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Low-Dose Naltrexone for Severe Fibromyalgia Syndrome: A Report of a Case With Two-Year Follow-Up
Ulrich Moser | Published: May 10, 2025
Abstract
Fibromyalgia syndrome (FMS) is characterized by diffuse musculoskeletal pain associated with daytime fatigue, sleep disturbance, cognitive deficits, and often further somatic symptoms. While some patients with FMS respond to standard treatment with amitriptyline, pregabalin, or duloxetine in combination with outpatient multimodal pain management, there are still many who do not benefit sufficiently from this treatment or suffer intolerable side effects. Effective treatment options are therefore needed to supplement conventional therapies. Naltrexone is used in many countries as an off-label therapy in low doses for several chronic immunomodulatory disorders, including FMS. However, the strength of evidence from previous randomized controlled trials is low. I report a patient with severe FMS who did not respond to conventional therapy. Instead, low-dose naltrexone (LDN) (4.5 milligrams per day) resulted in a significant and sustained improvement in most FMS symptoms. The results of this case report suggest that an off-label use of LDN in severe refractory FMS may be a viable option. However, the information base is currently limited, and studies are conflicting.
Introduction
Fibromyalgia syndrome (FMS) is a chronic, centralized, and generalized pain syndrome with a strong female predilection, characterized primarily by widespread musculoskeletal pain, fatigue, non-restorative sleep, mood disorders, and cognitive impairment. There is a wide range of somatic and psychological symptoms that contribute to significant symptom burden and functional impairment. The prevalence of FMS is estimated to be 1-5% in the general population, depending on the diagnostic criteria used. Despite the high prevalence of FMS, it often takes two years or more for a diagnosis to be made. Established screening criteria are still rarely used in clinical practice, and clinicians often rely on subjective or experiential criteria to decide whether someone has FMS or not [1,2]. FMS alone or in combination with comorbidities such as rheumatic diseases, psychiatric disorders, chronic fatigue syndrome, and sleep disorders poses a challenge to pain practitioners, not only in terms of diagnosis, but also in terms of uncertainty about the efficacy of different pain treatment options [1,2].
A growing body of evidence supports the hypothesis that biological and immune-mediated mechanisms may be central to explaining the symptoms associated with FMS. This has the potential to offer new avenues for therapeutic intervention [2]. Recently, there has been a shift in focus toward the concept of central sensitization as a central pathophysiological process. This suggests that an increase in central and peripheral pain perception and sensory processing within the ascending and descending sensory pathways may be a key factor in disease development [2]. The above findings, combined with the presence of abnormalities on brain imaging in the absence of known peripheral pain generators, have led to the suggestion that the central nervous system may serve as the primary source of pain associated with fibromyalgia [2]. Recent research has demonstrated the possible involvement of an underlying neuroinflammatory process in the pathogenesis of central sensitization in FMS [2]. A number of immune cells, including macrophages, glial cells, monocytes, mast cells, and neutrophils, have been implicated in the development of this inflammatory substrate in FMS [3]. Activation of toll-like receptor 4 in microglia and central nervous system neurons has been shown to facilitate the release of pro-inflammatory cytokines, which have been shown to mediate neuropathic pain. These pro-inflammatory cytokines serve to increase the excitatory tone of the neuronal networks associated with the perception of pain. This can lead to increased pain perception, as well as fatigue, cognitive impairment, and mood and sleep disturbances [4]. In light of these findings, the concept of neuroplastic pain has been proposed as a means of characterizing this chronic pain disorder, which has not previously been encompassed by the pain entities of nociceptive and neuropathic pain [5].
The management of FMS is a major challenge for everyone involved, from the patients and their families to the healthcare professionals responsible for their care. The approach is multidisciplinary and includes physical, psychosocial, and pharmacological interventions [1]. Non-pharmacological therapies, including low-intensity aerobic exercise and psychological techniques, such as pain management training, should be considered as primary interventions. Psychiatric-psychotherapeutic treatment is recommended for psychological comorbidity [1]. Pharmacological treatment (amitriptyline, duloxetine, pregabalin, tramadol) aims to reduce pain and comorbidities such as depression, anxiety, fatigue, and pain [1]. A discrepancy between patient views and guideline recommendations is evident when pharmacological therapies for fibromyalgia are evaluated using patient surveys. A significant number of people with FMS feel that the medications recommended in the guidelines are inadequate or that they are ineffective [2]. In fact, there is evidence that the currently recommended first-line drugs have limited efficacy due to adverse effects, minimal benefit over placebo, and no improvement in patient fatigue or quality of life [6]. Therefore, there is an urgent need for further research into alternative medications that may prove safe and effective for people with FMS.
Naltrexone is an opiate receptor antagonist at a dose of 50 mg, but at lower doses of 1 mg to 4.5 mg, it appears to have analgesic and immunomodulatory effects. Low-dose naltrexone (LDN) was originally introduced into clinical practice in the 1980s at doses of 1.5 mg to 3 mg as an alternative option for a variety of autoimmune diseases [7].
The potential analgesic effect of LDN results from blockade of mu-, delta-, and, to a lesser extent, kappa-opioid receptors in the central nervous system. This appears to lead to a feedback increase in these receptors and an up-regulation of the endorphin system. This "opioid rebound" effect could have several beneficial effects on health and quality of life, including enhanced endogenous analgesia and suppression of critical immune factors [7]. The anti-inflammatory effect of LDN appears to be due to blockade of toll-like receptor 4 on microglial cells in the central nervous system, antagonism of the opioid growth factor receptor, immunomodulation of macrophages and microglia, inhibition of T and B lymphocytes, and other as yet unknown mechanisms. Younger et al. [8] argue that microglial cells may produce a number of pro-inflammatory cytokines, substance P, nitrogen, nitric oxide, and excitatory amino acids when chronically stimulated, as is suspected in FMS. De Carvalho et al. [9] postulate that these substances are associated with what is commonly referred to as sickness behavior: cognitive impairment, mood and sleep disturbances, fatigue, and increased pain and discomfort, symptoms similar to those experienced by people with FMS.
Conclusions
The hypothesis that LDN can be used to treat severe refractory FMS in circumstances where conventional use is ineffective, inappropriate, or even contradictory appears to be valid. This hypothesis warrants further investigation. The present case report lends further support to this contention. The findings of this report suggest that LDN has the potential to effectively control pain and improve quality of life in patients with severe refractory FMS, particularly when administered in the setting of systemic inflammation and in the absence of psychiatric comorbidities. However, it is important to note that the existing literature on this subject is still limited. To substantiate this hypothesis, further neurophysiological studies are needed to evaluate the pathophysiology of FMS and the potential of LDN in chronic pain conditions. Furthermore, the identification of factors such as concomitant systemic inflammation and other conditions, including psychiatric comorbidity, may be essential in predicting which patients with FMS will respond to LDN treatment and which will not.