition extend beyond the immediate postoperative period.
The opioid-sparing effect seen with a single dose of parecoxib 40 mg IV followed by valdecoxib 40 mg qd is similar to previous studies of parecoxib and valdecoxib in more invasive surgical procedures (9–12). Studies using both oral and parenteral NSAIDs in ambulatory surgery have also demonstrated reduced opioid consumption, improved pain scores, earlier discharge, and early return to normal function (4,13,14). However, as nonspecific NSAIDs such as ketorolac are associated with increased risk of inhibition of platelet function and bleeding resulting from inhibition of COX-1, these analgesics are commonly administered at the end of the surgical procedure rather than preoperatively (15). In contrast, the lack of platelet inhibition allows COX-2 specific inhibitors like parecoxib to be administered preoperatively (16). Preoperative dosing allows time for large drug concentrations to be achieved in the target tissues before COX-2 is expressed as a result of tissue injury, potentially achieving optimal inhibition. Additionally, Joris et al. (17) found that although pain peaked within 4–8 h after LC, a significant number of patients continued to experience pain for up to a week. Upregulated COX-2 may continue to increase pain sensitivity during this period. Therefore a rational approach would be to include preoperative COX-2 inhibition in the analgesic regimen with regular postoperative dosing for 5–7 days as well as opioid supplementation as required. This study showed that preoperative dosing with parecoxib produced significant benefits as early as 2–4 h after LC. Furthermore, sustained postoperative administration of valdecoxib over a period of days significantly reduced opioid intake, and improved pain scores and Global Evaluation scores, suggesting that continued inhibition of COX-2 would improve analgesia throughout the recovery period.
This study was not designed or powered adequately to compare the safety profiles of the two treatment groups. However, the results indicate that the use of parecoxib and valdecoxib does not contribute to the inherent risk posed by elective LC and its concomitant anesthetic and analgesic regimens, nor were the COX-2 specific inhibitors associated with wound infection or delayed wound healing. Adverse events causing withdrawal and serious adverse events were slightly more frequent for placebo, suggesting that parecoxib and valdecoxib were not associated with an increased severity of events.
We conclude that preoperative parecoxib is a valuable opioid-sparing adjunct to standard opioid treatment of pain after LC and that subsequent treatment with oral valdecoxib extends this benefit in a clinically meaningful manner. Finally, the availability of an IV prodrug, parecoxib, and an oral form, valdecoxib, might be particularly useful in ambulatory surgeries such as LC.
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Acknowledgments |
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Supported, in part, by Pharmacia Corporation and Pfizer Inc.
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References |
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- Bisgaard T, Klarskov B, Rosenberg J, et al. Characteristics and prediction of early pain after laparoscopic cholecystectomy. Pain 2001; 90: 261–9.[Medline]
- Hession MC. Factors influencing successful discharge after outpatient laparoscopic cholecystectomy. J Perianesth Nurs 1998; 13: 11–5.[Medline]
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