Ketorolac
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Ketorolac: From Acute Pain Management to Headache Disorder
One-Sentence Summary
Ketorolac is a potent nonsteroidal anti-inflammatory drug (NSAID) established for short-term management of moderate-to-severe acute pain, but it currently holds no marketing authorization on file in this dataset. The TxGNN model predicts it may be effective for Headache Disorder, and this direction is already strongly supported by 36 clinical trials and 19 publications, including multiple completed Phase 3/4 RCTs and society guidelines on migraine management.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not on file — no marketing authorization record in this evidence pack; drug is broadly known as a parenteral/intranasal NSAID for acute pain |
| Predicted New Indication | Headache Disorder |
| TxGNN Prediction Score | 99.43% |
| Evidence Level | L1 |
| EU Market Status | Not Marketed |
| Number of Authorizations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data was not returned in this evidence pack. Based on well-established pharmacology, Ketorolac is a non-selective cyclooxygenase (COX-1/COX-2) inhibitor that blocks prostaglandin synthesis, producing potent systemic analgesic and anti-inflammatory effects. It is typically administered IV, IM, or intranasally for fast onset in acute, moderate-to-severe pain.
Although no licensed original indication is recorded in this dataset, Ketorolac’s global clinical use for acute pain control (post-surgical pain, renal colic, orthopedic trauma) shares a common pharmacological basis with headache/migraine pain: prostaglandin-mediated sensitization of trigeminal nociceptors and neurogenic inflammation are both implicated in migraine and tension-type headache pathophysiology.
This mechanistic overlap explains why Ketorolac has, in practice, already become a first-line parenteral abortive therapy for acute migraine and tension-type headache in emergency department settings for over three decades — a pattern reflected directly in the clinical trial and literature evidence below, which substantially predates and corroborates the TxGNN prediction rather than merely being consistent with it.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT01267864 | Phase 4 | Completed | 330 | RCT comparing IV valproate, metoclopramide, and ketorolac for acute migraine |
| NCT00483717 | Phase 2 | Completed | 173 | Double-blind, placebo-controlled RCT of intranasal ketorolac for acute migraine |
| NCT01807234 | Phase 4 | Completed | 72 | Ketorolac nasal spray vs. sumatriptan nasal spray vs. placebo for acute migraine |
| NCT01011673 | Phase 4 | Completed | 123 | RCT of metoclopramide/diphenhydramine vs. ketorolac alone for tension-type headache |
| NCT02358681 | Phase 3 | Completed | 59 | Intranasal vs. IV ketorolac non-inferiority trial for pediatric migraine |
| NCT03081416 | Phase 3 | Completed | 80 | THINK Trial: intranasal ketamine vs. standard therapy (incl. ketorolac) for primary headache |
| NCT01596166 | Phase 4 | Completed | 56 | IV ketorolac + metoclopramide combination therapy for pediatric migraine |
| NCT05641363 | Phase 3 | Completed | 171 | RCT comparing ketorolac at three doses in children with acute pain |
| NCT01789216 | Phase 3 | Completed | 450 | Multimodal pharmacologic pain management (incl. ketorolac) after orthopedic trauma |
| NCT03221569 | Phase 4 | Unknown | 60 | Sub-dissociative ketamine vs. ketorolac for acute tension-type headache |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35670115 | 2022 | RCT | Headache | Randomized trial of ketorolac + metoclopramide vs. metoclopramide alone for pediatric ED migraine |
| 30783794 | 2019 | RCT | Neurological Sciences | Double-blind RCT of dexamethasone, metoclopramide, ketorolac, and chlorpromazine for migraine pain relief and recurrence prevention |
| 1514724 | 1992 | RCT | Annals of Emergency Medicine | Randomized, prospective, double-blind trial: ketorolac vs. meperidine/hydroxyzine for acute migraine |
| 7893296 | 1995 | RCT | American Journal of Emergency Medicine | Double-blind comparison of ketorolac vs. meperidine-promethazine for migraine |
| 35138658 | 2022 | Systematic Review / Meta-analysis | Academic Emergency Medicine | Efficacy of parenteral ketorolac in acute migraine attack treatment |
| 37849443 | 2024 | Systematic Review / Meta-analysis | Advances in Clinical and Experimental Medicine | Updated comparison of IV ketorolac vs. metoclopramide for adult migraine |
| 39674934 | 2025 | Systematic Review / Network Meta-analysis | Annals of Emergency Medicine | Bayesian network meta-analysis of pharmacologic therapies for ED migraine, including ketorolac |
| 41321235 | 2026 | Guideline / Evidence Assessment | Headache | American Headache Society 2025 update on parenteral pharmacotherapies for acute migraine in the ED |
| 25600718 | 2015 | Guideline / Evidence Assessment | Headache | American Headache Society evidence assessment of acute migraine pharmacotherapies |
| 24875925 | 2015 | Systematic Review | Cephalalgia | Canadian Headache Society systematic review and recommendations on migraine pain treatment in emergency settings |
Safety Considerations
Please refer to the SmPC for safety information.
Conclusion and Next Steps
Decision: Hold
Rationale: The clinical evidence for Ketorolac in headache disorder is strong (L1: multiple completed Phase 3/4 RCTs plus current society guidelines), and this use is already well established in emergency-medicine practice. However, this candidate has no EU marketing authorization on file (0 licenses, not marketed) and is missing essential label safety data — a blocking gap (DG001) that prevents entry into the S1 safety pre-screen.
To proceed, the following is needed:
- Official label warnings/contraindications document (SmPC or equivalent) — resolves blocking gap DG001
- Confirmed mechanism-of-action data via DrugBank API — resolves gap DG002
- Clarification of Ketorolac’s EU regulatory status, since no marketing authorization currently exists in this jurisdiction
- A completed drug-drug interaction (DDI) query, as the current query returned no results
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.