ESKETamine for FIBromyalgia Treatment

Study Overview
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Brief Summary
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Fibromyalgia is a cause of chronic pain, classified by the Internal Classification of Diseases (ICD) as a primary chronic pain with specific diagnostic criteria established by the American College of Rheumatology (ACR). No treatment to its complete cure is available at this time, all treatments having as purpose pain relief and an improvement of quality of life by combining pharmacologic and nonpharmacologic treatments. One of the mechanisms proposed in fibromyalgia is the central sensitisation phenomenon, by which the central nervous system becomes hypersensitive to nociceptive or non-nociceptive stimuli. The receptor involved in this phenomenon is the N-methyl-D-aspartate receptor to which ketamine binds. Ketamine has therefore been proposed as a co-treatment in chronic pain with central sensitization phenomena, such as fibromyalgia.

Detailed Description
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Ketamine is a drug used for anesthesia since the 1970s, acting as an antagonist to the N-methyl-D-aspartate receptor located in the central nervous system. It has two stereoisomers : R +ketamine and S - ketamine, the latter being about two to four times more potent. S-ketamine also has the advantages of producing less psychotropic effects, less tiredness and a lower temporary cognitive impairment than the racemic mixture at equianalgesic doses. Being first used as an anesthetic, in the last twenty years, ketamine's indications expanded to other domains, such as treatment of depression or off label use for chronic pain relief. Chronic pain is a multidimensional syndrome that touches 17-44% of the population of western countries. Fibromyalgia is a cause of chronic pain, classified by the Internal Classification of Diseases (ICD) as a primary chronic pain with specific diagnostic criteria established by the American College of Rheumatology (ACR). No treatment to its complete cure is available at this time, all treatments having as purpose pain relief and an improvement of quality of life by combining pharmacologic and nonpharmacologic treatments (as given by the European League Against Rheumatism (EULAR) guidelines). One of the mechanisms proposed in fibromyalgia is the central sensitisation phenomenon, by which the central nervous system becomes hypersensitive to nociceptive or non-nociceptive stimuli. The receptor involved in this phenomenon is the N-methyl-D-aspartate receptor to which ketamine binds. Ketamine has therefore been proposed as a co-treatment in chronic pain with central sensitization phenomena, such as fibromyalgia.

Official Title
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Intravenous Infusions of S-KETAMINE in Fibromyalgia Syndromes: an Exploratory Study.

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Active comparator
* Drug: S-Ketamine Low dose
* Drug: S-Ketamine High dose


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: patients suffering from chronic pain (as defined by International Association for the Study of Pain) being diagnosed as fibromyalgia according to the American College of Rheumatology 2016 criteria patients qualified for the treatment by S-ketamine as established by our latest clinical practice patients aged 18-65 years old

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Patients will be randomized in a 2:1 ratio (S-ketamine : placebo) per block of 15 patients sequentially into the first 2 groups, one with placebo and one with first dose of S-Ketamine Low Dose (0.2mg/kg). A second group will receive S-Ketamine High Dose (0.4 mg/kg) with the same randomized ratio (2:1).
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Placebo<br>Clonidine at a dose of 1 microg/kg Magnesium sulfate at a dose of 40 mg/kg | Drug: Active comparator<br>* The active comparator is composed of clonidine 1 microg/kg combined with magnesium sulfate 40 mg/kg diluted in 45 ml of sodium chloride<br>|
| Experimental: S-Ketamine Low dose<br>S-Ketamine at a dose of 0.2 mg/kg | Drug: Active comparator<br>* The active comparator is composed of clonidine 1 microg/kg combined with magnesium sulfate 40 mg/kg diluted in 45 ml of sodium chloride<br>Drug: S-Ketamine Low dose<br>* The arm 1 is composed of esketamine 0.2 mg/kg and clonidine 1 microg/kg combined with magnesium sulfate 40 mg/kg diluted in 45 ml of sodium chloride.<br>|
| Experimental: S-ketamine High dose<br>S-ketamine at a dose of 0.4 mg/kg | Drug: Active comparator<br>* The active comparator is composed of clonidine 1 microg/kg combined with magnesium sulfate 40 mg/kg diluted in 45 ml of sodium chloride<br>Drug: S-Ketamine High dose<br>* The arm 2 is composed of esketamine 0.4 mg/kg and clonidine 1 microg/kg combined with magnesium sulfate 40 mg/kg diluted in 45 ml of sodium chloride.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary outcome is twofold, aiming on one side pain relief and on the other the improvement of the patient's functional status | Pain relief will be considered as a two point decrease on the Brief Pain Inventory (BPI) pain severity index at twelve weeks follow-up. (Two points being established as the Minimal Clinically Important Difference (MCID) for fibromyalgic patients). The functional status will be evaluated by the BPI Interference scale. An improvement will be considered as a one point reduction on this index (as established by the MCID). The primary outcome is to determine whether the association of S-ketamine to the analgesic treatment will increase the number of patients showing a clinically significant improvement of pain and/or functional status. | 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients showing 50 % reduction in the BPI (Brief Pain Inventory) pain index | Measures will be done with different questionnaires | 12 weeks |