Trial findings were published in the study, “Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis–related fatigue,” in the Multiple Sclerosis Journal.
Fatigue is one of the most common symptoms associated with MS. However, it is often not a focus of MS research, and currently no medications are approved for the management of MS-related fatigue in the U.S.
Previous research has indicated that people with MS treated with medications that block the activity of glutamate — a molecule called a neurotransmitter used in the communication between neurons — experience increased fatigue. This suggests that increasing glutamate activity might have the opposite effect — that is, reducing fatigue.
Ketamine is a medication used for anesthesia. Among its effects, ketamine increases the amount of glutamate in certain regions of the brain.
Researchers at Johns Hopkins University School of Medicine conducted a randomized Phase 1/2 pilot trial (NCT03500289) to evaluate whether low doses of ketamine could be used to treat fatigue in people with MS.
A total of 18 MS patients with reported fatigue were recruited. Of these, 12 were randomly assigned to receive a single low-dose infusion of ketamine (0.5 mg/kg). The remaining six participants were given a single infusion of midazolam, a short-acting benzodiazepine.
Midazolam has no known effects on fatigue, but some of its other known effects are similar to those of ketamine. Thus, midazolam was used as an active placebo, “so the sedative and psychomimetic effects of ketamine would not unblind the staff and the participants,” the researchers wrote.
The two treatment groups were similar demographically, being predominantly white and female. The only significant difference noted was that participants in the ketamine group had significantly lower depression scores, indicating fewer depressive symptoms.
The study’s primary endpoint — its main measurement of effectiveness — was the change in daily fatigue severity, rated on a scale from zero (no fatigue) to 10 (extreme fatigue), over the first week after the infusion.
Secondary endpoints were other measures of fatigue, including the fatigue-specific part of the Quality of Life in Neurological Disorders questionnaire (NeuroQoL), the Fatigue Severity Scale (FSS), and the Modified Fatigue
Impact Scale (MFIS), at various time points after the infusion. Broadly, lower scores on these assessments indicate less fatigue.
Results showed no significant differences between the ketamine and midazolam groups in daily fatigue scores after one week of treatment — the study’s primary endpoint.
Regarding secondary endpoints, no significant differences were seen between the groups in NeuroQoL scores. For FSS scores, the ketamine group trended toward lower scores one week after infusion. However, FSS results did not reach statistical significance, so it is impossible to confidently exclude the possibility that the difference was just due to random chance.
In the ketamine group, average MFIS scores decreased from 47.1 just prior to the infusion to 34.1 about a month after infusion. In contrast, no change was observed in average MFIS scores in the midazolam group — 48.3 prior to infusion and 48.8 after a month.
The difference between the groups’ MFIS scores was statistically significant, and remained so after adjusting for the differences between the groups in terms of depression. This decrease in MFIS score was likely clinically relevant and thus noticed by the patients.
“The effects of ketamine on the fatigue severity were not only statistically significant … the effects might have been clinically meaningful too. Also, the difference in MFIS at day 28 (which was the most robust and significant finding) may point to the prolonged anti-fatigue effects of ketamine,” the researchers wrote.
Ketamine treatment was generally safe and well tolerated, with no serious adverse events reported. The most commonly reported ketamine-associated adverse events were euphoria, dizziness, numbness, impaired concentration, and drowsiness. All these events were transient, resolving within an hour of the infusion.
Adverse events reported in the first week after infusion included depression, impaired concentration, stiffness, and feeling feverish.
Some participants experienced a spike in blood pressure during ketamine infusion. For these participants, the infusion was slowed or stopped until blood pressure normalized, and then continued with no further incidents reported.
“Although the primary outcome of this study was negative, because ketamine infusion was associated with large, clinically significant and long-lasting changes in well-validated and multidimensional fatigue measures, we think these results can be the basis for performing a larger study of ketamine or other glutamate modulating agents for MS-related fatigue,” the researchers concluded.
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