Milnacipran

The dual ability for milnacipran to inhibit the reuptake of both serotonin (5HT) and norepinephrine (NE) facilitates its treatment of both fibromyalgia and major depressive disorder (MDD).

In particular, it is generally believed that 5HT and NE participate in the modulation of endogenous analgesic mechanisms by way of the descending inhibitory pain pathways in the brain and spinal cord. Although the specific mechanism of action remains unclear, some studies have proposed that low levels of 5HT may be associated with increased sensitivity to pain - a condition that could subsequently be improved by milnacipran's capacity to enhance the presence of 5HT by inhibiting its reuptake via serotonin transporters at synaptic clefts. Furthermore, in the CNS it is also generally believed that NE released from descending pathways can mitigate pain sensations via eliciting inhibitory effects on alpha-2A-adrenoceptors on central terminals of primary afferent nociceptors, by direct alpha-2-adrenergic action on pain-relay neurons, and by alpha-1-adrenoceptor-mediated activation of inhibitory interneurons. Such NE pain mitigation is consequently also enhanced by milnacipran's ability to enhance the presence of NE by inhibiting its reuptake via norepinephrine transporters at synaptic clefts.

Concurrently, milnacipran's capacity to inhibit the reuptake of both 5HT and NE also facilitates its treatment of MDD. Given the monoamine hypothesis' assertion that decreased 5HT can be associated with anxiety, obsessions, compulsions, and decreased NE can result in lowered alertness, energy, attention, and general interest in life, it is proposed that milnacipran's basic activities as a serotonin and norepinephrine reuptake inhibitor could assist in treating such symptoms of MDD by increasing the presence of both 5HT and NE in the body by inhibiting their reuptake.