Ketorolac
| Evidence Level: L1 | Predicted Indications: 3 |
Table of Contents
Ketorolac: From Atopic, Papillary and Vernal Conjunctivitis to Headache Disorder
One-Sentence Summary
Ketorolac is a non-steroidal anti-inflammatory drug (NSAID) whose originally recorded indications are atopic, papillary and vernal conjunctivitis. The TxGNN model predicts it may be effective for Headache Disorder (including migraine and tension-type headache), with 17 clinical trials and 18 publications currently supporting this direction.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Atopic conjunctivitis, papillary conjunctivitis, vernal conjunctivitis |
| Predicted New Indication | Headache disorder |
| TxGNN Prediction Score | 99.43% |
| Evidence Level | L1 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 4 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Based on the known pharmacology of the drug class, ketorolac is a non-selective COX-1/COX-2 inhibitor. By blocking prostaglandin synthesis, it reduces the peripheral and central sensitization and the neurogenic inflammation involved in migraine and tension-type headache.
Its original indications are inflammatory conditions of the ocular surface, where reducing prostaglandin-driven inflammation and itching is the goal. The same anti-prostaglandin action underlies its use as an analgesic, so extending it to acute headache is a plausible and well-established step. Parenteral ketorolac is already used in emergency departments for acute migraine and tension-type headache, as reflected in the trials and reviews below.
Two other predictions were also generated, but both are weak. Rosacea conjunctivitis (score 99.40%) has no trials or literature, and topical NSAIDs carry a corneal toxicity risk on an already compromised ocular surface. Trigeminal autonomic cephalalgia (score 99.39%) is mechanistically plausible, but cluster headache generally responds poorly to standard NSAIDs, and the only trial was withdrawn. Both are rated Hold.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01807234 | Phase 4 | Completed | 72 | Ketorolac nasal spray vs sumatriptan nasal spray vs placebo for acute migraine |
| NCT01011673 | Phase 4 | Completed | 123 | Metoclopramide/diphenhydramine vs ketorolac alone in tension-type headache |
| NCT01596166 | Phase 4 | Completed | 56 | IV ketorolac plus metoclopramide for pediatric migraine in the emergency department |
| NCT01267864 | Phase 4 | Completed | 330 | IV valproate vs metoclopramide vs ketorolac for acute migraine |
| NCT02358681 | Phase 3 | Completed | 59 | Intranasal vs IV ketorolac in children with migraine (non-inferiority) |
| NCT00483717 | Phase 2 | Completed | 173 | Double-blind, placebo-controlled study of intranasal ketorolac for acute migraine |
| NCT03221569 | Phase 4 | Unknown | 60 | Ketamine vs ketorolac in tension-type headache |
| NCT06083571 | Phase 2 | Terminated | 41 | Intranasal ketorolac-based cocktail vs IV ketorolac in pediatric migraine |
| NCT03081416 | Phase 3 | Completed | 80 | Intranasal ketamine vs standard therapy for primary headache in the emergency department |
| NCT06729047 | Phase 1/2 | Not yet recruiting | 330 | Neostigmine plus atropine vs ketorolac for post-dural puncture headache |
Several of these trials use ketorolac as a comparator or part of a combination, so effect attribution to ketorolac alone is limited. Other registered trials not listed here are withdrawn, of unclear relevance, or only indirectly related.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35138658 | 2022 | Systematic review / meta-analysis | Acad Emerg Med | Efficacy of parenteral ketorolac in acute migraine |
| 37849443 | 2024 | Systematic review / meta-analysis | Adv Clin Exp Med | IV ketorolac vs metoclopramide in adult migraine |
| 23298250 | 2013 | Systematic review | Headache | Effectiveness of parenteral ketorolac in acute migraine; evidence described as conflicting |
| 41321235 | 2026 | Guideline | Headache | American Headache Society update on parenteral treatment of migraine in the emergency department |
| 25600718 | 2015 | Guideline / evidence assessment | Headache | American Headache Society assessment of acute migraine pharmacotherapies |
| 24433525 | 2014 | Systematic review | Headache | Parenteral treatment of episodic tension-type headache |
| 34822214 | 2022 | RCT | Acad Emerg Med | Intranasal vs IV ketorolac for migraine in children |
| 35670115 | 2022 | RCT | Headache | IV metoclopramide with or without ketorolac in pediatric migraine |
| 30783794 | 2019 | RCT | Neurol Sci | IV dexamethasone, metoclopramide, ketorolac and chlorpromazine compared for migraine pain relief and recurrence |
| 1514724 | 1992 | RCT | Ann Emerg Med | IM ketorolac vs meperidine plus hydroxyzine in acute migraine |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN16401P | XEVOLAC SOLUTION FOR INJECTION 30 MG/ML | Injection, solution | Not stated in the data |
| SIN11189P | ACULAR OPHTHALMIC SOLUTION 0.5% | Solution | Not stated in the data |
| SIN11340P | KETOROLAC TROMETHAMINE INJECTION 30 mg/ml | Injection | Not stated in the data |
| SIN10330P | KETO FILM COATED TABLET 10 mg | Tablet, film coated | Not stated in the data |
All four registrations are valid single-ingredient products. Injectable, ophthalmic and oral forms are all available.
Safety Considerations
- Contraindications / conditions of concern (from knowledge-graph links, not label text): hypertension, gastric and peptic ulcer disease, liver disease, gallbladder disease, rheumatoid arthritis, inflammatory bowel disease, asthma, diabetes mellitus and diabetic ketoacidosis, blood coagulation disorders and hemophilia, stroke and cerebrovascular disorders, myocardial infarction and other cardiovascular or heart disease, anemia and hemoglobinopathy, impaired renal function, and dry eye syndrome.
- Drug Interactions: 222 interactions are recorded. Examples include:
- Major: acetylsalicylic acid
- Moderate: corticosteroids (betamethasone, budesonide, dexamethasone, hydrocortisone), sulfonylureas (acetohexamide, chlorpropamide, glimepiride, glipizide, glyburide), exenatide, kanamycin, levofloxacin, balsalazide, fenfluramine and dexfenfluramine
- Minor: H2 blockers (famotidine, ranitidine, cimetidine), linaclotide
- Additional considerations: Class risks include GI bleeding, renal toxicity, cardiovascular risk and bleeding, so a short course (generally 5 days or less) is advised, with caution in renal impairment, in patients on anticoagulants or antiplatelets, and in the elderly. A published case report describes lithium toxicity when ketorolac was co-administered. Repeated NSAID use also raises the risk of medication-overuse headache.
Please also refer to the package insert, since label warnings were not available in the data compiled for this report.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple completed Phase 3/4 trials, several systematic reviews and meta-analyses, and guideline-level literature support parenteral ketorolac for acute migraine and tension-type headache, and the COX-inhibition mechanism is plausible. The significant GI, renal, cardiovascular and bleeding risks and the large number of drug interactions require strict controls. Ketorolac is already registered in Singapore in injectable form.
To proceed, the following is needed:
- Retrieve the HSA package insert to confirm approved indications, warnings and contraindications. This was a blocking data gap for safety screening.
- Obtain official mechanism of action data from DrugBank.
- Define dose, route and duration limits (short course) and exclusion criteria, including renal impairment, bleeding risk, ulcer history, cardiovascular disease, and anticoagulant or antiplatelet use.
- Review concomitant medications against the interaction list, with particular attention to aspirin, corticosteroids and lithium.
- Check whether a headache indication is already covered by the labels of the registered injectable products, and confirm which routes (for example, intranasal) are actually available locally.
- Keep rosacea conjunctivitis and trigeminal autonomic cephalalgia on Hold until supporting clinical evidence emerges.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.