Randomised Controlled Trial of Memantine in Fibromyalgia

Study Overview
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Brief Summary
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Fibromyalgia (FM) is a chronic rheumatic disease of high prevalence and great clinical impact. However, the treatment for FM has limited efficacy, with an effect size of about 0.5. Recent studies have found raised levels of glutamate in the insula, hippocampus and posterior cingulate cortex regions of the brain. This has led a number of authors to suggest the usefulness of glutamate blocking drugs in the treatment of FM. Aims: To evaluate the efficacy of memantine in the treatment of pain and other symptoms of FM and to assess its efficacy in reducing brain glutamate levels in patients with FM. Material and methods: Randomized controlled trial, of six months duration (including a dose adjustment period of one month). 60 patients with FM will be recruited for inclusion in the study upon fulfillment of selection criteria, and they will be randomized in two groups: A) Treatment group (n=30), will receive 20 mg of memantine o.d ; B) Control group (n=30) will receive placebo. The main objective is to assess the efficacy of memantine in the treatment of pain (pain threshold, pain perception) and other symptoms in fibromyalgia (cognitive state, health status, state of anxiety and depression, quality of life and perceived improvement. Discussion: There is a need for the development of innovative and more effective alternatives for the treatment of FM. This clinical trial will determine whether memantine can be considered as an option in the treatment of FM patients.

Official Title
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Efficacy of Memantine in the Treatment of Fibromyalgia: a Double-blind Randomized Trial

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Memantine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female aged between 18 and 65 years. Ability to understand Spanish. Diagnosis of fibromyalgia carried out by a rheumatologist according to the American College of rheumatology criteria (ACR1990). Ability to read and understand the Patient Information Sheet Signature of Informed Consent Form. 6 .In the case of women of childbearing age, commitment not to become pregnant during the entire duration of the study. Exclusion Criteria: Undergoing drug treatment for fibromyalgia. Patients undergoing treatment for fibromyalgia will stop treatment and perform a washout period of one week. During that week the patient may take, if necessary, analgesic such as paracetamol, ibuprofen and other NSAIDS to minimize the influence of medication on brain imaging. Currently taking memantine or having taken memantine during the 2 months prior to recruitment. Another Axis I psychiatric disorder using SCID-I that might hinder adherence to the protocol (e.g.: dementia, alcohol and/or substance abuse/dependence, schizophrenia, chronic delirium, acute depression). Pregnancy or breast-feeding. Hypersensitivity to the active ingredient, memantine, or to the excipients. Medical conditions that require special precautions when administering memantine according to the summary of product characteristics: Epilepsy. Circumstances that may cause high urine pH owing to Proteus urinary infection, renal tubular acidosis or vegetarian diet, recent myocardial infarction, congestive heart disease and uncontrolled arterial hypertension. Clinically significant and active evidence of liver or kidney disease, haematological, respiratory, endocrine or cardiovascular disease or disorders (patients with controlled diabetes and patients with controlled hypertension and complete or incomplete right bundle branch block can be included in the study). Use of prescription drugs that may cause relevant drug interactions with memantine according to the summary of product characteristics: NMDAR antagonists (amantadine, ketamine, dextromethorphan), L-Dopa, dopamine agonists and cholinergic agonists. Use of non-permitted concomitant medication during the week prior to the first evaluation visit or when the patient is expected to require treatment (with at least one of the drugs not permitted during the study): antidepressants (duloxetine, venlafaxine, mirtazapine, bupropion, SSRI, etc.), analgesics (pregabalin, gabapentin, opiates, etc.)

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Patients randomised to this group will receive film-coated placebo tablets (similar to drug tablets.<br>|
| Active Comparator: Memantine<br> | Drug: Memantine<br>* Patients randomised to this arm will receive memantine 20 mg daily. This dose will be reached following this schema: 1st week: 5 mg daily 2nd week: 10 mg daily 3rd week: 15 mg daily From 4th week up to 24th week: 20 mg daily<br>* Other names: Ebixa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in pain threshold at month 1 | It will be measured by sphygmomanometry, a clinical test widely used and very efficient to identify patients with fibromyalgia. | Month 1 | 
| Change from baseline in pain threshold at month 3 | It will be measured by sphygmomanometry, a clinical test widely used and very efficient to identify patients with fibromyalgia. Pain perception will be evaluated with the Pain Visual Analogue Scale (VAS pain). It is a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain and very severe pain) | Month 3 | 
| Change from baseline in pain threshold at month 6 | It will be measured by sphygmomanometry, a clinical test widely used and very efficient to identify patients with fibromyalgia. | Month 6 | 
| Change from baseline in pain perception at month 1 | Pain perception will be evaluated with the Pain Visual Analogue Scale (VAS pain). It is a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain and very severe pain) | Month 1 | 
| Change from baseline in pain perception at month 3 | Pain perception will be evaluated with the Pain Visual Analogue Scale (VAS pain). It is a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain and very severe pain) | Month 3 | 
| Change from baseline in pain perception at month 6 | Pain perception will be evaluated with the Pain Visual Analogue Scale (VAS pain). It is a horizontal line, 10 cm in length, anchored by word descriptors at each end (no pain and very severe pain) | Month 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess improvement in cognitive state | It will be measured by the Cognition Mini-Exam (MEC).In people under 65 years old, like the population in our study, the threshold that suggests a probable case is <27 points. The Spanish version of the questionnaire will be used. Cognitive state will also be measured by qEEG event-related desynchronization (ERD) at absolute power of upper alpha rhythms in the parieto-occipital region while cognitive tasks are performed. | Baseline, month 1, month 3 and month 6 | 
| To assess improvement in Health Status | It will be evaluated with the Fibromyalgia Impact Questionnaire (FIQ). FIQ is a 10-Item self-questionnaire to measure the Health Status in patients with fibromyalgia. The Spanish version will be used. | Baseline, month 1, month 3 and month 6 | 
| To assess Anxiety and depression levels | This will be evaluated with the Hospital Anxiety Depression Scale (HADS).Spanish version will be used. | Baseline, month 1, month 3 and month 6 | 
| To assess Quality of life | It will be measured by the EuroQol 5D questionnaire. Spanish version will be used. | Baseline, month 1, month 3 and month 6 | 
| To assess Clinical Global Impression | It will be evaluated with the Clinical Global Impression scale. | Baseline, month 1, month 3 and month 6 | 
| Glutamate levels in different brain regions (insula, hippocampus and posterior cingulate cortex). | This will be assessed with magnetic resonance spectroscopy (MRS) and by quantitative encephalography and electroencephalic cordance. | Baseline, month 6 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fibromyalgia, Magnetic Resonance Spectroscopy, Memantine, electroencephalic cordance