Low Dose Naltrexone for Treatment of Pain in Patients With Fibromyalgia - Effect Via a Central Mechanism?

Study Overview
=================
Brief Summary
-----------------
This study evaluates the effect and mechanism of low dose naltrexone for treatment of pain in patients with fibromyalgia. It s a randomised, double-blinded, placebo-controlled, cross-over study. It is a 2-center study that takes place at The Multidisciplinary Pain Center in Copenhagen and at The Multidisciplinary Pain Center in Give.

Detailed Description
-----------------
Fibromyalgia syndrome is a prevalent musculoskeletal disorder characterized by pain, profound fatigue, sleep disorder, mood disturbance etc. The prevalence is estimated to be 2-8%. Treatment of pain in patients with fibromyalgia is often based on opioids. However, opioids may lead to tolerance, addiction and hyperalgesia and alternative treatments are therefore warranted. Low dose naltrexone (3-5mg) (LDN) has shown promising results in the treatment of pain in patients with fibromyalgia, but there is a need for further research. At the typical dose of naltrexone, 50 mg, it is an opioid antagonist. However LDN demonstrates analgesic and anti-inflammatory effects, possibly involving an antagonism of microglia in the CNS. The investigators hypothesize, that LDN has a better pain relieving effect than placebo in in patients with fibromyalgia (FM). The investigators also hypothesize that LDN has a better effect upon experimentally induced pain in FM-patients, compared to placebo. A tentative mechanism is a central facilitation of the endogenous pain inbitory system.

Official Title
-----------------
Low Dose Naltrexone for Treatment of Pain in Patients With Fibromyalgia - Effect Via a Central Mechanism? A Randomized, Double-blinded, Placebo-controlled, Crossover Study.

Conditions
-----------------
Fibromyalgia

Intervention / Treatment
-----------------
* Drug: Low dose naltrexone
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Patients diagnosed with fibromyalgia based on the criteria of American College of Rheumatology. Inclusion Criteria: Widespread pain in patients with fibromyalgia (based on the above criteria) Enrolled as a patient in one of the multidisciplinary pain clinics involved in the project Inflammatory rheumatic disease (peripheral inflammation, including arthritis), must be excluded Women must be treated with a contraceptive measure, if not menopausal Exclusion Criteria: Cancer Treatment with opioids (other analgesic treatments in stabile dose 14 days prior to study start are allowed) Change in stabile treatment (p.n. paracetamol is allowed, but must be registered) Pregnant/breastfeeding Does not speak/understand Danish Allergy to the ingredient Severe liver impairment Severe kidney impairment Acute hepatitis

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

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose naltrexone<br>Low dose naltrexone 4.5 mg/tablet, 1 tablet a day for 21 days | Drug: Low dose naltrexone<br>* Active comparator<br>* Other names: Naltrexone;|
| Placebo Comparator: Placebo<br>Placebo tablet 1 tablet a day for 21 days | Drug: Placebo<br>* Placebo comparator<br>* Other names: Inert substance;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain scores (during rest, during household activity, during personal daily hygienic procedures) | The patient indicates using a questionnaire-based numerical rating scale (0 = no pain; 100 = worst imaginable pain) mean values of pain at rest, pain during household activity and pain during personal hygienic procedures in the preceding 24 hrs. The cumulated pain scores are used in the statistical analyses. | Baseline: Day -2 to day 1 (baseline before treatment 1); Treatment 1: Day 19 to 21 ; Washout: Day 33 to 35 (baseline before treatment 2); Treatment 2: Day 54 to 56 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fibromyalgia Impact Questionnaire Revised (FIQR) | The FIQR is a fibromyalgia-specific questionnaire containing three domains: function domain, impact domain and symptom domain. The total score of FIQR is calculated by: the function domain sum is divided by 3 (upper limit 30) the impact domain sum is unchanged (upper limit 20) the symptom domain sum is divided by 2 (upper limit 50) The three resulting processed domain scores are summed to obtain the total score of the FIQR (range 0-100) | Before baseline: Day -3; Treatment 1: Baseline (Day 1) + Day 14 + 21 ; Washout: Before baseline day -3; Treatment 2: Baseline (Day 35) + Day 49 + 56 | 
| Daily Sleep Interference Scale (DSIS) | Pain-related sleep interference is evaluated with the DSIS (0 =pain does not interfere with sleep, 10 = pain completely interferes with sleep]). | Diary (Treatment 1: baseline (Day 1) to Day 21; Treatment 2: baseline (Day 35) to Day 56) | 
| Pressure algometry (1 sq.cm probe) | Pressure algometry in pre-specified points: right occipital region at insertion of m. subocipitalis right m. trapezius at the midpoint of the upper border right paraspinal region, 3 cm lateral of the midline at level of mid-scapula right second costochondral junction right lateral epicondyle right knee region, at the medial fat pad proximal of the meniscus margin In addition at following control sites: right lower arm, at the dorsal lower third right fingernail of first digit right third metatarsal bone at midpoint Cut-off point is 400 kPa, rate 10-30 kPa/s | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Hospital Anxiety and Depression Scale (HADS) | HADS is a 14-item questionnaire used to evaluate the subject's level of anxiety and depression; the subjects can rate between 0-21 with a score of eleven as the cutoff point for anxiety or depression | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Pain Catastrophizing Scale (PCS) | The PCS is a 13-item self-report scale to measure pain catastrophizing: each item is rated on a 5-point nominal scale (0 = not at all, 4 = all the time). It is constructed with three subscales being magnification, rumination, and helplessness. | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Adverse effects | Self-reported adverse effects related to the treatment: CNS: irritability, mood changes, drowsiness, lethargy, sleep dysfunction, dizziness cardiovascular system: palpitations, orthostatic hypotension g.i.-system: dyspepsia, nausea, obstipation, diarrhoea urogenital system: urinary retention, urinary incontinence autonomic system: diaphoresis, shivering | Diary + Treatment 1: Baseline (day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Quantitative Sensory Testing (QST) | Cold pressor test (1min, 10C) - Pressure tolerance threshold before and after Cold Water. Heat/Capsaicin test - 5min, 45C heat, followed by 30min capsaicin cream 0.075%, Measurement of allodynic (brush, Somedic) and hyperalgesic (Pinprick stimulator 128nm) areas. | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Plasma concentrations of naltrexone and β-Naltrexon |  | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Pain DETECT | Measurement of neuropathic component | Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 | 
| Brief Pain Inventory - Short Form (BPI-SF) questionnaire | BPI-SF allows patients to rate the severity of their pain and the degree to which their pain interferes with common dimensions of feeling and function. BPI-SF is a widely used Measurement Tool for assessing clinical pain. | Before baseline: Day -3 to -1; Washout: Before baseline Day 32 to 34 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Low dose naltrexone, Pain