Natural Products as Promising Pharmacological Tools for the Management of Fibromyalgia Symptoms – A Review

Abstract

Fibromyalgia (FM) is the second most common rheumatologic disorder, affecting 5% of the world population, and has a serious effect on the quality of life of patients, as well as an economic impact through lost workdays. This pain syndrome is a common cause of chronic widespread pain and is characterized by reduced pressure pain thresholds with hyperalgesia and allodynia, nonrestorative sleep, fatigue, cognitive dysfunction, and mood disturbances. The pharmacological treatment strategies for FM include the use of antidepressants, calcium channel modulators, muscle relaxants, and analgesics but have shown limited efficacy and therapeutic adherence. Thus, researchers have been seeking potential substances (new chemical entities or through drug repositioning) that could be used for FM treatment. In this context, natural products (NPs) have been shown to be promising pharmacological tools due to the variety of their pharmacological activity and the number of molecular sites available as possible active targets. Recent clinical and preclinical studies have been conducted to verify the possible applicability of NPs such as essential oils (EOs), plants extracts, terpenes, sapogenins, and alkaloids in the treatment of FM. The results have shown that natural products have an analgesic effect in different animal models of FM, probably by activation of inhibitory descending pathways, such as the periaqueductal gray and rostroventromedial medulla. Natural products and their secondary metabolites could therefore be a promising source for FM management. However, translational studies that seek to validate the preclinical studies are scarce, incipient, and lacking an approach focused on the traditional pharmaceutical market.

Analgesic Potential of Monoterpenes from Citrus Essential Oils

“…Monoterpenes are key holders of analgesic potential in Citrus essential oils, especially D-limonene and linalool. Essential oils are generally considered as safe; however, due to low bioavailability and stability, monoterpenes are complexed with β-cyclodextrin to improve their analgesic activity [62,69]. Further studies are encouraged to determine the analgesic potential of Citrus essential oils in managing daily activities of people with a long-term history of chronic pain.…”

“…Moreover, α-terpineol showed higher COX-2 activity inhibition than aspirin, the most popular NSAID, and most potently inhibited the expression of pro-inflammatory cytokines and NF-κB activation [7,61]. α-Terpineol also showed antinociceptive effect in the capsaicin (neurogenic origin), glutamate, and formalin-induced orofacial nociception tests [51,62,63]. Anti-inflammatory effects that α-terpineol from orange juice demonstrated in vitro (suppressed IL-6 and increased IL-10) were further analyzed by ex vivo experiments, and results have shown anti-inflammatory action in macrophages after incubation of human blood with α-terpineol [61].…”

“…They found that both formulations had an anti-hyperalgesic effect, with the complexed form being more effective and producing a longer lasting effect (for 24 h after administration) [68]. Analgesic effect of linalool on acute central nociception (hot plate), visceral (acetic acid), and chronic pain models of neuropathic origin, and the opioid and glutamatergic systems are probably involved in this action [51,62,67,69]. One preclinical trial showed that linalool from rosewood was able to reduce the action potential amplitude assessed using an isolated nerve in the single sucrose gap technique, showing it blocked neuronal excitability [70].…”

Introductory Chapter: A Challenge to the Concept that Inflammation Plays a Prominent Pathogenic Role in Fibromyalgia

“…Among the chapters in this monograph are those that examine the treatment of fibromyalgia syndrome (FMS) using nonpharmacologic natural products and other relatively novel agents [1][2][3]. Although the modes of therapy described are diverse, a role for disordered immune mechanisms is implicit in each of the three chapters.…”

“…Although the modes of therapy described are diverse, a role for disordered immune mechanisms is implicit in each of the three chapters. These include reference to sulfur springs considered to inhibit interleukin-2 and interferon-gamma [1], introductory explanations of FMS pathogenesis that invokes inflammatory dysfunction [2], and mention of inflammatory cytokine production associated with autonomic nervous system dysfunction-stimulated microglial and astrocyte cell activation [3]. The discussion in the fourth chapter about the impact of FMS on the evaluation of inflammatory diseases assumes the opposite that clinically significant inflammation is not a feature of FMS [4].…”