What is the evidence supporting a 5-day maximum duration of ketorolac use, and is there any evidence suggesting the ideal interval between treatment courses?

Comment by InpharmD Researcher

Data consistently indicate that the recommended maximum duration of ketorolac use is five days primarily due to safety considerations. Available evidence suggests short-term use is generally well tolerated, while longer use may increase the risk of acute kidney injury and serious gastrointestinal complications (e.g., lesion formation, hemorrhage, or perforation). Notably, there is no consensus on when ketorolac may be safely restarted after a full course, and patients requiring extended analgesia may benefit more from alternative agents. Assessment of patient-specific factors, such as previous clinical response, anticipated duration of use, and gastrointestinal risk are likely most influential in determining appropriate restart time.

Background

A large United States postmarking surveillance study published in 1996 brought up a concern that the longer duration of parenteral ketorolac therapy (> 5 days) was associated with a higher risk of GI bleeds (odds ratio [OR], 2.20; p= 0.04). Adverse events were dose-dependent with high doses (>105 mg/day) associated with increased risk. Additionally, older patients appeared to be the most vulnerable population with extended use of ketorolac. [1]

To address this safety concern, the prescribing information for ketorolac has been revised and now restricts the duration of ketorolac treatment not to exceed 5 consecutive days and recommends that oral ketorolac should only be used as a continuation of intravenous or intramuscular treatment, if necessary, with a total duration of use capped at 5 days as well. Ketorolac is not indicated for chronic painful conditions due to its limited duration of therapy. [2]

References: [1] Strom BL, Berlin JA, Kinman JL, et al. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA. 1996;275(5):376-382.
[2] Toradol (ketorolac tromethamine) [prescribing information]. Roche Laboratories Inc.; 2008.
Relevant Prescribing Information

Ketorolac tromethamine
BOXED WARNING [3]
Ketorolac tromethamine, a nonsteroidal anti-inflammatory drug (NSAID), is indicated for the short-term (up to 5 days in adults) management of moderately severe acute pain that requires analgesia at the opioid level. Oral ketorolac tromethamine is indicated only as continuation treatment following intravenous or intramuscular dosing of ketorolac tromethamine, if necessary. The total combined duration of use of oral ketorolac tromethamine and ketorolac tromethamine injection should not exceed 5 days.

Ketorolac tromethamine is not indicated for use in pediatric patients and it is NOT indicated for minor or chronic painful conditions. Increasing the dose of ketorolac tromethamine beyond the label recommendations will not provide better efficacy but will increase the risk of developing serious adverse events.

CONTRAINDICATIONS [3]
Previously demonstrated hypersensitivity to ketorolac tromethamine
Patients with active peptic ulcer disease, in patients with recent gastrointestinal bleeding or perforation and in patients with a history of peptic ulcer disease or gastrointestinal bleeding
Patients who have experienced asthma, urticaria, or allergic-type reactions after taking aspirin or other NSAIDs
As a prophylactic analgesic before any major surgery.
In the setting of coronary artery bypass graft (CABG) surgery
Patients with advanced renal impairment or in patients at risk for renal failure due to volume depletion
In labor and delivery because it may adversely affect fetal circulation and inhibit uterine musculature, thus increasing the risk of uterine hemorrhage
Patients with suspected or confirmed cerebrovascular bleeding, hemorrhagic diathesis, incomplete hemostasis and those at high risk of bleeding
Patients currently receiving aspirin or NSAIDs because of the cumulative risks of inducing serious NSAID-related adverse events
Concomitant use of ketorolac tromethamine and probenecid
Concomitant use of ketorolac tromethamine and pentoxifylline
For neuraxial (epidural or intrathecal) administration due to its alcohol content

DOSAGE AND ADMINISTRATION [3]
Ketorolac tromethamine is indicated for the short-term (≤ 5 days) management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting. Therapy should always be initiated with intravenous or intramuscular dosing of ketorolac tromethamine, and oral ketorolac tromethamine is to be used only as continuation treatment, if necessary.

The total combined duration of use of ketorolac tromethamine injection and oral ketorolac tromethamine is not to exceed 5 days of use because of the potential of increasing the frequency and severity of adverse reactions associated with the recommended doses. Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

References: [3] Ketorolac tromethamine. Prescribing information. SOLA Pharmaceuticals, LLC; 2025.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What is the evidence supporting a 5-day maximum duration of ketorolac use, and is there any evidence suggesting the ideal interval between treatment courses?

Level of evidence

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


Please see Tables 1-5 for your response.

 

Comparison of Long-Term Safety of Ketorolac Tromethamine and Aspirin in the Treatment of Chronic Pain

Design

Randomized, multicenter, double-blind trial

N= 823

Objective

To compare the long-term safety and efficacy of orally administered ketorolac with that of aspirin, with the primary focus on safety

Study Groups

Ketorolac (n= 553)

Aspirin (n= 270)

Inclusion criteria

21 years or older, orthopedic pain (osteoarthritis, chronic fibromyopathies or fibromyalgias), other nonarticular chronic soft tissue pain syndromes, or chronic headaches

Exclusion criteria

N/A

Methods

Patients were randomized 2:1 to receive either ketorolac tromethamine 10 mg or aspirin 650 mg QID PRN.

Duration

Follow-up: up to 52 weeks of therapy

Outcome Measures

PrimaryL safety

Baseline Characteristics

  

Ketorolac (n= 553)

Aspirin (n= 270)
Age

21 to 88 years

21 to 88 years

Average daily dose

 30 mg  1,850 mg 

Source of pain

Osteoarthritis

Fibrositis

 

74%

6%

 

71% 

5%
Completed 52 weeks of treatment 241 (44%) 85 (31%)

Reasons for withdrawals

Total withdrawal

Adverse events

Adverse events and lack of efficacy

Lack of efficacy

Lost to follow up

Other

 

312 (56%)

131 (24%)

18 (3%)

94 (17%)

36 (7%)

33 (6%)

 

185 (69%)

64 (24%)

18 (7%)

68 (25%)

18 (7%)

17 (6%)

Results

 

 

 

 

 

 

 

 

Ketorolac (n= 553)

Aspirin (n= 270)

Gastrointestinal pain

Peptic ulcer/gastrointestinal bleeding

24%

9 (1.6%)*

21%

3 (1.1%)

Central Nervous system

Headache

Dizziness

Somnolence

 

30%

14%

8%

 

24%

12%

6%

Dyspepsia

22%

30%

Nausea

18%

19%

Diarrhea

14%

9%

Constipation

8%

10%

*8 of these patients had been taking ketorolac for 84 days or longer, and most had one or more of the following risk factors: advanced age (5 were over age 70 yrs), recent history of peptic ulcer, and recent use of other NSAIDs. 

Study Author Conclusions

Early withdrawal for safety-related reasons alone was similar for those taking aspirin and ketorolac. As with all drugs that inhibit prostaglandin synthesis, ketorolac may contribute to gastrointestinal bleeding and peptic ulcer disease, particularly in high-risk patients (age >70 yrs, > l l wks dosing, concurrent or recent use of other NSAlDs, and a history of recent peptic ulcers), but this risk appears to be similar to that of other agents of this therapeutic class.

InpharmD Researcher Critique

Patients were able to take other NSAIDs while in the trial, which may have introduced confounding. There was no defined length of therapy for patients, with less than half completing the full 52 weeks. 



References:
[1] [1] Rubin P, Yee JP, Ruoff G. Comparison of long-term safety of ketorolac tromethamine and aspirin in the treatment of chronic pain. Pharmacotherapy. 1990;10(6 ( Pt 2)):106S-110S.

 

A Multi-institutional Evaluation of the Analgesic Efficacy and Safety of Ketorolac Tromethamine, Acetaminophen plus Codeine, and Placebo in Cancer Pain

Design

Multicenter, double-blind, randomized, controlled trial

N= 75

Objective

To compare the analgesic efficacy and toxicity of ketorolac tromethamine to those of acetaminophen (APAP) plus codeine and of placebo in patients with moderate to severe cancer pain

Study Groups

Placebo (n= 26)

Ketorolac (n= )

APAP plus codeine (n= 27)

Inclusion criteria

Cancer diagnosis, moderate to severe cancer pain for at least 1 week, ≥18 years old, able to take oral medications, were willing to abstain from using narcotics during the study period, platelet count of 100,000 or greater, no known coagulopathy

Exclusion criteria

Pregnant or nursing, had received methadone within 6 hours or other narcotics within 4 hours of study initiation, on any medications, or had any pre-existing conditions that would interact with the study drugs

Methods

Patients were randomly assigned in a double-blind fashion to receive a single dose of placebo, ketorolac tromethamine 10 mg, or acetaminophen 600 plus codeine 60 mg, and were observed for an initial 6 hours.

Patients assigned to ketorolac tromethamine or acetaminophen plus codeine continued on their current dose QID for 7 additional days. Those who initially received placebo were randomly assigned in a double-blind fashion to receive one of those medications with the same dosing schedule.

Duration

7 days

Outcome Measures

Primary outcome: pain intensity and adverse events 

Baseline Characteristics

  

Placebo (n= 26)

Ketorolac (n= 22)

APAP + codeine (n= 27)

Age, years

 65 58  63

Women

9 (35%) 9 (41%)  14 (52%)

Results

 

Ketorolac (n= 34)

APAP + codeine (n= 40)

Any complaint

 21 (62%)  19 (48%) 

Digestive complaint

Nausea

Diarrhea

Vomiting

Gastrointestinal pain

 

7 (21%)

6 (18%)

3 (9%)

5 (15%)

 

12 (30%)

0

5 (13%)

4 (10%)

Adverse Events

Common Adverse Events: Nausea and vomiting were both slightly more common with acetaminophen plus codeine; diarrhea occurred in 18% of patients taking ketorolac and none of those receiving acetaminophen plus codeine. Headache was noted in 21 % of the ketorolac group but in only 3% of the acetaminophen plus codeine group.

Percentage that Discontinued due to Adverse Events: 5 patients (15%) from the ketorolac group and 4 patients (10%) from the acetaminophen and codeine group

Study Author Conclusions

The results of the current study suggest that ketorolac, in the dose and schedule used, may play an important role in the treatment of cancer pain in patients who require nonopioid analgesics alone, or perhaps in combination with an opioid in patients with pain refractory to treatment with a nonopioid only. 

InpharmD Researcher Critique

The baseline characteristics are not reflective of the groups once those receiving placebo were assigned to drug treatment. Both treatments were carried out for 7 days, and although more side effects were noted in the ketorolac group, there were no reported episodes of gastrointestinal bleeding or ulcers.



References:
[1] [1] Carlson RW, Borrison RA, Sher HB, Eisenberg PD, Mowry PA, Wolin EM. A multiinstitutional evaluation of the analgesic efficacy and safety of ketorolac tromethamine, acetaminophen plus codeine, and placebo in cancer pain. Pharmacotherapy. 1990;10(3):211-6.

 

 

Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain

Design

Multicenter, randomized, double-blind, parallel-group study

N= 115

Objective

To evaluate the efficacy and safety of orally administered dexketoprofen trometamol (25 mg q.i.d.) in comparison to ketorolac as the reference drug for the treatment of cancer pain associated with bone metastases.

Study Groups

Dexketoprofen group (n= 57)

Ketorolac group (n= 58)

Inclusion criteria

Patients presenting with metastatic bone pain.

Exclusion criteria

Current or recent (past 15 days) treatment with the following: oral anti-coagulants, systemic corticosteroids, sulfonylurea, antitussives, anti-convulsants, anti-psychotics, tricyclic anti-depressants, lithium, and methotrexate. Known hypersensitivity to ketorolac, acetylsalicylic acid, or other NSAIDs. History of peptic ulcer or NSAID-related gastropathy, clinically significant renal, liver, or cardiac disease (acute myocardial infarction within the last 6 months), blood dyscrasia, asthma, bronchospasm or angioedema, poorly controlled hypertension or diabetes mellitus, epilepsy, psychosis or other personality disorders; drug or alcohol abuse; and participation in a clinical study in the previous 3 months. Pregnant/nursing mothers, women of childbearing potential not on adequate contraception.

Methods

Patients were randomized to receive either dexketoprofen trometamol 25 mg QID or ketorolac 10 mg QID Q6H for 7 (+1) days preferably with meals. Rescue medication with paracetamol 500 mg plus codeine phosphate 30 mg was allowed. If more than 1g paracetamol/60 mg codeine per day was needed, patients were withdrawn from the study.

Duration

 Enrollment period: December 1997 to August 1999

Outcome Measures

Primary outcome: Pain intensity as measured on the visual analog scale (VAS) at day 7 (+1)

Secondary outcome: Treatment-related adverse events (TEAEs)

Baseline Characteristics

  

Dexketoprofen group (n= 57)

Ketorolac group (n= 58)

 

Age, years

 72 ± 7 68 ± 10  

Women/men

 14/42 13/44  

Weight, kg

 69 72  

Height, cm

 164 164  

Concomitant medication

 37 (66%) 27 (47%)  

Current cancer

Prostate

Breast

Lung

Other

 

26 (46%)

8 (14%)

7 (13%)

15 (27%)

 

26 (46%)

10 (17%)

7 (12%)

14 (25%)

  

VAS score at baseline, mm

69 ± 15

75 ± 16

  

Results

Endpoint

Dexketoprofen group (n= 57)

Ketorolac group (n= 58)

p-value

VAS score at 7-day follow-up

 32 ± 24 40 ± 30 Not significant

Treatment-related adverse events (TEAEs)

Gastrointestinal system

Constipation

Diarrhea

Nausea/vomiting

Gastrointestinal hemorrhage

Other GI adverse events

Liver and biliary system

Nervous system/psychiatric

Skin and appendages

Other

Total TEAEs

 

8 (12%)

3 (5%)

0

2 (3%)

0

3 (5%)

2 (3%)

1 (2%)

0

1 (2%)

12

 

12 (21%)

2 (3%)

2 (3%)

4 (7%)

1 (2%)

3 (5%)

4 (7%)

0

1 (2%)

2 (3%)

19

  

Most TEAEs were mild/moderate. Both groups had 3.5% of participants experience serious adverse events. One of the serious TEAE's was gastrointestinal hemorrhage thought to be due to ketorolac.

Study Author Conclusions

Dexketoprofen trometamol 25 mg q.i.d. oral route is a good analgesic therapy in the treatment of bone cancer pain, comparable to ketorolac 10 mg q.i.d., with a good tolerability profile.

InpharmD Researcher Critique

The study was primarily observing a drug versus control which was ketorolac and failed to achieve the sample size of 160 patients for their statistical analysis. For the inquiry, it can be inferred that this study observed over 20% of patients taking ketorolac experienced a GI-related adverse event from 7 days of therapy with one report of GI hemorrhage believed to be due to ketorolac. The time of TEAE onset was not reported so it is unknown if patients developed these symptoms beyond the 5-day recommended use.





References:
[1] [1] Rodrguez MJ, Contreras D, Glvez R, et al. Double-blind evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and ketorolac in bone cancer pain. Pain. 2003;104(1-2):103-110. doi:10.1016/s0304-3959(02)00470-0

Parenteral Ketorolac: The Risk for Acute Renal Failure
Design

Retrospective cohort study

N= 20,364 (10,219 courses of ketorolac and 10,145 courses of opioids)
Objective To compare the risk for acute renal failure associated with ketorolac with that associated with opioids
Study Groups

Ketorolac (n= 10,219 courses)

Opioids (n= 10,145 courses)
Inclusion Criteria Patients identified from hospital pharmacy records as having received parenteral ketorolac or opioids during the data collection period
Exclusion Criteria Patients receiving long-term dialysis
Methods Data were abstracted from hospital charts, including demographic characteristics, medical history, dose and duration of ketorolac or opioid therapy, and adverse events. Acute renal failure was defined by specific increases in serum creatinine concentration. Multivariate proportional hazards models were used to adjust for confounding variables. 
Duration Data collection: 18 November 1991 to 31 August 1993
Outcome Measures Incidence of acute renal failure 
Baseline Characteristics   Ketorolac (n= 10,219) Opioids (n= 10,145)
Men 40% 43%
White 87% 87%
Black 9% 9%
Mean age, years 51 ± 20 52 ± 21
Results   Ketorolac (n= 10,219) Opioids (n= 10,145) p-value
Incidence of acute renal failure 1.07% 1.11% 0.97
Rate ratio for >5 days of therapy (ketorolac vs. opioids) 2.08 (95% CI 1.08 to 4.0) 0.03
Adverse Events Acute renal failure was uncommon overall. No significant difference in risk between ketorolac and opioids for therapy ≤5 days. Increased risk for therapy >5 days. 
Study Author Conclusions Overall, acute renal failure was uncommon in this hospitalized population. Compared with opioids, ketorolac administered for 5 days or less did not increase the rate of renal failure. However, among patients who were treated with analgesics for more than 5 days, ketorolac may be associated with an elevated rate of acute renal failure
Critique The study's retrospective design may limit the ability to establish causality. The matching of patients by hospital and service helps control for confounding, but the lack of randomization could introduce bias. The study's large sample size is a strength, but the potential for unmeasured confounders remains a limitation. The findings suggest caution with prolonged ketorolac use, but further research is needed to confirm these results
References:
[1] [1] Feldman HI, Kinman JL, Berlin JA, et al. Parenteral ketorolac: the risk for acute renal failure. Ann Intern Med. 1997;126(3):193-199. doi:10.7326/0003-4819-126-3-199702010-00003

Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy
Design

Cohort and nested case-control study

N= 201,357
Objective

To compare the risk of hospitalization for gastroduodenal ulcer associated with the use of ketorolac and other non-steroidal anti-inflammatory drugs (NSAIDs)
Study Groups

All patients (N= 201,357)
Inclusion Criteria

Residents of Umbria aged 35-84 years with at least one NSAID prescription from January 1993 to December 1994
Exclusion Criteria

Patients hospitalized for gastroduodenal ulcer, liver cirrhosis, alcohol-related causes, coagulopathies, cancer, or pregnant women during the study period
Methods

Exposure periods were classified as current (dispensing date through expected duration plus 30 days), recent (30 days after current exposure), and past (time thereafter). Hospitalizations for gastroduodenal ulcer, perforation, or hemorrhage were identified through linked discharge records and confirmed by chart review. Person-time incidence rates and adjusted rate ratios were calculated, and a nested case-control analysis with 10 matched controls per case assessed prior NSAID use, gastrotoxic medications, and anti-ulcer therapy in the preceding months.
Duration

January 1993 to December 1994
Outcome Measures Rate ratios of hospitalization for gastroduodenal ulcer and rate ratios for gastrointestinal hemorrhage or perforation
Baseline Characteristics  

All patients (N= 201,357)
Median age

62
Male/female ratio

0.7
Results

 

 Rate ratio for peptic ulcer and upper gastrointestinal haemorrhage or perforation (95% CI)

Piroxicam

 4.6 (3.2-6.7)

Ketorolac

 3.4 (1.4-8.3)

Piroxicam beta

 3.0 (1.6-5.7)

Ketoprofen

 2.7 (1.4-5.3)

Diclofenac

 2.5 (1.7-3.7)

Naproxen

 2.1 (1.0-4.3)

Nimesulide

 2.0 (1.1-3.4)

Other NSAIDs

 1.4 (0.8-2.6)

Any NSAID

 2.8 (2.3-3.6)

Abbreviations: CI, confidence interval.

During the study, 201,357 subjects received at least one NSAID prescription, with a median prescription duration of 6 days for ketorolac and 33 days for naproxen (19 days for other NSAIDs). Of 681 potential hospitalization cases identified, 326 met inclusion criteria after chart review. Incidence of hospitalization for gastroduodenal ulcer increased with age and was lower in women than men. Current NSAID use was associated with a rate ratio of 2.8 (95% CI 2.3 to 3.6), and recent use with 1.4 (1.0 to 2.1). For severe events, ketorolac had the highest rate ratio (5.9). In the nested case-control analysis, concomitant gastrotoxic drug use (odds ratio [OR] 3.5), gastroprotective agent use (OR 2.4), and prior NSAID use (OR 1.2) were associated with hospitalization, but adjustment for these factors did not materially change risk estimates for current NSAID use. When current exposure was restricted to 15 days, the adjusted rate ratio for any NSAID increased to 4.2, with ketorolac at 8.3 and piroxicam at 7.0.
Adverse Events

See above.
Study Author Conclusions

In conclusion, considering the number of hospitalizations for ulcer, ketorolac does not currently appear to present a significant public health problem in Italy. Nonetheless, our findings support the need for adhering to the restrictions of indication and duration, and suggest that its use in general practice requires distinct caution. Ketorolac is among the more gastrotoxic NSAIDs, despite a very short typical duration of therapy (6 days for ketorolac vs a median of 19 days for other NSAIDs). At present, piroxicam requires attention because it is among the most gastrotoxic substances and is one of the most commonly prescribed NSAIDs in Italy. Given the already large amount of evidence available in the literature, the choice in general practice should be reoriented toward less gastrotoxic NSAIDs.
Critique

The study provides insights into NSAID gastrotoxicity, particularly for ketorolac. Limitations include lack of clinical indications, potential exposure misclassification, and reliance on prescription claims that may not reflect actual use. As the analysis was conducted within a single Italian regional NHS database, generalizability to other populations and health care systems is uncertain.
References:
[1] [1] Menniti-Ippolito F, Maggini M, Raschetti R, Da Cas R, Traversa G, Walker AM. Ketorolac use in outpatients and gastrointestinal hospitalization: a comparison with other non-steroidal anti-inflammatory drugs in Italy. Eur J Clin Pharmacol. 1998;54(5):393-397. doi:10.1007/s002280050481