Fibromyalgia and Naltrexone: The FINAL Study

Study Overview
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Brief Summary
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This study evaluates the effect of low dose naltrexone (LDN) on pain in women with fibromyalgia (FM). The study is designed as a parallel randomized (1:1) double blind, placebo-controlled superiority trial. Half of the participants will receive treatment with LDN while the other half will receive treatment with placebo.

Detailed Description
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Low dose naltrexone (LDN) is used widely as off label treatment in patients with fibromyalgia, despite the lack of larger randomized controlled trials (RCT) supporting an effect. LDN has antagonistic effect on both opioid receptors and on toll-like receptors in glia cells. Mediated via those receptors, LDN can potentially reduce neuroinflammation and induce homeostasis in the endorphin system in patients with fibromyalgia. The aim of the trial is to investigate whether treatment with LDN has a superior effect compared to placebo on pain among female patients with fibromyalgia, evaluated after 12 weeks of treatment. The study is also exploring secondary aims regarding a possible improvement of other fibromyalgia core symptoms and a possible improvement of global assessment, daily functioning and health-related quality of life. Among the exploratory secondary objectives are changes in muscle exhaustion, physical fitness, pain sensitivity, inhibition of pain, augmentation of pain, and pro-inflammatory cytokines.

Official Title
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Fibromyalgia and Naltrexone: The FINAL Study

Conditions
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Fibromyalgia

Intervention / Treatment
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* Drug: Naltrexone Pill
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Women aged 18-64 years Understands and writes Danish Fulfills the American College of Rheumatology 1990 criteria for fibromyalgia A minimum score of 4 in self-reported average pain during the last 7 days on a 0-10 numeric rating scale at baseline All fertile women have to use safe anti conception (Spiral, birth control pills, contraceptive patch, contraceptive vaginal ring or gestagen injections) for 3 weeks before and 1 week after the trial. If the patients' normal lifestyle includes sexual abstinence, they do not have to use anti conception. Instead they can give an oral informed consent, that they will be sexually abstinent during the trial. A woman is considered non-fertile if she is sterilized, hysterectomized, bilateral oophorectomized or is postmenopausal. A woman is considered postmenopausal when vaginal bleeding has been absent for 1 year and is confirmed by measurement of follicle-stimulating hormone. Exclusion Criteria: Known allergy against naltrexonehydroclorid Pregnancy or breastfeeding. A negative pregnancy test has to be available for all fertile subjects at baseline Use of opioids or NSAIDs during the 4 weeks before inclusion in the trial Abuse of alcohol or other substances Inflammatory rheumatic diseases Demyelinating diseases Active cancer Liver dysfunction Kidney dysfunction Psychotic diseases History of suicide attempts Suicide ideation - evaluated using Patient Health Questionnaire-9 (Item 9 has to be answered never)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 Years

Sexes Eligible for Study
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Female

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
Interventional Model Description: A parallel randomized (1:1) double blind, placebo-controlled superior trial
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Naltrexone<br>Low Dose Naltrexone (LDN) is administered for 12 weeks, including a titration phase of 4 weeks. Participants will be titrated up to 6 mg following a dose escalation scheme: Initial dosage of 1.5 mg daily, escalated every seventh day by 1.5 mg up to 6 mg at week 4. Dose escalation will be based on safety and tolerability, and if dose escalation is not feasible, delayed increments are allowed. After end of titration (week 4) the subjects will be maintained at the highest tolerated dose level for the last 8 weeks of the treatment period. Subjects are not allowed to change dose during the last 8 weeks of the treatment period. The medicine is taken orally as tablets once daily in the evening. | Drug: Naltrexone Pill<br>* Treatment with LDN for 12 weeks, including af titration phase of 4 weeks. Initial dosage of 1.5 mg, dose is increased by 1.5 mg every 7th day to 6 mg at week 4. Dosing is increased based on safety and tolerability and delayed increments are allowed. The participants are maintained on the highest tolerable dose for the last 8 weeks of the treatment period.<br>* Other names: LDN;|
| Placebo Comparator: Placebo<br>LDN-placebo is administered for 12 weeks, including a titration phase of 4 weeks. Participants will be titrated up to 6 mg following a dose escalation scheme: Initial dosage of 1.5 mg daily, escalated every seventh day by 1.5 mg up to 6 mg at week 4. Dose escalation will be based on safety and tolerability, and if dose escalation is not feasible, delayed increments are allowed. After end of titration (week 4) the subjects will be maintained at the highest tolerated dose level for the last 8 weeks of the treatment period. Subjects are not allowed to change dose during the last 8 weeks of the treatment period. The medicine is taken orally as tablets (similar in size, shape and taste to the active medication), once daily in the evening. | Drug: Placebo oral tablet<br>* Treatment with LDN-placebo for 12 weeks, including af titration phase of 4 weeks. Initial dosage of 1.5 mg, dose is increased by 1.5 mg every 7th day to 6 mg at week 4. Dosing is increased based on safety and tolerability and delayed increments are allowed. The participants are maintained on the highest tolerable dose for the last 8 weeks of the treatment period.<br>* Other names: LDN-placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Average pain during the last 7 days | Assessed by asking the participants about the level of average pain during the last 7 days on a 11 point rating scale, ranging from 0-10 (0 = no pain and 10 = unbearable pain) using the first item from the symptom part of the Fibromyalgia Impact Questionnaire Revised. A lower score indicates lower severity. | Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global assessment | Measured by Patient Global Impression of Change on a 1-7 Verbal Rating Scale. The participants are asked how they rate their overall fibromyalgia symptoms after 4, 8 and 12 weeks of treatment compared with before treatment. A score of 4 indicates no change, a score of 1 is characterized by a lot worse and a score of 7 is characterized by a lot better. A higher score indicates higher degree of improvement. | Change in overall fibromyalgia symptoms from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Impact of fibromyalgia | Measured by the Fibromyalgia Impact Questionnaire Revised (FIQR) total score. The FIQR asks patients to rate how difficult it is to perform a list of 9 common activities over the previous 7 days on an 11 point scale, ranging from 0-10 (0 = no difficulty and 10 = very difficult). The FIQR then asks patients to indicate how often their fibromyalgia impacts their quality of life over the last 7 days on an 11 point scale, ranging from 1-10 (0 = never and 10 = always). Finally, the FIQR asks patients to assess the severity of 10 different symptoms on an 11 point scale, ranging from 0-10 (0 = no symptoms and 10 = extreme symptoms). These three sub-scales are summed to represent an overall FIQR score. A lower score indicates lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Pain distribution | Assessed by the Widespread Pain Index (WPI) from The American College of Rheumatology 2016 revised criteria for fibromyalgia (ACR-2016). The body is divided into 19 body parts and number of pain full body parts during the last 7 days is counted, giving rise to the WPI. A lower score indicates lower spreading of pain. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of pain | Assessed by the Fibromyalgia Impact Questionnaire Revised level of pain question, asking the participants to rate the average level of pain during the last 7 days on a 11 point rating scale, ranging from 0-10 (0 = no pain and 10 = unbearable pain). A lower score indicates lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of tenderness | Assessed by the Fibromyalgia Impact Questionnaire Revised level of tenderness to touch question, asking the participants to rate the average level of tenderness to touch during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = no tenderness and 10 = very tender). A lower score indicates a lower severity. AND Assessed by measurement of pressure pain threshold, using a handheld algometer. Points measured: Right Quadriceps 15 cm proximal of apex patella and left Trapezius 10 cm from acromion. Each point is measured 3 times. Pressure pain threshold is measured in kilopascal (kPa). A higher value indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of fatigue | Assessed by the Fibromyalgia Impact Questionnaire Revised level of energy question, asking the participants to rate the average level of energy during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = lots of energy and 10 = no energy). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of sleep disturbance | Assessed by the Fibromyalgia Impact Questionnaire Revised quality of sleep question asking the participants to rate the average quality of sleep during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = awoke well rested and 10 = awoke very tired). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of depression | Assessed by the Fibromyalgia Impact Questionnaire Revised level of depression question, asking the participants to rate the average level of depression during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = no depression and 10 = very depressed). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of anxiety | Assessed by the Fibromyalgia Impact Questionnaire Revised level of anxiety question, asking the participants to rate the average level of anxiety during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = not anxious and 10 = very anxious). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of cognition | Assessed by the Fibromyalgia Impact Questionnaire Revised level of memory problems question, asking the participants to rate the average level of memory problems during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = good memory and 10 = very poor memory). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of stiffness | Assessed by the Fibromyalgia Impact Questionnaire Revised level of stiffness question, asking the participants to rate the average level of stiffness during the last 7 days on an 11 point rating scale, ranging from 0-10 (0 = no stiffness and 10 = severe stiffness). A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Level of physical function | Assessed by the physical function domain of Fibromyalgia Impact Questionnaire Revised; asking participants to rate how difficult it is to perform a list of 9 common activities over the previous 7 days on an 11 point scale, ranging from 0-10 (0 = no difficulty and 10 = very difficult). The score is characterized by the sum of the 9 scores (0-90). A lower score indicates better function. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - mobility | Measured by the European Quality of Life 5 Dimensions (EQ-5D) mobility domain; asking the participants to rate their mobility on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - self care | Measured by the European Quality of Life 5 Dimensions (EQ-5D) self care domain; asking the participants to rate their ability for self care on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - usual activities | Measured by the European Quality of Life 5 Dimensions (EQ-5D) usual activities domain; asking the participants to rate their ability to perform usual activities on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - pain/discomfort | Measured by the European Quality of Life 5 Dimensions (EQ-5D) pain/discomfort domain; asking the participants to rate their level of pain or discomfort on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - anxiety/depression | Measured by the European Quality of Life 5 Dimensions (EQ-5D) anxiety/depression domain; asking the participants to rate their level of anxiety or depression on a 1-5 Verbal Rating Scale, a score of 1 indicating no problems, and a score of 5 indicating extreme problems. A lower score indicates a lower severity. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Health-related quality of life - global | Measured by European Quality of Life Visual Analogue Scale (EQ-VAS), which asks the participant to rate their overall health 'today' on a 0-100 VAS. A higher score indicates a better quality of life. | Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo | 
| Number of responders with a more than 15% improvement of pain | A responder is defined as a subject who reports a more than 15% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group. | Number of responders after 12 weeks of treatment with LDN or LDN placebo | 
| Number of responders with a more than 30% improvement of pain | A responder is defined as a subject who reports a more than 30% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group. | Number of responders after 12 weeks of treatment with LDN or LDN placebo | 
| Number of responders with a more than 50% improvement of pain | A responder is defined as a subject who reports a more than 50% improvement of the primary outcome (average pain during the last 7 days) after 12 weeks of treatment with LDN or LDN-placebo. Number of responders are calculated for both the LDN group and the LDN-placebo group. | Number of responders after 12 weeks of treatment with LDN or LDN placebo |