The place of S-ketamine in fibromyalgia treatment (ESKEFIB): study protocol for a prospective, single-center, double-blind, randomized, parallel-group, dose-escalation controlled trial

Zuzana Javorcikova, Michel Dangoisse, Stéphane Nikis, Jean-Paul Lechat, Aline Gillain, Jean-François Fils, Philippe Van der Linden, Zuzana Javorcikova, Michel Dangoisse, Stéphane Nikis, Jean-Paul Lechat, Aline Gillain, Jean-François Fils, Philippe Van der Linden

Abstract

Background: Fibromyalgia is a chronic multidimensional pain disease with no curative treatment currently available. Its management relies on a multimodal approach involving pharmacologic and non-pharmacologic elements. Because a suggested factor in its etiology is a central sensitization phenomenon involving the N-methyl-D-aspartate receptor (NMDAR), NMDAR antagonists have been proposed as a treatment target. Ketamine and its levogyre form, S-ketamine, have been used to treat chronic pain for many years without consensus about their therapeutic efficiency. We aim to assess the efficacy of S-ketamine as a co-treatment for fibromyalgia.

Methods: This prospective, randomized, single-center, double-blind, parallel-group, dose-escalation trial will compare a co-treatment with S-ketamine (intervention) to a control treatment without S-ketamine (control). It will consist of two successive cohorts with 2:1 randomization ratio (S-ketamine at two different doses: control) with 105 participants in each cohort. The protocol follow-up time will be 12 weeks, including 3 visits for the treatment (week 0, week 2, and week 4) and 3 visits for follow-up (week 6, week 9, and week 12). Our primary outcome, pain relief and/or better patient function, will be assessed with the Brief Pain Inventory questionnaire. The statistical analysis will be performed on an intention-to-treat basis. If the primary outcome is reached at the end of follow-up in the first cohort with low-dose S-ketamine (0.2 mg/kg), the trial will end. If not, the trial will continue with the second cohort and high-dose S-ketamine (0.4 mg/kg).

Discussion: The challenge of our trial is the inclusion of a large number of participants in comparison to other trials involving ketamine or S-ketamine infusions for chronic pain management. The originality of our protocol is to include functionality in addition to pain relief as a primary outcome because these two endpoints are not linked in a linear way. For some patients, functional status is more important than pain relief.

Trial registration: EudraCT reference: 2020-000473-25, ClinicalTrials.gov : NCT04436250, first posted June 18, 2020; last updated July 21, 2020. Protocol version 2.2 issued on September 30, 2020, after a revision by the ethics committee. https://ichgcp.net/clinical-trials-registry/NCT04436250.

Keywords: Chronic pain; Fibromyalgia; N-Methyl-D-aspartate receptor; S-ketamine; Treatment.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Trial design
Fig. 2
Fig. 2
Treatment preparation steps. ⏏, laminar flow hood; S-ket, S-ketamine; N°, recognition number; MgSO4, magnesium sulfate; Clo, clonidine; IMD, Investigational Medication Drug; NIMD, non-investigational medication drug
Fig. 3
Fig. 3
Recruitment process. CSI, Central Sensitization Inventory; EULAR, European League Against Rheumatism

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