Low-dose naltrexone (LDN) has been demonstrated to reduce symptom severity in conditions such as fibromyalgia, Crohn’s disease, multiple sclerosis, and complex regional pain syndrome. We review the evidence that LDN may operate as a novel anti-inflammatory agent in the central nervous system, via action on microglial cells. These effects may be unique to low dosages of naltrexone and appear to be entirely independent from naltrexone’s better-known activity on opioid receptors. As a daily oral therapy, LDN is inexpensive and well-tolerated. Despite initial promise of efficacy, the use of LDN for chronic disorders is still highly experimental. Published trials have low sample sizes, and few replications have been performed. We cover the typical usage of LDN in clinical trials, caveats to using the medication, and recommendations for future research and clinical work. LDN may represent one of the first glial cell modulators to be used for the management of chronic pain disorders.

There is increasing evidence that chronic pain problems are characterised by alterations in brain structure and function. Chronic back pain is no exception. There is a growing sentiment, with accompanying theory, that these brain changes contribute to chronic back pain, although empirical support is lacking. This paper reviews the structural and functional changes of the brain that have been observed in people with chronic back pain. We cast light on the clinical implications of these changes and the possibilities for new treatments but we also advise caution against concluding their efficacy in the absence of solid evidence to this effect.

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Objectives: We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition.Methods: Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models.Results: Twenty-two studies were included in the systematic review and 15 in the meta-analysis.In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFa, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferong, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1b, and IL-6 in blister fluid; and 3) IL-1b and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule-1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria. Conclusion:CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases. GLOSSARY CI 5 confidence interval; CGRP 5 calcitonin gene-relaxed peptide; CRPS 5 complex regional pain syndrome; ET-1 5 endothelin-1; IL 5 interleukin; IP-10 5 interferon-inducible protein-10; MCP-1 5 monocyte chemoattractant protein-1; NPY 5 neuropeptide Y; PGE2 5 prostaglandin E2; SP 5 substance P; sTNF-R 5 soluble tumor necrosis factor receptor; TNF 5 tumor necrosis factor.Complex regional pain syndrome (CRPS) is characterized by severe pain, allodynia, hyperalgesia, and motor and autonomic signs and symptoms.1 Although the precise etiology of CRPS is unknown, persistent inflammatory activity has been demonstrated in a number of methodologically diverse studies.2-6 Although narrative reviews have attempted to synthesize these results, no systematic review including a rigorous quality assessment of original studies has been conducted. As such, no definitive conclusions can be drawn about the presence of inflammatory activity in CRPS, which limits the identification of potential targets for therapy. Therefore, we conducted a systematic review and meta-analysis of the literature. We aimed firstly to determine whether, in adults, CRPS is associated with a...

The evidence for a difference in function of the primary somatosensory cortex in CRPS compared with controls is clouded by high risk of bias and conflicting results, but reduced representation size seems consistent.

The introduction of STEPS was associated with reduced wait-times and costs at public pain medicine units and increased both the use of active pain management strategies and patient satisfaction.

Fibromyalgia (FM) is a complex, multi-symptom condition that predominantly affects women. The majority of those affected are unlikely to gain significant symptomatic control from the few treatments that are approved for FM. In this 10-week, single-blind, crossover trial we tested the immune effects of eight weeks of oral administration of low-dose naltrexone (LDN). We enrolled eight women with an average age of 46 years, symptom severity of 62 out of 100, and symptom duration of 14 years. We found that LDN was associated with reduced plasma concentrations of interleukin (IL)-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-15, IL-17A, IL-27, interferon (IFN)-α, transforming growth factor (TGF)-α, TGF-β, tumor necrosis factor (TNF)-α, and granulocyte-colony stimulating factor (G-CSF). We also found a 15% reduction of FM-associated pain and an 18% reduction in overall symptoms. The findings of this pilot trial suggest that LDN treatment in fibromyalgia is associated with a reduction of several key pro-inflammatory cytokines and symptoms. The potential role of LDN as an atypical anti-inflammatory medication should be explored further.

Despite widely held assumptions of primary motor cortex dysfunction in complex regional pain syndrome, there is only evidence to support bilateral disinhibition, and there is high risk of bias across the literature.