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

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

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.

The study takes place at The Multidisciplinary Pain Center in Grindsted.

Study Overview

• Status: Completed
• Conditions: Fibromyalgia
• Intervention / Treatment: Drug: Placebo; Drug: Low dose naltrexone

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.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Mads U Werner, PhD, MD; Email: mads.u.werner@gmail.com
• Study Contact Backup: Name: Trine Andresen, PhD; Phone Number: 004579718098; Email: trine.andresen2@rsyd.dk

Study Locations

• Denmark
  • Grindsted, Denmark, 7200
    • Multidisciplinary Pain Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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 Names: Naltrexone
Placebo Comparator: Placebo; Placebo tablet 1 tablet a day for 21 days	Drug: Placebo; Placebo comparator; 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

Collaborators and Investigators

• Sponsor: Rigshospitalet, Denmark
• Investigators: Principal Investigator: Kirsten M Bested, MD, Multidisciplinary Pain Clinic

Publications and helpful links

General Publications

• Younger J, Parkitny L, McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014 Apr;33(4):451-9. doi: 10.1007/s10067-014-2517-2. Epub 2014 Feb 15.
• Gaskin DJ, Richard P. The economic costs of pain in the United States. J Pain. 2012 Aug;13(8):715-24. doi: 10.1016/j.jpain.2012.03.009. Epub 2012 May 16.
• Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Katz RS, Mease P, Russell AS, Russell IJ, Winfield JB, Yunus MB. The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Res (Hoboken). 2010 May;62(5):600-10. doi: 10.1002/acr.20140.
• Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014 Apr 16;311(15):1547-55. doi: 10.1001/jama.2014.3266.
• Gilron I, Jensen TS, Dickenson AH. Combination pharmacotherapy for management of chronic pain: from bench to bedside. Lancet Neurol. 2013 Nov;12(11):1084-95. doi: 10.1016/S1474-4422(13)70193-5. Epub 2013 Sep 25.
• Younger JW, Zautra AJ, Cummins ET. Effects of naltrexone on pain sensitivity and mood in fibromyalgia: no evidence for endogenous opioid pathophysiology. PLoS One. 2009;4(4):e5180. doi: 10.1371/journal.pone.0005180. Epub 2009 Apr 13.
• Younger J, Noor N, McCue R, Mackey S. Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38. doi: 10.1002/art.37734.

Study record dates

Study Major Dates

• Study Start: June 1, 2016
• Primary Completion (Actual): December 1, 2019
• Study Completion (Actual): September 1, 2022

Study Registration Dates

• First Submitted: June 16, 2016
• First Submitted That Met QC Criteria: June 17, 2016
• First Posted (Estimated): June 20, 2016

Study Record Updates

• Last Update Posted (Actual): February 23, 2024
• Last Update Submitted That Met QC Criteria: February 21, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Pain; Low dose naltrexone
• Additional Relevant MeSH Terms: Nervous System Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Muscular Diseases; Neuromuscular Diseases; Fibromyalgia; Myofascial Pain Syndromes; Physiological Effects of Drugs; Peripheral Nervous System Agents; Sensory System Agents; Narcotic Antagonists; Alcohol Deterrents; Naltrexone
• Other Study ID Numbers: 2015-002972-26

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Anonymized IPD will be made available in a public research database as part of the final publication.