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PO1-3-29

Effect of single dose imipramine on urethral opening pressure - a randomized, placebo-controlled, double-blind crossover study in healthy women

[Speaker] Jonatan Kornholt:1
[Co-author] David P Sonne:1, Troels Riis:1, Jesper Sonne:1, Klarskov Niels:2
1:Department of Clinical Pharmacology, University Hospital Bispebjerg and Frederiksberg, Denmark, 2:Herlev and Gentofte Hospital, Department of Gynecology and Obstetrics, Denmark

Introduction
Imipramine affects multiple neurotransmitter systems, which may affect the function of the lower urinary tract. It acts as a serotonergic and norepinephrine reuptake inhibitor, and is an antagonist to the muscarinic acetylcholine receptors and adrenergic receptors. Imipramine has previously been shown to exert beneficial effects in patients with stress urinary incontinence, where the treatment resulted in reduced symptoms and increased maximum closure pressure. However, this finding has never been confirmed in a placebo-controlled study, and imipramine is continuously being used off-label for the treatment of stress urinary incontinence.
Urethral pressure reflectometry (UPR) is a technique which can detect pharmacological induced pressure changes in the urethra. The aim of this study was to investigate the effect of single-dose imipramine on the opening urethral pressure (OUP) in healthy women using UPR.

Methods
We conducted a randomized, double-blind, placebo-controlled, crossover study to investigate the effect of a single-dose 50 mg imipramine on OUP. From previous UPR studies, we expected a within-subject SD of 5.4 and a minimally relevant difference (MIREDIFF) of 10 cmH2O. With a = .05 and n = 16, we had power = 99% to detect the MIREDIFF. The hospital pharmacy produced the matching placebo tablets, and randomized and packaged the blinded dosing kits. OUP was measured pre-dose and one hour post-dose (equal to tmax for imipramine). A washout period of minimum 1 week (equal to 8.4 half lifes of imipramine) was chosen. The study was approved by the local ethics committee and conducted according to Good Clinical Practice guidelines. The study was registered on ClinicalTrials.gov and EudraCT.

Results
We recruited and included 16 subjects. All of the subjects completed the study. Imipramine increased OUP with 6.5 cmH2O [95% CI: 0.5, 13.5], p = 0.07. No serious adverse events (AEs) were reported. There were seven adverse events (AEs) related to imipramine, one AE related to placebo and two AEs related to UPR.

Conclusions
Imipramine insignificantly increased the OUP 6.5 cmH2O. Thus, the effect of imipramine is not clinically relevant and we do, therefore, not recommend the off-label use of imipramine for the treatment of stress urinary incontinence.

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