RECONSTRUCTIVE UROLOGY

Facilitatory Neuromodulative Effect of Duloxetine on Pudendal Motor Neurons Controlling the Urethral Pressure: A Functional Urodynamic Study in Healthy Women
Boy S, Reitz A, Wirth B, Knapp PA, Braun PM, Haferkamp A, Schurch B
Neuro-Urology, Swiss Paraplegic Center, Balgrist University Hospital, Zurich, Switzerland
Eur Urol. 2006 Jan 18; [Epub ahead of print]

• Objective: The aim of this functional urodynamic experiment in healthy women was to study the effect of duloxetine, which is a combined serotonin and norepinephrine (5-HT/NE) reuptake inhibitor, on urethral resting pressure, excitability of pudendal motor neurons, and urethral sphincter contractility.
• Methods: In 11 healthy female subjects three baseline urethral pressure profiles (UPPs) were obtained to study resting pressure. Afterward the individual motor threshold (MT) for external urethral sphincter (EUS) contraction in response to transcranial magnetic stimulation (TMS) was determined to study the excitability of pudendal motor neurons. Another three UPPs were recorded while sacral root magnetic stimulation (SMS) was performed to evoke reproducible urethral contractions to study urethral sphincter contractility. Then the women received 40 mg duloxetine and the protocol was repeated 4h after drug administration. The resting pressure values, MT values following TMS, and the EUS pressure amplitudes in response to SMS obtained at baseline were statistically compared to the corresponding values at follow-up after duloxetine.
• Results: Oral administration of duloxetine significantly lowered MT for EUS contraction in response to TMS (p = 0.013). In addition, duloxetine significantly increased EUS pressure amplitudes in response to SMS (p = 0.0007, 5 of 11 subjects evaluated) but did not change urethral resting pressures.
• Conclusions: This is the first functional, urodynamic controlled study to show that the combined 5-HT/NE reuptake inhibitor duloxetine has a significant effect on the excitability of pudendal motor neurons and on urethral sphincter contractility in healthy women in vivo but no significant effect on urethral resting tone. Our data confirm a facilitatory neuromodulative effect of duloxetine on sphincter motor neurons in humans.
  
  
• Editorial Comment
  The first investigation regarding the norepinephrine-serotonin (NE/5-HT) reuptake inhibitor duloxetine was performed in the cat model with induced cystitis causing the symptom of overactive bladder and stress urinary incontinence. The authors reported relaxing the bladder and increasing the outlet resistance (1). The paper presented here is the first dealing with the influence of the NE/5-HT reuptake inhibitor to the pelvic floor muscles in females. The authors recorded responses of transcranial and spinal cord magnetic stimulation thereby demonstrating individual increases in the urethral sphincter pressure with duloxetine. Although it is an elegant way to demonstrate the effect of the NE/5-HT reuptake inhibitor, the magnetic stimulation field is not very selective and stimulates all (efferent as well as afferent) nerve fibers in the field of the coil. Efferent motor neurons stimulated by these methods supply the striated muscles of the pelvis but cannot be subdivided to the urethral sphincter only. Vodusek & Zidar suggested using a needle to record from the sphincter to identify specific urethral muscle functions from a general “mass contraction” (2).
  The authors reported a decreased threshold for significant urethral pressure spikes in the mid urethra after sacral root magnetic stimulation through the influence of the NE/5-HT reuptake inhibitor in 45% of the subjects. This is in line with reports of decreased incontinence episode frequency of 50 – 100% in 51.4% of the trial group (n = 344) receiving duloxetine (3). An additional double-blind trial with a more representative sample of subjects should validate the drug effect on urethral pressure after magnetic stimulation.
  In addition, the outcome of the single intake of the NE/5-HT reuptake inhibitor causes under normal physiological conditions does not lead to significant stimulation of postsynaptic 5-HT receptors.
  After the administration of a NE/5-HT reuptake inhibitor all 5-HT transporters at the pre-synaptic membrane are blocked, leading to higher 5-HT levels in the synaptic cleft. At the same time, these increased 5-HT levels activate 5-HT1A and 5-HT1B auto-receptors, located at the pre-synaptic membrane. These pre-synaptic auto-receptors inhibit as negative feedback regulators the release of 5-HT (4-6). The simulated on-demand use causes only a mild or no increase of 5-HT neurotransmission, which might be an explanation of the experimental outcome.
  Still this elegant approach might serve as a single dose-screening test to predict patients with beneficial treatment responses to the duloxetine effect in a potential patient avoiding possible side effects. The blood pressure rises induced by the magnetic coil stimulation might ask for other tests than the magnet coil stimulation to underline the outcome of this approach and demonstrate the effect to motor thresholds resulting in increased urethral pressure amplitude even in a higher proportion of subjects.

References
1. Danuser H, Thor KB: Spinal 5-HT2 receptor-mediated facilitation of pudendal nerve reflex in the anesthetized cat. Br. J. Pharmacol. 1996; 118: 150-4.
2. Vodusek D, Zidar J: Perineal motor evoked responds. Neurourol Urodyn. 1988; 7: 236-7.
3. Dmochowski RR, Miklos JR, Norton PA, Zinner NR, Yalcin I, Bump RC: Duloxetine Urinary Incontinence Study Group. Duloxetine versus placebo for the treatment of North American women with stress urinary incontinence. J Urol. 2003; 170 (4 Pt 1): 1259-63.
4. Fuller RW: Uptake inhibitors increase extracellular serotonin concentration measured by brain microdialysis. Life Sci. 1994; 55: 163-7.
5. Waldinger MD, Schweitzer DH, Olivier B: On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions. J Sex Med. 2005; 2: 121-31.
6. Blier P, Chaput Y, de Montigny C: Long-term 5-HT reuptake blockade, but not monoamine oxidase inhibition, decreases the function of terminal 5-HT autoreceptors: an electrophysiological study in the rat brain. Naunyn Schmiedebergs Arch Pharmacol. 1988; 337: 246-54.

Dr. Karl-Dietrich Sievert,
Dr. Bastian Amend & Dr. Arnulf Stenzl
Department of Urology
Eberhard-Karls-University Tuebingen
Tuebingen, Germany