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

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ClinicalTrials.gov Identifier: NCT02806440
Recruitment Status : Unknown
Verified August 2016 by Mads Werner, Rigshospitalet, Denmark.
Recruitment status was:  Recruiting
First Posted : June 20, 2016
Last Update Posted : August 23, 2016
Information provided by (Responsible Party):
Mads Werner, Rigshospitalet, Denmark

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.

Condition or disease Intervention/treatment Phase
Fibromyalgia Drug: Low dose naltrexone Drug: Placebo Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 140 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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.
Study Start Date : June 2016
Estimated Primary Completion Date : August 2017
Estimated Study Completion Date : December 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Fibromyalgia

Arm Intervention/treatment
Active Comparator: Low dose naltrexone
Low dose naltrexone 4.5 mg/tablet, 1 tablet a day for 21 days
Drug: Low dose naltrexone
Active comparator
Other Name: Naltrexone

Placebo Comparator: Placebo

Placebo tablet

1 tablet a day for 21 days

Drug: Placebo
Placebo comparator
Other Name: Inert substance

Primary Outcome Measures :
  1. Change in pain scores (during rest, during household activity, during personal daily hygienic procedures) [ Time Frame: 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 ]
    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.

Secondary Outcome Measures :
  1. Fibromyalgia Impact Questionnaire Revised (FIQR) [ Time Frame: 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 ]

    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)

  2. Daily Sleep Interference Scale (DSIS) [ Time Frame: Diary (Treatment 1: baseline (Day 1) to Day 21; Treatment 2: baseline (Day 35) to Day 56) ]
    Pain-related sleep interference is evaluated with the DSIS (0 =pain does not interfere with sleep, 10 = pain completely interferes with sleep]).

  3. Pressure algometry (1 sq.cm probe) [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]

    Pressure algometry in pre-specified points:

    1. right occipital region at insertion of m. subocipitalis
    2. right m. trapezius at the midpoint of the upper border
    3. right paraspinal region, 3 cm lateral of the midline at level of mid-scapula
    4. right second costochondral junction
    5. right lateral epicondyle
    6. right knee region, at the medial "fat pad" proximal of the meniscus margin

    In addition at following control sites:

    1. right lower arm, at the dorsal lower third
    2. right fingernail of first digit
    3. right third metatarsal bone at midpoint Cut-off point is 400 kPa, rate 10-30 kPa/s

  4. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]
    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

  5. Pain Catastrophizing Scale (PCS) [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]
    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.

  6. Adverse effects [ Time Frame: Diary + Treatment 1: Baseline (day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]

    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

  7. Quantitative Sensory Testing (QST) [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]

    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.

  8. Plasma concentrations of naltrexone and β-Naltrexon [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]
  9. Pain DETECT [ Time Frame: Treatment 1: Baseline (Day 1) + Day 14 + Day 21; Treatment 2: Baseline (Day 35) + Day 49 + Day 56 ]
    Measurement of neuropathic component

  10. Brief Pain Inventory - Short Form (BPI-SF) questionnaire [ Time Frame: Before baseline: Day -3 to -1; Washout: Before baseline Day 32 to 34 ]

    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.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02806440

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Contact: Mads U Werner, PhD, MD mads.u.werner@gmail.com
Contact: Trine Andresen, PhD 004579718098 trine.andresen2@rsyd.dk

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Multidisciplinary Pain Centre Recruiting
Give, Denmark, 7323
Contact: Trine Andresen, PhD       trine.andresen2@rsyd.dk   
Sponsors and Collaborators
Rigshospitalet, Denmark
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Principal Investigator: Anette Bendiksen, MD Multidisciplinary Pain Clinic
Publications of Results:
Other Publications:
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Responsible Party: Mads Werner, MD, PhD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02806440    
Other Study ID Numbers: 2015-002972-26
First Posted: June 20, 2016    Key Record Dates
Last Update Posted: August 23, 2016
Last Verified: August 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Anonymized IPD will be made available in a public research database as part of the final publication.
Keywords provided by Mads Werner, Rigshospitalet, Denmark:
Low dose naltrexone
Additional relevant MeSH terms:
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Myofascial Pain Syndromes
Muscular Diseases
Musculoskeletal Diseases
Rheumatic Diseases
Neuromuscular Diseases
Nervous System Diseases
Alcohol Deterrents
Narcotic Antagonists
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents