milnacipran

Milnacipran works by blocking presynaptic reuptake transporters for both serotonin (5-HT) and norepinephrine (NE), increasing synaptic concentrations of these neurotransmitters. Unlike duloxetine (also approved for fibromyalgia and depression), milnacipran has a more balanced to NE-favoring reuptake inhibition ratio and is specifically indicated for fibromyalgia management in the US, not for major depressive disorder (though it is used for depression in other countries, e.g., Europe, under the name Ixel). It has minimal effects on dopamine reuptake and negligible affinity for histaminic, cholinergic, or adrenergic receptors, contributing to a relatively favorable side effect profile compared to tricyclic antidepressants. Clinical use focuses on reducing fibromyalgia-associated pain, fatigue, and improving physical function, though effects on mood symptoms are also noted given its antidepressant mechanism. Common adverse effects include nausea, headache, constipation, dizziness, hyperhidrosis, hot flashes, and increased heart rate or blood pressure (due to noradrenergic activity) which requires caution in patients with cardiovascular disease, uncontrolled hypertension, or urinary retention (e.g., BPH) due to its anticholinergic-like effects on urinary sphincter tone. Should not be combined with MAOIs due to risk of serotonin syndrome, and caution is needed with other serotonergic drugs. Discontinuation should be tapered gradually to avoid withdrawal/discontinuation syndrome. It is metabolized primarily via glucuronidation (not CYP450-dependent), making drug-drug interactions with CYP-metabolized drugs less of a concern compared to other antidepressants.