Serotonin-norepinephrine reuptake inhibitors and the influence of binding affinity (Ki) on analgesia

Abstract

SummaryWhat is known and objective: Serotonin-norepinephrine reuptake inhibitors (SNRIs) are commonly used for various psychiatric conditions and neuropathic pain syndromes.SNRIs inhibit the reuptake of serotonin (5-HT) and norepinephrine (NE); however, NE reuptake inhibition is thought to be the primary mediator for their analgesic effect. Comment: Key differences in pharmacodynamics and receptor affinities exist betweenSNRIs. The selectivity for each monoamine differs among SNRIs based on the agent's affinity and activity at the monoamine reuptake transporter. We review differences in receptor affinities and monoamine selectivity among SNRIs and the corresponding clinical impact. What is new and conclusion:The varying selectivity for 5-HT and NE among the SNRIs may help explain the therapeutic dosing required for neuropathic pain as well as dose-related adverse effects. It is important to understand the pharmacologic differences among SNRIs, in addition to the data from clinical trials, to guide their safe and effective use. K E Y W O R D Santidepressants, binding affinity, neuropathic pain, pain, serotonin-norepinephrine reuptake inhibitors

Desvenlafaxine-associated hyperglycemia: A case report and literature review

“…However, because the mechanism of glucose dysregulation has not been elucidated, there could be other causes, especially because no hyperglycemia has been observed with duloxetine, and it has a higher binding affinity to norepinephrine than either venlafaxine and desvenlafaxine. 8,17 Finally, in this patient, the glucose dysregulation could not be due to weight gain, which is 1 theorized cause, as this patients weight remained stable throughout the 6-month evaluation time.…”

“…The binding affinity for venlafaxine for the norepinephrine receptors is lower (ki 1920 6 158 nmol/L) compared to desvenlafaxine (ki 558 6 121 nmol/L). 17 It should be noted that both are relatively low compared to other available SNRIs: duloxetine (1.17 6 0.11 nmol/L), milnacipran (22 6 2.58 nmol/L), and levomilnacipran (92.2 nmol/L). 17 Furthermore, the serotonin to norepinephrine selectivity ratio for venlafaxine is 30:1 compared to desvenlafaxine, which is 14:1.…”

“…17 It should be noted that both are relatively low compared to other available SNRIs: duloxetine (1.17 6 0.11 nmol/L), milnacipran (22 6 2.58 nmol/L), and levomilnacipran (92.2 nmol/L). 17 Furthermore, the serotonin to norepinephrine selectivity ratio for venlafaxine is 30:1 compared to desvenlafaxine, which is 14:1. 17 These differences in pharmacogenomics, binding affinity, and selectivity to receptors could indicate why differences were observed between these 2 drug compounds.…”

“…17 Furthermore, the serotonin to norepinephrine selectivity ratio for venlafaxine is 30:1 compared to desvenlafaxine, which is 14:1. 17 These differences in pharmacogenomics, binding affinity, and selectivity to receptors could indicate why differences were observed between these 2 drug compounds. However, because the mechanism of glucose dysregulation has not been elucidated, there could be other causes, especially because no hyperglycemia has been observed with duloxetine, and it has a higher binding affinity to norepinephrine than either venlafaxine and desvenlafaxine.…”

LPM580098, a Novel Triple Reuptake Inhibitor of Serotonin, Noradrenaline, and Dopamine, Attenuates Neuropathic Pain

“…Numerous studies suggest that antidepressants especially the SNRIs (e.g., duloxetine, venlafaxine) have demonstrated therapeutic efficacy for neuropathic pain (McCleane, 2008; Zhang et al, 2016b; Obata, 2017; Raouf et al, 2017). In particular duloxetine hydrochloride, which is a Food and Drug Administration-approved prescription drug indicated for the management of major depressive disorder, generalized anxiety disorder, diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain.…”