Ketamine
| Evidence Level: L3 | Predicted Indications: 1 |
Table of Contents
Ketamine: From Anaesthesia to Headache Disorder
One-Sentence Summary
Ketamine is an NMDA-receptor antagonist established internationally as a general anaesthetic and, in its S-enantiomer form (esketamine), licensed for treatment-resistant depression. The TxGNN model predicts it may also be effective for Headache Disorder, with 41 clinical trials and 20 publications currently identified as related evidence, though only a minority directly and specifically test ketamine in headache populations.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not recorded in this evidence pack. Ketamine is internationally established as a general anaesthetic agent (background knowledge only — not sourced from the evidence pack) |
| Predicted New Indication | Headache Disorder |
| TxGNN Prediction Score | 99.33% |
| Evidence Level | L3 |
| UK Market Status | Not marketed |
| Number of Marketing Authorisations | 0 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Ketamine is an NMDA-receptor antagonist. Blocking NMDA receptors interrupts central sensitisation and the abnormal synaptic plasticity that underlies several difficult-to-treat headache disorders, including chronic migraine, cluster headache and trigeminal neuralgia. This gives a plausible pharmacological rationale for repurposing.
Currently, detailed original-indication data is not available in this evidence pack. Based on known pharmacology, ketamine’s established use is as a general anaesthetic (and, as esketamine, for treatment-resistant depression), and its central NMDA-antagonist mechanism may mechanistically extend to refractory headache syndromes.
Low-dose (“sub-dissociative”) ketamine has already been used off-label in emergency departments and headache clinics for acute migraine, tension-type headache, cluster headache and chronic daily headache, generally in small case series or single-centre trials. One completed Phase 3 RCT (the THINK trial, NCT03081416) and a retrospective cohort study (PMID 35356451) provide the most direct supporting evidence, but a large proportion of the identified trials/literature relate to ketamine’s use in depression, sickle-cell pain or perioperative analgesia rather than headache disorder specifically — this is reflected in the many “C” or “pending” relevance grades in the evidence pack.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT03081416 | Phase 3 | Completed | 80 | THINK Trial — randomised, single-blind, placebo-controlled comparison of sub-dissociative intranasal ketamine vs standard therapy for primary headache syndromes in the ED |
| NCT02657031 | Phase 4 | Completed | 54 | CHECK Trial — low-dose ketamine vs compazine (prochlorperazine) for headache control in the ED |
| NCT02697071 | N/A | Completed | 34 | Randomised, placebo-controlled trial of sub-dissociative ketamine for acute migraine-type headache in the ED |
| NCT05306899 | Phase 3 | Recruiting | 56 | KetHead Study — multicentre RCT of high-dose IV ketamine infusion for chronic daily headache |
| NCT04814381 | Phase 4 | Recruiting | 90 | Single infusion of ketamine + magnesium sulfate for refractory chronic cluster headache |
| NCT04179266 | Phase 1/2 | Completed | 23 | Proof-of-concept study of intranasal ketamine spray for chronic cluster headache |
| NCT03221569 | Phase 4 | Unknown | 60 | Ketamine vs ketorolac for acute tension-type headache/migraine in the ED |
| NCT04860713 | Phase 4 | Completed | 5 | Oral ketamine + aspirin + rimegepant (Nurtec) vs standard care for acute headache in the ED (small pilot, low statistical power) |
| NCT06608277 | Phase 2 | Recruiting | 175 | Multicentre RCT of ketamine, stellate ganglion block, or combination for TBI-associated headache and PTSD |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 35356451 | 2022 | Cohort | Frontiers in Neurology | Retrospective cohort assessing efficacy, duration and safety of inpatient IV lidocaine and ketamine infusions for headache disorders |
| 34919214 | 2022 | Review | Drugs | Review of drug treatment for cluster headache, covering acute and prophylactic options |
| 38870050 | 2024 | Review | Expert Review of Neurotherapeutics | Update on pharmacotherapy for trigeminal neuralgia; notes ketamine among promising adjuvant options |
| 37421541 | 2023 | Review | Current Pain and Headache Reports | Evidence-based review of Complex Regional Pain Syndrome, including conventional and less conventional treatments |
UK Market Information
Ketamine currently holds no UK marketing authorisation recorded in this evidence pack (market status: Not marketed; 0 licences on file). No product-specific dosage form or approved-indication data is available for extraction from this dataset.
Safety Considerations
Please refer to the SmPC and BNF for safety information. Report suspected adverse reactions via the Yellow Card Scheme.
(Note: the evidence pack flags a Blocking data gap — MHRA/SmPC-equivalent warnings and contraindications are not yet available, which prevents a full initial safety assessment.)
Conclusion and Next Steps
Decision: Hold
Rationale: Only one completed Phase 3 RCT (THINK trial) and one retrospective cohort study directly and robustly support ketamine’s use in headache disorder; the majority of identified trials/literature relate to other indications (depression, sickle-cell pain, perioperative analgesia) or remain unrated (“pending”) for relevance. Combined with the absence of UK marketing authorisation and a Blocking safety data gap, the evidence is not yet sufficient to proceed.
To proceed, the following is needed:
- MHRA/SmPC-equivalent warnings, contraindications and controlled-drug handling requirements (currently a Blocking data gap)
- Confirmed DrugBank mechanism-of-action record to formally support the mechanistic rationale
- Full-text review and outcome data from the completed THINK (NCT03081416) and CHECK (NCT02657031) trials
- Completion and publication of ongoing Phase 3 trials (KetHead, NCT05306899) specifically in chronic headache populations
- A structured relevance re-grading of the “pending” trial/literature entries to separate headache-specific evidence from general pain/depression evidence
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.