What is the safety data for ketorolac 60 mg IM injection dose compared with 30 mg IM injection? Are there any clinical considerations to avoid ketorolac 60 mg IM injections?

Comment by InpharmD Researcher

While there are limited studies directly comparing 60 mg and 30 mg IM ketorolac, one study directly comparing low-dose (15 mg IV or 30 mg IM) and high-dose ketorolac (30 mg IV or 60 mg IM) observed no differences in adverse events or requirement for rescue analgesia. Another study directly comparing 15 mg and 60 mg IM ketorolac similarly found no differences in adverse events. Pooled data from a single meta-analysis also determined there to be no safety differences between low-dose (<30 mg) and high-dose (≥30) ketorolac. However, it should be noted that this analysis included studies utilizing IV and IM ketorolac. Prescribing information for ketorolac recommends against exceeding a total daily dose of 60 mg for patients 65 years or older, under 50 kg of body weight, or with moderately elevated serum creatinine. In general, the risk of gastrointestinal effects associated with ketorolac should be taken into consideration, but available data does not currently suggest an increased incidence of such events with higher IM doses.

Background

A 2023 meta-analysis compared the efficacy and safety of low-dose (<30 mg) and high-dose (≥ 30 mg) ketorolac dosing strategies for acute pain relief in the emergency department (ED). A total of 5 randomized clinical trials (N= 627) comparing low-dose and high-dose ketorolac were identified for analysis. The upper age for the trials ranged from 55 to 70 years, while the sources of acute pain included renal colic, musculoskeletal, flank, abdominal, and headache-related pain. Of note, the dosing strategies between trials varied, with two trials using intramuscular ketorolac, and the remaining three trials using intravenous ketorolac. It was determined that low-dose parenteral ketorolac (15-20 mg) may have no difference in effect on pain scores than a higher dose of 30-90 mg (mean difference [MD] -0.05 mm; 95% confidence interval [CI] -4.91 mm to 5.01 mm). A low dose of ketorolac at 10 mg was also determined to have potentially no effect on pain scores compared to high-dose ketorolac (MD -1.56 mm; 95% CI -8.82 to 5.69). [1]

Additionally, low-dose ketorolac was found to require an increased need for rescue analgesia (relative risk [RR] 1.27; 95% CI 0.86 to 1.87) and without affecting the risk of pooled adverse events including nausea, headache, dizziness, and flushing (RR 0.84; 95% CI 0.54 to 1.33); no episodes of gastrointestinal bleeding or new renal dysfunction were reported in any of the reviewed trials. A post-hoc sensitivity analysis, which excluded high-dose comparators not seen in clinical practice, further confirmed no difference in pain scores between groups. The overall small sample size and low certainty of evidence reduced the validity of the analysis. As a result, heterogeneity was high (>50%) when reviewing pooled adverse events. This, and the exclusion of patients with a risk of NSAID-related adverse events (bleeding, peptic ulcer, renal dysfunction) decrease the generalizability of the data. Overall, it was determined that low-dose parenteral ketorolac is likely as safe and effective in relieving acute pain compared to high-dose parenteral ketorolac. However, it should be taken into consideration that patients receiving low doses may be more likely to require rescue medication. More extensive studies are necessary to further address the incidence of more serious adverse events that might occur due to high-dose ketorolac use in clinical practice. [1]

References:

[1] Forestell B, Sabbineni M, Sharif S, Chao J, Eltorki M. Comparative Effectiveness of Ketorolac Dosing Strategies for Emergency Department Patients With Acute Pain. Ann Emerg Med. 2023;82(5):615-623. doi:10.1016/j.annemergmed.2023.04.011
Relevant Prescribing Information

Boxed Warning:
Dosage should be adjusted for patients 65 years or older, for patients under 50 kg (110 lbs.) of body weight, and for patients with moderately elevated serum creatinine. Doses of ketorolac tromethamine injection are not to exceed 60 mg (total dose per day) in these patients. [2]

Dosage & Administration:
Multiple-Dose Treatment (Intravenous or Intramuscular)
Patients <65 years of age: The recommended dose is 30 mg ketorolac tromethamine injection every 6 hours. The maximum daily dose for these populations should not exceed 120 mg.
Patients ≥65 years of age, renally impaired patients, and patients less than 50 kg (110 lbs): The recommended dose is 15 mg ketorolac tromethamine injection every 6 hours. The maximum daily dose for these populations should not exceed 60 mg. [2]

Gastrointestinal Effects – Risk of Ulceration, Bleeding and Perforation: Ketorolac tromethamine is contraindicated in patients with previously documented peptic ulcers and/or gastrointestinal (GI) bleeding. Ketorolac tromethamine can cause serious GI adverse events including bleeding, ulceration and perforation, of the stomach, small intestine, or large intestine, which can be fatal. These serious adverse events can occur at any time, with or without warning symptoms, in patients treated with ketorolac tromethamine. [2]

References:

[2] Ketorolac Tromethamine Injection. Prescribing information. Alembic Pharmaceuticals Inc; January 2024.
Literature Review

A search of the published medical literature revealed 3 studies investigating the researchable question:

What is the safety data for ketorolac 60 mg IM injection dose compared with 30 mg IM injection? Are there any clinical considerations to avoid ketorolac 60 mg IM injections?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-3 for your response.

 

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

Design

Single-center, retrospective chart review

N= 312

Objective

To assess if 15 mg intravenous (IV) or 30 mg intramuscular (IM) of parenteral ketorolac (low-dose ketorolac [LDK]) provides similar pain reduction as 30 mg IV or 60 mg IM of parenteral ketorolac (high-dose ketorolac [HDK]) in emergency department (ED) patients 65 years and older

Study Groups

LDK (n= 260)

HDK (n = 52)

Inclusion Criteria

Elderly adults (age ≥65 years) admitted to the ED who had received at least 1 dose of parental ketorolac

Exclusion Criteria

Patients with no pain assessment documented in medical record

Methods

Data were extracted and analyzed from the electronic medical record. Of the initial patients identified (n= 665), patients who received ketorolac 30 mg IV or 60 mg IM were selected and included in the HDK cohort, while patients who received ketorolac 15 mg IV or 30 mg IM were randomly selected from the remaining population (LDK cohort). Pain scores were measured using a numeric scale (0 to 10) reported 30 minutes to 2 hours post injection. Adverse events were reported if they occurred within 72 hours of ketorolac injection.

Duration

August 1, 2018 to July 31, 2021

Outcome Measures

Primary: analgesic efficacy (needing rescue analgesia within 30 minutes to 2 hours after ketorolac administration)

Secondary: change in pain score after ketorolac administration, incidence of adverse drug events

Baseline Characteristics

  

LDK (n= 260)

HDK (n= 52)

p-value

  

Age, years

 73 ± 7 70 ± 5 0.003  

Female

 155 (60%) 24 (46%)    

Weight <50, kg

 10 (4%) 1 (2%)    

Renal function, mL/min

eGFR >50

eGFR 30-50

eGFR <30

eGFR unavailable

 

189 (73%)

31 (12%)

2 (1%)

38 (15%)

 

44 (85%)

4 (8%)

-

4 (8%)

    

Medical history

Gastrointestinal bleed

Coronary artery disease

Congestive heart failure

Anticoagulant use

Antiplatelet use

 

18 (7%)

88 (34%)

23 (9%)

33 (13%)

204 (78%)

 

4 (8%)

16 (31%)

3 (6%)

2 (4%)

45 (87%)

    

Source of pain

Back

Abdominal

Flank

Extremities

Head

Other

 

49 (19%)

41 (16%)

16 (6%)

49 (19%)

31 (12%)

74 (28%)

 

12 (23%)

7 (14%)

5 (10%)

8 (15%)

9 (17%)

11 (21%)

  

 

Analgesia prior to keterolac

Opioid

Non-opioid

58 (22%)

42 (66%)

22 (34%)

20 (38%)

19 (83%)

4 (17%)

0.002

  

Concomitant analgesia

Opioid

Non-opioid

64 (25%)

19 (28%)

50 (72%)

12 (23%)

4 (29%)

10 (71%)

    

Pain score

7.14 ± 2.4

7.9 ± 1.7

    

eGFR, estimated glomerular filtration rate

Results

Endpoint

LDK (n= 260)

 HDK (n= 52) OR* (95% CI)

p-value

Need for rescue analgesia*

 17 (6.5%) 7 (13.5%) 2.07 (0.79 to 5.39) 0.138

Change in pain score

 2.8 ± 2.9 2.9 ± 3.1 N/A 0.154

Adverse Events

Gastrointestinal

Acute kidney injury

Thrombotic Event

Edema

Central Nervous System

 

-

5 (2%)

1 (<1%)

9 (3%)

1 (<1%)

 

-

-

-

2 (4%)

1 (< 1%)

N/A

 Not reported

*Multivariate analysis adjusted for the presence of concomitant analgesia or baseline pain score

CI, confidence interval; OR, odds ratio

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: Not disclosed

Percentage that Discontinued due to Adverse Events: Not disclosed

Study Author Conclusions

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.

InpharmD Researcher Critique

Due to the skewed number of LDK patients compared to HDK patients, caution should be utilized when interpreting these results. Additionally, the short duration of follow-up, setting of the study (emergency room), and restrictive inclusion criteria (age ≥65) may limit the generalizability and external validity of the results.

 

References:

Platt E, Neidhardt JM, End B, et al. 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. 2023;15(6):e40333. Published 2023 Jun 12. doi:10.7759/cureus.40333

 

Comparing two doses of intramuscular ketorolac for treatment of acute musculoskeletal pain in a military emergency department

Design

Single-blinded, randomized controlled non-inferiority trial

N= 110 

Objective

To assess the efficacy and adverse effects of low-dose (15 mg) versus high-dose (60 mg) of IM ketorolac

Study Groups

Ketorolac 15 mg IM (n= 55) 

Ketorolac 60 mg IM (n= 55) 

Inclusion Criteria

Adult (18-55 years) Department of Defense or Veteran Association patients presenting for acute (< 30 days) musculoskeletal (MSK) pain with a rating ≥ 20 on a standard 100 mm visual analog scale (VAS) and triaged as an emergency severity index (ESI) category 4 or 5

Exclusion Criteria

Patients weighing >50 kg (110 lbs), pregnant or breastfeeding, with a nonsteroidal anti-inflammatory drugs (NSAID) allergy or hypersensitivity, any analgesic medication use within 12 hours, and those with a history of renal disease, gastrointestinal disease, or a bleeding diathesis

Methods

Patients were randomized to either a 15 mg IM dose or a 60 mg IM dose and were blinded to the dose administered. Participants annotated their pain on a VAS immediately prior to ketorolac administration. The VAS was a non-graduated horizontal scale measuring 100 mm, with the left margin representing “no pain” and the right margin representing “severe pain”. The participant's pain level was assessed after 30 and 60 minutes. Additionally, patients were assessed for objective adverse effects and questioned for any subjective adverse effects due to medication administration. The study was designed as a per-protocol analysis, in which only patients who received the initial dose of ketorolac were included in the analysis. A minimal clinically relevant difference and non-inferiority margin of 13 mm on the VAS was chosen based on prior studies. If the difference between the two doses is found to be less than 13 mm, the doses would be considered to be non-inferior. 

Duration

July 2020 to December 2020

Outcome Measures

Primary outcome: Change in VAS pain score 60 minutes after IM ketorolac administration.
Secondary outcomes: Change in VAS score at 30 minutes and the incidence of reported adverse effects

Baseline Characteristics

  

15 mg (n= 55) 

60 mg (n= 55)

    

Age, years

 31.1 ± 9.5  30.7 ± 8.6    

Weight, kg

 82.8 ± 16.5 84.5 ± 16.4    

Female

 13 (24%) 17 (31%)    

Location of pain*

Back/neck

Small joint

Large joint

Other location

 

20 (36%)

12 (22%)

11 (20%)

11( 20%)

 

17 (31%)

10 (18%)

13 (24%)

15 (27%)

    

Duration of pain

≤ 24 hours

> 24 hours

 

22 (40%)

33 (60%) 

 

37 (67%)

18 (33%)

    

*Small joints= Wrist, finger joints, ankle, and toe joints; Large joints= Shoulder, elbow, hip, and knee. Other= Muscle belly, rib, and hand/feet

Results

Endpoint

15 mg (n = 55) 

60 mg (n= 55)

Difference (95% CI)

P-value

VAS pain score

Pre-treatment

At 30 minutes

At 60 minutes

 

69.8 ± 16.5

50.8 ± 23.9

40 ± 27.3

 

66.3 ± 19.1

48.9 ± 24.3

36.4 ± 27.1

 

-

 

 

- 

 

Pain reduction

At 30 minutes

At 60 minutes

 

- 18.9 ± 18.9

- 29.7 ± 22.5

 

-17.3 ± 18.3

-29.9 ± 23.1

 

-1.7 (8.49 to 5.14)

0.1 (8.50 to 8.74)

 

0.63

0.98

Reported adverse effects

Burning at injection site

Fatigue

Headache

Nausea

 

0

1 (1.8%)

0

0

 

4 (7.3%)

2 (3.6%)

2 (2.6%)

1 (1.8%)

 

-

0.16

Abbreviations: CI= confidence interval; VAS= visual analog scale

Patients with back or neck pain reported statistically significantly less pain reduction at 30 min (p= 0.02) and 60 min (p= 0.01) regardless of IM ketorolac dosage compared to patients with pain in other locations. 

Adverse Events

Common Adverse Events: See results

Serious Adverse Events: No major adverse effects reported

Percentage that Discontinued due to Adverse Events: N/A 

Study Author Conclusions

A 15 mg IM dose of ketorolac was found to be non-inferior to a 60 mg dose for short-term pain relief of acute MSK pain in adults presenting to an ED. Subjective adverse effects, while not numerous, were more often reported with the 60 mg dose. Discontinuing the practice of ordering 60 mg IM doses of ketorolac in place of a lower dose for acute MSK pain should be considered.

InpharmD Researcher Critique
Due to the study comparing ketorolac 15 mg IM to 60 mg IM, the findings may not be generalizable to the 30 mg IM dose. The patient exclusion criteria included those with renal, gastrointestinal, or bleeding conditions, limiting generalizability to all patient populations. Additionally, while the non-inferiority margin was met, a non-inferiority trial does not indicate that one dose is superior to another.



References:

Turner NJ, Long DA, Bongiorno JR, et al. Comparing two doses of intramuscular ketorolac for treatment of acute musculoskeletal pain in a military emergency department. Am J Emerg Med. 2021;50:142-147. doi:10.1016/j.ajem.2021.07.054

 

Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial

Design

Randomized, double-blind trial 

N= 240 

Objective

To evaluate the analgesic efficacy of three different doses of intravenous (IV) ketorolac in treating acute pain in emergency department (ED) patients

Study Groups

10 mg (n= 80)

15 mg (n= 80)

30 mg (n= 80)

Inclusion Criteria

Adults aged 18 to 65 years presenting to the ED with moderate to severe acute pain (numeric rating scale score ≥ 5)

Exclusion Criteria

 Patients >65 years; pregnancy or breastfeeding; active peptic ulcer disease; acute gastrointestinal hemorrhage; renal or hepatic insufficiency; allergy to non-steroidal anti-inflammatory drugs (NSAIDs); unstable vital signs; prior analgesic medication use

Methods

Subjects were randomized to receive IV push ketorolac at doses of 10 mg, 15 mg, or 30 mg. Pain scores were measured at baseline and at intervals up to 120 minutes. Rescue analgesia with intravenous morphine was offered if needed.

Duration

Trial duration: March 2014 to December 2015

Follow-up: Up to 120 minutes post-medication administration

Outcome Measures

Primary: pain reduction at 30 minutes

Secondary: rates of adverse effects and the need for rescue analgesia

Baseline Characteristics

The groups were similar in demographics and baseline vital signs. Mean ages were 41.5, 40.1, and 38.8 years for the 10 mg, 15 mg, and 30 mg groups, respectively. Baseline pain scores were equivalently high in all three groups. 

Results

 Pain reduction at 30 minutes was similar across all three doses. No statistically significant differences were observed in pain score reductions or the need for rescue analgesia among the groups. Common adverse effects were similar across groups.

Adverse Events

No serious adverse events were reported. Common adverse effects included dizziness, nausea, and headache, with similar incidence rates across all three dose groups.

Study Author Conclusions

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.

InpharmD Researcher Critique

Although findings suggest that IV ketorolac at doses of 10, 15, and 30 mg has similar analgesic efficacy and similar incidence of adverse effects, caution is warranted in interpretation due to the use of IV rather than intramuscular administration. Additionally, it was noted that the study duration was inadequate to compare the different doses with respect to their adverse effect profiles such as gastrointestinal bleeding and renal impairment because there was a lack of follow-up after 120 minutes after study drug administration and after discharge. Evaluation of doses as high as 60 mg were was not within the scope of this study.

 

References:

Motov S, Yasavolian M, Likourezos A, et al. Comparison of Intravenous Ketorolac at Three Single-Dose Regimens for Treating Acute Pain in the Emergency Department: A Randomized Controlled Trial. Ann Emerg Med. 2017;70(2):177-184. doi:10.1016/j.annemergmed.2016.10.014