Duloxetine: mechanism of action at the lower urinary tract and Onuf?s nucleus

Abstract

Urinary incontinence is the inability to willingly control bladder voiding. Stress urinary incontinence (SUI) is the most frequently occurring type of incontinence in women. No widely accepted or approved drug therapy is yet available for the treatment of stress urinary incontinence. Numerous studies have implicated the neurotransmitters, serotonin and norepinephrine in the central neural control of the lower urinary tract function. The pudendal somatic motor nucleus of the spinal cord is densely innervated by 5HT and NE terminals. Pharmacological studies confirm central modulation of the lower urinary tract activity by 5HT and NE receptor agonists and antagonists. Duloxetine is a combined serotonin/norepinephrine reuptake inhibitor currently under clinical investigation for the treatment of women with stress urinary incontinence. Duloxetine exerts balanced in vivo reuptake inhibition of 5HT and NE and exhibits no appreciable binding affinity for receptors of neurotransmitters. The action of duloxetine in the treatment of stress urinary incontinence is associated with reuptake inhibition of serotonin and norepinephrine at the presynaptic neuron in Onuf's nucleus of the sacral spinal cord. In cats, whose bladder had initially been irritated with acetic acid, a dose-dependent improvement of the bladder capacity (5-fold) and periurethral EMG activity (8-fold) of the striated sphincter muscles was found. In a double blind, randomized, placebo-controlled, clinical trial in women with stress urinary incontinence, there was a significant reduction in urinary incontinence episodes under duloxetine treatment. In summary, the pharmacological effect of duloxetine to increase the activity of the striated urethral sphincter together with clinical results indicate that duloxetine has an interesting therapeutic potential in patients with stress urinary incontinence.

Current Trends in the Management of Post-Prostatectomy Incontinence

“…Although currently there is no pharmacologic treatment approved for SUI in men, some studies of the effect of duloxetine in male SUI, which was proved to be an effective and safe treatment for women with SUI, have been reported. Duloxetine, a combined serotonin/norepinephrine reuptake inhibitor, increases the activity of the striated urethral sphincter and the effects on the excitability of pudendal motor neurons by stimulating the Onuf's nucleus [40,41]. Filocamo et al [42] made a comparison between PFMT and duloxetine with PFMT only in the treatment of PPI and demonstrated a facilitative effect of duloxetine on early continence recovery.…”

Systematic review and economic modelling of the effectiveness and cost-effectiveness of non-surgical treatments for women with stress urinary incontinence

“…It is now licensed as a continence-promoting drug in women with SUI. 55 Although it has been shown to improve symptoms of SUI, the usefulness of duloxetine is limited by side effects, particularly nausea, which result in up to 20% of women being unable to tolerate the drug. 56 There is some evidence to suggest that this drug may be more useful as an adjunct to other conservative therapies, such as PFMT.…”

Urodynamic investigation by telemetry in Beagle dogs: validation and effects of oral administration of current urological drugs: a pilot study

“…Duloxetine also plays a role in initiating urethral striated muscle contraction during bladder filling [72,73]. In women with SUI, the clinical efficacy of duloxetine is based on stronger urethral contraction and persistent sphincter tone during the storage phase [74,75]. In this study, after 8 days of oral administration of duloxetine, an increase in urethral smooth muscle electrical activity was recorded, while no change in bladder function was observed.…”