SNRIs: Comprehensive Pharmacotherapy

Serotonin-norepinephrine reuptake inhibitors (SNRIs) are a class of antidepressants that block the presynaptic reuptake of both serotonin and norepinephrine, increasing their synaptic availability. The dual mechanism provides broader neurotransmitter modulation compared to SSRIs. Serotonin's role: mood regulation, anxiety reduction, sleep-wake cycle, appetite, impulse control. Norepinephrine's role: alertness, energy, concentration, pain modulation (descending inhibitory pain pathways from locus coeruleus to spinal cord dorsal horn), motivation. The pain benefit of SNRIs arises specifically from enhanced noradrenergic tone in the descending inhibitory pain pathway: NE released from brainstem nuclei activates α2-adrenergic receptors on dorsal horn neurons, inhibiting ascending pain signal transmission. This mechanism explains why SNRIs are effective for neuropathic pain, fibromyalgia, and chronic musculoskeletal pain. Key class differences: Venlafaxine — dose-dependent NE effect, extensive CYP2D6 metabolism, shortest half-life; Duloxetine — balanced SERT/NET, broadest FDA indications, CYP2D6 inhibitor; Desvenlafaxine — active metabolite of venlafaxine, minimal CYP interactions, flat dose-response; Levomilnacipran — most NET-selective, approved for MDD only; Milnacipran — FDA-approved for fibromyalgia only in US.