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Anesth Analg 2007;104:1521-1527 © 2007 International Anesthesia Research Society doi: 10.1213/01.ane.0000262039.69513.9d
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Abstract |
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BACKGROUND: Parecoxib, a selective cyclooxygenase-2 inhibitor, may reduce postoperative pain without increasing bleeding when administered before surgery.
METHODS: We randomly assigned 62 patients scheduled for total hip arthroplasty to the following IV dosing schedule: 1) placebo at induction, at wound closure, and 12 h after induction (control); 2) parecoxib 40 mg at induction, placebo at wound closure, and parecoxib 40 mg 12 h after induction (pre); or, 3) placebo at induction, parecoxib 40 mg at wound closure, and parecoxib 40 mg 12 h after induction (post). Pain scores at rest and with movement were recorded every 4 h for 24 h using a visual analog scale. Treatment side effects were recorded every 4 h. Red cell loss for 5 days after surgery was calculated.
RESULTS: Postoperative pain scores were less in the pre and post groups than in the control group. Postoperative bleeding was similar in the three groups. There were no significant differences between the pre and post groups, nor was their any trend suggesting a preemptive analgesic efficacy from preincision administration of parecoxib. Morphine use in the Postanesthesia Care Unit was reduced in the pre and post groups compared with the control group (14.2 ± 2.0, and 15.7 ± 2.0, vs 20.4 ± 2.3 mg), although the trend was only significant (P < 0.05) in the pre group. The first pain score was also reduced in the pre and post groups compared to the control group (56.1 ± 7.5 and 64.2 ± 7.0 vs 78.3 ± 5), but this was also only significant for the pre group (P = 0.001). The delay for first analgesic demand was increased for both the pre and post group compared to the control group (38 ± 9 and 28.2 ± 6.6 vs 18 ± 6 min) but, again, this was only significant for the pre group (P = 0.05). Twenty-four hour consumption of morphine was similar in the pre (26 ± 12 mg) and post groups (25 ± 13 mg); both were significantly less than in the control group (47 ± 27 mg, P < 0.001).
CONCLUSIONS: Administration of parecoxib before hip arthroplasty did not provide preemptive analgesia. There was a trend towards improved analgesia immediately after surgery with preincision administration, consistent with the expected time course of nonsteroidal antiinflammatory drug’s effect. Perioperative parecoxib administration, consisting of two injections spaced 12 h apart, improved postoperative analgesia over the first 24 h without increasing bleeding.
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Introduction |
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Tissue injury and inflammation induce cyclooxygenase-2, both in the periphery and the central nervous system (CNS). (1) Cyclooxygenase-2 is responsible for the synthesis of prostaglandins, which sensitize the nociceptor (2) and act as excitatory neuromediators in the CNS (2,3). In animal models, the inhibition of constitutive cyclooxygenase-2 and reduction of its inducible form reduce the peripheral and central sensitization that occurs after tissue injury (3,4). Additionally, rofecoxib limited both primary and secondary hyperalgesia in a human pain model (5). Therefore, we hypothesized that inhibition of cyclooxygenase-2 before tissue injury might enhance the analgesia provided by parecoxib for postoperative pain control.
Initial clinical studies of preemptive analgesia were negative (6), but a recent systematic review analyzed 66 studies related to five groups of interventions: epidural analgesia, peripheral local anesthetic infiltration, systemic N-Methyl-d-Aspartate receptor antagonists, systemic nonsteroidal antiinflammatory drugs (NSAIDs), and systemic opioids (7). The authors report a significant preemptive effect with epidural analgesia, local infiltration, and systemic NSAID administration. However, this review included only a single clinical study that examined a possible preemptive analgesic effect of a cyclooxygenase-2 inhibitor, and that for arthroscopic surgery (8).
The preoperative administration of NSAIDs may, therefore, offer improvement in the quality of postoperative pain management. However, the main limitation of perioperative use of nonselective NSAIDs is increased bleeding, with an estimated incidence of 1% after major surgery (9). This risk of bleeding is increased even when nonselective NSAIDs are given before surgery (10,11). Therefore, despite data suggesting the possible preemptive effect of nonselective NSAIDs, the preoperative administration of these drugs is not presently part of postoperative pain control guidelines.
Parecoxib (Pfizer, Paris, France) is a selective inhibitor of cyclooxygenase-2 available for postoperative IV analgesia and a pro-drug, which is metabolized by the liver to valdecoxib. It is effective for postoperative pain control after various types of surgery (12,13). Preoperative administration of parecoxib also provides effective analgesia (14–17); however, no study has tested the preemptive analgesic effect of parecoxib in major surgery using recommended methodologies (18). We therefore conducted a prospective, randomized study to test the hypothesis that the preoperative administration of parecoxib for total hip arthroplasty provides better analgesia than postoperative administration, and that neither increases perioperative bleeding.
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METHODS |
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The local ethics committee (Comité Consultatif de Protection des Personnes pour le Recherche Biomédicale, Boulogne Billancourt, France) approved the study, and all patients gave written informed consent. We recruited 76 patients scheduled for total hip arthroplasty from two institutions (Hôpital Raymond Poincaré, Garches, and Hôpital Cochin, Paris, France)
The inclusion criteria included total hip arthroplasty under general anesthesia. Patients were excluded when they had contraindications to parecoxib, including cardiovascular pathology and renal insufficiency, previous hip surgery, hip trauma, or preoperative use of opioid or NSAIDs within 48 h before surgery. Patients were withdrawn from the study if they 1) withdrew consent during the follow-up period; 2) developed a complication that required intervention within 24 h after surgery; or 3) required prolonged (>60 min) mechanical ventilation after surgery.
Protocol
All patients were premedicated with hydroxyzine, 100 mg, before surgery. The same surgeon performed all total hip arthroplasties under a standardized anesthesia protocol combining propofol, sufentanil, a muscle relaxant, sevoflurane, and N2O. Sufentanil was administered in bolus according to arterial blood pressure and heart rate with a 0.15 mcg/kg sufentanil bolus in case of 15% heart rate and/or 20% arterial blood pressure increase compared with preoperative values. After surgery, postoperative pain was controlled by IV morphine given via a patient-controlled analgesia pump (PCA). No patient was given a peripheral nerve block, paracetamol or other NSAIDs.
Patients were randomly allocated to three groups: control, pre, and post. All patients received three IV injections: the first with anesthesia induction, a second at wound closure, and a third, 12 h after induction. All solutions were colorless and given in a volume of 2 mL, prepared in the operating room by an anesthesiologist not otherwise involved in the study. The control group received three placebo injections. The pre group received 40 mg parecoxib at induction, placebo for the second injection, and 40 mg parecoxib for the third injection. The post group received placebo for the first injection, 40 mg parecoxib for the second injection, and 40 mg parecoxib for the third injection. This study design was based on previous recommendations (18). A randomization list for each center, randomly assigned to groups was based on computer-generated codes. The randomization instructions were stored in sequentially numbered opaque envelopes opened the day of surgery before induction of anesthesia.
Measurements
As soon as possible after arrival in the Postanesthesia Care Unit (PACU), patients rated their pain on a 100-mm-long visual analog scale (VAS) (0 mm = no pain; 100 mm = worst imaginable pain). When the VAS pain score was more than 30 mm, IV morphine was titrated to effect. Patients could receive up to 3 mg of morphine, given every 5 min. Patients then used a PCA delivery system for IV morphine (1 mg bolus with a lockout time of 5 min). VAS pain scores at rest and movement (no standardized movement in the bed) were monitored every 4 h for 24 h after surgery by a nurse not aware of patient allocation.
Morphine-related side effects were monitored every 4 h for 24 h after surgery. Sedation was quantified using a sedation score (0: no sedation; 1: patient intermittently sedated; 2: patient continuously sedated, but arousable with verbal stimuli; 3: patient continuously sedated, not arousable). Urinary retention was monitored with a score (0: no difficulties voiding; 1: difficulty voiding, no bladder catheterization; 2: bladder catheterization). Nausea and vomiting were monitored using a score (0: no nausea or vomiting; 1: nausea or vomiting with no treatment; 2: nausea and vomiting requiring treatment). The duration of stay in the PACU was not monitored, since the duration of stay after total hip arthroplasty in our institution is mainly related to blood transfusion rather than pain control.
The hematocrit (Hct) was determined on the day before surgery (D – 1) and on Day 5 after surgery (D5). The total numbers of autologous or homologous red blood cell concentrate (RBCC) transfusions were tabulated on Day 5. Blood loss was calculated as follows: the calculated blood loss corresponded to the sum of the uncompensated blood loss shown by the reduction in Hct and the blood loss compensated by transfusion. Uncompensated loss was calculated using the formula of Mercuriali and Inghilleri (19) and was expressed in mL of red blood cell volume (RBCV): uncompensated loss = (RBCV x Hct D – 1) – (RBCV x Hct D5). The compensated loss corresponds to the sum of all the transfusions (autologous units and homologous units). For the calculations, we considered that RBCC have a Hct of 60%. The mean volume is about 250 mL, with 150 mL of pure RBC added to 100 mL of saline–adenine–glucose–mannitol. Therefore, in the calculation of the compensated loss, we considered that each RBCC compensates for 150 mL of blood with a Hct of 100%.
Statistical Analysis
Previous results on the preemptive analgesic effect of NSAIDs (7) described a 48% reduction in supplemental analgesic consumption (range 0.31–0.65). According to previous results on morphine consumption after total hip arthroplasty in our institution (mean ± sd; 43 ± 23),20 a total of 60 patients (20 in each group) was thus necessary to detect a 50% reduction in morphine use over 24 h in the pre group compared with the post group with a Type 1 error value of 0.05 and a Type 2 error value of 0.10.
The main outcome was cumulative individual morphine consumption over the first 24 h after surgery. Secondary outcomes were morphine titration in the PACU, morphine PCA use, VAS pain score in the PACU, time to first analgesic demand in the PACU, VAS pain score, morphine- and parecoxib-related side effects during the follow-up period, and total RBC loss over 5 days.
The morphine consumption and VAS pain scores were compared with ANOVA and Fisher’s test. The frequency of dichotomous outcomes was compared with 
2 test; P < 0.05 was considered statistically significant.
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RESULTS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONSREFERENCES |
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Eleven patients were eliminated from the study: two patients withdrew consent, one required prolonged postoperative mechanical ventilation, two were inadvertently given paracetamol (one of the exclusion criterion), four because of inadequate order of treatment attribution (third injection made instead the second), one had a surgical complication that required intervention, and one because the patient’s data were lost. Thus, data from 65 patients were analyzed for the PACU period (n = 21 control group; n = 22 pre group; n = 22 post group). Two additional patients were eliminated from the study after morphine titration in the PACU: one patient withdrew consent and another was dropped because of lack of a third injection. A last patient was eliminated after PACU due to one ketamine bolus administration in the PACU after the morphine titration. Thus, data from 62 patients were analyzed for morphine consumption over 24 h and morphine-related side effects (n = 21 control group; n = 22 pre group; n = 19 post group) and 63 patients for postoperative bleeding (n = 21 control group; n = 22 pre group; n = 20 post group).
Patient, surgery, and anesthesia characteristics were similar in the groups (Table 1).
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Cumulative morphine consumption for the 24 h after surgery (combined PCA use and PACU titration) was reduced by approximately 45% in both the pre and post group compared with the control group (Table 2). The average PCA morphine-sparing effect was 66% in the pre group and 72% in the post group compared with the control group (Table 2). The 4-h intervals dose of IV PCA morphine was significantly reduced in the pre and post groups compared with the control group (Fig. 1).
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Four of 22 patients in the pre group did not require morphine in the PACU whereas all those in the post group did and 1 of 21 in the control group did not (Table 2). The average reduction of morphine consumption for titration in the PACU was 32% in the pre group and 23% in the post group compared with the control group (Table 2, Fig. 1).
The preoperative administration of parecoxib more than doubled the time to first analgesic demand in the PACU, but postoperative administration only increased it by 26%.
The first VAS pain score in the PACU before morphine titration was 29% less in the pre group than in the control group, but only 18% less in the post group than in the control group (Table 2, Fig. 2). However, the pre and post scores were not significantly different (Fig. 2).
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Between 4 and 24 h after surgery, VAS pain scores at rest and during movement were always lower in the pre and post groups than in the control group. However, this difference was statistically significant only between 12 and 24 h after surgery (Figs. 2 and 3). The incidence of analgesic-related complications was similar in all groups (Table 3). Bleeding and Hct 5 days after surgery were also comparable in each group (Table 3, Fig. 4).
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DISCUSSIONS |
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TopAbstractIntroductionMETHODSRESULTSDISCUSSIONSREFERENCES |
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The review by Ong et al. (7) and the accompanying editorial by Kissin (18) define preemptive analgesia as superiority of preoperative versus postoperative administration, and preventive analgesia as an effect persisting beyond the presence of the analgesic drug in the biophase. A preventive analgesic effect seems to be offered by drugs such as N-Methyl-d-Aspartate receptor antagonists like ketamine (21), while preemptive analgesia may be more specific to analgesic techniques such as epidural anesthesia, peripheral local anesthetic infiltration, or systemic NSAIDs (7).
Authors comparing the preoperative administration of parecoxib to a placebo treatment found that preoperative parecoxib significantly reduced rescue analgesia over 24 h (14,15,22,23). However, we did not observe a preemptive analgesic effect of parecoxib according to currently accepted criteria, since preoperative administration of parecoxib had no significant impact on the amount of morphine consumed, pain scores, or time to first analgesic demand compared with postoperative administration.
Only one report has compared preoperative to postoperative administration of parecoxib and found a significant advantage to preoperative administration after general surgery (17). This study, though, was limited by a vague schedule of drug administration. Our results also contradict the recent meta-analysis (7) observing that the preoperative administration of NSAIDs offers a preemptive analgesic effect as reflected by a reduction in analgesic consumption and time to first analgesic demand. One explanation may be that all studies included in this meta-analysis, except for one using rofecoxib (8), referred to nonspecific NSAIDs (7). In fact, animal and clinical data suggest that inflammatory pain is not exclusively mediated by cyclooxygenase-2 induction (24,25). Cyclooxygenase-1 inhibition thus contributes to analgesia, and may be necessary for a preemptive analgesic effect. Another plausible explanation may be that the limited power of our study was unable to detect the preemptive analgesic effect reported in the meta-analysis (7). Nonetheless, as seen by Figures 1, 2, and 3, our study does not even show a hint of preemptive analgesic benefit in terms of sustained analgesic benefit beyond the initial benefit that can be explained by the slow onset of the dose given on wound closure in the post group. Thus, if there is preemptive analgesia with parecoxib, the benefit is modest at best.
In fact we added a post hoc power analysis using the actual results. The difference between the pre and post groups in terms of morphine consumption over 24 h has a 95% confidence interval of (–6.9 mg, 8.8 mg). Therefore, it seems to us that the largest detectable difference between the pre and post groups lies within bounds that are not clinically important.
Although we were unable to demonstrate preemptive or preventive analgesia, our results show that preoperative administration of parecoxib improved analgesia in the PACU. The time to first analgesic demand was doubled in patients given preoperative parecoxib, and the first postoperative pain score and amount of morphine for PACU titration were both reduced by one-third compared with the control group. However, we did not observe any impact on morphine-related side effects in the PACU, and duration of stay in the PACU was mainly influenced by the need for blood transfusion.
The trend towards improved analgesia immediately after surgery following preincision administration of parecoxib, compared with parecoxib administered at wound closure, reflects the expected slow onset of NSAIDs’ analgesic effect (26). Parecoxib is a prodrug for valdecoxib, which is the active cyclooxygenase-2 selective moiety. Data from IM administration of parecoxib demonstrate that the conversion to valdecoxib is rapid, and likely does not contribute to the delay in onset suggested by our data (27). However, blood-brain equilibration could account for some of the delay, as suggested by the modest delay in CNS concentration seen with oral administration of valdecoxib (28).
In our study preoperatively administered parecoxib did not affect perioperative bleeding. Increased surgical site bleeding is a major problem with nonselective NSAIDs (9,11) and perioperative NSAID use increases bleeding with total hip arthroplasty (29,30). Experimental data have shown that valdecoxib does not interfere with platelet aggregation (31). Clinical studies have suggested that bleeding was not increased when rofecoxib (32) or valdecoxib (33) was given before major orthopedic surgery. Our study reaches similar conclusions, based on specific calculations of RBC loss. The difference between the control and pre groups in terms of blood loss (RBC loss over 5 postoperative days) h has a 95% confidence interval (–15 mL, 190 mL) suggesting no clinically significant difference (Fig. 4). However, the study was not powered for blood loss comparisons, and this may limit the meaning of this observation.
Cardiovascular toxicity has been responsible for the recent concerns about rofecoxib and has resulted in new recommendations for the use of selective cyclooxygenase-2 inhibitors. Parecoxib is responsible for acute cardiovascular toxicity in the specific situation of cardiac surgery (34). Since the frequency of such toxicity is more related to prolonged use of cyclooxygenase-2 inhibitors or acute administration in a specific population at risk of cardiovascular complications, our study does not offer any additional information on this subject. Our study was not powered to identify cardiac complications, and none was observed.
In conclusion, parecoxib does not provide clinically significant preemptive analgesia. However, it improves postoperative analgesia, reduces the dose of morphine required by patients, and does not increase perioperative bleeding. The analgesic effects are still evident at 24 h when two injections, spaced 12 h apart, are given.
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Footnotes |
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Accepted for publication February 21, 2007.
Supported by NIH Grant GM 061655 (Bethesda, MD), the Gheens Foundation (Louisville, KY), the Joseph Drown Foundation (Los Angeles, CA), and the Commonwealth of Kentucky Research Challenge Trust Fund (Louisville, KY).
No financial support of Pfizer
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