Fibromyalgia and Naltrexone: The FINAL Study (FINAL)

• ClinicalTrials.gov Identifier: NCT04270877
• Recruitment Status: Completed
• First Posted: February 17, 2020
• Last Update Posted: December 29, 2022
• Sponsor: Odense University Hospital
• Collaborators: University of Southern Denmark; University Hospital Bispebjerg and Frederiksberg
• Information provided by (Responsible Party): Karin Bruun Plesner, Odense University Hospital

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Fibromyalgia	Drug: Naltrexone Pill; Drug: Placebo oral tablet	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 99 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: A parallel randomized (1:1) double blind, placebo-controlled superior trial
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Fibromyalgia and Naltrexone: The FINAL Study
• Actual Study Start Date: January 6, 2021
• Actual Primary Completion Date: December 27, 2022
• Actual Study Completion Date: December 27, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Naltrexone; 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; 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.; Other Name: LDN
Placebo Comparator: Placebo; 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; 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.; Other Name: LDN-placebo

Outcome Measures

Primary Outcome Measures :

1. Average pain during the last 7 days [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   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.

Secondary Outcome Measures :

1. Global assessment [ Time Frame: Change in overall fibromyalgia symptoms from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
2. Impact of fibromyalgia [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
3. Pain distribution [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
4. Level of pain [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
5. Level of tenderness [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]

   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.

6. Level of fatigue [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
7. Level of sleep disturbance [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
8. Level of depression [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
9. Level of anxiety [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   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.
10. Level of cognition [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
11. Level of stiffness [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
12. Level of physical function [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
13. Health-related quality of life - mobility [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
14. Health-related quality of life - self care [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
15. Health-related quality of life - usual activities [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
16. Health-related quality of life - pain/discomfort [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
17. Health-related quality of life - anxiety/depression [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
18. Health-related quality of life - global [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
    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.
19. Number of responders with a more than 15% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    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.
20. Number of responders with a more than 30% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    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.
21. Number of responders with a more than 50% improvement of pain [ Time Frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo ]
    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.

Other Outcome Measures:

1. Variation in pain [ Time Frame: Change from baseline when assessed after 4, 8, and 12 weeks of treatment with LDN or LDN-placebo ]
   Measured using a diary of daily average pain rated on an 11 point rating scale, ranging from 0-10, during 7 days before visits at baseline, and after 8 and 12 weeks of treatment. The variation in pain is characterized by the highest score minus the lowest score. A lower score indicates a lower variation.
2. Muscle exhaustion [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   Measured by an isometric muscle exhaustion test of the deltoid muscle. Measured by asking the participant to complete an isometric muscle exhaustion task by maintaining 90° shoulder abduction (dominant arm) for as long as possible with the elbow extended and the hand pronated (hand facing downwards). Task failure (test position can no longer be maintained) defines the test duration. The participants are instructed to maintain the position until they feel maximal muscle exhaustion (corresponding to a score of 10 on a 0-10 scale with 0 being "no muscle fatigue" and 10 being 'maximal muscle fatigue/exhaustion'). Surface electromyography (EMG) will be recorded from the anterior, middle and posterior deltoid muscle at 3000 Hz during the entire test. A longer duration of test is indicative of lower levels of exhaustion.
3. Physical fitness [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   Measured by the 30-second chair stand test. The test starts with the subject seated on a chair with her back touching the backrest. Subjects rise to a full stand with the back straight and then sit down again to regain this cycle as many times as they can within 30 seconds. A higher number of cycles is indicative of better physical fitness.
4. Pain sensitivity [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs in all patients to assess pressure pain threshold and pressure pain tolerance. Pressure pain threshold and pressure pain tolerance are measured in kilopascal (kPa). A higher value is indicative of lower severity.
5. Inhibition of pain [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   Measured by Conditioned pain modulation (CPM). Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs to assess increase in pressure pain threshold during cuff pain conditioning on the contralateral leg. Pressure pain threshold and pressure pain tolerance are measured in kilopascal (kPa). A higher value is indicative of lower severity.
6. Augmentation of pain [ Time Frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo ]
   Measured by Temporal Summation of Pain (TSP). Assessments are conducted as recommended by the 'International Association for the Study of Pain'. Computer-controlled cuff algometry is performed on lower legs to assess increase in pain scores to ten repeated stimulations. Pain is rated on a 0-100 Visual Analogue Scale. A lower value indicates a lower severity.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 64 Years (Adult)
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Criteria

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")

Contacts and Locations

Locations

Denmark

Pain centre, Odense University Hospital

Odense, Denmark, 5000

Sponsors and Collaborators

Odense University Hospital

University of Southern Denmark

University Hospital Bispebjerg and Frederiksberg

Investigators

• Principal Investigator: Karin D Bruun, Consultant; Odense University Hospital

  Study Documents (Full-Text)

Documents provided by Karin Bruun Plesner, Odense University Hospital:

Study Protocol  [PDF] July 27, 2021

Statistical Analysis Plan  [PDF] May 18, 2022

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Bruun KD, Amris K, Vaegter HB, Blichfeldt-Eckhardt MR, Holsgaard-Larsen A, Christensen R, Toft P. Low-dose naltrexone for the treatment of fibromyalgia: protocol for a double-blind, randomized, placebo-controlled trial. Trials. 2021 Nov 15;22(1):804. doi: 10.1186/s13063-021-05776-7.

• Responsible Party: Karin Bruun Plesner, Principal Investigator, Odense University Hospital
• ClinicalTrials.gov Identifier: NCT04270877
• Other Study ID Numbers: 18021; 2019-000702-30 ( EudraCT Number ); R177-A6158 ( Other Grant/Funding Number: The Danish Reumatism Association ); A3650 ( Other Grant/Funding Number: The OUH PhD Committee for Operating Costs ); 21-10-0037 ( Other Grant/Funding Number: Aase and Ejnar Danielsens fund )
• First Posted: February 17, 2020
• Last Update Posted: December 29, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Fibromyalgia; Myofascial Pain Syndromes; Muscular Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Neuromuscular Diseases; Nervous System Diseases; Naltrexone; Alcohol Deterrents; Narcotic Antagonists; Physiological Effects of Drugs; Sensory System Agents; Peripheral Nervous System Agents