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Effect of imipramine on urethral opening pressure - a randomized, double-blinded, placebo-controlled crossover study in healthy women
IUGA Academy. Klarskov N. Jun 30, 2018; 212969
Topic: Stress Incontinence
Niels Klarskov
Niels Klarskov

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346

Effect of imipramine on urethral opening pressure – a randomized, double-blinded, placebo-controlled crossover study in healthy women

Kornholt, J1; Sonne, D1; Riis, T1; Sonne, J1;Klarskov, N2

1: University Hospital Bispebjerg and Frederiksberg, Department of Clinical Pharmacology, Copenhagen, Denmark; 2: Herlev and Gentofte Hospital, Department of Gynecology and Obstetrics, Herlev, Denmark

Introduction: Imipramine, an old tricyclic antidepressant, 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 receptor and adrenergic receptors. Imipramine has previously been shown to exert beneficial effects in patients with stress urinary incontinence—the treatment resulted in reduced symptoms and increased maximum urethral closure pressure (1,2). 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 and mixed urinary incontinence. Urethral pressure reflectometry (UPR) is a reliable and repeatable technique which can detect pharmacological induced pressure changes in the urethra (3).

Objective: The purpose of this study was to investigate the effect of single dose imipramine on the urethral opening pressure (OUP) in healthy women using UPR.

Methods: A randomized, double-blinded, placebo-controlled, crossover study investigating the effect of single dose 50 mg imipramine on OUP. The trial was undertaken in one trial unit. From previous UPR studies, we expected a within-subject SD of 5.4 and a minimally relevant difference (MIREDIFF) of 10 cmH2O. With α = .05 and n = 16, we had power = 99% to detect the MIREDIFF. The hospital pharmacy produced the matching placebo tablets, performed the randomization, and packaged the blinded dosing kits. OUP was measured pre-dose and one hour post-dose (corresponding to tmax for imipramine) during rest and squeeze. 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 prior to recruitment of subjects. Funding was provided by clinical department.

Results: We recruited 16 subjects, and 16 subjects were randomized. All of them completed the study.

Imipramine increased OUP in the resting condition with 6.5 cmH2O [95% CI ?0.5, 13.5], p = 0.07 (see figure), and in the squeeze condition with 7.9 cmH2O [95% CI ?0.3, 16.1], p = 0.06.

There were no serious adverse events. There were seven adverse drug reactions (ADRs) related to imipramine, one ADR related to placebo and two adverse events (AEs) related to UPR.

Conclusion: Imipramine insignificantly increased the OUP with 6.5 cmH2O. In a similar study, the OUP increased with 9.3 cmH2O after midodrine, with 24.2 cmH2O after duloxetine, and with 44.9 cmH2O after reboxetine (3). 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 or mixed urinary incontinence.


References:

  1. J Urol. 1984 Nov;132(5):909–11.
  2. BJOG An Int J Obstet Gynaecol. 1999 Oct;106(10):1089–92.
  3. Neurourol Urodyn. 2017 Apr;37(1):244–9.

Disclosure:

Work supported by industry: no.

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