Ketamine for Refractory Chronic Migraine: an Observational Pilot Study and Metabolite Analysis

This metabolite analysis and observation study (n=6) found that both lidocaine and ketamine infusions significantly reduced pain, with ketamine providing slightly more relief. But a week after each treatment, patients were back at the same level of pain. This is the first study to investigate if one of ketamine’s metabolites, (2R,6R)-hydroxynorketamine, could reduce pain.


Introduction: Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia.

Methods: In this prospective, observational pilot study of 6 patients we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine’s metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking.

Results: All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment (p<0.05) but increased to 7.0 ± 1.4 by the post-discharge visit at 4 weeks (p>0.05 versus baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization (p<0.05), but increased to 7.2 ± 1.7 by the post-discharge visit at 6 weeks (p>0.05 versus baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 versus -2.8, p<0.05) but this has minimal clinical significance.

Discussion: Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.”

Authors: Eric S. Schwenk, Marc C. Torjman, Ruin Moaddel, Jacqueline Lovett, Daniel Katz, William Denk, Clinton Lauritsen, Stephen D. Silberstein & Irving W. Wainer


Psychedelics are known for their ability to relieve mental pain. From depression to PTSD, different molecules have proven to be effective in the reduction of suffering. Now researchers are asking themselves if the same can be done for physical pain.

Ketamine has been used for anesthetics and pain reduction purposes for many decades now. Studies find that ketamine reduces pain in the body. But what about some of the worst pain that people can experience, refractory chronic migraines.

On a scale of 1 to 10, people rate this pain at a (constant!) 7. Not all patients are being helped with the current methods and some are already turning towards psychedelics. Studies on LSD and psilocybin are showing favorable results.

The current study investigated the potential of ketamine to treat refractory chronic migraines. Ketamine was pitted against lidocaine, a local anaesthetic. The hypothesis is that a metabolite, a molecule that is formed when ketamine is being broken down, named (2R,6R)-hydroxynorketamine reduces pain as it has been shown to be effective in animal studies.

What made the pain go away?

  • The pain level decreased from 7.4 to 3.7 at the end of hospitalization
  • The numbers were slightly less pronounced for the lidocaine group (7.6 to 4.8)
  • But in both groups, six weeks later the pain was back at the same (high) level

The difference in pain between both groups was significant, with the ketamine group experiencing less pain after treatment. Alas, for patients this difference might not be clinically significant (it would then have to be 2.0 or greater contrast). What the study did find is that ketamine reduced pain within 3 days, whilst for lidocaine it took until the end of treatment (5 days).

The current study is very small (6 participants) but provides another data point that psychedelics can be a tool to help with some of the worst pain that people suffer from.

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Ketamine for Refractory Chronic Migraine: an Observational Pilot Study and Metabolite Analysis

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Published in
Journal of Clinical Pharmacology
June 14, 2021
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Open-Label Within-Subject


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