Mechanisms of disease: pain in fibromyalgia syndrome.
ABSTRACT Despite extensive research, the pathogenesis of pain in fibromyalgia syndrome is incompletely understood. Fibromyalgia pain is consistently felt in deep tissues including ligaments, joints and muscles. Increasing evidence points towards these tissues as relevant contributors of nociceptive input that might either initiate or maintain central sensitization, or both. Persistent or intense nociception can lead to transcriptional and translational changes in the spinal cord and brain resulting in central sensitization and pain. This mechanism represents a hallmark of fibromyalgia and many other chronic pain syndromes, including irritable bowel syndrome, temporomandibular disorder, migraine, and low back pain. Importantly, after central sensitization has been established, only minimal nociceptive input is required for the maintenance of the chronic pain state. Other factors, including pain-related negative affect, have been shown to significantly contribute to clinical fibromyalgia pain. An improved understanding of the mechanisms that characterize central sensitization and clinical pain will provide new approaches for the prevention and treatment of fibromyalgia and other chronic pain syndromes.
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ABSTRACT: Milnacipran, a serotonin and norepinephrfrine reuptake inhibitor with preferential inhibition of norepinephrine reuptake over serotonin, is approved in the United States for the management of fibromyalgia. Owing to its effects on norepinephrine and serotonin, as well as its lack of activity at other receptor systems, it was hypothesized that milnacipran would provide improvements in pain and other fibromyalgia symptoms without some of the unpleasant side effects associated with other medications historically used for treating fibromyalgia. The clinical safety and efficacy of milnacipran 100 and 200 mg/day in individuals with fibromyalgia has been investigated in four large, randomized, double-blind, placebo-controlled studies and three long-term extension studies. The clinical studies used composite responder analyses to identify the proportion of individual patients reporting simultaneous and clinically significant improvements in pain, global status, and physical function, in addition to assessing improvement in various symptom domains such as fatigue and dyscognition. In the clinical studies, patients receiving milnacipran reported significant improvements in pain and other symptoms for up to 15 months of treatment. Most adverse events were mild to moderate in severity and were related to the intrinsic pharmacologic properties of the drug. Long-term exposure to milnacipran did not result in any new safety concerns. As with other serotonin and norepinephrine reuptake inhibitors, increases in heart rate and blood pressure have been observed in some patients with milnacipran treatment.Therapeutic advances in musculoskeletal disease 08/2010; 2(4):201-20. DOI:10.1177/1759720X10372551
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ABSTRACT: Whereas acute stress often results in analgesia, chronic stress can trigger hyperalgesia/allodynia. This influence of long-term stress on nociception is relevant to numerous painful pathologies, such as fibromyalgia (FM), characterized by diffuse muscular pain (hyperalgesia) and/or tenderness (allodynia). Hence, there is a need for pre-clinical models integrating a chronic-stress dimension to the study of pain.Here, we assessed the effects of protracted/intermittent stress produced by daily, 1 h restraint periods in cylinders, 4 days/week over 5 weeks, on eight models of hyperalgesia and allodynia in rats. This type of stress potentiated chemical hyperalgesia in the formalin model (160 and 76% increase of pain score above controls, during the early and late phases, respectively). It also produced thermal allodynia in response to cold (paw acetone test: 200% increase of allodynia score during week 3–5) and heat (42 °C tail immersion test: 15% decrease of withdrawal threshold, from week 2 onward). This stress also resulted in mechanical allodynia in the von Frey filaments model (60% decrease in threshold during week 2–5). However, such a stress regimen had no influence in the Randall–Selitto test of mechanical hyperalgesia, and in the tail immersion models of cold (4 °C) or hot (48 °C) thermal hyperalgesia, as well as cold (15 °C) allodynia.This model of prolonged/intermittent restraint stress may be useful in investigating the mechanisms linking stress and pain, and provide an assay to assess the potential therapeutic efficacy of drugs targeted against painful pathologies with a strong stress component, including but not restricted to FM.Behavioural brain research 12/2009; DOI:10.1016/j.bbr.2009.07.005 · 3.39 Impact Factor
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ABSTRACT: Fibromyalgia is a syndrome of widespread chronic pain associated with sleep disorders, depressed mood, cognitive impairment and fatigue. Its etiology and pharmacopathology are poorly understood but it is thought to result from a dysfunction of central pain processing mechanisms leading to generalised pain sensitisation. Pain perception is the result of a bidirectional process of ascending and descending pathways. Nociceptive input from peripheral afferent neurons is sent via the dorsal horn of the spinal cord to the higher brain centres involved in pain perception. Some descending inhibitory projections to the spinal cord attenuate the nociceptive effects. Numerous neurotransmitters including serotonin, dopamine, noradrenaline and substance P are involved in these processes. In other neuronal pathways in the brain, the same neurotransmitters are involved in mood control, sleep regulation and cognitive function providing a neurochemical substrate for the wide range of symptoms seen in fibromyalgia. Attenuation of neuronal hyperactivity through ligands acting at the alpha2-delta subunits of voltage-dependent calcium channels and increased inhibitory activity of the descending pathways by inhibition of serotonin and noradrenaline reuptake are two mechanisms that are currently exploited by new medication for the treatment of fibromyalgia.Human Psychopharmacology Clinical and Experimental 06/2009; 24 Suppl 1(S1):S11-7. DOI:10.1002/hup.1029 · 1.85 Impact Factor