Three studies examined the effect of 30 mg ketorolac on postoperative opioid consumption compared with saline.26,30,35 One study provided data for 2 comparisons and both were included in the analysis.26 The aggregate effect of 30 mg ketorolac on postoperative opioid consumption compared with placebo demonstrated a wide CI relative to a clinically significant difference (Fig. 6). The analysis was limited by some heterogeneity (I2 = 37). All the studies examined IM ketorolac. One hundred percent of the total variance was explained by the time of drug administration (preincision versus postincision). The removal of the only comparison that examined the postincision administration of ketorolac substantially reduced the heterogeneity between the remaining comparisons studies (I2 = 0).
Eight studies evaluated the effect of 60 mg ketorolac on postoperative opioid consumption demonstrating an opioid-sparing effect of −1.64 (−2.90, −0.37) (summary point on milligrams of IV morphine equivalents) compared with placebo.23,24,27,28,31–34 Two studies provided data for 2 comparisons and both were included in the analysis. The analysis was limited by heterogeneity (I2 = 71). Heterogeneity was high when the medication was given IM (I2 = 86) and low when the medication was given IV (I2 = 0). A subgroup analysis was performed to evaluate the effect of route of administration of the drug (IM or IV) on opioid sparing. Four studies examined the 60-mg ketorolac dose given IM24,28,32,34 and 4 studies examined the effects of the 60-mg dose given IV.23,27,31,33 Among the studies evaluating IV administration, 2 provided 2 comparisons and both were included in the analysis.27,31 Ketorolac administered IM had greater opioid-sparing effects than ketorolac administered IV with a mean difference (95% CI) of −2.13 mg (−4.1 to −0.21 mg) (summary point on milligrams of IV morphine equivalents) (P = 0.03).
None of the included studies reported on chronic pain.
Two studies examined the effect of systemic ketorolac on time to hospital discharge.27,33 One study provided data for 2 comparisons and both were included in the analysis.27 The combined effects resulted in a wide CI relative to a clinically significant difference in the reduction in time to hospital discharge of systemic ketorolac compared with placebo (Table 2).
Eight studies examined the effect of ketorolac on postoperative nausea and vomiting.23–25,27,28,31,33,35 Two studies provided 2 comparisons and both were included in the analysis.27,31 The overall effect of ketorolac in reducing postoperative nausea and vomiting, odds ratio (95% CI), was 0.57 (0.36–0.88) (Fig. 8). Number needed to treat was 12.5 patients. There was no evidence of an asymmetric funnel plot (P = 0.29).
Three studies examined the effect of 30 mg ketorolac on postoperative nausea and vomiting.24,25,35 The aggregate effect did not demonstrate a statistically significant benefit of 30 mg ketorolac compared with placebo (Fig. 8). Five studies evaluated the effect of 60 mg ketorolac on postoperative nausea and vomiting.25,27,28,31,33 Two studies provided 2 comparisons and both were included in the final analysis.27,31 The combined effect suggested a reduction in postoperative nausea and vomiting with 60 mg ketorolac compared with placebo with an odds ratio (95% CI) of 0.50 (0.29–0.85).
Several important findings have emerged from this quantitative systematic review. Although a single dose of systemic ketorolac can be effective to prevent postoperative pain, the effect may be dependent on the dose and route of administration. The 60-mg dose decreased early postoperative pain and had opioid-sparing effects but there was a lack of evidence for a statistically significant effect for the 30-mg dose. Our analysis also suggests a greater analgesic effect of IM administration compared with IV administration but the analysis was limited by a low number of patients in the subgroups. These findings may have important clinical implications because anesthesia providers frequently administer IV 30-mg dose of ketorolac.36
Previous investigators have demonstrated a beneficial effect of the 30-mg dose of ketorolac for the treatment of postoperative pain.5 The question examined by those investigators was different than the one examined in the current analysis. They evaluated the effect of ketorolac to treat moderate to severe pain after surgery, whereas in the current study, we examined the preventive effect of a single dose of perioperative ketorolac on postoperative pain. Our subgroup analysis examining dose efficacy was limited by the small size of the available studies. Nonetheless, because anesthesia providers frequently use 30 mg ketorolac preoperatively to prevent postoperative pain, it is important to state that evidence corroborating this practice is still needed.
Another important finding that has emerged from this study is the beneficial effect of ketorolac in reducing postoperative nausea and vomiting. These findings are significant because there are not enough data showing the beneficial role of opioid-sparing strategies in improving patients' recovery.37 The effects of ketorolac in reducing postoperative nausea and vomiting were present for the 60-mg dose but our analysis failed to detect an effect for the 30-mg dose group. This finding is parallel to the opioid-sparing effects of the different dose groups suggesting a possible association between postoperative opioid reduction and a decrease in postoperative nausea and vomiting.
The lack of effect of a single dose of ketorolac on late pain is expected because of the relatively short half-life of the drug (5 hours).38 The lack of strong antiinflammatory properties can also be a possible explanation for the absence of longer duration effects.39 The longer time to peak concentration of the 60-mg IM injection (30–50 minutes) compared with the 30-mg IV dose (3–5 minutes) of ketorolac with a similar peak concentration is a possible reason for the higher analgesic effect during the postoperative course when the medication is given in the intraoperative period. The analgesic effect of ketorolac is based on the racemic concentration of S and R enantiomers but this fact was not considered in early pharmacokinetic studies of the drug.40 The IM administration of drug may have a slower clearance of the active (S) enantiomer form than the IV administration, which can result in better analgesic effects as we observed in clinical studies.41,42
It is conceivable that by promoting greater patient comfort in the immediate postoperative period, the administration of a single dose of systemic ketorolac would result in faster hospital discharge. We were unable to demonstrate that effect in our analysis. The studies involved in our analysis did not measure time to meet hospital discharge criteria but did measure the actual hospital discharge time. Not using validated discharge criteria has been considered a major reason for the inability to demonstrate an effect of better postoperative pain control in reducing hospital discharge time.43 The use of actual hospital discharge time was probably responsible for the high heterogeneity observed in our analysis.
Our analysis demonstrated a wide CI relative to a clinically significant difference of a single dose of ketorolac 30 mg to prevent postoperative pain; the studies included in the analysis did not involve the use of other non-opioid analgesic strategies and only examined the effect of a single dose of ketorolac administration. It is possible that 30 mg ketorolac, when used as part of a multimodal therapy in conjunction with other analgesics such as acetaminophen or when given as multiple doses, may reduce postoperative pain; however, further studies are necessary to confirm this assumption.
Our systematic review was not able to detect an increase in complications, including postoperative bleeding and gastrointestinal symptoms, caused by the use of ketorolac. Because only few studies reported on the incidence of these side effects, the analysis was limited by a low number of subjects per group. Cases of renal failure were also not reported by any of the studies. Despite the fact that 2 studies reported on abnormal bleeding effects of ketorolac, those reports were not based on objective laboratory information and they did not result in more meaningful outcomes such as the need for allogenic blood transfusion or surgical reoperation. Clinical investigations designed to examine the effect of single dose systemic ketorolac in increasing postoperative bleeding failed to detect a harmful effect.44–46 It is important to note the potential for increased side effects when higher doses of perioperative ketorolac (60 mg) are followed by other nonsteroidal antiinflammatory drugs during the postoperative period.
The findings of this systematic review are only valid when interpreted in light of its limitations. We included a diversity of surgical procedures, types of rescue analgesics, and described outcomes. Ideally, a meta-analysis would only include homogeneous studies with a similar group of patients. Different surgical procedures were used to optimize the number of subjects and to generalize our findings to different surgical settings. We attempted to minimize heterogeneity by only including trials using a single dose of systemic ketorolac and rejecting the ones using the drug in the postoperative period. Another potential limitation is that most trials had a small sample size and most were performed before the year 2000; since then, significant changes have occurred in the perioperative management of patients. The quality of included studies is an important factor to achieve reliable results in meta-analysis of small trials.47 The median Jadad score for the studies included in our systematic review was 4, indicating an overall good quality of the included studies.
Some areas for future research on the effect of a single dose of ketorolac as part of a multimodal strategy to prevent postoperative pain were identified by this systematic review. Large randomized trials, adequately powered to examine dose-response effects, are clearly needed. Studies examining the analgesic effects of both IV and IM 30-mg dose are also necessary. Further direct comparisons of the IM administration versus the IV administration are also warranted to confirm our findings. Because the effect of ketorolac seems to be more pronounced in the earlier postoperative period, studies examining ambulatory patients should include time to discharge using validated criteria such as the Post-Anesthetic Discharge Scoring System (PADSS) as one of the evaluated outcomes.48
In conclusion, systemic single dose ketorolac is an effective multimodal strategy to reduce postoperative pain. Benefits on postoperative analgesia and postoperative nausea and vomiting outcomes can be achieved by using a 60-mg dose but there is a lack of current evidence that the frequently used 30-mg single systemic dose has a beneficial effect on postoperative pain outcomes. The 60-mg IM route may provide greater opioid-sparing effects than the IV route. More studies examining the efficacy of different dose regimens of systemic ketorolac to prevent postoperative pain are necessary to help anesthesiologists achieve the very much needed improvement in the management of postoperative pain.
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