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PAIN MEDICINE

Patients’ Global Evaluation of Analgesia and Safety of Injected Parecoxib for Postoperative Pain: A Quantitative Systematic Review

Peter Kranke, MD^*, Astrid M. Morin, MD DEAA, Norbert Roewer, MD^*, and Leopold H. Eberhart, MD

*Department of Anesthesiology, University of Würzburg, Germany; and Department of Anesthesiology, University of Marburg, Germany

Address correspondence and reprint requests to Peter Kranke, MD, Department of Anesthesiology, University of Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany. Address e-mail to kranke_p{at}klinik.uni-wuerzburg.de

	Abstract

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Parecoxib is the only parenterally administered cyclooxygenase-2-selective inhibitor available. We performed a systematic review, including full reports of randomized comparisons of parecoxib compared with any other analgesic intervention for prophylaxis or treatment of postoperative pain. Dichotomous data on patients’ global evaluation of their analgesic regimen were extracted by means of the fraction of patients who rated their medication as "good" or "excellent." For safety analysis, data on any reported adverse effects were extracted. Relative risk (RR), number needed to treat (NNT), or number-needed-to-harm were calculated with 95% confidence intervals (CI). Data from 9 trials of 50 initially screened were finally analyzed. One thousand thirteen patients were randomized to receive parecoxib, 218 patients were allocated to an active control, and 507 patients received a placebo. With prophylactic administration, the pooled NNT to obtain the desired outcome ("good"/"excellent" rating) with parecoxib 20 and 40 mg compared with placebo was 4.5 (RR, 1.42; 95% CI, 0.91–2.24) and 4.0 (RR, 1.40; 95% CI, 1.10–1.79), respectively. In the treatment trials, the NNT to obtain the outcome of interest with parecoxib 20 mg was 2.1 (RR, 3.44; 95% CI, 1.49–7.96), 5.3 (RR, 1.43; 95% CI, 1.01–2.02), and –8.3 (RR, 0.85; 95% CI, 0.75–0.97) for the comparisons with placebo, morphine, and ketorolac, respectively. The corresponding NNT for treatment with parecoxib 40 mg was 1.7 (RR, 4.65; 95% CI, 2.04–10.61), 3.7 (RR, 1.62; 95% CI, 1.21–2.16), and 50 (RR, 1.03; 95% CI, 0.89–1.18) for the comparisons with placebo, morphine, and ketorolac, respectively. Overall adverse effects for parecoxib 20 and 40 mg were not different from those with placebo, morphine, or ketorolac. These results suggest a favorable profile for parecoxib compared with inactive or active controls. The optimal dose, timing, and frequency of administration need to be determined.

IMPLICATIONS: Parecoxib significantly improved patients’ global evaluation with the study medication compared with placebo when it was used for prophylaxis and treatment of perioperative pain. In the treatment of pain, the tolerability and efficacy of parecoxib 40 mg in terms of patients’ global evaluation were comparable to those with 30–60 mg of ketorolac.

	Introduction

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In addition to opioid analgesics, nonsteroidal antiinflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX) enzymes, which are involved in the synthesis of prostaglandins, have been established as useful adjuncts in the management of pain (1). Nonselective NSAIDs block both COX-1 and COX-2. COX-2 activation is thought to be responsible for proinflammatory prostanoid production, whereas COX-1 activation is thought to be involved in homeostatic prostanoid synthesis (2).

Nonselective COX-1 inhibitors may alter platelet function and may lead to increased perioperative bleeding. Gastrointestinal and wound bleeding may be why clinicians are reluctant to use NSAIDs in the perioperative period, even for minor surgery. Furthermore, most NSAIDs are inconvenient to administer. The oral route may be unavailable (e.g., during general anesthesia) for medication administration. The use of suppositories is inconvenient for both patients and staff. The efficacy of NSAIDs, however, would encourage a more widespread use (3).

The introduction of COX-2-selective inhibitors such as celecoxib, rofecoxib, and valdecoxib may overcome some of these limitations, and the gain in safety has been demonstrated in controlled trials (4). For perioperative use, the injectable parecoxib, a water-soluble prodrug that undergoes complete and rapid biotransformation to valdecoxib, is suitable when there is need for an analgesic in surgical patients who cannot tolerate oral medication or in whom oral medication is contraindicated.

The clinical studies included in this systematic review often involve a basic analgesic regimen that consists of an NSAID or COX-2 inhibitor that is supplemented by unrestricted access to rescue medication—for instance, via self-administered (patient-controlled analgesia; PCA) or nurse-administered pain control with opioids.

The effect of injected parecoxib on pain relief in placebo-controlled trials has been evaluated by using the proportion of patients with at least 50% pain relief over 4 to 6 h (5). Cumulative data on patient-related outcome descriptions are lacking, although this aspect might become more important in obtaining the true value of interventions that should improve patient well-being. The aim of this systematic review was to evaluate the efficacy and harm of parenteral parecoxib versus active comparators or inactive control for the treatment or prophylaxis of postoperative pain by means of patients’ global evaluation with the applied analgesic regimen and the observed incidence of adverse effects.

	Methods

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The study was performed in accordance with the QUORUM statement (Quality of Reporting of Meta-Analyses) for conducting systematic reviews (6). Features not described extensively were comparable to other analyses on related topics of perioperative care (7,8).

Relevant studies were full reports of randomized, double-blinded comparisons of IV or IM injected parecoxib compared with placebo or any other analgesic regimen for acute postoperative pain. Outcomes of interest were patients’ global evaluation of the applied analgesic regimen measured on a four-point Likert scale ("good," "excellent," "fair," or "poor") or a visual analog scale. Dichotomous data were derived by

1. Using the fraction of patients who rated their analgesic regimen as either good or excellent. In terms of the patients’ global evaluation, this means that the binary outcome of interest was patients who rated the postoperative analgesia "good" or "excellent" as compared with "poor" and "fair." Patients’ global evaluations of analgesic regimens close to the 24-h observation period were used for further analyses.
   
2. Using all information on any observed adverse effects as stated by the included articles and on distinct adverse effects as reported in the studies. We analyzed the number of patients with any observed adverse event only if the study reported exactly that outcome. Calculation of "overall adverse events" on the basis of distinctive symptoms may be misleading because of the occurrence of more than one symptom in a single patient.
   

We searched MEDLINE, EMBASE, CENTRAL within the Cochrane Library, and the Science Citation Index up to June 2003. "Parecoxib" was the free text search term. The German manufacturer of parecoxib (Dynastat®; Pfizer GmbH, Karlsruhe, Germany) was contacted and asked for additional references. All relevant references and review articles were examined for potential additional references.

All retrieved reports were screened by one author. Irrelevant data were excluded at this stage. Potentially relevant reports were then read by at least two other authors to assess the adequacy of randomization, blinding, description of withdrawal, and, finally, scoring according to the validated 3-item, five-point Oxford scale as in previous analyses (9).

We graphically explored the interstudy variability and analyzed the robustness of the results for clinically homogeneous subgroups by using L’Abbé plots. No further statistical testing of heterogeneity was performed because these tests were not helpful (10). Separate analyses were performed for different doses. It was intended to pool IV and IM regimens if no obviously different efficacy could be detected. Repetitive dosing regimens (e.g., overall three or four doses administered in intervals of 12 h) were grouped together with the single- or double-dose regimen because patients’ global evaluation of the study medication was measured within a time interval (24 h) in which even a single dose should exert some analgesic effects, considering the elimination half-life of 8–11 h (11). Furthermore, the restriction of the analysis of the patients’ assessment near 24 h after surgery guarantees that even the studies that used multiple dosing regimens did not administer three or four times the amount of parecoxib as the single-dose prophylaxis study. This approach is useful to answer the question of whether patients have rated parecoxib as good or excellent, but it does not answer the question of how much parecoxib needs to be given in 24 h for patients to rate treatment as good or excellent. Trials that investigated parecoxib given as prophylactic analgesia before the patients’ request and in the subsequent time period at distinct intervals were analyzed separately from trials in which parecoxib was first administered at the patients’ request or if a certain pain level was present.

Data entry and statistical calculations were performed with the computer program Review Manager 4.2, provided by the Cochrane Collaboration. A random-effects model was applied to calculate relative risks (RR) and numbers needed to treat (NNT) with 95% confidence intervals (CI).

	Results

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A search in the electronic databases revealed 50 hits overall. Exclusion of trials that did not match the inclusion criteria was unambiguous. All trials that were judged relevant on the basis of the information given in the abstract were finally included. The pharmaceutical company did not provide additional relevant references. We eventually analyzed data from nine randomized trials (Table 1). In those trials, including 1738 subjects, 1013 patients had been randomized to receive parecoxib, 218 patients had been allocated to an active control (morphine 4 mg, n = 84; ketorolac 30 and 60 mg, n = 134), and 507 patients had received a placebo. In all trials, access to rescue medication (consisting of NSAIDs or opioids via nurse-administered bolus doses or PCA) was accessible. In six of the nine studies, the medication was administered for prophylaxis (12–17), for instance, during the induction of anesthesia. In the remaining three studies, the study medication (parecoxib versus an active or inactive control) was given as a treatment when there was need for postoperative analgesia. In these cases, medication was usually repeated every 12 h in the subsequent period to constitute the basis of an available regimen of rescue analgesia with NSAIDs or opioids on patient request. Doses of 20 mg (n = 7 trials) and 40 mg (n = 9 trials) of parecoxib were investigated in most of the trials, whereas one study reported efficacy of 80 mg (12). Summary analyses could not be conducted if information was available from only a single small trial or one comparison. This applies to the comparison with a bolus dose of parecoxib 80 mg and some reported adverse events. One trial investigated IM parecoxib (18). The obtained data were analyzed and summarized with the respective dosages given via the IV route. Key study characteristics, including doses, surgical sites, patient characteristics, and quality scores of the reported methodology, are summarized in Table 1.

Dichotomous data on the patients’ global evaluation of study medication could be obtained from all but one article (15). This article was included for analysis of adverse effects. In one article (16), the patients’ global evaluation with analgesia was assessed when IV administration was changed to oral administration 72 h after the initiation of treatment and for the entire period. Assessment was subsequently repeated, and a range of "excellent" and "good" ratings was presented in the article, but no ratings for distinct time intervals were given. We decided not to exclude the study, because the range was very small, but we further analyzed the presented data assuming a worst-case (i.e., low efficacy of parecoxib) and best-case (i.e., high efficacy of parecoxib) scenario for the assessment of interest because no precise data could be obtained.

All 17 comparisons of IM or IV injected parecoxib versus placebo across all doses and regimens (prophylaxis or treatment) showed better overall patient global evaluations with the study medication (Fig. 1A). In one comparison (14), 20 mg of IV parecoxib, when administered as prophylaxis, was as effective as placebo for yielding the desired outcome (Fig. 1A).

View larger version (21K): [in this window] [in a new window]   Figure 1. L’Abbé plots of trials investigating patients’ global evaluation of study medication with parecoxib versus placebo (A) and morphine or ketorolac (B). Symbols represent the ratios of patient ratings of "good" or "excellent" between parecoxib and control. The line with a 45° slope indicates equality. P = prophylaxis; T = treatment.

Only two trials were eligible for inclusion that dealt with the comparison of 20 or 40 mg of injected parecoxib versus 4 mg of morphine given as an analgesic treatment. All four comparisons with both investigated doses of parecoxib showed a better effect with parecoxib compared with morphine, and the use of parecoxib was more frequently associated with the desired outcome of interest ("good" or "excellent" patients’ global evaluation of study medication) (Fig. 1B). The RR of 1.43 (95% CI, 1.01–2.02) for 20 mg and 1.62 (95% CI, 1.21–2.16) for 40 mg of parecoxib versus 4 mg of morphine suggests a significant effect of parecoxib and could be translated in the given setting to an NNT of 5.3 and 3.7, respectively (Table 3), indicating that 40 mg of the drug might be more effective.

It is of note that all observed effects were analyzed. This does not necessarily mean that all effects were treatment-related. In addition, this could well mean that certain interventions possess additional beneficial effects apart from providing analgesia (for instance, reduced fever or decreased headache).

When the overall incidence of any observed adverse effect was compared between treatment with parecoxib and placebo, there was no difference between groups (Table 5). The same results were obtained if the two investigated dosages of parecoxib were analyzed separately.

There were fewer reports of adverse effects with parecoxib compared with morphine, but there was no statistically significant difference between groups (RR, 0.89; 95% CI, 0.73–1.10). The same applies for somnolence, which was less frequent in the parecoxib group, but without statistical significance (RR, 0.45; 95% CI, 0.11–1.82). Again, the incidence of fever was significantly reduced when patients received parecoxib instead of morphine (RR, 0.27; 95% CI, 0.12–0.62).

The incidence of any adverse effect between parecoxib and ketorolac across all doses was comparable. The RR for the cumulative incidence of adverse effects was 0.93 (95% CI, 0.85–1.01) across all trials and doses (Table 5). However, as shown with the previous analyses, the incidence of fever was reduced by the administration of parecoxib compared with ketorolac (RR, 0.15; 95% CI, 0.07–0.33). No incidence of other adverse effects differed significantly between the parecoxib- and ketorolac-treated patients. Pooled RRs for the occurrence of distinct adverse effects between groups are presented in Table 5.

	Discussion

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This quantitative systematic review pooled data from randomized trials that used comparable methods and one important patient-centered outcome: the patients’ global evaluation of study medication. This was assessed at distinct comparable time intervals, and analyses are based on the assessment near 24 hours after the first administration of the investigated analgesic regimen. All identified trials used the same outcome on an identical Likert scale ("poor," "fair," "good," or "excellent"). This makes the data eligible to be included into a meta-analysis and ensures that homogeneous data are pooled and that apples are not compared with oranges.

Together with an analysis of the observed adverse effects, the patients’ view allows a good approximation of the balance between benefit and harm. The main findings of the review are as follows:

1. Patients are more likely to rate the prophylactic analgesic regimen as "good" or "excellent" when parecoxib is given compared with placebo and morphine.
   
2. With treatment trials, it is easier to show whether parecoxib works and to differentiate between interventions. In the preventive trials, the fact that we do not know how much pain, if any, patients will have after surgery leads to the observed phenomenon that parecoxib is judged better when given as treatment. Thus, patients’ global evaluation with parecoxib compared with placebo is better when patients receive treatment when they experience acute pain compared with prophylactic treatment, even though unrestricted rescue analgesics were guaranteed in all trials.
   
3. Injected parecoxib (40 mg) can substitute for ketorolac 30–60 mg and is equally effective in terms of patients’ global assessment when it is used as treatment for postoperative pain.
   
4. Parecoxib appears not to cause more adverse effects than placebo and other active analgesics (i.e., morphine or ketorolac) when used for prophylaxis and treatment.
   
5. When parecoxib was used for prophylaxis of postoperative pain, the resulting baseline analgesia associated with the use of parecoxib was correlated with better patients’ global evaluation. Interestingly, this was not necessarily correlated with an obvious decrease of adverse effects in the parecoxib group (less nausea due to a potential opioid-sparing effect, for instance).
   
6. The investigated outcome of patients’ global evaluation with the study drug and the dichotomous analysis of patients rating the treatment "good" or "excellent" rather than "fair" or "poor" seem to be valuable end-points for the investigated setting and are sensitive for differences between treatment groups.
   

Because the statistical technique of combining results from randomized controlled trials in quantitative systematic reviews is well established and because there are increasingly more articles that use this method to improve the level of confidence, we focus on two major issues that arise from this meta-analysis.

Choosing a Relevant Clinical Outcome.
The use of NSAIDs in the investigated pain models was not able to totally abolish the need for rescue analgesia, usually IV-administered opioids. Taking into account that most of the trials were performed with major abdominal or orthopedic surgery patients, this could be expected. In this case, the use of surrogate outcomes such as opioid consumption is widespread. The underlying assumption is that by preventing the need for rescue analgesics, usually narcotics, patients experience fewer opioid-related side effects and thus feel better in the postoperative period. Because opioids have a unique safety profile and are easy to titrate according to individual need, this is a valid concept only if patients judge the quality of their balanced analgesic regimen better than the conventional one, relying, for instance, solely on morphine administered via a PCA device. Even the need for more rescue treatment per se does not necessarily reflect dissatisfaction with the regimen if the patients are able to control the situation by themselves.

Consequently, it seems worthwhile to let patients decide what they think about the pain management as a type of "true outcome." This concept bears the risk that, from a theoretical point of view, it is conceivable that satisfaction as judged by patients is not necessarily accompanied with real analgesic effects. One might argue that a drug that primarily enhances the patient’s mood would be judged superior to an effective but not mood- or vigilance-influencing drug. However, once the ability to relieve pain and not only to enhance the patient’s mood is established, it seems sensible to encourage such outcomes and to test whether our supposed achievements, in terms of pain relief and related outcomes (5), correlate with a real benefit in the patient’s view, as expressed by the patient’s global evaluation. Pain relief with parecoxib compared with placebo has been tested by using the total-pain-relief method and then obtaining an NNT with the calculated proportion of patients in each treatment group who achieved at least 50% of maximum possible pain relief (5). The investigation concerning whether improved patients’ global evaluation with parecoxib observed in single trials is robust, and, thus, to overcome the threat of random chance, is a typical area of application for meta-analyses because it has been shown that many patients are needed for credible estimates of the NNT or other related outcomes (19).

A popular and reliable tool for assessing a patient’s view is the four-point Likert scale (20). Such a scale is furthermore an appropriate means for use in analgesic trials because a satisfying correlation of a dichotomous end-point on a five-point Likert scale with actual observed pain relief has been demonstrated (21).

The fact that all trials consistently used the same scale for their assessment, thus keeping the variability between trials as small as possible, means that the patients’ global evaluation of study medication is an ideal dichotomous outcome when a separation between the proportion of patients being rather dissatisfied versus satisfied is performed. A good correlation between these patient-related subjective results and objective ones (for instance, at least 50% pain relief or remedication time) in previous analyses and the individual trials was reassuring and indicated that no irrelevant numbers were generated via this method.

Drug-Related Adverse Effects.
One potential advantage of systematic reviews may lie in the detection of significant associations of adverse outcomes with certain interventions that occur less frequently than the investigated treatment effect. These adverse effects cannot be estimated with the requested level of certainty from single studies that are usually designed to accept or reject a null hypothesis of a more frequent treatment effect. Fortunately, this potential methodological strength was present in this analysis, although only nine valid trials were found, because reporting of adverse effects was good and the incidences of adverse outcomes were reported separately. However, even a systematic review of nine randomized trials may be underpowered to detect very rare effects. For this purpose, other methodological approaches and types of studies are needed when parecoxib is more widely used.

Safety issues in terms of unwarranted adverse effects were also one major reason that anesthesiologists were reluctant to perioperatively administer conventional NSAIDs. In the systematically reviewed trials on parecoxib, this is represented by the circumstance that head-to-head comparisons with an active analgesic (ketorolac) were performed only if the study drugs were first administered after surgery (treatment trials).

In contrast to long-term use in chronic pain patients, where gastrotoxicity plays a major role, acute effects on platelet aggregation and subsequent bleeding disorders limit perioperative use. For both of these adverse effects, the retrieved trials were not suited to provide adequate answers, because trial size and follow-up time were not suited; relevant outcomes, such as erosions and ulcers diagnosed via endoscopy, were not assessed; or bleeding was not monitored routinely and consequently throughout the trials. Furthermore, as described above, active comparisons were performed only in trials that focused on postoperative administration. Therefore, safety with respect to these questions must be extrapolated from other trials and analyses not performed in the perioperative setting (4,22). However, transferring these data to a single or short-term perioperative dose regimen seems dangerous and the relevance questionable.

The pooled data allow for a solid assumption that the perioperative use of parecoxib is not associated with increased overall adverse effects or with any of the single observed adverse effects compared with placebo. The relevance of sternal wound infections in cardiac surgery (16), a potential serious adverse effect, has yet to be determined. Interestingly, even though peripheral analgesics such as parecoxib have opioid-sparing effects, this did not result in any detectable difference in the incidence of nausea and vomiting between groups. However, parecoxib seems to be protective against fever and headache.

Data comparing morphine with parecoxib are sparse, so conclusions with respect to adverse effects should be drawn with caution. In comparison to injected ketorolac, data were sufficient to allow for an initial statement that there appeared to be no differences in minor complications between parecoxib (20 and 40 mg) and ketorolac (30–60 mg).

In conclusion, in the perioperative setting, injected parecoxib significantly improves patients’ global evaluation of the analgesic regimen compared with placebo. Parecoxib was judged better by means of dichotomous patients’ global assessment of the study drug if it was administered the first time as treatment instead of as prophylaxis. Parecoxib 40 mg seems to be more effective than 20 mg without being associated with additional side effects. Both doses were equally well tolerated compared with placebo and in head-to-head comparisons versus morphine or ketorolac. Parecoxib 40 mg is equally effective compared to ketorolac 30–60 mg, from the patients’ point of view. Since intraoperative use might be safer compared with ketorolac and since a greater margin of safety can be obtained even with short-term use (22), parecoxib could become a valuable non-opioid analgesic for the perioperative period, if the IV route is necessary.

	Acknowledgments

 
We thank Doris Denner, Pfizer GmbH, Karlsruhe (Germany), for responding to our inquiry.

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