A 2023 systematic review and meta-analysis published in Annals of Emergency Medicine synthesized data from five randomized controlled trials (RCTs) encompassing 627 adult patients presenting to emergency departments (EDs) with acute pain. The review evaluated the comparative effectiveness and safety of low-dose (10-20 mg) versus high-dose (≥30 mg) parenteral (both intravenous and intramuscular) ketorolac; pain etiologies ranged from renal colic and musculoskeletal pain to abdominal and headache-related discomfort. Results from pooled analyses showed that parenteral ketorolac at doses of 15-20 mg likely produces no clinically meaningful difference in analgesia compared to doses ≥30 mg (mean difference -0.05 mm on a 100 mm visual analog scale [VAS], 95% CI -4.91 to +5.01; moderate certainty). Similarly, 10 mg dosing showed no significant effect on pain scores versus higher doses (mean difference -1.58 mm, 95% CI -8.86 to +5.71; low certainty). Low-dose ketorolac may be associated with a higher likelihood of requiring rescue analgesia (risk ratio 1.27, 95% CI 0.86 to 1.87; low certainty), although the absolute difference was modest. Importantly, no statistically significant differences were observed in adverse event rates (risk ratio 0.84, 95% CI 0.54 to 1.33; low certainty), and across all included RCTs, no cases of gastrointestinal bleeding or new-onset renal dysfunction were reported, regardless of dose. Findings support the analgesic ceiling effect of ketorolac and reinforce the potential clinical utility of lower doses for robust pain control while minimizing dose-related toxicity. [1]
A 2021 randomized, double-blind, noninferiority trial, published as an editorial, evaluated the analgesic ceiling effect of intravenous ketorolac in adult patients presenting to the emergency department (ED) with renal colic. Investigators enrolled 165 patients and assigned them evenly into three dosing groups: 10 mg, 20 mg, or 30 mg IV ketorolac. Baseline pain scores were recorded using a 100-point visual analog scale (VAS). At 30 minutes post-administration, all three groups experienced a median VAS pain reduction to 40, irrespective of the dose administered. The 30-mg group reported a decline from 90 to 40, the 20-mg group from 80 to 40, and the 10-mg group from 90 to 40. These findings demonstrated that lower doses of ketorolac were noninferior in pain reduction compared to the standard 30-mg dose, supporting the presence of a clinically relevant analgesic ceiling at or below 10 mg, with lower doses offering comparable efficacy and potentially minimizing adverse drug reactions. Additional evidence from a 2017 randomized controlled trial published in Annals of Emergency Medicine further corroborated this ceiling effect. This study enrolled 240 adults presenting to the ED with moderate pain from renal colic, musculoskeletal etiologies, or acute headaches. Participants were randomized to receive 10 mg, 15 mg, or 30 mg of IV ketorolac, with pain intensity measured on a 0-to-10 numeric rating scale at 30 minutes post-dose. Noninferiority analysis demonstrated that all three dosing groups achieved similar reductions in pain intensity without a statistically significant difference between them. Similarly, a 2021 single-blinded, randomized trial published in the American Journal of Emergency Medicine compared IM ketorolac 15 mg versus 60 mg for acute musculoskeletal pain in 110 military ED patients. Researchers found no significant difference in pain relief between both groups. Collectively, these trials support the recommendation from the American Academy of Emergency Medicine to use the lowest effective ketorolac dose (typically 10 to 15 mg), thereby optimizing safety while maintaining analgesic efficacy. [2]
According to a review on the analgesic efficacy of ketorolac, the most important disadvantage of ketorolac is that there is an analgesic “ceiling.” Doses above 30 mg for parenteral ketorolac and (10 mg PO) provide little additional analgesic benefit. Intravenous ketorolac, as a single agent, also has limited utility in patients with moderate-to-severe pain because a significant percentage of patients fail to obtain adequate relief. This review claims a dose of 0.5 mg/kg appears to be effective in children, but the mention of a dose ceiling in the pediatric population is not discussed. [3]
Sickle cell disease (SCD) is one of the most commonly inherited diseases worldwide that is characterized by chronic hemolytic anemia, and one of the most intractable problems encountered by children with this disease is painful episodes that result from tissue ischemia due to vaso-occlusion. Mild pain is treated using acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs), such as ketorolac. Ketorolac generally is not used as a first-line agent due to lack of data regarding the efficacy and adverse effects when used for pain associated with pediatric SCD. Instead, ketorolac can be added to opioids for additional analgesia in situations where opioids provide insufficient analgesia after optimal titration, or more commonly as an adjunct to opioid analgesia in the presence of opioid-related adverse effects. However, ketorolac should not be used for more than 5 days because of the increased risk of toxicity. If ketorolac is to be used, the authors recommend an initial IV loading dose of 1.0 mg/kg, then 0.5 mg/kg q6h to a maximum of 2 mg/kg/day or 10mg PO q4-6h to a maximum of 40 mg/day. [4]
A 2018 Cochrane review and meta-analysis evaluated the use of ketorolac for postoperative pain in children through 13 studies, totaling 920 patients ranging from 356 days to 13.9 years old. The majority of studies chose a dose of either 0.5 mg/kg (as a single or multiple dose regimen) or 1 mg/kg (single dose with 0.5 mg/kg for any subsequent doses), and one study administered ketorolac 1.2 mg/kg q6h. Unfortunately, the authors were unable to assess the total amount of patients with at least a 50% reduction in pain after ketorolac due to insufficient data. There was no clear difference between ketorolac and placebo in the need for rescue medications (relative risk [RR] 0.85; 95% confidence interval [CI] 0.71 to 1.00). Whether ketorolac has an important effect on opioid consumption was also unable to be assessed. The authors conclude the overall was insufficient to support or reject the use of ketorolac in pediatric patients postoperatively due to a lack of data and substantial heterogeneity between available studies. [5]
A 2012 meta-analysis on perioperative ketorolac efficacy stated that a single dose of systemic ketorolac is an effective adjunct in multimodal regimens to reduce postoperative pain. Improved postoperative analgesia achieved with ketorolac was also accompanied by a reduction in postoperative nausea and vomiting. Thirteen randomized clinical trials with 782 subjects who were given ketorolac 30 to 60 mg (either IV or IM) were included. The weighted mean difference (95% confidence interval [CI]) of combined effects showed a difference for ketorolac over placebo for early pain at rest of -0.64 (-1.11 to -0.18) but not at late pain at rest, -0.29 (-0.88 to 0.29) summary point (0-10 scale). The authors state that 60 mg doses may offer better opioid-sparing benefits compared to 30 mg. It should be noted there was significant heterogeneity present in this analysis which may invalidate the authors' conclusions. [6]