Efficacy and Safety of Adjunctive Therapy Using Single High-Dose S-Ketamine Infusion for Fibromyalgia: A Multicenter, Prospective, Randomized, Controlled, Open-Label, Blinded-Endpoint Study Protocol.

Abstract

<h4>Background</h4>Fibromyalgia (FM) is a chronic pain syndrome with limited response and delayed onset to current treatments. Esketamine (ESK) shows potential as a rapid-acting analgesic in FM patients, but previous low-dose studies have had limited efficacy and are constrained by single-center designs, monotherapy approaches, and small sample sizes. The efficacy of higher-dose ESK administered as an adjunct to guideline-recommended pharmacotherapy in FM remains unclear.<h4>Study design</h4>Multicenter, prospective, randomized, controlled, open-label, blinded-endpoint trial.<h4>Methods and analysis</h4>A total of 92 adult FM patients will be randomized in a 1:1 ratio to either the treatment group (single intravenous infusion of ESK plus oral pregabalin and venlafaxine) or the control group (oral pregabalin and venlafaxine alone). In the treatment group, ESK will be administered as a single intravenous infusion at a dose of 1 mg/kg on the day of enrollment. Both groups will follow identical dose titration regimens for pregabalin and venlafaxine, with dose escalation individualized according to patient tolerability and clinical response. Plasma concentrations of ESK and its metabolites will be measured at the end of infusion to enable a limited characterization of systemic exposure and to support exploratory exposure-response analyses. Participants will be followed for 12 weeks. The primary outcome is the change from baseline in the mean pain intensity during the first week after treatment. The secondary outcomes include average pain intensity, worst pain intensity, and proportion of patients achieving ≥50% and ≥30% pain reduction, median pain relief time, maximal tolerated doses of pregabalin and venlafaxine, patient-reported outcomes (Revised FM Impact Questionnaire, Hospital Anxiety and Depression Scale, Short Form 36 Health survey, Multidimensional Fatigue Inventory, and Medical Outcomes Study Sleep Scale), plasma concentrations of ESK and its metabolites at the end of infusion, and adverse events throughout the study period.<h4>Trial registration</h4>ClinicalTrails.gov identifier: NCT07230171. Registered on November 13, 2025 (https://www.clinicaltrials.gov/search?term=NCT07230171).

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