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      Milnacipran for the management of fibromyalgia syndrome

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          Fibromyalgia syndrome (FMS) is a widespread pain condition associated with fatigue, cognitive dysfunction, sleep disturbance, depression, anxiety, and stiffness. Milnacipran is one of three medications currently approved by the Food and Drug Administration in the United States for the management of adult FMS patients. This review is the second in a three-part series reviewing each of the approved FMS drugs and serves as a primer on the use of milnacipran in FMS treatment including information on pharmacology, pharmacokinetics, safety and tolerability. Milnacipran is a mixed serotonin and norepinephrine reuptake inhibitor thought to improve FMS symptoms by increasing neurotransmitter levels in descending central nervous system inhibitory pathways. Milnacipran has proven efficacy in managing global FMS symptoms and pain as well as improving symptoms of fatigue and cognitive dysfunction without affecting sleep. Due to its antidepressant activity, milnacipran can also be beneficial to FMS patients with coexisting depression. However, side effects can limit milnacipran tolerability in FMS patients due to its association with headache, nausea, tachycardia, hyper- and hypotension, and increased risk for bleeding and suicidality in at-risk patients. Tolerability can be maximized by starting at low dose and slowly up-titrating if needed. As with all medications used in FMS management, milnacipran works best when used as part of an individualized treatment regimen that includes resistance and aerobic exercise, patient education and behavioral therapies.

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          Most cited references 6

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          Milnacipran versus other antidepressive agents for depression.

          Although pharmacological and psychological interventions are both effective for major depression, antidepressant drugs are frequently used as first-line treatment in primary and secondary care settings. Milnacipran, a dual serotonin-norepinephrine reuptake inhibitor (SNRI), is one of the antidepressant drugs that clinicians use for routine depression care. To assess the evidence for the efficacy, acceptability and tolerability of milnacipran in comparison with tricyclic antidepressants (TCAs), heterocyclics, SSRIs and other newer antidepressive agents in the acute-phase treatment of major depression. The Cochrane Collaboration Depression, Anxiety & Neurosis review group Controlled Trials Register (CCDANCTR-Studies and CCDANCTR-References) were electronically searched in August 2008. References of relevant trials and other reviews were also checked. Trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished trials were hand-searched in 2007. All relevant authors were contacted for supplemental data. No language restriction was applied. Randomised controlled trials comparing milnacipran with any other active antidepressive agents (including non-conventional agents such as herbal products like hypericum) as monotherapy in the acute phase of major depression were selected. Two reviewers independently checked eligibility, assessed methodological quality and extracted data from the eligible trials using a standardised data extraction form. The number of participants who responded to treatment or those who achieved remission were calculated on an intention-to-treat basis. Random-effects meta-analyses were conducted, combining data from the included trials. A total of 16 randomised controlled trials (n=2277) were included in the meta-analysis.Despite the size of this sample, the pooled 95% confidence intervals were rather wide and there were no statistically significant differences in efficacy, acceptability and tolerability when comparing milnacipran with other antidepressive agents. However, compared with TCAs, patients taking milnacipran were associated with fewer dropouts due to adverse events (OR 0.55; 95%CI 0.35 to 0.85). There was also some weak evidence to suggest that patients taking milnacipran experienced fewer adverse events of sleepiness/ drowsiness, dry mouth or constipation compared with TCAs. Currently, there is inadequate evidence to conclude whether milnacipran is superior, inferior or the same as other antidepressive agents in terms of efficacy, acceptability and tolerability in the acute phase treatment of major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of dropouts due to adverse events (acceptability) and the rates of experiencing adverse events (tolerability). Information about other clinically meaningful outcomes such as cost-effectiveness and social functioning, including the ability to return to work, is lacking. Further study is needed to answer whether milnacipran would be the better choice of antidepressant for acute major depression.
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            Pharmacokinetics of milnacipran in renal impairment.

             C Puozzo,  N Pozet,  D Deprez (1998)
            The pharmacokinetics of a single 50 mg dose of milnacipran, a new non tricyclic antidepressant drug, were compared in 8 chronic renal failure subjects (Clc(reat) between 9 to 84.5 ml.min(-1)) and in 6 healthy volunteers. Concentrations of unchanged (F2207 racemate and F2695 and F2696, enantiomers) and glucuroconjugated drug (main metabolite) were measured using HPLC and GC-MS. As for drugs mainly eliminated via renal route, the pharmacokinetics of milnacipran were markedly affected by impaired renal function with the elimination half-life of severely impaired subject being approximately three times that of the control group. Milnacipran apparent total clearance and renal clearance were positively correlated with glomerular filtration rate, while non-renal clearance and apparent volume of distribution were unaffected by renal impairment. Plasma concentrations of the glucuroconjugate were gradually increased in plasma, while its total urine excretion remained unchanged. As for the racemate, pharmacokinetics of each enantiomer were modified by renal failure, although, as predictable from its higher renal clearance value, it was more marked for F2696 than for F2695. Considering that modifications were shown to be proportional to the degree of renal impairment and that milnacipran presents low variability, the necessary dose adjustment is therefore easy to predict.
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              The neurobiology of pain and its modulation.

              Recent research advances indicate that specialized neural pathways are involved in the encoding of pain sensations and that these pathways are sensitive to changes in stimulus features, such as intensity, quality, duration, and location. It has also been established that there are three major families of opioid peptides in the brain: the enkephalins, the dynorphins, and the endorphins. In addition to these opioid peptides, other neurochemicals such as serotonin and norepinephrine play a role in the modulation of signals related to tissue damage. These advances in research are being used to develop improved methods for the control of acute and chronic pain. Nonsteroidal anti-inflammatory drugs suppress noxious signals by reducing the sensitization of peripheral nociceptors. Opioid drugs are administered into the membranes surrounding the spinal cord to provide long-lasting pain relief. Peripherally acting opioid drugs may represent a new functional class of analgesics devoid of the undesirable side effects of centrally acting opioids. Tricyclic antidepressant drugs are used in the treatment of neuropathic pain, based on their effects on noradrenergic and serotoninergic pathways in the central nervous system.

                Author and article information

                J Pain Res
                Journal of Pain Research
                Journal of pain research
                Dove Medical Press
                01 March 2010
                : 3
                : 15-24
                Division of Rheumatology and Immunology, Vanderbilt University, Nashville, TN, USA
                Author notes
                Correspondence: Chad S Boomershine, Division of Rheumatology and Immunology, Vanderbilt University, T3219 MCN, 1161 21st Ave South, Nashville, TN37232-2681, USA, Email chad.boomershine@
                © 2010 Ormseth et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.


                Anesthesiology & Pain management

                milnacipran, fibromyalgia, treatment


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