The Efficacy and Safety of Short Term S-ketamine Infusion as an Adjunctive Therapy in Patients With Fibromyalgia

This randomised, open‑label, parallel trial (n=106) will evaluate the efficacy and safety of a single intravenous esketamine infusion as adjunctive therapy to optimised pregabalin and venlafaxine in adults with fibromyalgia who have had insufficient symptom relief; the primary outcome is median pain relief time measured over a 12‑week follow‑up. The study’s purpose is treatment-focused, assessing whether adding a short‑term esketamine infusion produces faster or greater pain relief than optimisation of conventional therapy alone. Participants are randomised to either control therapy (pregabalin and venlafaxine with a dose‑escalation regimen to maximal tolerated or recommended doses — maximum daily pregabalin 450 mg and venlafaxine 225 mg) or the same regimen plus a single intravenous esketamine infusion given on the day of enrolment. Plasma concentrations of esketamine and its metabolites will be collected at the end of the infusion for limited characterisation of systemic exposure and exploratory exposure–response analyses. Pain will be assessed at 15 minutes, 1 hour and 3 hours after treatment termination, on days 1, 3 and 5, and at weeks 1, 2, 4, 8 and 12. Key eligibility criteria include adults ≥18 years meeting ACR fibromyalgia criteria with baseline average pain NRS ≥4; major exclusions include prior treatment with pregabalin or venlafaxine, prior intravenous ketamine/esketamine for chronic pain, significant psychiatric or medical contraindications, substance abuse, and pregnancy or lactation.