As the day is winding down in your urgent care, a 55-year-old male presents to one of your examination rooms complaining of lower back pain. He was painting his shed for the past 2 days and just woke up this morning with a terrible back ache. He says he can barely lay down to rest or do much of anything else. As you palpate his lower right paraspinal muscles, he feels very tender. You ask him if he took anything to aid with his pain. The patient said he took some Tylenol last night, but it was not really helping. You ask him if he is okay with taking a shot of pain medication in his arm, and he says that would be wonderful.

Search Question:

For adults presenting with acute musculoskeletal pain does the administration of low-dose Ketorolac give equivocal or better pain relief scores within 30 minutes of administration than a higher dose of Ketorolac?

Question Type: What kind of question is this? (boxes now checkable in Word)

☐Prevalence                             ☐Screening                  ☐Diagnosis

☐Prognosis                              ☒Treatment                 ☐Harms

Assuming that the highest level of evidence to answer your question will be meta-analysis or systematic review, what other types of study might you include if these are not available (or if there is a much more current study of another type)? Please explain your choices.

– If meta-analysis or systematic review are not available, randomized controlled clinical trials will also offer great supporting evidence as they are carefully planned experiments, reduce the potential for bias, and allow for comparison between intervention and control groups.

– Cohort studies could also be used since they allow to follow the patients who have already received a particular treatment forward over time. This is not as reliable as randomized controlled clinical trials since patients might differ in ways other than in the variable that is being observed.

PICO search terms:

P	I	C	O
Adults with acute musculoskeletal pain	Lower dose of Ketorolac	Higher dose of Ketorolac	Equivocal or better pain relief scores after 30 minutes of administration
Acute musculoskeletal pain
Musculoskeletal pain

Search tools and strategy used:

Please indicate what data bases/tools you used, provide a list of the terms you searched together in each tool, and how many articles were returned using those terms and filters.
Explain how you narrow your choices to the few selected articles.

Results found:

TRIP Database

• Adults with acute musculoskeletal pain AND lower dose of Ketorolac – 104
• Adults with acute musculoskeletal pain AND lower dose of Ketorolac AND higher dose of Ketorolac – 36

PubMed

• Acute musculoskeletal pain AND lower dose of Ketorolac (last 10 years) – 26
• Adults with acute musculoskeletal pain AND lower dose of Ketorolac (last 10 years) – 5

Google Scholar

• Adults with acute musculoskeletal pain AND lower dose of Ketorolac AND higher dose of Ketorolac – 10,800
• Adults with acute musculoskeletal pain AND lower dose of Ketorolac AND higher dose of Ketorolac (last 10 years) – 8,100

The articles I chose were a mixture of systematic review and meta-analysis, two randomized clinical trials, and a retrospective cohort study that dealt with my topic. There were too many other topics dealing with other disease states and pathologies that included Ketorolac (Toradol) administration for patients with nephrolithiasis pain, dental pain, or cancer pain. There were also other articles that dealt with which pain medication worked better for patients between Ketorolac and either acetaminophen, diclofenac, or codeine. 

Identify at least 4 articles (or other appropriate reputable sources) that answer your specific question with the highest available level of evidence (you will probably need to look at more than 4 articles to get the 4 most focused and highest-level articles to address your question). Please make sure that they are Medline indexed.

Citation: Forestell, B., Sabbineni, M., Sharif, S., Chao, J., & Eltorki, M. (2023). Comparative Effectiveness of Ketorolac Dosing Strategies for Emergency Department Patients With Acute Pain. Annals of Emergency Medicine, 82(5), 615–623. https://doi.org/10.1016/j.annemergmed.2023.04.011

Type of article: Systematic Review and Meta-analysis

Abstract   Study objectives: Ketorolac is a commonly used nonopioid parenteral analgesic for treating emergency department (ED) patients with acute pain. Our systematic review aims to summarize the available evidence by comparing the efficacy and safety of differing ketorolac dosing strategies for acute pain relief in the ED.   Methods: The review was registered on PROSPERO (CRD42022310062). We searched MEDLINE, PubMed, EMBASE, and unpublished sources from inception through December 9, 2022. We included randomized control trials of patients presenting with acute pain to the ED, comparing ketorolac doses less than 30 mg (low dose) to ketorolac doses more than or equal to 30 mg (high dose) for the outcomes of pain scores after treatment need for rescue analgesia, and incidence of adverse events. We excluded patients in non-ED settings, including postoperative settings. We extracted data independently and in duplicate and pooled them using a random-effects model. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool and the overall certainty of the evidence for each outcome using the Grading Recommendations Assessment, Development, and Evaluation approach.   Results: This review included 5 randomized controlled trials (n=627 patients). Low-dose parenteral ketorolac (15 to 20 mg), as compared to high-dose ketorolac (≥30 mg), probably has no effect on pain scores (mean difference 0.05 mm lower on 100 mm visual analog scale, 95% confidence interval [CI] -4.91 mm to +5.01 mm; moderate certainty). Further, low-dose ketorolac at 10 mg may have no effect on pain scores compared to high-dose ketorolac (mean difference 1.58 mm lower on 100 mm visual analog scale, 95% CI -8.86 mm to +5.71 mm; low certainty). Low-dose ketorolac may increase the need for rescue analgesia (risk ratio 1.27, 95% CI 0.86 to 1.87; low certainty) and may have no difference on rates of adverse events (risk ratio 0.84, 95% CI 0.54 to 1.33; low certainty).   Conclusion: In adult ED patients with acute pain, parenteral ketorolac given at doses of 10 mg to 20 mg is probably as effective in relieving pain as doses of 30 mg or higher. Low-dose ketorolac may have no effect on adverse events, but these patients may require more rescue analgesia. This evidence is limited by imprecision and is not generalizable to children or those at higher risk of adverse events.

Key Points: – This systematic review and meta-analysis included 5 randomized control trials from the PubMed, MEDLINE, and Embase databases – There were 627 adult patients who were included in this study – Half of the patients were given a low-dose of Ketorolac (10 – 20 mg)The other half of the patients were given a higher-dose of Ketorolac (30 – 90 mg) – The mean baseline pain scores used for this study was between 0-mm (no pain) to 100-mm (maximum amount of pain) – There were no statistically significant differences in pain scores after 60 minutes of administration of either the lower-dose or the higher dose of Ketorolac – As an additional variable, there were no adverse events that came up with patients who were given the lower dose pain medication

Why I chose it: I chose this article because it was the only systematic review/meta-analysis I could find regarding different dosages of Ketorolac administration and how it equates to pain scores after administration. I was pleased to see that a lowered dose of Ketorolac was just as efficacious in treating a patient’s pain profile as a higher dose was. I was also interested in seeing that rescue analgesia (IV morphine) was ready to be administered to patients who were given the low-dose Ketorolac in case of treatment failure, but was pleasantly surprised to see that patients did not need to use the morphine for pain control. I was also happy to see there were not any adverse events that came from the lower dosage.

Citation: Motov, S., Yasavolian, M., Likourezos, A., Pushkar, I., Hossain, R., Drapkin, J., Cohen, V., Filk, N., Smith, A., Huang, F., Rockoff, B., Homel, P., & Fromm, C. (2017). Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Annals of Emergency Medicine, 70(2), 177–184. https://doi.org/10.1016/j.annemergmed.2016.10.014

Type of article: Randomized Controlled Trial

Abstract Study objective: Nonsteroidal anti-inflammatory drugs are used extensively for the management of acute and chronic pain, with ketorolac tromethamine being one of the most frequently used parenteral analgesics in the emergency department (ED). The drugs may commonly be used at doses above their analgesic ceiling, offering no incremental analgesic advantage while potentially adding risk of harm. We evaluate the analgesic efficacy of 3 doses of intravenous ketorolac in ED patients with acute pain. Methods: We conducted a randomized, double-blind trial to assess the analgesic efficacy of 3 doses of intravenous ketorolac (10, 15, and 30 mg) in patients aged 18 to 65 years and presenting to the ED with moderate to severe acute pain, defined by a numeric rating scale score greater than or equal to 5. We excluded patients with peptic ulcer disease, gastrointestinal hemorrhage, renal or hepatic insufficiency, allergies to nonsteroidal anti-inflammatory drugs, pregnancy or breastfeeding, systolic blood pressure less than 90 or greater than 180 mm Hg, and pulse rate less than 50 or greater than 150 beats/min. Primary outcome was pain reduction at 30 minutes. We recorded pain scores at baseline and up to 120 minutes. Intravenous morphine 0.1 mg/kg was administered as a rescue analgesic if subjects still desired additional pain medication at 30 minutes after the study drug was administered. Data analyses included mixed-model regression and ANOVA. Results: We enrolled 240 subjects (80 in each dose group). At 30 minutes, substantial pain reduction was demonstrated without any differences between the groups (95% confidence intervals 4.5 to 5.7 for the 10-mg group, 4.5 to 5.6 for the 15-mg group, and 4.2 to 5.4 for the 30-mg group). The mean numeric rating scale pain scores at baseline were 7.7, 7.5, and 7.8 and improved to 5.1, 5.0, and 4.8, respectively, at 30 minutes. Rates of rescue analgesia were similar, and there were no serious adverse events. Secondary outcomes showed similar rates of adverse effects per group, of which the most common were dizziness, nausea, and headache. Conclusion: Ketorolac has similar analgesic efficacy at intravenous doses of 10, 15, and 30 mg, showing that intravenous ketorolac administered at the analgesic ceiling dose (10 mg) provided effective pain relief to ED patients with moderate to severe pain without increased adverse effects.

Key Points: – This randomized double-blinded control trial looked at the analgesic efficacy of three different dosages of IV Ketorolac – There was a total of 240 patients from the Maimonides Hospital emergency room in Brooklyn, NY – The patients were between the ages of 18-65 who came into the hospital with either musculoskeletal pain, headache pain, or abdominal pain over 5 on the pain scale – The pain scale that was used was a numeric scale between 0 (no pain) to 10 (maximum pain) – The treatment arms included administering 10mg, 15 mg, and 30 mg of IV Ketorolac – The treatment groups were all divided equally (80 patients each)After 30 minutes post administration, the group that got the 10 mg of IV Ketorolac saw a pain rating scale that went from 7.7 to 5.2. The group that got the 15 mg of IV Ketorolac saw a pain rating scale that went from 7.5 to 5.1. The group that got the 30 mg of IV Ketorolac saw a pain rating scale that went from 7.8 to 4.8 – There were no statistically significant differences regarding pain scores across all three treatment arms

Why I chose it: I chose this article because I wanted an article that looked at how real patients perceived pain relief from different dosages of pain medication. This article directly looks at, and answers, my PICO question. The group that got the low-dose IV Ketorolac saw the same pain reduction as the highest dose of IV Ketorolac. I was also happy to see that the treatment arms were evenly distributed throughout. As mirrored from the last article, there were no differences across the treatment arms regarding adverse effects like nausea, headache, flushing, or dizziness.

Citation: Turner, N. J., Long, D. A., Bongiorno, J. R., Katoski, T. P., Jin, L. M., Horsch, J. P., & Ahern, B. J. (2021). Comparing two doses of intramuscular ketorolac for treatment of acute musculoskeletal pain in a military emergency department. The American Journal of Emergency Medicine, 50, 142–147. https://doi.org/10.1016/j.ajem.2021.07.054

Type of article: Single-blinded, randomized controlled, non-inferiority trial

Abstract Study objective: The goal of the study was to assess a low-dose versus a high-dose of intramuscular (IM) ketorolac for non-inferiority in adults with acute MSK pain in an emergency department (ED). Methods: This was a single-blinded, randomized controlled, non-inferiority trial of adults presenting to an ED with a chief complaint of acute MSK pain. Patients were randomized to either a 15 mg or a 60 mg IM ketorolac dose. The primary outcome was the mean difference of change in pain from baseline to 60-min between the two groups as reported on a 100-mm (mm) visual analog scale (VAS). Secondary outcomes included the mean difference of change in VAS scores at 30-min and the incidence of reported adverse effects associated with the administration of ketorolac. Results: One hundred ten patients were randomized with 55 in each group. The mean difference in pain between groups at 60-min (0.2 mm [95% CI -8.5–8.7]; p = .98) and 30 min (−1.7 mm [95% CI -8.5–5.1; p = .63) was less than the predetermined non-inferiority margin of 13 mm. There were no major adverse effects reported. Minor adverse effects were more frequent in the 60 mg group (n = 9; 16.4% vs. n = 1; 1.8%; p = .016) with burning at the injection site being the most commonly reported. Conclusions: A 15 mg dose of IM ketorolac was found to be non-inferior to a 60 mg dose for acute MSK pain in adults presenting to the ED. Discontinuing the practice of ordering 60 mg doses of IM ketorolac in place of a lower dose for acute MSK pain should be considered.

Key Points: – This randomized control trial had 110 patients ages 18-55 years old in an emergency room setting – The groups were split evenly (55 patients per treatment arm) – The first group got a low-dose of IM Ketorolac at 15 mg – The second group got a high-dose of IM Ketorolac at 60 mg – Patients were asked their pain levels on a numeric pain scale between 0-mm (no pain) to 100-mm (maximum amount of pain) at 30-minute and 60-minute intervals – The average pain scale measurement pre-administration of pain medication was 69.78 mm for the 15 mg group and 66.26 mm for the 60 mg group. The low-dose IM Ketorolac treatment arm went down to 50.78 mm at 30 minutes and the high dose treatment arm went down to 48.95 mm. As this is was non-inferiority trial, the article found that a 15 mg IM dose of Ketorolac was non-inferior to a 60 mg IM dose

Why I chose it: I chose this article because it was the only article that had such a vast difference between treatment dosages and looked at whether those dosages (especially the lower dose) would lead to suboptimal pain relief that would need to be supplemented with rescue analgesia. I was pleasantly surprised to see that the patients who got the 15 mg dose of IM Ketorolac were as pain free as those who got quadruple the dose. I was also glad to see that the treatment arms were split evenly down the middle.

Citation: Platt, E., Neidhardt, J. M., End, B., Cundiff, C., Fang, W., Kum, V., Tucker, H., & Quedado, J. M. (2023). Safety and Efficacy of Low-Dose Versus High-Dose Parenteral Ketorolac for Acute Pain Relief in Patients 65 Years and Older in the Emergency Department. Cureus, 15(6), e40333. https://doi.org/10.7759/cureus.40333

Type of article: Retrospective Cohort Study

Abstract Background: There is limited data surrounding acute pain management in elderly ED patients. Ketorolac is a potent non-steroidal anti-inflammatory drug (NSAID) with dose/duration-dependent side effects. There is evidence that an analgesic ceiling effect exists for parenteral ketorolac doses greater than 10 milligrams (mg); however, this has not been studied in patients 65 years and older. Methods: This was a retrospective chart review of ED patients 65 years and older who received at least one dose of parenteral ketorolac. Patients were separated into two cohorts based on the ketorolac dose received: 15 mg IV or 30 mg intramuscular (IM) and 30 mg IV or 60 mg IM. The primary objective was to evaluate the analgesic efficacy of parenteral ketorolac doses measured as needing rescue analgesia from 30 minutes to 2 hours after ketorolac administration. Secondary objectives included changes in pain scores and the occurrence of adverse drug events commonly associated with ketorolac. Results: Two-hundred and sixty patients received ketorolac doses of 15 mg IV or 30 mg IM, and 52 received 30 mg IV or 60 mg IM. The primary outcome occurred in seven of 52 patients who received ketorolac 30 mg IV or 60 mg IM and 17 of 260 patients who received ketorolac 15 mg IV or 30 mg IM (13.5% vs. 6.5%, p=0094; OR: 2.22, 95% CI: 0.87-5.67). The average change in pain scores were 2.9 (±3.1) and 2.8 (±2.9) for patients who received doses 30 mg IV or 60 mg IM compared to doses 15 mg IV or 30 mg IM, respectively (p=0.154). The occurrence of adverse events was low in both groups. Conclusion: Parenteral ketorolac doses of 15 mg IV or 30 mg IM did not demonstrate a greater need for rescue analgesia compared to doses of 30 mg IV or 60 mg IM.

Key Points: – This retrospective cohort study looked at 312 patients who were over the age of 65 years old who were being treated in a West Virginia emergency room – 260 patients received the low-dose Ketorolac [LDK] (15 mg IV or 30 mg IM) – 52 patients received the high-dose Ketorolac [HDK] (30 mg IV or 60 mg IM) – There was a numeric pain scale that was used between 0 (no pain) to 10 (maximum amount of pain) – The changes in pain scores were not statistically significant between either treatment arm (with a 2.9 pain score reduction with the HDK and 2.8 pain score reduction with the LDK at the 30-minute interval) – There was also no need for any rescue analgesia between the low-dose and high-dose treatment arms

Why I chose it: I chose this article because the other articles I had never included any data on patients who were over 65 years old and were getting IV or IM Ketorolac. As mirrored by the other articles, the lower dosage of Ketorolac was just as effective in treating the patient’s pain as the higher dose. I was also surprised to see that the route of administration (whether it was IM or IV) did not change the effectiveness of how much pain relief the patient’s felt

What is the clinical “bottom line” derived from these articles in answer to your question?

Ketorolac remains to be one of the most frequently used analgesics across emergency rooms and urgent cares alike. Until very recently, there were not too many papers or RCTs that looked at whether a lower dose of Ketorolac was just as efficacious as a higher dose. Ketorolac, as other NSAIDS, have a high risk of gastrointestinal bleeding, among other serious adverse effects, which may have curbed insight in whether a higher dose of the medication is needed for maximum pain relief. Thankfully, with many recent randomized controlled trials and systematic reviews/meta-analysis, the question can be answered. A lower dose of Ketorolac (10 mg – 15 mg) is just as efficient in reducing pain in a short amount of time as a higher dose is.