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.
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 Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
99
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.
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.
Pain centre, Odense University Hospital
Odense, Denmark
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.
Time frame: Change from baseline when assessed after 12 weeks of treatment with LDN or LDN-placebo
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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: Number of responders after 12 weeks of treatment with LDN or LDN placebo