Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia syndrome (Review)

Psychosomatic Medicine and Psychotherapy,Technische Universität München, München,
Cochrane database of systematic reviews (Online) (Impact Factor: 6.03). 01/2013; 1(1):CD010292. DOI: 10.1002/14651858.CD010292
Source: PubMed


Fibromyalgia syndrome (FMS) is a clinically well-defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. Patients often report high disability levels and poor quality of life (QOL). Drug therapy focuses on reducing key symptoms and improving quality of life.
To assess the benefits and harms of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo for treating FMS symptoms in adults.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library 2012, Issue 9), MEDLINE (1966 to September 2012), EMBASE (1980 to September 2012), (U.S.-marketed pharmaceuticals) (to September 2012) and (to September 2012) for published and ongoing trials and examined the reference lists of reviewed articles.
We selected randomized, controlled trials of any formulation of SNRIs against placebo for the treatment of FMS in adults.
Two review authors independently extracted the data from the included studies, and assessed the risks of bias of the studies. Discrepancies were resolved by discussion.
Ten studies were included with a total of 6038 participants. Five studies investigated duloxetine against placebo, and five investigated milnacipran against placebo. A total of 3611 participants were included into duloxetine or milnacipran groups and 2427 participants into placebo groups. The studies had a low risk of bias in general. Duloxetine and milnacipran had a small incremental effect over placebo in reducing pain (standardized mean difference (SMD) -0.23; 95% confidence interval (CI) -0.29 to -0.18; 6.1% relative improvement). One-hundred and ninety-two participants per 1000 on placebo reported an at least 50% pain reduction compared to 280 per 1000 on SNRIs (Risk ratio (RR) 1.49, 95% CI 1.35 to 1.64; number needed to treat to benefit (NNTB) 11, 95% CI 9 to 15). Duloxetine and milnacipran did not reduce fatigue substantially (SMD -0.14; 95% CI -0.19 to -0.08; 2.5% relative improvement; NNTB 17, 95% CI 12 to 29), and did not improve QOL substantially (SMD -0.20; 95% CI -0.25 to -0.14; 4.6% relative improvement; NNTB 12, 95% CI 9 to 17) compared to placebo. There were no statistically significant differences between either duloxetine or milnacipran and placebo in reducing sleep problems (SMD -0.07; 95% CI -0.16 to 0.03; 2.5% relative improvement). One-hundred and seven participants per 1000 on placebo dropped out due to adverse events compared to 196 per 1000 on SNRIs. The dropout rate due to adverse events in the duloxetine and milnacipran groups was statistically significantly higher than in placebo groups (RR 1.83, 95% CI 1.53 to 2.18; number needed to treat to harm (NNTH) 11, 95% CI 9 to 13). There was no statistically significant difference in serious adverse events between either duloxetine or milnacipran and placebo (RR 0.78, 95% CI 0.55 to 1.12).
The SNRIs duloxetine and milnacipran provided a small incremental benefit over placebo in reducing pain. The superiority of duloxetine and milnacipran over placebo in reducing fatigue and limitations of QOL was not substantial. Duloxetine and milnacipran were not superior to placebo in reducing sleep problems. The dropout rates due to adverse events were higher for duloxetine and milnacipran than for placebo. The most frequently reported symptoms leading to stopping medication were nausea, dry mouth, constipation, headache, somnolence/dizziness and insomnia. Rare complications of both drugs may include suicidality, liver damage, abnormal bleeding, elevated blood pressure and urinary hesitation.

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Available from: Winfried Häuser, Sep 29, 2015
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    • "us in the treatment of fibromyalgia and are frequently used in pharmacological treatment regimens . The way 5 - HT and NE reuptake inhibitors act to re - duce pain is still a matter of debate as spinal , subcortical , and cortical mechanisms have all been proposed . However the overall effect of any of these individual treatments has been modest ( Häuser et al . , 2013 ) ."
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    ABSTRACT: Fibromyalgia is a chronic pain syndrome characterized by widespread pain, fatigue, and memory and mood disturbances. Despite advances in our understanding of the underlying pathophysiology, treatment is often challenging. New research indicates that changes in functional connectivity between brain regions, as can be measured by magnetic resonance imaging (fcMRI) of the resting state, may underlie the pathogenesis of this and other chronic pain states. As such, this parameter may be able to be used to monitor changes in brain function associated with pharmacological treatment, and might also be able to predict treatment response. We performed a resting state fcMRI trial using a randomized, placebo-controlled, cross-over design to investigate mechanisms of action of milnacipran (MLN), a selective serotonin and norepinephrine reuptake inhibitor (SNRI), in fibromyalgia patients. Our aim was to identify functional connectivity patterns at baseline that would differentially predict treatment response to MLN as compared to placebo. Since preclinical studies of MLN suggest that this medication works by augmenting antinociceptive processes, we specifically investigated brain regions known to be involved in pain inhibition. 15 fibromyalgia patients completed the study, consisting of 6 weeks of drug and placebo intake (order counterbalanced) with an interspersed 2 week wash out period. As a main finding we report that reductions in clinical pain scores during MLN were associated with decreased functional connectivity between pro-nociceptive regions and antinociceptive pain regions at baseline, specifically between the rostral part of the anterior cingulate cortex (ACC) and the insular cortex (IC), as well as between the periaqueductal gray (PAG) and the IC: patients with lower preexisting functional connectivity had the greatest reduction in clinical pain. This pattern was not observed for the placebo period. However a more robust placebo response was associated with lower baseline functional connectivity between the ACC and the dorsolateral prefrontal cortex. This study indicates that ACC–IC connectivity might play a role in the mechanism of action of MLN, and perhaps more importantly fcMRI might be a useful tool to predict pharmacological treatment response.
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    • "Another factor is that participants could have had a previous episode of major depression that could account for the current inverse association with inflammation, illustrating a case of selective survival. Furthermore, in order to avoid misclassification, we excluded participants taking antidepressants who have been shown to have some potential anti-inflammatory effect (Häuser et al., 2013). Different methodological approaches could explain the inconsistent associations among prior studies of depression with inflammation (Capuron et al., 2008). "
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    • "In the last decade, antidepressant drugs have emerged as firstline drugs for neuropathic pain, a chronic condition, severe, and resistant to most analgesics (Attal et al., 2006; Mico et al., 2006). It has been clinically and pre clinically demonstrated that treatment with drugs that increase extracellular concentrations of serotonin (5-HT), dopamine (DA), and noradrenaline (NA) seems to be effective in improving both pain and depression symptoms (Attal et al., 2006; Blier and Abbott, 2001; Hauser et al., 2013; Thaler Contents lists available at ScienceDirect Neuropharmacology j o u rn a l h o m e p a g e : w w w . e l s e v ie r . "
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