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

J Clin Pharmacol. 2021 Nov;61(11):1421-1429. doi: 10.1002/jcph.1920. Epub 2021 Jul 9.


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. 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. 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 . 05 ) but increased to 7.0 ± 1.4 by the postdischarge visit at 4 weeks (P > .05 vs 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 . 05 ) but increased to 7.2 ± 1.7 by the postdischarge visit at 6 weeks (P > .05 vs baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 vs -2.8; P . 05 ), but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.

Keywords: anesthesiology/pain management; clinical pharmacology; drug metabolism; neurology; pain management.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't