Abstract
Background
We compared the clinical efficacy and safety between a new injectable cyclooxygenase-2 selective inhibitor, parecoxib, and an old nonselective, ketorolac combined with morphine in patient-controlled analgesia (PCA) for management of post-cesarean delivery pain.
Methods
In this randomized, open-label study, 66 parturients undergoing cesarean section were divided into two groups: In Group P the patients received an initial intravenous bolus of 40 mg parecoxib as a loading dose post-operatively and then two bolus doses of 20 mg parecoxib were subsequently given at intervals of 24 h. Morphine was basically used in PCA manner during the 3-day study course; and in Group K patients received an intravenous loading bolus of 30 mg ketorolac post-operatively and then 90 mg ketorolac combined with morphine in PCA fashion throughout the study course. Efficacy was evaluated by Verbal ranking scale (0–10) for pain intensity, Ramsay sedation score (1–6), profile of mood state (0–3) and quality of sleep (0–3), and patient satisfaction (0–4) with the analgesia. Efficacy evaluations and adverse effects were recorded every 24 h and at 72 h after initial loading boluses. The duration of hospital stay and total dose of morphine used throughout the study were also recorded.
Results
There were no significant differences of sedation scale, mood state, quality of sleep and satisfaction between two groups, except patients of Group P had a lower pain scores than those of the Group K at 24 h (3.1, range 0–5 vs. 4.3, range 0–8, p = 0.005) and 72 h (1.1, range 0–3 vs. 1.9, range 0–4, p = 0.005). Moreover, there were also no significant differences in the duration of hospital stay, but there was a lower total morphine requirement (22% reduction) in Group P in comparison with Group K (43.5 ± 19.2 vs. 55.5 ± 21.5, p = 0.02). Regarding adverse effects, there were no statistical differences between two groups.
Conclusions
We noted that parecoxib with PCA morphine can be used for post-cesarean delivery analgesia with the same efficacy as ketorolac for an opioid-sparing effect.
Keywords
cyclooxygenase 2 inhibitors: parecoxib; cesarean section; pain, postoperative; analgesia, patient-controlled;
1. Introduction
Regarding pain at the site of injury or trauma, cyclooxygenase type-2 (COX-2) plays an important role in both peripheral and central mechanisms of pain. An ideal agent for the treatment of acute inflammatory pain is one that can inhibit COX-2 both peripherally and centrally.1, 2
A newer COX-2 inhibitor, parecoxib sodium (parecoxib), has demonstrated powerful analgesic efficacy in well-documented clinical trials. It is the only injectable COX-2 inhibitor with fast onset and long-lasting analgesic effect. Furthermore, it enhances pain relief in multimodal therapy with a significant reduction in opioid consumption, along with overall safety and tolerability profile.3 Moreover, its analgesic efficacy has been proven in a wide range of surgical procedures, such as total knee and hip arthroplasty, gynecologic laparotomy surgery, total abdominal hysterectomy and oral surgery.4, 5, 6, 7, 8, 9, 10, 11, 12
However, the post-cesarean delivery pain is caused by surgical incision and uterus contraction with multiple mechanisms, which include both central and peripheral sensitization, and also descending inhibition pathway. Therefore, COX-2 inhibitors and opioids played an important role in the control of such pain. Crews stated that the rational use of combined of analgesic medications can improve pain relief, reduce postoperative adverse effects, and improve functional postoperative recovery.13 Furthermore, there are few reports mentioning the combination usage of parecoxib with morphine in a patient-controlled analgesia (PCA) manner for routine postoperative pain control for obstetric surgery. In addition, no other study of parecoxib for management of post-cesarean delivery pain is available. For these reasons we ventured to design the study of the combination of a new injectable COX-2 selective inhibitor, parecoxib, and the potent opioid, morphine, for post-cesarean delivery analgesia.
The aim of this study was to compare the clinical efficacy and safety between parecoxib and a common nonsteroidal anti-inflammatory drug (NSAID), ketorolac with nonselective COX inhibition in combination with morphine PCA respectively for post-cesarean delivery pain management.
2. Methods
The study was a randomized, open-label clinical trial of parecoxib and ketorolac, combined with morphine for post-cesarean section pain control. The protocol was approved by the Research and Ethics Committee of our hospital, and patients’ informed consents were obtained after detailed explanation.
The 66 parturients enrolled in this study were between 20 and 40 years of age, of ASA physical status I or II, weighing 60–90 kg, and standing 155–170 cm. The parturients were free of specific cardiovascular, neurological, hematological or gastrointestinal diseases, and were scheduled for elective cesarean section at term, under spinal anesthesia.
No premedication and opioids were given peri-operatively. The parturients were hydrated before anesthesia and monitored on continuous electrocardiogram, pulse oximetry, and noninvasive arterial blood pressure, peri-operatively and post-operatively.
When the parturients were transferred to Post-Anesthesia Recovery Room, abdominal pain usually set in. They were divided into two groups: Group P patients received an intravenous bolus of 40 mg parecoxib (Dynastat® _ Pfizer Limited, USA) as a loading dose post-operatively; then two subsequent bolus doses of 20 mg parecoxib were separatively given at 24-h and 48-h intervals, after the initial dose. Morphine was given in patient-controlled analgesia (PCA) manner during the 3-day study course; and Group K patients received a loading intravenous bolus of 30 mg ketorolac, then 90 mg ketorolac combined with morphine in a PCA fashion throughout the study course. All parturients were informed that they could receive additional pain medication if pain control was unsatisfactory, by pushing the control button of the PCA to deliver a reinforced dose.
Furthermore, PCA machines were programmed to deliver the drugs pursuant to the respective formula, i.e. morphine in continuing dose of 0.2 mg/h, and the bolus dose of 2 mg (each bag of basic PCA solution contained morphine 50 mg in normal saline 250 mL). As to patients of Group K, katabolic 90 mg was only added into each basic analgesic solution.
Breast-feeding was prohibited during the first 3 days post-delivery, and observations and assessments were performed throughout the 3-day study course post-operatively.
2.1. Assessment and evaluation
Efficacy was evaluated by using a verbal ranking scale of five parameters, including 0–10 pain intensity scale (0 = no pain, 10 = excruciating pain) for pain intensity; 1–6 Ramsay sedation score (1 = anxious, agitated, restless, 2 = cooperative, tranquil, oriented, 3 = drowsy, response to verbal command, 4 = asleep, brisk response to light glabellas tap and loud auditory stimulus, 5 = asleep, sluggish response to light glabellas tap and loud auditory stimulus, 6 = coma); 0–3 mood profile scale (0 = no interference, 1 = mild, 2 = moderate, 3 = severe interference); 0–3 quality of sleep scale (0 = normal sleep, 1 = occasionally awakened by pain, 2 = always awakened by pain, 3 = insomnia); and 0–4 scale of satisfaction (0 = very unsatisfied, 1 = unsatisfied, 2 = fair, 3 = satisfied, 4 = very satisfied). Adverse effects including gastrointestinal upset, nausea/vomiting, dizziness, somnolence, headache, itching, etc. were recorded. The duration of hospital stay and total dosage of morphine used throughout the study were also recorded (Fig. 1).
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2.2. Statistical analyses
Data were presented as mean ± standard deviation, or as frequencies, and were analyzed by two-tailed unpaired Student’s t-test and Chi-squared (χ2) test/Fisher’s exact test; except pain scale was presented as median with range, and analyzed by a non-parametric test. A p value less than 0.05 was considered statistically significant.
3. Results
All parturients completed the study. Both groups had comparable demographic data, including age, height, weight, gravida, infant birth weight and Apgar score. The duration of operation (operation time), anesthesia (anesthesia time) and hospital stay were also compared. There were no significant differences concerning the above data between the two groups. (Table 1) There were no significant differences in the sedation scale, mood state, quality of sleep and satisfaction between groups, except Group P had lower pain scores than Group K at 24 h (3.1, range 0–5 vs. 4.3, range 0–8, p = 0.005), and 72 h (1.1, range 0–3 vs. 1.9, range 0–4, p = 0.005); and a lower total consumption of morphine, in 72-hour course in of Group P, as compared with Group K (43.5 ± 19.2 vs. 55.5 ± 21.5, p = 0.02). (Table 2). However, there were no statistical differences in the adverse effects between two groups. (Table 3)
4. Discussion
Our results proved that parecoxib was as effective as ketorolac for post-cesarean delivery analgesia; again, it could reduce the morphine requirement by 22% in patients with lower pain scores, when compared with ketorolac. However, it did not significantly reduce the morphine requirement in the first 24 h, probably by reason of stronger analgesic effect offered by the loading dose of parecoxib in the first day, and more significant reduction of the morphine requirement on the following study days. It was perceivable that the analgesic effect offered by the loading dose of parecoxib was more potent than the low dose of ketorolac infusion given in the second and third days. We are of the opinion if we increase the dose of ketorolac in the second and third day, the total morphine requirement and the analgesic efficacy would equate in both groups.
Previous studies revealed that immediate post-operative treatment with parecoxib for orthopedic, gynecologic and oral surgeries was proven to have an opioid sparing effect.4, 5, 6, 7, 8, 9, 10, 11 It could also exhibit its analgesic efficacy even administered pre-operatively.12 Although its onset time is considered rapid (10–23 min) with efficacious analgesia, it takes a significantly longer (two-to-threefold) time to be an analgesia rescuer as compared with ketorolac for post-operative pain, following gynecologic laparotomy surgery.7 It was well tolerated over several days and provided improved pain control after gynecologic surgery in a multidose study.10 Moreover, another multiple-dose study by Malan et al. in total hip arthroplasty revealed that administration of parecoxib with PCA Morphine had improved significantly the postoperative analgesic management, in terms of reduction in opioid requirement, lowering pain score, reduced time for needing PCA morphine, and higher global evaluation ratings when compared with placebo; however, parecoxib 20 mg and 40 mg, also reduced the total amount of morphine required over 36 h by 22.1% (56.5 mg morphine), and 40.5% (43.1 mg morphine), respectively.5
Tang et al. in the report on their study concluded that intravenous parecoxib (20 or 40 mg) was effective in decreasing the PCA opioid requirement after lower abdominal surgical procedures; but it failed to reduce opioid-related side effects in the early post-operative period.14 Furthermore, we could not prove that parecoxib has less adverse effects than ketorolac during our 3-day study course by reason of our restrictive exclusion criteria for the selection of patients. However, according to previous studies, COX-2 selective inhibitors could offer a number of advantages over classical nonsteroidal anti-inflammatory drugs (such as ketorolac) when used to treat postoperative pain. These included a reduced incidence of gastrointestinal ulceration and absence of inhibitory effect on platelet function, and thereby reduced the risk of blood loss. They also less inflected impairment of bone healing, and did not induce bronchospasm in patients with aspirin-sensitive asthma.15
Lastly, Kranke et al. in their quantitative systemic review of parecoxib for post-operative pain concluded that, in treatment trails, the number needed to treat (NNT), in order to obtain the outcome of interest with parecoxib 20 mg was 2.1, 5.3, and, 8.3; and with parecoxib 40 mg was 1.7, 3.7 and 50; in the comparison with placebo, morphine, and ketorolac, respectively.16
In conclusion, we compared the clinical efficacy and safety between parecoxib and ketorolac, combined with PCA morphine for post-cesarean delivery pain management. We found that the total dose of morphine requirement in the parecoxib treatment group was lower than that in ketorolac group. Therefore, our study reveals that parecoxib in conjunction with PCA morphine can be used for post-cesarean delivery analgesia with the efficacy equating ketorolac with PCA morphine for an opioid-sparing effect.
Acknowledgments
The authors wish to thank the staff of the Post-Anesthesia Recovery Room for their assistance in follow-up and data collection; also the Staff of the Departments of Obstetrics and Anesthesiology at St. Martin de Porres Hospital for kindly providing cases; and Pfizer Limited for providing the drug (Parecoxib).