Fibromyalgia and Low Dose Naltrexone: Studies of Diagnostic Accuracy and Treatment Efficacy in a Specialised Pain Care Setting

Fibromyalgia is a common disorder associated with a high symptom burden and a low healthrelated quality of life, impacting daily functioning, working capacity, and social participation. Fibromyalgia is characterised by diffuse pain and tenderness related to healthy tissues and constitutes a prototype of nociplastic pain, where the pain is caused by augmented central pain processing. Its prevalence in the general population is about 2%, with a small female predominance. However, due to controversies and different beliefs among physicians, fibromyalgia is underdiagnosed in clinical patient populations, and the gender distribution is skewed, with more than 90% of the diagnosed being women. Diagnosing fibromyalgia timely and when appropriate can prevent unnecessary
 investigations and worries related to diagnosis uncertainty, support better self-care and guide a targeted pharmacological treatment strategy. In Denmark, patients with fibromyalgia can be referred to a specialised pain care centre where treatment is offered individually, combining pharmacological treatments with cognitive and behavioural therapeutic interventions. Guideline-recommended pharmacological treatments for fibromyalgia are centrallyacting drugs which influence neurotransmitters involved in central pain processing, e.g. pregabalin, which inhibits facilitatory neurotransmitters, or duloxetine, which promotes the release of inhibitory neurotransmitters. However, effect sizes are small, side effects are common, and only a minority of fibromyalgia patients benefit substantially from these treatments. During the last decade, an increased use of low-dose naltrexone (LDN) as an off-label treatment for fibromyalgia has been observed. A few small preliminary studies on the efficacy of LDN on fibromyalgia have shown promising results. However, these studies are potentially biased by several methodological weaknesses, with a risk of overestimating the effect. The aim of this thesis is twofold. Firstly, investigating how new survey-based diagnostic criteria for identifying fibromyalgia perform among patients with mixed chronic pain syndromes, and secondly, investigating the efficacy of LDN for treating fibromyalgia pain using robust methodology. The studies presented here include one diagnostic accuracy study (Study I) and two drug trials with LDN (Study II and Study III). 

Study I (published in Scand J Pain 2021) investigated the diagnostic accuracy of the survey-based 2016 diagnostic criteria for fibromyalgia in a population of patients with mixed chronic pain syndromes referred to specialised pain care. No similar studies have previously been performed. The 2016 criteria showed a high sensitivity and an acceptable specificity in the present population, thus bringing new evidence that these criteria are valuable for the clinical identification of fibromyalgia and for identifying fibromyalgia for research purposes in specialised pain care settings. 

Due to a skewed gender distribution among patients diagnosed with fibromyalgia, only women with fibromyalgia were included in the LDN trials. Study II (published in Pain Med 2020) investigated dose-response relationships using the “up-and-down” method, and results and experiences from Study II served to qualify the feasibility of Study III. Study III (published in Lancet Rheum 2023) investigated the clinical efficacy of 6 mg naltrexone on pain in women with fibromyalgia using a randomised, placebo-controlled, double-blind (RCT) design. Results from the RCT showed no general pain-relieving effect of LDN compared to placebo in women with fibromyalgia. Differences regarding 30% pain responders approached statistical significance, indicating that there might be more pain responders to LDN than to placebo. Among the secondary outcomes, a significant positive effect on memory problems was observed in favour of LDN. No concerns were raised about safety. Study III was performed according to the highest standards for conducting and reporting clinical trials, represents the largest trial of its kind to date, and thus contributes substantially to the current knowledge about the efficacy of LDN for treating fibromyalgia.

To summarise, the findings from the current thesis support the use of the survey-based 2016 diagnostic criteria for fibromyalgia as an easy-to-apply tool for fibromyalgia identification in clinical practice and for research purposes in specialised pain care settings. The RCT could not demonstrate that LDN has a general effect on fibromyalgia pain. However, a trend towards more pain responders was found for the LDN group compared to placebo, and subgroups that benefit from LDN treatment might exist and call for further studies.