Efficacy of ketamine in the treatment of migraines and other unspecified primary headache disorders compared to placebo and other interventions: a systematic review

This review and meta-analysis (2021) explores the current evidence on using ketamine to treat migraines and other primary headache disorders. The authors found inconclusive evidence across five randomized-controlled trials (RCTs) which was attributed to the high risk of bias, small sample sizes, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups.

Abstract

Background: Migraine headaches are the second leading cause of disability worldwide and are responsible for significant morbidity, reduction in the quality of life, and loss of productivity on a global scale. The purpose of this systematic review and meta-analysis was to evaluate the efficacy of ketamine on migraines and other primary headache disorders compared to placebo and other active interventions, such as midazolam, metoclopramide/diphenhydramine, and prochlorperazine/diphenhydramine.

Methods: An electronic search of databases published up to February 2021, including Medline via PubMed, EMBASE, Web of Science, and Cochrane Library, a hand search of the bibliographies of the included studies, as well as literature and systematic reviews found through the search was conducted to identify randomized controlled trials (RCTs) investigating ketamine in the treatment of migraine/headache disorders compared to the placebo. The authors assessed the risk of bias according to the Cochrane Handbook guidelines.

Results: The initial search strategy yielded 398 unduplicated references, which were independently assessed by three review authors. After evaluation, this number was reduced to five RCTs (two unclear risk of bias and three high risk of bias). The total number of patients in all the studies was 193. Due to the high risk of bias, small sample size, heterogeneity of the outcomes reported, and heterogeneity of the comparison groups, the quality of the evidence was very low. One RCT reported that intranasal ketamine was superior to intranasal midazolam in improving the aura attack severity, but not duration, while another reported that intranasal ketamine was not superior to metoclopramide and diphenhydramine in reducing the headache severity. In one trial, subcutaneous ketamine was superior to saline in migraine severity reduction; however, intravenous (I.V.) ketamine was inferior to I.V. prochlorperazine and diphenhydramine in another study.

Conclusion: Further double-blind controlled studies are needed to assess the efficacy of ketamine in treating acute and chronic refractory migraines and other primary headaches using intranasal and subcutaneous routes. These studies should include a long-term follow-up and different ketamine dosages in diagnosed patients following international standards for diagnosing headache/migraine.

Authors: Neysan Chah, Mike Jones, Steve Milord, Kamal Al-Eryani & Reyes Enciso

Summary

INTRODUCTION

Primary headache disorders include migraine, tension-type headache, trigeminal autonomic cephalalgias, and other primary HA disorders. Migraine is the second leading cause of disability worldwide and affects one in four homes, one in five women, one in sixteen men, and one billion people worldwide.

Ketamine is an N-methyl-D-aspartate receptor (NMDAR) antagonist that acts on the central nervous system (CNS) and other CNS receptors. Its side effects include laryngeal spasms, transient apnea, gastrointestinal effects, cardiovascular effects, hallucinations, dissociative anesthesia, and repeated anesthesia and analgesia leading to tolerance.

Ketamine has shown positive results in other pain conditions, and it has been shown to reduce the wind-up phenomenon, which is associated with migraine pain. This review and meta-analysis aimed to determine the efficacy of ketamine as a therapeutic agent for migraines.

1. Research question

This systematic review adhered to PRISMA guidelines and included studies on HAs, ketamine, and outcomes such as HA frequency and pain intensity, aura severity and duration, maximal duration of relief, and need for rescue medications.

Studies on the efficacy of ketamine in patients with migraines or other primary HA were excluded.

3. Search methods for identification of studies

The following electronic databases were searched: MEDLINE via PubMed, Web of Science, Cochrane Library, and EMBASE. The reference lists of all eligible trials and reviews/systematic reviews were manually searched for additional studies.

4. Data collection and analysis

The studies identified by the PICOS search were reviewed by three investigators for inclusion/exclusion. If the three investigators disagreed on inclusion/exclusion, the full article was reviewed by a fourth investigator.

5. Data extraction and management

Each investigator extracted relevant data from the full texts of all eligible RCTs, and any disagreements were resolved by consensus with a fourth author.

7. Statistical analyses

Due to the heterogeneity of the comparison groups, subgroup analyses were undertaken for each outcome (pain intensity, satisfaction scores, and the need for rescue medications). The treatment effects were expressed as difference in means (DM) with 95% confidence intervals (CI), and risk ratios (RR) with 95% CI.

The initial search strategy yielded 554 references and 20 additional records identified through other sources up to 3/12/2020. Five manuscripts were included in this study, and the PRISMA flowchart provides a summary of the results.

2) Population

The studies included men and women patients, and ranged in age from 18 to 65 years old. The number of participants ranged from 17 to 54.

Intranasal ketamine was compared to midazolam, intranasal saline plus I.V. metoclopramide and diphenhydramine, intranasal ketamine and ondansetron with saline, and s.c. ketamine in a crossover fashion.

In one study, patients received intranasal treatment for migraine, in another study it was given by s.c. route, and in another study it was given over one minute by slow I.V. push.

5) Setting

In three studies, rescue medications were used to control HA. However, the use of ergotamine and triptans was prohibited, and four unspecified patients were permitted to use migraine preventive medications.

4. Adverse events

The side effects of ketamine are presented in Table 4. Fatigue, vomiting, and nausea are reported most commonly.

5. Primary outcomes reported in the migraine studies

Intranasal ketamine at 25 mg/ml performance was superior to intranasal midazolam in the composite reduction of aura severity, but not in the aura duration.

One study found that low-dose I.V. ketamine performed inferior to normal saline in reducing pain intensity, while another study found that s.c. ketamine significantly reduced pain in chronic migraineurs.

In one primary HA study, intranasal ketamine at 50 mg/ml combined with I.V. saline therapy was not superior to standard HA therapy of combination intranasal I.V. therapy (saline, metoclopramide, and diphenhydramine) in the measured analgesic effect from baseline.

Afridi et al. reported an aura composite score, not a VAS scale, and Nicolodi and Sicuteri did not report baseline and post-treatment severity of migraines.

HA pain intensity: In one study, intranasal ketamine and I.V. saline were no more effective than intranasal saline and I.V. diphenhydramine and metoclopramide at reducing post-treatment pain.

The number of patients in need of rescue medication was not significantly different in the ketamine group compared to the control group. However, satisfaction with the drug received was higher in the prochlorperazine and diphenhydramine group.

9. Quality of the evidence (GRADE)

The quality of the evidence was low due to bias, small sample sizes and low number of studies.

This systematic review found that ketamine failed to show consistently superior benefits to the placebo or active intervention in the treatment of migraine and acute primary HAs.

2. Discussion

Ketamine has shown promise in the management of chronic pain conditions and refractory HA pain. The low-dose range of 0.3 mg/kg or less appears to be effective, but has more adverse effects. Two studies evaluated the intranasal route of administration of ketamine for the management of chronic pain. Both studies determined that the analgesia, safety profile, and ability to utilize the intranasal route of administration were distinct advantages of using ketamine.

or reviews

The conclusions obtained by our systematic review are in agreement with another review by Bilhimer et al. [33], but definite conclusions cannot be drawn at this time to recommend ketamine as a first-line treatment in the management of migraines and other primary HAs.

Although ketamine has been used for the management of migraine, it does not translate to primary HA patients. Ketamine is best reserved for patients who are refractory to other first-line and second-line treatments.

4. Overall completeness and applicability of evidence

The review authors searched several databases and manually searched the reference sections of included studies and reviews to find RCTs on acute migraine or other primary HAs in 18 to 65-year old patients.

5. Heterogeneity of the review

The five RCTs included in this review had clinical and methodological heterogeneity, and the results are unclear how these parameters may have affected the results.

6. Implications for research and clinical practice

Ketamine has been shown to antagonize NMDAR and change the patient’s response to pain. It has shown promise for the treatment of acute migraines and primary HAs, but additional studies are needed to evaluate the efficacy and side effects of higher doses of ketamine.

Ketamine long-term infusions may have analgesic effects for up to three months, and at least 4 – 5 days of continuous infusion are required to reduce allodynia.

Ketamine has side effects, particularly the feeling of unreality and insobriety. However, a short infusion fashion rather than an I.V. push reduced these side effects without compromising its analgesic efficacy.

Ketamine may be a valuable tool in the management of migraine and other primary HAs, if the efficacy and side effect profile are established with additional research and follow-up.

Two retrospective studies showed promising results with the use of I.V. ketamine in patients with refractory migraine and other intractable HA disorders.

This systematic review and meta-analysis evaluated the efficacy of ketamine in the management of migraine and other primary HAs. It found that ketamine was not uniformly superior to traditional treatments, but did show varying amounts of benefits.

The limitations of this study include the small number of included studies and the method of delivery varied throughout the studies.

The protocol for this systematic review was registered with PROSPERO and Drs. Chah, Jones, Milord, Al-Eryani, and Enciso contributed to its conceptualization, methodology, investigation, and validation.