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AMBULATORY ANESTHESIA

Preoperative Parenteral Parecoxib and Follow-Up Oral Valdecoxib Reduce Length of Stay and Improve Quality of Patient Recovery After Laparoscopic Cholecystectomy Surgery

Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina

Address correspondence and reprint requests to Tong J. Gan, MD, Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710. Address e-mail to gan00001{at}mc.duke.edu

	Abstract

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In this randomized, double-blinded, placebo-controlled study, we evaluated the effects of preoperative IV parecoxib sodium (parecoxib) followed by postoperative oral valdecoxib on length of stay, resource utilization, opioid-related side effects, and patient recovery after 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 the 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 once daily on postoperative Days 1–4 and then 40 mg once daily as needed on Days 5–7. Patients in the parecoxib/valdecoxib group had a shorter length of stay in the postanesthesia care unit (78 ± 47 min) compared with those taking placebo (90 ± 49 min; P < 0.05). Patients in the parecoxib/valdecoxib group also had reduced pain intensity and, after discharge, experienced a significant reduction in vomiting in the first 24 h, slept better, returned to normal activity earlier, and expressed greater satisfaction than placebo patients (P < 0.05). Preoperative parecoxib followed by postoperative valdecoxib is a valuable adjunct for treating pain and improving patient outcome after laparoscopic cholecystectomy.

IMPLICATIONS: The administration of preoperative IV parecoxib followed by oral valdecoxib after surgery resulted in a shorter length of stay in the postoperative anesthesia care unit, a better quality of postoperative recovery, and a faster return to normal activity, with greater patient satisfaction, after laparoscopic cholecystectomy.

	Introduction

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Minimally invasive surgery, such as laparoscopic surgery, is one of the rapidly expanding fields of surgery (1). An increasing number of laparoscopic procedures, including laparoscopic cholecystectomy surgery (LCS), are now performed on an outpatient basis (2). The growth in outpatient surgical procedures has forced ambulatory surgical facilities to increase their efficiency. Postoperative complications, such as pain, nausea, and vomiting, have been shown to significantly affect the recovery process and delay discharge from the postanesthesia care unit (PACU) and discharge home (3–5). Pain is a key independent predictor of recovery time, and patients who require additional postoperative analgesics are discharged later than those who do not require additional analgesic therapy (5).

Numerous clinical studies indicate that pain after LCS is not always effectively treated, and the incidence of postoperative nausea and vomiting (PONV) may be as frequent as 70% (6). The pain associated with LCS is usually managed with parenteral and oral opioids. Although these drugs provide a rapid onset of action, they are associated with side effects in the postoperative period, such as somnolence, PONV, constipation, clouded sensorium, and respiratory depression (7). Such adverse effects not only are distressing to the patient, but also can delay discharge (8). Therefore, non-opioid analgesics are increasingly used in the perioperative period (9–11).

Cyclooxygenase (COX)-2 specific inhibitors lack many of the side effects associated with nonspecific nonsteroidal antiinflammatory drugs (NSAIDs) because they spare the COX-1 enzyme and have no clinically significant effect on platelet or gastrointestinal function (12,13). Parecoxib sodium (parecoxib) is the parenterally administered prodrug of valdecoxib, a potent, orally administered COX-2 specific inhibitor. In vivo parecoxib is rapidly hydrolyzed to valdecoxib. Both drugs have demonstrated opioid-sparing analgesic efficacy in postoperative pain settings (14,15), and both lack the gastrointestinal and platelet safety issues associated with nonspecific NSAIDs such as ketorolac (12,13,16).

The efficacy and safety of parecoxib and valdecoxib to treat pain and reduce opioid consumption after LCS have been reported (17). However, there is a paucity of data on resource utilization and quality of recovery after this surgery. We report the results of health outcome measures evaluated in this study to assess the effect of a single preoperative dose of parecoxib 40 mg IV followed by up to 7 days of oral valdecoxib 40 mg when compared with placebo (in addition to standard-of-care opioid analgesia) on the following: length of stay (LOS), in-hospital resource utilization to manage pain, and patient recovery with respect to functional recovery, side-effect experience, patient satisfaction, and pain interference with daily activities.

	Methods

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This was a multicenter study conducted in 24 centers in North America. After local independent review board approval and signed informed patient consent, adult patients aged between 18 and 75 yr with ASA physical status I, II, and III who were scheduled to have elective cholecystectomy as outpatients were enrolled. Patients were excluded from participation if they had clinically diagnosed acute pancreatitis, required urgent or emergent cholecystectomy, had acute preoperative pain other than biliary colic, had a chronic pain condition requiring chronic treatment, had active gastrointestinal bleeding or upper gastrointestinal ulceration, had been treated in the last 6 mo for any cancer other than basal cell carcinoma, or had any condition that would contraindicate participation in a surgical study of this nature.

On the day of surgery (Day 0), patients were randomized to receive either treatment or placebo. Premedication consisting of midazolam 1–2 mg was administered to all patients. In addition, patients received a single IV dose of either parecoxib 40 mg or placebo, in a double-blinded fashion, 30–45 min before the induction of anesthesia. 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. All patients were given a single dose of prophylactic ondansetron 4 mg IV, and anesthesia was maintained with sevoflurane 2%–3% end-tidal concentration. No local anesthetic was administered. Twenty minutes before the anticipated end of surgery, sevoflurane concentration was reduced, and neuromuscular blockade was reversed with neostigmine 70 µg/kg and glycopyrrolate 0.05 µg/kg IV. The tracheal tube was removed after the patient had regained consciousness and was able to maintain adequate ventilation and follow commands. The time of waking was defined as when patients were first able to open their eyes on command after extubation.

Patients were transferred to the PACU, where the protocol specifically asked sites to keep patients for the entire period of visual analog scale (VAS) pain assessments (or as long as possible) so as not to confound data collected with movement. When patients requested additional analgesia, 25-µg doses of fentanyl were administered and titrated to comfort. Additional ondansetron 4 mg was used as a rescue antiemetic if requested. No steroids, NSAIDs, or local/regional nerve blocks were used during the study.

Patients received their first oral dose of valdecoxib 40 mg or placebo on the day of surgery, between 6 and 12 h after the IV dose of study medication. Patients receiving IV parecoxib were assigned to receive oral valdecoxib, and those receiving IV placebo also received oral placebo. On postoperative Days 1–4, patients took oral valdecoxib 40 mg or placebo once daily in the morning, regardless of the pain they were experiencing. From Days 5 to 7, patients took their assigned oral study medication only as needed. Patients and study personnel were blinded as to which treatment patients were receiving. From Day 0 to 7, patients who experienced insufficient pain relief were allowed to take supplementary hydrocodone 5 mg/acetaminophen 500 mg (Vicodin®; 1–2 tablets orally every 4–6 h as needed; a total of 6 tablets on Day 1 and up to 8 tablets per day thereafter). Four clinical efficacy variables were identified for this study and are reported elsewhere (17): the proportion of patients who took fentanyl during the early postoperative period (0–240 min in the PACU), time to the first dose of fentanyl in the PACU, the amount of fentanyl consumed during the early postoperative period (0–240 min in the PACU), and time-specific pain intensity (PI) VAS area under the curve (AUC_0–24) during the early postoperative period (0–240 min in the PACU) (17).

In addition, the following health outcome measures were evaluated during this study: LOS was assessed by the time to discharge on the basis of predefined criteria for transfer from the PACU to the step-down unit or for discharge home. Eligibility for transfer from the PACU was assessed by the Aldrete scoring system, which assigns a score of 0, 1, or 2 to activity, respiration, circulation, color, and consciousness, with a score of 9 indicating eligibility for transfer from the PACU. Eligibility for discharge was based on the Postanesthesia Discharge Scoring System (recorded every 15 min), which assigns a score of 0, 1, or 2 to the vital signs activity level, PONV, pain and surgical bleeding, time to voiding, retention of oral fluids, ability to dress, and ability to walk without assistance. Patients had to score 9, be able to take oral fluids, and pass urine before discharge. Also, reasons for patients not being discharged within 30 min of being in the PACU were requested.

At 240 min after surgery, an in-hospital resource utilization survey was used to record the extent of symptoms experienced (pain, nausea, vomiting, respiratory depression, urinary retention, rash, dyspepsia, and sedation), the amount of time spent managing these symptoms (not applicable or number of minutes), and the types of activities needed to manage these episodes (not applicable, nothing, anesthesiology consult/call, surgical consult/call, other medical services consult/call, additional laboratory tests, additional diagnostic procedures, other drug treatment, or other nondrug treatment).

Throughout Days 1–7, patients used a diary to record any adverse events experienced and all medications taken, including supplemental analgesia. On Days 1 and 2, detailed patient recovery information reflective of the prior 24 h was collected via telephone calls placed by study personnel. On subsequent days, patients recorded recovery information at home in patient diaries. Information from the modified Brief Pain Inventory-short form (mBPI-sf) was collected from the patient diary on each postdischarge day (patients were asked only about items relevant to acute pain). At the Day 7 visit, the patient diary was collected and reviewed with the patient by research personnel.

In the hospital, patients’ pain was assessed at predefined intervals by using the VAS measured on a scale of 0–100 mm, where 0 = no pain and 100 = worst possible pain, and maximum PI was assessed with a categorical scale on a four-point scale, where 1 = no pain and 4 = severe pain; the primary pain efficacy end-point was assessed 240 min after surgery. Postdischarge pain was assessed with the mBPI-sf, which was completed by the patient every evening and referred to the previous 24-h period. This questionnaire assessed PI and the interference of pain with various daily activities by using a 0–10 numerical rating scale, where 0 = none and 10 = worst possible (Appendix 1) (18). The "frequency," "severity," and "bothersomeness" of each symptom were also recorded (Appendix 1).

The Health Outcomes Recovery Survey (HORS) was administered by telephone on Days 1 and 2. An abbreviated form was completed as a diary on Days 3–7 at bedtime. Each evaluation assessed the following: the percentage of patients who experienced pain; difficulty sleeping because of pain; waking from sleep because of pain; nausea; and vomiting in the previous 24-h period. The HORS also measured patients’ ability to eat and drink (five-point scale where 1 = nothing in 24 h and 5 = normal solids/liquids) and problems voiding (three-point scale where 1 = able to void normally and 3 = not able to void normally) within each 24-h period, as well as their daily activity levels. Patients were asked to report how many of their normal activities they were able to perform, where 100% = full activity and 0% = no activity. Each day patients were also asked to rate their maximum activity level within the last 24 h on a five-point scale, where 1 = normal activity and 5 = sleeping, and were asked to report the reason for their activity being less than normal (pain, nausea, vomiting, by choice, fatigue, surgeon’s orders, and other).

Patient satisfaction with study medication with respect to pain relief and the overall performance of the study pain medication was evaluated at 240 min in the hospital and on Days 1, 2, and 7 with a categorical scale, where they rated themselves very dissatisfied, somewhat dissatisfied, slightly dissatisfied, neither satisfied nor dissatisfied, slightly satisfied, somewhat satisfied, or very satisfied.

The sample size for this study was based on the assumption that, compared with placebo, parecoxib would produce a reduction in PI AUC_0–240 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, a total of 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 otherwise specified. Analyses of pretreatment data included all patients who were randomized and took at least one dose of study medication.

All analyses were performed on the intent-to-treat population, which included all patients who were randomized into the study and received at least one dose of study medication. Multivariate comparisons of LOS between treatment groups were performed with one-way analysis of variance. For categorical variables expressed as percentages of patients, groups were compared by using Fisher’s exact test. Resources used to manage symptoms in the early postoperative period were summarized as categorical variables and analyzed with Fisher’s exact test. Responses to the HORS on Days 1–7 were summarized as categorical variables and were analyzed with Fisher’s exact test. The mBPI scores were analyzed by using one-way analysis of variance with treatment as the variable factor. In all statistical analyses, the Type I error for hypothesis testing was set at 0.05, and all tests were two sided unless otherwise specified.

	Results

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A total of 276 patients were randomized: 134 in the parecoxib group and 129 in the placebo group received treatment, and 13 patients did not take any study medication. There was no statistically significant difference in patient demographics between the two groups (Table 1). As previously reported, maximal PI (categorical) and AUC of VAS PI within 4 h of waking were significantly reduced in the parecoxib group compared with placebo (P = 0.031 and P = 0.083, respectively), and patients in the parecoxib group also required 21% less fentanyl (P = 0.011) (17).

In the immediate postoperative period (0–4 h), fewer resources were used to manage pain in the parecoxib/valdecoxib group. Also, fewer patients in this group required consultation with an anesthesiologist (9% versus 13%) and nonpharmacologic treatments (0.8% versus 5%) to manage pain. Postdischarge, fewer parecoxib/valdecoxib patients sought surgery-related consultation with a health professional compared with placebo patients on Day 1 (4% versus 11%, respectively; P < 0.05), and fewer patients in this group required assistance at home on Day 2 of the study period (29%) compared with placebo patients (44%) (P< 0.05).

Compared with placebo patients, patients in the parecoxib/valdecoxib group demonstrated statistically significantly improved mBPI-sf scores for each measure of postoperative pain (pain now, average pain, and worst pain) on postoperative Days 0–5 (Fig. 1). Patient responses relating to interference of pain with general activity and walking were also significantly improved in the parecoxib/valdecoxib-treated patients from Days 0 to 5 compared with placebo patients (Fig. 2). Pain frequency, severity, and bothersomeness were also significantly less on Days 1 and 2 in the parecoxib/valdecoxib group (frequency, P < 0.05 on both days; severity, P < 0.01 on Day 1; bothersomeness, P < 0.001 on Day 1 and P < 0.05 on Day 2).

View larger version (18K): [in this window] [in a new window]   Figure 1. Modified Brief Pain Inventory-short form. Patients recorded (a) pain now, (b) average pain, and (c) worst pain within each 24-h period on a 10-point scale where 0 = none and 10 = worst possible pain. Observed scores (mean ± SD) were calculated for responses to each question on postdischarge Days 0–7. Patients who received parecoxib/valdecoxib reported significant improvements for pain now, average pain, and worst pain on Days 0–5 after surgery (P < 0.05).

View larger version (20K): [in this window] [in a new window]   Figure 2. Modified Brief Pain Inventory-short form (mBPI-sf). Patients recorded the interference of pain with their (a) general activity and (b) walking ability within each 24-h period on a 10-point scale where 0 = none and 10 = worst possible pain. Observed scores (mean ± SD) were calculated for each question on postdischarge Days 0–7. Patients who received parecoxib/valdecoxib reported significant improvement in (a) general ability and (b) walking ability compared with those who received placebo on Days 0–5 after surgery (P < 0.05).

View larger version (38K): [in this window] [in a new window]   Figure 3. Patient activity levels. Patients who received parecoxib/valdecoxib reported significant improvement in activity levels after surgery compared with the placebo group: they reported significant improvement (a) in the overall percentage of their normal daily activities that they were able to perform (0%–100%) on Days 0 through 5 (P < 0.01) and (b) in activity levels (categorical) on Days 1 (P < 0.001) and 2 (P < 0.01).

View larger version (32K): [in this window] [in a new window]   Figure 4. Overall patient satisfaction with study medication at 4 h and on Days 1, 2, and 7 after surgery. Patients who received parecoxib/valdecoxib reported a significant improvement in satisfaction with their study medication compared with the placebo group at 4 h after surgery (P < 0.05) and on Day 1 (P < 0.05), Day 2 (P < 0.01), and Day 7 (P < 0.05) postdischarge.

	Discussion

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COX-2 specific inhibitors have been shown to be important in postoperative adjunctive analgesic regimens (19–21). In different surgical models, COX-2 specific inhibitors have demonstrated efficacy and a longer duration of action when compared with opioid-containing oral analgesics. In a large study of patients undergoing oral surgery, a single dose of valdecoxib 40 mg was as effective as oxycodone 10 mg/acetaminophen 1000 mg but had the advantage of a longer duration of analgesic effect (20). COX-2 specific inhibitors have similarly demonstrated equivalent efficacy to nonspecific NSAIDs. In a placebo-controlled study, single doses of parecoxib 20 or 40 mg and ketorolac 30 mg demonstrated equal or superior analgesia when compared with single doses of morphine 4 mg and placebo (22,23).

Opioids are associated with numerous side effects that may result in significant patient discomfort and a delay in fast-tracking and home discharge (24). PONV, a common side effect associated with opioid use, is one of the most unpleasant symptoms rated by patients (25), and patients would be willing to pay up to US$100 out of pocket for an effective antiemetic (26). The incidence of opioid-related adverse events depends on variables such as the route of administration, the type and duration of surgery, patient age, and concomitant medication (8), but their consistent occurrence in hospitalized patients increases LOS and total hospital costs (27).

PONV is the main cause of delay in discharge home and of unanticipated hospital admission after ambulatory surgery (7). Other opioid-related side effects include urinary retention, pruritus, respiratory depression, drowsiness, and sleeping disturbances. COX-2 specific inhibitors have demonstrated opioid-sparing properties without compromising pain relief in many studies (14,15). The reduced requirement for opioids or opioid-containing analgesics may account for many of the findings in this study, in which the parecoxib/valdecoxib group demonstrated better analgesia, a reduction in opioid consumption by 21% in the immediate postoperative period, and a reduction in the need for rescue analgesics up to five days postdischarge (17).

LOS after outpatient surgery is one of the major outcome measures and has significant pharmacoeconomic consequences (25,28). Therefore, time spent in the hospital is becoming an increasingly relevant issue from both a clinical and cost standpoint. Because clinical trials are protocol driven, we sought to use a different approach to measure LOS. By asking clinicians when they would have discharged the patient, we tried to overcome this limitation. On the basis of that assessment, this study demonstrates that IV administration of parecoxib 40 mg before LCS reduces time in the PACU. Additionally, fewer resources were used during the recovery period in the hospital.

LOS as a final outcome measure can be difficult to quantify accurately because it represents the composite of multiple intermediate variables, including pain, nausea, vomiting, sedation, and self-care. LOS can also be influenced by variables such as staffing, practice patterns, and patient or provider preference (29). Patients in the parecoxib/valdecoxib group met transfer criteria from the PACU unit earlier than those taking placebo, and more patients in this group were deemed ready for transfer within 30 minutes after the end of surgery. Factors resulting in delay in discharge of ambulatory patients have been examined previously (3–5). Pavlin et al. (4) reported that determinants of discharge time include anesthetic technique, drowsiness, pain, nausea, and vomiting. Additionally, system factors can play a significant role in Phase II delays (41% in the Pavlin et al. study), which we tried to overcome by assessing the time at which patients met discharge criteria.

The most significant effect of treatment was seen in postdischarge recovery up to seven days. Symptoms occurring after discharge have an important effect on both patient recovery and the economic burden on patients and their caregivers (30). This study demonstrated that the addition of COX-2 specific inhibitors improves pain relief, the quality of recovery, and normal daily activity. Also, the improvement in resumption of normal activity in the parecoxib/valdecoxib group showed consistency within the variety of ways it was measured (mBPI, 0%–100% scale, and categorical scale). Pain after discharge can be disabling and can impair the recovery process. Previous studies have reported an incidence of moderate to severe postdischarge pain of up to 80% (31). Moreover, nearly one third of patients in the treatment arm resumed normal or light activity outside as early as Day 1 (versus 7% in the placebo arm). By Day 2, more than 50% were functioning normally or were able to perform light activity outside, versus only 36% in the placebo group. This can potentially provide a savings to society, because patients and care providers may be able return to work earlier.

In this study, fewer treatment patients sought a consultation with a health care professional compared with those who received placebo. This may be due to reduced pain scores and a reduction in opioid-related side effects. The reduction in medical consultations in the parecoxib/valdecoxib group may also have reduced health care costs.

There are limitations to this study. In practice, institutional and clinician variation, as well as system factors and protocol-driven artifacts, can obscure "true" differences in resource use, although we did see positive results in LOS in this study. Additionally, we did not compare the use of COX-2 specific inhibitors with traditional NSAIDs, such as ketorolac, which also exhibits opioid-sparing properties and improved postoperative analgesia (28). However, because of its inhibitory effects on platelets, ketorolac is relatively contraindicated before surgery because of the risk of bleeding (32). Even a single dose of ketorolac inhibits platelet aggregation (33), which may increase bleeding during and after surgery (34). Also, routine clinical practice limits the postoperative use of ketorolac to three to five days (oral and parenteral combined) because of an increase in gastrointestinal side effects, including ulcers, and operative site bleeding. Indeed, one study (35) suggests that the risk of gastrointestinal bleeding is increased with even short-term use of ketorolac in the elderly population.

In conclusion, the administration of parecoxib given before surgery and continued with oral valdecoxib after surgery resulted in a better quality of postoperative recovery, fewer opioid-type side effects, and a faster return to normal activity, with greater patient satisfaction, after LCS.

	Acknowledgments

 
This study was supported by Pfizer Global Pharmaceuticals and Pharmacia Corporation.

	References

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				V. Martinez, A. Belbachir, A. Jaber, K. Cherif, A. Jamal, Y. Ozier, D. I. Sessler, M. Chauvin, and D. Fletcher The Influence of Timing of Administration on the Analgesic Efficacy of Parecoxib in Orthopedic Surgery Anesth. Analg., June 1, 2007; 104(6): 1521 - 1527. [Abstract] [Full Text] [PDF]

				R. Pollak, G. A. Raymond, R. M. Jay, H. J. Hillstrom, K. T. Mahan, D. Riff, E. L. Jacobs, M. T. Brown, and K. M. Verburg Analgesic efficacy of valdecoxib for acute postoperative pain after bunionectomy. J Am Podiatr Med Assoc, September 1, 2006; 96(5): 393 - 407. [Abstract] [Full Text] [PDF]

				T. J. Gan Risk factors for postoperative nausea and vomiting. Anesth. Analg., June 1, 2006; 102(6): 1884 - 1898. [Abstract] [Full Text] [PDF]

				P. F. White Safety of Cox-2 Selective Nonsteroidal Antiinflammatory Drugs for Postsurgical Pain Anesth. Analg., February 1, 2006; 102(2): 646 - 646. [Full Text] [PDF]

				S. S. Liu, W. M. Strodtbeck, J. M. Richman, and C. L. Wu A Comparison of Regional Versus General Anesthesia for Ambulatory Anesthesia: A Meta-Analysis of Randomized Controlled Trials Anesth. Analg., December 1, 2005; 101(6): 1634 - 1642. [Abstract] [Full Text] [PDF]

				M. Beaussier, H. Weickmans, C. Paugam, S. Lavazais, J. P. Baechle, P. Goater, A. Buffin, J. F. Loriferne, J. F. Perier, J. P. Didelot, et al. A Randomized, Double-Blind Comparison Between Parecoxib Sodium and Propacetamol for Parenteral Postoperative Analgesia After Inguinal Hernia Repair in Adult Patients Anesth. Analg., May 1, 2005; 100(5): 1309 - 1315. [Abstract] [Full Text] [PDF]

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