Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacipran in patients with fibromyalgia

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The Journal of Rheumatology (Impact Factor: 3.19). 11/2005; 32(10):1975-85.
Source: PubMed


Fibromyalgia (FM) is a common musculoskeletal condition characterized by widespread pain, tenderness, and a variety of other somatic symptoms. Current treatments are modestly effective. Arguably, the best studied and most effective compounds are tricyclic antidepressants (TCA). Milnacipran, a nontricyclic compound that inhibits the reuptake of both serotonin and norepinephrine, may provide many of the beneficial effects of TCA with a superior side effect profile.
One hundred twenty-five patients with FM were randomly assigned in a 3:3:2 ratio to receive milnacipran twice daily, milnacipran once daily, or placebo for 3 months in a double-blind dose-escalation trial; 92% of twice-daily and 81% of once-daily participants achieved dose escalation to the target milnacipran dose of 200 mg.
The primary endpoint was reduction of pain. Both the once- and twice-daily groups showed statistically significant improvements in pain, as well as improvements in global well being, fatigue, and other domains. Response rates for patients receiving milnacipran were equal in patients with and without comorbid depression, but placebo response rates were considerably higher in depressed patients, leading to significantly greater overall efficacy in the nondepressed group.
In this Phase II study, milnacipran led to statistically significant improvements in pain and other symptoms of FM. The effect sizes were equal to those previously found with TCA, and the drug was generally well tolerated.

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    • "Eligible patients were adults meeting the 1990 ACR criteria for fibromyalgia [4] who entered directly from a long-term, open-label, flexible-dose, lead-in study in which they received milnacipran 50 mg/day to 200 mg/day for up to 3.25 years [22]. Prior to this lead-in study, patients had received up to 15 months of treatment with milnacipran 100 mg/day or 200 mg/day during double-blind studies [20,21,23-27], resulting in up to 4.5 years of milnacipran exposure prior to entering into the current discontinuation study. "
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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.
    Arthritis research & therapy 08/2013; 15(4):R88. DOI:10.1186/ar4268 · 3.75 Impact Factor
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    • "They found that the visual analog scale score decreased significantly after treatment in comparison with the baseline score. To our knowledge, this is the only study to use milnacipran in the treatment of AO, although the effectiveness of milnacipran on other pain disorders has been established [56–62]. High-quality clinical research such as a randomized controlled trial should be performed to assess the effectiveness of milnacipran in the treatment of AO. "
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    ABSTRACT: Patients with atypical odontalgia (AO) complain of medically unexplained toothache. No evidence-based diagnostic criteria or treatment guidelines are yet available. The present paper addresses seven clinical questions about AO based on current knowledge in the literature and discusses diagnostic criteria and guidelines for treatment and management. The questions are (i) What is the prevalence of AO in the community? (ii) What psychological problems are experienced by patients with AO? (iii) Are there any comorbidities of AO? (iv) Is local anesthesia effective for the relief of pain in AO? (v) Are there any characteristic symptoms of AO other than spontaneous pain? (vi) Are antidepressants effective for treatment of AO? (vii) Are anticonvulsants effective for treatment of AO? Our literature search provided answers for these questions; however, there is insufficient evidence-based data to establish guidelines for the diagnosis and treatment of AO. Overall, some diagnostic criteria for neuropathic pain and persistent dentoalveolar pain disorder may be applied to AO patients. The patient's psychogenic background should always be considered in the treatment and/or management of AO. The clinicians may need to treat AO patients using Patient-Oriented Evidence that Matters approach.
    International Journal of Dentistry 07/2012; 2012(3):518548. DOI:10.1155/2012/518548
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    • "For this reason, ketamine is currently widely applied in the treatment of neuropathic pain and for some kinds of chronic pain, including fibromyalgia [48]. Although there is little evidence that NMDA receptor antagonism is involved in the antinociceptive effect of milnacipran, milnacipran has been widely used in patients with fibromyalgia and has provided them with pain relief [49,50]. These effects of milnacipran for chronic pain have been previously discussed from the perspective of one aspect: balanced inhibition of the reuptake of 5-HT and NA. "
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    ABSTRACT: Antidepressants, which are widely used for treatment of chronic pain, are thought to have antinociceptive effects by blockade of serotonin and noradrenaline reuptake. However, these drugs also interact with various receptors such as excitatory glutamatergic receptors. Thermal hyperalgesia was induced by intrathecal injection of NMDA in rats. Paw withdrawal latency was measured after intrathecal injection of antidepressants. The effects of antidepressants on the NMDA and AMPA-induced responses were examined in lamina II neurons of rat spinal cord slices using the whole-cell patch-clamp technique. The effects of milnacipran followed by application of NMDA on pERK activation were also investigated in the spinal cord. Intrathecal injection of milnacipran (0.1 μmol), but not citalopram (0.1 μmol) and desipramine (0.1 μmol), followed by intrathecal injection of NMDA (1 μg) suppressed thermal hyperalgesia. Milnacipran (100 μM) reduced the amplitude of NMDA (56 ± 3 %, 64 ± 5 % of control)-, but not AMPA (98 ± 5 %, 97 ± 5 % of control)-mediated currents induced by exogenous application and dorsal root stimulation, respectively. Citalopram (100 μM) and desipramine (30 μM) had no effect on the amplitude of exogenous NMDA-induced currents. The number of pERK-positive neurons in the group treated with milnacipran (100 μM), but not citalopram (100 μM) or desipramine (30 μM), followed by NMDA (100 μM) was significantly lower compared with the NMDA-alone group. The antinociceptive effect of milnacipran may be dependent on the drug's direct modulation of NMDA receptors in the superficial dorsal horn. Furthermore, in addition to inhibiting the reuptake of monoamines, glutamate NMDA receptors are also important for analgesia induced by milnacipran.
    Molecular Pain 06/2012; 8(1):45. DOI:10.1186/1744-8069-8-45 · 3.65 Impact Factor
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