Phosphodiesterase-5 (PDE-5) Inhibitors and Ototoxicity: A Systematic Review

Abstract

Objective: This study explores the current literature regarding associations between phosphodiesterase-5 (PDE-5) inhibitors and ototoxicity and provides a detailed summary and discussion of the findings. Data Sources: A comprehensive electronic search of PubMed/MEDLINE, Scopus, and Cochrane Library for studies published from database inception through March 21, 2018. Study Selection: Basic science articles, epidemiological studies, randomized controlled trials, cohort studies, case reports, reviews, meta-analyses, press releases, and newsletters were included. The PRISMA search strategy was used to select papers. Search terms are included in the appendix (http://links.lww.com/MAO/A733). Results: Twenty-two articles met the inclusion criteria. Among case reports, there were a total of nine patients, all male, with an average age of 57.4 years (37–79 years, SD = 13.87 years). Of the cases of hearing loss, 25% (2/8 cases) were bilateral and 75% (6/8) were unilateral; 22% (2/9) were associated with tinnitus; and 33% (3/9) had accompanying vestibular symptoms (including vertigo and dizziness). Among multipatient studies, all prospective studies failed to find a significant association between ototoxicity and PDE-5 inhibitor use. Results of the retrospective studies were also heterogeneous. Many key molecules in the PDE-5 inhibition pathway have been demonstrated to exist in the cochlea. However, mirroring the clinical studies, the basic science mechanisms have suggested both ototoxic and otoprotective effects. Conclusions: Currently, the literature is inconclusive regarding the interaction between PDE-5 inhibitor use and ototoxicity. Future study such as a double-blinded placebo controlled randomized trial with audiometric assessment would provide more sound evidence. Similarly, a unified molecular model is necessary.

Drug‐Induced Ototoxicity: A Comprehensive Review and Reference Guide

“…One explanation has been that PDE-5 decreases cGMP degradation, which may promote activation of mean arterial pressure kinase-mediated cellular stress responses and apoptosis. 28 Although the mechanisms described previously are among those more commonly studied, other mechanisms of ototoxicity have yet to be investigated. It is also worth noting that certain ototoxic medications might even be otoprotective against other ototoxic medications.…”

“…Hearing loss attributed to phosphodiesterase‐5 (PDE‐5) inhibitors, such as sildenafil, is believed to involve the nitric oxide–cyclic guanosine monophosphate (cGMP) pathway of cochlear vascular endothelium. One explanation has been that PDE‐5 decreases cGMP degradation, which may promote activation of mean arterial pressure kinase‐mediated cellular stress responses and apoptosis 28 …”

2-Hydroxypropyl-β-cyclodextrin Ototoxicity in Adult Rats: Rapid Onset and Massive Destruction of Both Inner and Outer Hair Cells Above a Critical Dose

“…Most of the drugs and chemicals known to cause hearing loss and damage to the sensory hair cells, neurons and support cells in the cochlea, have been largely identified and extensively studied over the past 100 years (Campbell and Le Prell, 2018, Manna et al, 2019, Prakash Krishnan Muthaiah et al, 2017, Roth and Salvi, 2016, Rybak, 1986. Nevertheless, considerable research continues to be conducted on these ototoxic compounds to elucidate the mechanisms by which they induce their toxic effects and to develop new methods to mitigate their ototoxic effects (Benkafadar et al, 2017, Kim et al, 2011, Kim et al, 2008, Majumder et al, 2015, Youn et al, 2015.…”

Phosphodiesterase type 5 inhibitors related hearing impairment: a real world study based on the FDA adverse event reporting system

“…The most commonly reported PTs were hypoacusis and tinnitus, other highly reported PTs involved deafness, deafness unilateral, which was consistent with the published literature. Manna et al summarized the clinical symptoms of case reports involving PDE5Is-related hearing impairment, they found that 75% of the cases indicated unilateral deficits, while 22% reported tinnitus 22 . Drugs-related hearing impairment usually indicates poor prognosis, which is the same for PDE5Is.…”