Fibromyalgia: From pathophysiology to therapy
Chronic Pain and Fatigue Research Center, Department of Anesthesiology, University of Michigan, Ann Arbor, 48106, USA. tobiass@ med.umich.edu Nature Reviews Rheumatology
(Impact Factor: 9.85).
07/2011; 7(9):518-27. DOI: 10.1038/nrrheum.2011.98
Individuals with fibromyalgia generally experience chronic widespread pain, which can be accompanied by further symptoms including fatigue, sleep disturbances, cognitive dysfunction, anxiety and depressive episodes. As the recognition and diagnosis of fibromyalgia has improved, the availability of therapeutic options for patients has increased. Furthermore, research into the neurobiological mechanisms that contribute to the chronic pain and concomitant symptoms experienced by patients with fibromyalgia has advanced our understanding of this debilitating disorder. In this Review, we aim to provide an overview of existing pathophysiological concepts. The roles of biological and psychological stress, genetic factors, and pain and sensory processing in the pathophysiology of fibromyalgia and related conditions are discussed. In addition, pharmacological treatments, including monoamine modulators, calcium channel modulators and γ-aminobutyric acid modulators, as well as nonpharmacological treatment options are considered.
Available from: Nathalia Sperotto
- "Neuropharmacology nociception transmission, as the patients experience reduced pain threshold with exaggerated pain sensation, likely dependent on central sensitization (Gracely et al., 2002; Jensen et al., 2012; Petersel et al., 2011; Smith et al., 2011; Staud, 2012). These sensorial alterations are linked to diminished levels of monoamines, and increased production of excitatory neurotransmitters throughout brain (Harris, 2010; Schmidt-Wilcke and Clauw, 2011). Furthermore , some studies point out the relevance of inflammatory pathways in the pathogenesis of fibromyalgia, considering that cytokines are implicated in both induction and maintenance of pain (Kadetoff et al., 2012; Üçeyler et al., 2011, 2006). "
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ABSTRACT: This study investigated whether the spinal or systemic treatment with the lipid resolution mediators resolvin D1 (RvD1), aspirin-triggered resolvin D1 (AT-RvD1) and resolvin D2 (RvD2) might interfere with behavioral and neurochemical changes in the mouse fibromyalgia-like model induced by reserpine. Acute administration of AT-RvD1 and RvD2 produced a significant inhibition of mechanical allodynia and thermal sensitization in reserpine-treated mice, whereas RvD1 was devoid of effects. A similar antinociceptive effect was obtained by acutely treating animals with the reference drug pregabalin. Noteworthy, the repeated administration of AT-RvD1 and RvD2 also prevented the depressive-like behavior in reserpine-treated animals, according to assessment of immobility time, although the chronic administration of pregabalin failed to affect this parameter. The induction of fibromyalgia by reserpine triggered a marked decrease of dopamine and serotonin (5-HT) levels, as examined in total brain, spinal cord, cortex and thalamus. Reserpine also elicited a reduction of glutamate levels in total brain, and a significant increase in the spinal cord and thalamus. Chronic treatment with RvD2 prevented 5-HT reduction in total brain, and reversed the glutamate increases in total brain and spinal cord. Otherwise, AT-RvD1 led to a recovery of dopamine levels in cortex, and 5-HT in thalamus, whilst it diminished brain glutamate contents. Concerning pregabalin, this drug prevented dopamine reduction in total brain, and inhibited glutamate increase in brain and spinal cord of reserpine-treated animals. Our data provide novel evidence, showing the ability of D-series resolvins AT-RvD1, and mainly RvD2, in reducing painful and depressive symptoms allied to fibromyalgia in mice.
Available from: Anthony Jones
- "Converging evidence suggests that the pathophysiology of chronic pain involves abnormalities of the central nervous system. In particular, it is thought that chronic pain might involve enhanced pain processing [11,12]. The cause of this enhanced pain processing remains unclear. "
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ABSTRACT: The lack of clear understanding of the pathophysiology of chronic pain could explain why we currently have only a few effective treatments. Understanding how pain relief is realised during placebo analgesia could help develop improved treatments for chronic pain. Here, we tested whether experimental placebo analgesia was associated with altered resting-state cortical activity in the alpha frequency band of the electroencephalogram (EEG). Alpha oscillations have been shown to be influenced by top-down processes, which are thought to underpin the placebo response.
Seventy-three healthy volunteers, split into placebo or control groups, took part in a well-established experimental placebo procedure involving treatment with a sham analgesic cream. We recorded ongoing (resting) EEG activity before, during, and after the sham treatment.
We show that resting alpha activity is modified by placebo analgesia. Post-treatment, alpha activity increased significantly in the placebo group only (p < 0.001). Source analysis suggested that this alpha activity might have been generated in medial components of the pain network, including dorsal anterior cingulate cortex, medial prefrontal cortex, and left insula.
These changes are consistent with a cognitive state of pain expectancy, a key driver of the placebo analgesic response. The manipulation of alpha activity may therefore present an exciting avenue for the development of treatments that directly alter endogenous processes to better control pain.
Available from: Robert H. Palmer
- "As the pathophysiology of fibromyalgia became better understood, research focused on other centrally acting analgesics that would likely improve this condition . This led to the approval of three medications by the US Food and Drug Administration (FDA) for the management of fibromyalgia: pregabalin, duloxetine and milnacipran. "
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ABSTRACT: Previous studies of long-term treatment response in fibromyalgia and other chronic pain states have generally been limited to approximately a year, leaving questions about the longer-term durability of response. The purpose of this study was to demonstrate continuing efficacy of milnacipran by characterizing changes in pain and other fibromyalgia symptoms after discontinuing long-term treatment. The mean length of milnacipran treatment at time of randomized withdrawal was 36.1 months from initial exposure to milnacipran (range, 17.9 to 54.4 months).
After completing a long-term, open-label, lead-in study of milnacipran (which followed varying periods of exposure in previous studies), adult patients with fibromyalgia entered the 4-week open-label period of the current study for evaluation of ongoing treatment response. After the 4-week period to confirm new baseline status, 151 patients taking milnacipran [greater than or equal to]100 mg/day and reporting [greater than or equal to]50% improvement from pre-milnacipran exposure in visual analog scale (VAS) pain scores were classified as responders. These responders entered the 12-week, double-blind, withdrawal period in which they were randomized 2:1 to continue milnacipran or switch to placebo. The prespecified primary parameter was loss of therapeutic response (LTR), defined as increase in VAS pain score to <30% reduction from pre-milnacipran exposure, or worsening of fibromyalgia requiring alternative treatment. Adverse events and vital signs were also monitored.
Time to LTR was shorter in patients randomized to placebo than in patients continuing milnacipran (P<0.001). Median time to LTR was 56 days with placebo and not calculable for milnacipran since less than half of these patients lost therapeutic response by study end. Additionally, 81% of patients continuing on milnacipran maintained clinically meaningful pain response ([greater than or equal to]30% improvement from pre-milnacipran exposure), compared with 58% of patients switched to placebo (sensitivity analysis II; P<0.001). Incidence of treatment-emergent adverse events was 58% and 47% for placebo and milnacipran, respectively. Mean decreases in blood pressure and heart rate were found in both groups, with greater decreases for patients switched to placebo.
Continuing efficacy of milnacipran was demonstrated by the loss of effect following withdrawal of treatment in patients who received an average of 3 years of milnacipran treatment.
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