Ketorolac trometamol (Toradol®; Syntex, Dee Why, New South Wales) is a pyrrole acetic acid nonsteroidal antiinflammatory drug (NSAID) designed for parenteral administration. It produces postoperative analgesia comparable to systemic opioids, but has a ceiling effect. Its bioavailability and dosage are similar for IM and IV administration (1).
After cesarean delivery, the efficacy of IM ketorolac and meperidine are similar, but ketorolac produces fewer side effects (2). Unfortunately, the quality of analgesia is variable (2) and ketorolac alone is often inadequate (2,3). When combined with an IV or IM opioid, ketorolac results in safe, effective analgesia after abdominal surgery, and may improve the response to patient-controlled morphine, reducing postoperative nausea and vomiting through an opioid-sparing effect (1). NSAIDs also effectively relieve uterine contraction pain in the postpartum period and after cesarean delivery. When combined with oral or parenteral opioid, they may reduce both wound and uterine cramping pain (4,5). Many different classes of NSAIDs and routes of administration are available. However, a parenteral preparation is favored as rectal drug administration is unpopular with many postpartum women, and in the early postoperative period oral administration may be unsuitable. Ketorolac is the only NSAID currently available for parenteral administration in Australia and is a popular choice in this setting.
No studies have investigated the effect of IV ketorolac after cesarean delivery. Advantages compared with IM administration include less discomfort and better patient acceptance. The transfer of ketorolac into breast milk has been quantified, and it is considered to be safe for use during lactation (6,7). The aim of this double-blinded, randomized trial was to investigate the efficacy of ketorolac administered over 24 hours as an IV infusion, as an adjunct to patient-controlled epidural analgesia (PCEA), in the management of postcesarean pain.
Institutional Research and Ethics Committee approval were obtained, and because ketorolac is not approved for IV administration, the trial was registered under the Clinical Trial Notification scheme of the Australian Therapeutic Goods Administration. Fifty women of ASA classification I-II scheduled for elective cesarean delivery were recruited. Exclusion criteria were contraindications to NSAIDs, opioid use, or unwillingness to use PCEA.
All women had combined spinal-epidural anesthesia using subarachnoid 0.5% hyperbaric bupivacaine 10–12.5 mg and fentanyl 12.5 mcg. Patients were randomized using a computer-derived random number sequence to receive an IV infusion, prepared by the hospital pharmacy, of 500 mL over 24 h of either normal saline (control, Group C) or ketorolac (Group K). Immediately after delivery of the fetus, pharmacy prepared our initial dose of either saline or ketorolac 30 mg and it was administered and, in the postanesthesia care room, the IV infusion commenced to deliver ketorolac 120 mg over 24 h. After six cases, when the product information for ketorolac was altered to recommend a smaller maximum daily dose, the protocol was adjusted to 15 mg initial dose and 105 mg IV over 24 h (total 120 mg). In addition, all patients had access to meperidine PCEA (6 mg/mL; 4 mL incremental dose; 15 min lockout interval, GO Medical PCA device; Subiaco, Western Australia). The study IV infusion ceased after 24 h and analgesia was continued with meperidine and oral acetaminophen 500 mg/codeine 30 mg (1–2 capsules 6 hourly as required). Pain scores were collected at 12, 24, 48, and 72 h postoperatively, and no other NSAIDs were permitted in this period.
Data was collected over 72 h by either a nurse or an investigator blinded as to the patient allocation. Data included patient and epidural demographics, time to first use of PCEA, and 0–100 mm visual analog scores for skin, wound, deep abdominal, cramping, and worst pain since the previous assessment. The latter were recorded at 24, 48, and 72 h, as was satisfaction (assessed using a visual analog score). Patient preference for analgesia on days 1, 2, or 3 was used as a further measure of satisfaction. At similar intervals to those used for pain scores, visual analog scores were used to measure side effects such as pruritus, drowsiness, and nausea, and analgesic use (meperidine PCEA dose and number of oral capsules) was recorded. The time to first passage of flatus and first oral intake of fluid and of food were documented. Vaginal blood loss, estimated from nursing inspection of perineal pads, was graded as small, moderate, or large.
It was estimated that a sample size of 50 patents would be able to detect a 30% reduction in the dose of postoperative meperidine used in the ketorolac group compared with the saline group with 80% power and type I error of 0.05. Two-sided tests were performed at the 5% level of significance using Student’s t-tests for normally distributed data or the Wilcoxon’s signed rank test for non-normally distributed data. Fisher’s exact test was used for categorical variables such as the presence of specific symptoms.
Six women could not be included because of a failure to obtain data, leaving 44 analyzed data sets (Group K, n = 24 and Group C, n = 20). Post hoc analysis indicated that the power of the study to detect a significant difference in the primary outcome was not affected by the reduction in sample size. Of the six patients enrolled before dose modification of ketorolac, two had been randomized to Group K and four to Group C. Their outcome data were within the distribution of the subsequent subjects. Demographic data did not significantly differ between groups (Table 1).
During the first 24 h, Group K used significantly less meperidine (P < 0.05, Table 2). However, total epidural meperidine use between 0 and 72 h did not differ (P = 0.13).
The difference in time (median [25%, 75% percentiles]) to first postoperative use of the PCEA device did not reach significance (155 (78,200) min in Group K versus 90 (63,125) min in Group C, P = 0.06). The interval pain scores with movement and for worst pain did not differ between groups, with the exception of worst pain at 12 h being significantly less in Group K (Table 3). The scores for skin pain, deep pain, and cramping pain did not significantly differ between groups. Supplementary analgesia, in addition to meperidine PCEA, was not required by 96% of Group K and 100% of Group C during the first 24 h postoperatively (P = 1.0), or by 75% and 90% of these respective groups during the first 48 h (P = 0.11). By 72 h, 71% of Group K and 75% Group C had still not used additional oral or parenteral analgesics (P = 1.0). Satisfaction with analgesia scores was similar for the periods 0–24 h (Table 3) and for 24–48 h and 48–72 h.
Patient outcome was similar postoperatively with respect to time to first ambulation, first ingestion of fluid or solid food, and first passage of flatus. The groups did not differ for the time to removal of the urinary catheter (Table 4). One patient (Group C) was subsequently unable to void and required temporary recatheterization.
There was no significant difference between groups with respect to assessment of vaginal blood loss postoperatively (P = 0.69). The percentage of patients free of pruritus was similar at 24 h (58% Group K versus 35% Group C) but significantly more in Group C at 48 h (4% Group K versus 40% Group C, P = 0.006). Neither the percentage of patients free of nausea at 24 and 48 h (75% and 92% Group K versus 75% and 90% Group C), nor the percentage free of sedation (33% and 33% Group K versus 20% and 45% Group C) differed between groups. The severity of pruritus, sedation, and nausea did not differ between groups (Table 5).
A single dose of antiemetic was given to one patient from Group C (5%) and two from Group K (8%) during the first 12 h and to one patient from Group K between 12 and 24 h (comparison of groups nonsignificant).
In this study, the combination of IV ketorolac with meperidine PCEA after cesarean delivery resulted in an opioid dose-sparing effect of approximately one-third in the first 24 hours postoperatively. It did not, however, improve the quality of analgesia or influence postoperative recovery, nor did it reduce opioid-induced side effects, these being infrequent in both groups.
Although NSAIDs are not satisfactory as sole analgesics, ketorolac is one of many NSAIDs that have been combined with opioids to manage postcesarean pain (2,3,8). Previous studies have administered IM ketorolac after cesarean delivery and found ketorolac has similar efficacy to IM meperidine and poorer efficacy than epidural morphine (2,3). We chose the IV route on the assumption that this would be a more acceptable alternative in postpartum patients, who routinely receive IV fluids after surgery. In addition, Ready et al. (1) found that IV infusion of ketorolac resulted in decreased morphine requirements and less nursing difficulty after major surgery than either intermittent IV boluses or placebo. IV administration of ketorolac is safe, based on available evidence from animal models, case reports, and clinical trials (1).
Shortly after commencing the study, the dosing schedule of ketorolac was changed, after a revision of the Product Information recommending that no more than 120 mg be administered in any 24-hour period. Results from women receiving ketorolac were analyzed as a single group. We believe this was justifiable and is unlikely to have affected results. Bolus IM doses of 10 and 30 mg are similar in analgesic effect (9,10) and our altered infusion rate of approximately 4.5 mg/hour is close to that of the original 5 mg/hour, a rate proven in a multicenter study after major surgery to have significant dose-sparing effects (1). Analysis of the subgroup of patients who received only the smaller total dose of ketorolac (n = 38) shows that the results with respect to the primary outcome remained statistically significantly different.
Opioid dose-sparing has been a consistent finding of most studies where opioids and NSAIDs were combined after major surgery. The magnitude of this effect has ranged from 25%–66%, depending on the method of opioid administration and the surgical setting (1,11,12). We used meperidine PCEA to investigate this possibility because it is a widely used approach to postcesarean pain management in Australia (13). Epidural meperidine is unlikely to have local anesthetic effects, and meperidine PCEA is more effective and preferred by patients to meperidine patient-controlled IV analgesia (13,14). Although dynamic pain scores are low with meperidine PCEA, those after subarachnoid morphine 200 mcg are lower in the first few postoperative hours, but side effects such as nausea and pruritus are more common and of greater severity (15).
Although we also found the primary outcome of this study, opioid requirement, was 36% less during the period of IV ketorolac infusion, this produced no maternal benefit, in that the incidence of opioid-induced side effects was unaffected. This probably reflects the very infrequent incidence and severity of nausea and the minor severity of pruritus, despite the fact that some pruritus occurred in the majority of those receiving epidural meperidine. Previous studies have also shown high levels of maternal satisfaction with epidural meperidine in the postpartum period (14–17), and the safety profile with respect to respiratory depression is excellent (13,14).
The potential effect of epidural meperidine on the breast-fed infant has not been investigated, but plasma meperidine levels after IV patient-controlled analgesia, with or without prior epidural morphine at delivery, produce sufficient drug transfer into breast milk to affect neurobehavior on the third day of life (18,19). As systemic absorption after epidural administration is significant, it is possible that a dose-sparing effect might be of benefit to the neonate. Ketorolac, like other NSAIDs, is considered safe to use during lactation (7). The levels in breast milk are undetectable or small, being between 0.16 and 0.4% of the maternal exposure, suggesting that ketorolac has a more favorable profile than acetaminophen and other NSAIDs (6).
In some studies after cesarean delivery in which a NSAID was used to supplement oral or parenteral opioids or a small dose of intraspinal morphine, the NSAID significantly reduced either uterine cramping (4,5,20) or wound or movement pain (3,5,9,20,21). In others, no effect was noted (8,12). We also found no significant effect on uterine contraction and wound pain or pain with movement. An explanation may be the high quality of analgesia provided by epidural meperidine, which is more effective than either IM or IV meperidine after cesarean delivery (14). This is consistent with studies in which NSAIDs were found not to be of benefit in reducing pain when used as an adjunct to epidural morphine, bupivacaine-morphine infusion (22) or effective doses of spinal morphine (23), even though the duration of spinal morphine was significantly prolonged (21,23). Alternatively, the sample size may have been inadequate to detect small differences in pain arising from each of the components of postoperative pain. This is supported by our observation that, in addition to significantly lower “worst pain” at 12 hours, there were trends to lower pain scores for skin pain at 24 hours and deep pain at 12 and 24 hours in those receiving ketorolac. The power of the study to detect a true difference in skin and deep pain at 24 hours was low (45% and 32% respectively).
We found no evidence of side effects from the short-term administration of ketorolac. We excluded patients with a known relative contraindication to NSAIDs, such as a history of peptic ulceration or renal impairment, and those with acute conditions such as severe preeclampsia, in which renal function might already have been impaired. Because NSAIDs inhibit prostaglandin synthesis, all have the potential to harm renal function. The reduction in approved dosage followed postmarketing reports of acute renal failure in younger patients with no identifiable risk factors (24). However, IV ketorolac for 72 hours after abdominal surgery does not significantly alter serum creatinine levels (25). Epidemiological evidence suggests renal failure is a rare event, the best estimate being 1 in 1,000–100,000 (26).
Ketorolac causes gastric irritation and alteration in platelet function. Extensive postmarketing surveillance indicates a very small risk of gastrointestinal or operative site bleeding, with no significant increase compared with opioids, when appropriate doses are used in young adult populations for less than five days (27). In addition to inhibition of platelet aggregation and thromboxane production, NSAIDs have tocolytic activity, raising concern that postpartum uterine bleeding might be increased (28). Several studies have used simple, but clinically relevant, assessments of vaginal blood loss or the need for oxytocics either intra- or postoperatively and report no significant effect in patients receiving NSAIDs (3,5,8,11,22). Similarly, we found no evidence of increased postoperative blood loss in those receiving ketorolac.
In conclusion, in this study IV ketorolac used for 24 hours as an adjunct to PCEA meperidine after cesarean delivery produced a meperidine dose-sparing effect of approximately 30%, but did not significantly improve pain relief, reduce opioid-related side effects or change patient outcome.
We wish to thank the recovery room and postnatal nursing staff who assisted in the conduct of this study and the Women and Infants Research Foundation for their support.
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