Viagra deafnesssensorineural hearing loss and phosphodiesterase5 inhibitors

Rhinological and Otological Society, Inc.
Viagra Deafness—Sensorineural Hearing Loss andPhosphodiesterase-5 Inhibitors Afroze Shah Khan, MRCS;* Zishan Sheikh, MBBS;* Shahnawaz Khan, MBBS; Raghav Dwivedi, MS; Background: Viagra and PDE-5 inhibitors use has mushroomed since its launch over a decade ago. A growing body of evidence indicates significant morbidity associated with the side effect profile of this class of drug. Hearing loss associatedwith PDE-5 inhibitor use has recently been reported, but few studies have evaluated the causal link.
Aim: To review and scrutinise the current literature on the subject and propose possible physiologic mechanisms and to investigate the global reporting of this side effect.
Methods and Materials: Pharmacovigilance agencies around North America, Europe, and Australasia were contacted requesting reports of hearing loss associated with PDE-5 inhibitors. Reports were scrutinised to exclude those where otherscauses of hearing loss existed.
Results: Forty-seven cases of sensorineural hearing loss with a temporal association with PDE-5 inhibitor ingestion were obtained from both published literature and pharmacovigilance agencies. Cases had a mean age 56.6 years, male-to-female ratio of 7:1. Eighty-eight percent of reports were unilateral with an even left/right distribution. Hearing loss occurredwithin 24 hours of ingestion of PDE-5 inhibitor in 66.7% (n ¼ 18) of cases. Sildenafil accounted for over 50% of cases.
Conclusion: There is increasing evidence that PDE-5 inhibitors may induce sensorineural hearing loss via plausible physiological mechanisms. There needs to be more awareness of this disabling side effect among healthcare professionalsresponsible for prescribing this drug.
Key Words: Hearing loss, deafness, sensorineural, sildenafil, viagra, phosphodiesterase inhibitors.
Level of Evidence: N/A.
hearing loss with PDE-5 inhibitor use.7 Two successive Phosphodiesterase-5 (PDE-5) inhibitors, originally experimental studies also support a possible causal developed for the treatment of angina, are the most com- link.8,9 Most reports of PDE-5 inhibitor related SSHL have come from the Food and Drug Agency (FDA) in the dysfunction (ED). They are largely well tolerated in clin- United States. To ascertain the global experience of this ical practice and have recently also used proved useful phenomenon we have surveyed pharmacovigilance agen- in the treatment of pulmonary hypertension.1–3 cies across America, Europe, and Australasia.
Sudden sensorineural hearing loss (SSHL) is a dis- tressing illness with up to one-third of patients left with permanent hearing impairment. It has an estimated In an effort to assess the number of suspected cases, phar- incidence of 5–20 per 100,000 people per year. It is diag- macovigilance agencies in Europe, the Americas, East Asia, and nosed to be mostly idiopathic, but viral or microvascular Australasia were contacted for adverse events of sudden hear- aetiologies are thought to be responsible.4 ing loss in patients taking PDE-5 inhibitors as shown in Table Recently, two authors have reported cases of SSHL I. Cases were individually analyzed and those with other causes occurring after PDE-5 inhibitor ingestion.5,6 An epide- of hearing loss present were excluded from the series. In addi- miologic study has also suggested a higher risk of tion, the temporality, PDE-5 inhibitor ingested and laterality ofhearing loss was obtained.
From the Ear, Nose and Throat Department (A.S.K., E.B.), Charing C r o s s H o s p i t a l , L o n d o n , U n i t e d K i n g d o m ; D e p a r t m e n t o fGastroenterology (Z.S.), Stoke Mandeville Hospital, Buckinghamshire,United Kingdom; Royal Marsden Hospital (S.K., R.C.D.), London, United A total of 53 cases of hearing loss-associated with Editor’s Note: This Manuscript was accepted for publication PDE-5 inhibitor use were reported to various pharmaco- vigilance agencies. After a review of individual case The authors have no financial disclosures for this article.
histories five were deemed to be related to other estab- The authors have no conflicts of interest to declare.
lished causes of hearing loss such as otitis media or *A.S.K. and Z.S. are joint first authors.
Send correspondence to Mr. Afroze Shah Khan, Ear, Nose and Meniere’s and these were excluded. Of remaining 47 Throat Department, Charing Cross Hospital, Fulham Road, London SW3 cases, 43 were submitted by pharmacovigilance agencies and four were from published literature (Table I). The mean age at presentation was 56.6 years with a male-to- Showing Details of All Reported Cases of PDE-5 Inhibitor-Associated Hearing Loss.
USA: United States of America, NR: Not recorded, d: Days, Y: Years.
female ratio of 7:1. Laterality was recorded in 70% (n ¼ dose dependent. More serious side effects are rare and 33) of reports and of these hearing loss was unilateral in include temporary loss of vision, retinopathy, seizures, 88% (n ¼ 29) and bilateral in 22% (n ¼ 4). There was myocardial infarction, ventricular arrhythmia, sudden even distribution of hearing loss affecting the right and cardiac death, cerebrovascular haemorrhage, and tran- left sides. The interval between onset of hearing loss sient ischaemic attacks.13,14 It was not until 2007 that a and PDE-5 inhibitor ingestion was recorded in 57.4% (n case of SSHL was reported as a potential side effect of ¼ 27) of reports. Hearing loss occurred within 24 hours of PDE-5 inhibitor use in 66.7% (n ¼ 18) of reports. Only SSHL has been defined as hearing loss of at least 30 38.3% (n ¼ 18) of the total reports confirmed the hearing dB in three or more continuous frequencies that occurs loss as sensorineural in nature. Sildenafil had the larg- within 72 hours of symptoms onset. It is a disturbing dis- est number of individual reports at 29 cases, followed by order that is usually unilateral with a varied incidence, tadalafil (n ¼ 10) and vardenafil (n ¼ 7).
with some authors estimating 15,000 cases diagnosed In addition to the 47 cases mentioned, raw data per year world wide.4 The true incidence is thought to be from the FDA’s Adverse Events Reporting System far higher than reported in the literature, as only a frac- (AERS) index yielded an additional 223 logged reports tion of cases present for medical assessment.
submitted after 2007 where hearing loss was reported Its etiology is controversial and often labeled as idi- with PDE-5 inhibitor ingestion. However, as there were opathic, because a cause is found in as little as 10% of no accompanying case histories these could not be patients.15 Vascular disease, autoimmune conditions, included in the final analysis. The FDA also noted that labyrinthine membrane rupture, viral infection, and psy- in clinical trials of PDE-5 inhibitors, of the nearly chosomatic disorders are all contenders as potential 60,000 subjects across four trial studies, there were 17 causes.16 The treatment of SSHL is no less controversial cases of temporally associated sudden hearing loss.
than its etiology and, in clinical practice, is often Again, no further case histories existed for these, and directed against a whole spectrum of possible causes. To they were not included in final the analysis.
cover possible vascular pathology vasodilators and rheo-logic agents have been used to reverse tissue hypoxia.
As a significant proportion of patients report a recent vi- ral illness, antiviral agents such as Acyclovir are PDE-5 inhibitors were first used to study cell and frequently used despite uncertain hearing improvement.
vascular physiology in the 1970s. However, it was not Hyperbaric oxygen has also been used and is thought to until 1995 that their physiologic importance in regulat- work by increasing oxygen tension in auditory tissue, ing vascular smooth muscle tone was understood.9a but its clinical benefit is uncertain at present. Repairs of Sildenafil was the first drug in this class developed for oval and round window perilymph fistulae can be per- commercial use. Synthesized at Pfizer’s laboratories in formed for cases of SSHL with positive fistula tests or a Sandwich, Kent, it was initially studied for use in hyper- history recent trauma, but diagnosis is difficult and the tension and angina pectoris. Phase two clinical trials benefit uncertain.17 Anti-inflammatory treatment with showed that the drug had little effect on angina, but cru- both oral and intratympanic corticosteroids has been cially observed that it could induce marked penile studied in cases of SSHL and was previously considered erections. Sildenafil citrate was patented in 1996, and as a gold standard in North America. However, a recent approved for use by the FDA in 1998 as the first oral Cochrane review has shown that their clinical value is treatment for erectile dysfunction in the United States.
open to debate.18 In fact, a meta-analysis recently stated Annual sales of Viagra in the period 1999–2001 exceeded no treatment for SSHL has been validated by large $1 billion. Since then, other PDE-5 inhibitors have been high-quality randomized controlled trials, probably due developed for use in ED with several countries produc- Mukherjee et al.5 first reported a case of SSHL in It is estimated that over 20 million men in the a 44-year-old man occurring 15 days after taking Silde- United States have used Sildenafil, and over 40 million nafil, 50 mg daily, in 2007. The patient had taken the prescriptions have been issued worldwide since its drug for 12 days continuously before developing pro- launch.10 In 2007, Sildenafil was the 65th most popular found bilateral hearing loss that was preceded by drug prescribed, exceeding such common drugs as Tyle- tinnitus but no other symptoms. Sensorineural hearing nol-codeine and albuterol in the United States. It is loss was subsequently confirmed on audiometric test- estimated that one in five men in the United States over the age of 40 have tried sildenafil.11 In the United King- treatment and eight cycles of carbogen therapy, there dom, pilot ‘‘pharmacist led prescribing’’ schemes have was no improvement in his symptoms. This resulted in lead to increased availability of Sildenafil, and the drug the FDA reviewing its postmarketing data on 113 cases of SSHL in patients taking PDE-5 inhibitors. Out of Sildenafil has proved to be an efficacious drug for this, a total of 23 cases were deemed to have been treating for ED.1 Its most common side effects are flush- potentially due to PDE-5 inhibitors. The FDA has since ing, headache, blocked nose, dyspepsia, and dizziness added SSHL onto the list of potential side effects for with some studies showing that up to one-third of men all PDE-5 inhibitors and is negotiating with manufac- taking the drug experience these with long-term use.1,2 turers to feature this effect more prominently on its The frequency of these side effects appears to be fairly Fig. 1. Diagram illustrating potential physiologic pathways for PDE-5 inhibitor-mediated hearing loss. [Color figure can be viewed in theonline issue, which is available at wileyonlinelibrary.com.] Maddox et al.5 subsequently combined these 23 high-dose Sildenafil during a 135-day period. Hearing cases with two novel reports in a review and found a loss was evaluated by recording auditory middle ear la- strong temporal association between drug ingestion and tency responses and otoacoustic emissions. High doses of the development of SSHL. They found that 88% (n ¼ 15/ Sildenafil increased hearing thresholds as measured by 17) of patients in their series who reported developing auditory brainstem responses. It also delayed the latency SSHL had ingested a PDE-5 inhibitor 24 hours prior to of both auditory brainstem responses and auditory mid- the development of symptoms. Of these 15 patients, 87% dle ear responses. This demonstrated that Sildenafil (n ¼ 13/15) had symptoms beginning less than 12 hours administration at high doses induces hearing impair- In this current analysis we added a further 23 More recently, Okuyucu et al.8 have performed the reports to the existing 26 in the literature. On further only prospective observational study in humans to date.
review of FDA data analyzed by Maddox et al.,5 it was Eighteen patients who had been using a PDE-5 inhibitor found that four cases had comorbid otologic disease that for ED were studied. Audiometric testing was carried out would account for the hearing loss. The patient demog- on all patients between frequencies 250 and 16,000 Hz raphy in the current series was similar to those prior to and after 1, 5, and 72 hours of 10 mg vardenafil ingestion. Four patients demonstrated a statistically sig- observed in 66.7% of cases, where hearing loss occurred within 24 hours of PDE-5 inhibitor ingestion. This is compatible with ototoxic criteria within 72 hours of drug lower than that reported by Maddox et al. However, this ingestion. In addition, all patients showed a significant difference is removed if the four suspect cases of hearing unilateral threshold decrease at 10,000 Hz. However, all loss are excluded from the 15 cases they reported as hearing loss resolved with discontinuation of the drug.
having significant temporality. The overwhelming major-ity of hearing loss appears to be unilateral, consistentwith both Maddox et al. as well as the FDA’s own analy- sis of its postmarketing safety data. Sildenafil remains Nitrous oxide–cyclic GMP pathway. The nitrous the most commonly implicated PDE-5 inhibitor with oxide (NO)/cyclic guanosine monophosphate (cGMP) hearing loss, reflecting the fact that it is also the most pathway is an established major regulatory system in cochlear physiology and has been implicated in the To date, only two studies have investigated the pos- pathophysiology of hearing loss.20 It is this pathway sibility of a direct causal association between PDE-5 that is regulated by the PDE-5 inhibitor class of drugs inhibitor ingestion and hearing loss. A recent in vivo (Fig. 1). It is the mechanism that induces smooth muscle study assessed hearing thresholds in mice injected with relaxation in endothelial cells. NO activates guanylate cyclase, which converts guanosine triphosphate (GTP) Nuclear factor-kappa beta (NF-jB) is another im- into to guanosine monophosphate (GMP). This depletes portant regulator of the inflammatory cellular stress intracellar calcium stores to cause smooth muscle relax- response, and apoptosis and is found in significant quan- ation. Smooth muscle relaxation induces vasodilation in tities in the cochlea. Based on this, it has been the corpus cavernosum vessels to result in penile erec- postulated as a possible etiologic agent in SSHL of all tion. The production of cGMP is regulated by PDE-5, causes.29 However, there are no physiologic studies that which recycles cGMP to GTP. Sildenafil and other PDE- corroborate a causal ototoxic link. Lang et al.30 (2006) 5 inhibitors act to inhibit the breakdown of cGMP and showed that knock out mice lacking the gene for the p50 hence potentiate the smooth muscle relaxation that subunit of NF-jB, suffered accelerated auditory nerve degeneration induced by noise and aging. This suggests NO and cGMP have been implicated in the litera- that NF-jB may in fact be otoprotective rather than a ture to exert ototoxic effects via secondary messengers.
Blasits et al.21 (2000) conducted an experimental studyinto the effect of NO donor sodium nitroprusside on gapjunction electrical coupling in Deiter’s cells (cells sup- porting primary hair cells) in guinea pig cochlea. It was In our review we found 47 reports implicating PDE- found that the introduction of sodium nitroprusside 5 inhibitors as a cause for SSHL. However, there are at induced uncoupling of the gap junctions, a function nec- least a further 240 potential cases from clinical and essary for maintaining normal cochlear sensory function.
recent FDA adverse events reports where PDE-5 inhibi- It was likewise observed that a cGMP analogue 8- tors may be related to hearing loss. However, due to bromo-cGMP also uncouples Deiter’s cells, whereas an incomplete data and case histories no further comment NO-synthase inhibitor blocked this effect. Known oto- can be made with respect to these. In the course of our toxic drugs like gentamicin have also been known to study we have noted a large variance in the detail and cause uncoupling in Deiter cell gap junctions.22 Hence, format of individual adverse event reports between the as a potentiator of the NO/cGMP pathway PDE-5 inhibi- various pharmacovigilance agencies contacted. Overall, tors can may induce ototoxicity in a similar fashion.
there also was a poor response rate from national phar- In an in vivo study Chung et al.23 (2007) studied macovigilance agencies and transnational organizations the effect of halothane and isolfurane, known NO-cGMP such as the EMEA. The World Health Organization pathway inhibitors, in mice exposed to broad band white (WHO) Collaborating Centre for International Drug noise designed to simulate noise induced hearing loss.
Monitoring based at Uppsala was also contacted. How- After 1 week of exposure, it was found that both anaes- ever, due to prohibitive administrative fees, in excess of thetic agents had a protective effect, hence suggesting £2,000 (Great British Pounds), this information could the involvement of cGMP in mediating ototoxicity.
In their case series Maddox et al.5 considered that as SSHL is a relatively common condition and that, as PDE-5 inhibitors like Sildenafil are frequently pre- The NO driven accumulation of intracellular cGMP scribed drugs, it is possible that reported cases simply activates various protein kinases and nuclear factors that reflect the normal incidence of SSHL in this patient pop- act as secondary messengers, activating various cellular processes. Of interest is the activation of various mitogen- prescriptions of Sildenafil were issued in a year then activated protein (MAP) kinases. These protein kinases based on an incidence of 10 per 100,000 one would respond to extracellular stimuli and regulate gene expres- expect 440 cases of SSHL in this population group sion, mitosis, cell differentiation, and apoptosis. MAP yearly. They further asserted that if Sildenafil was taken kinase c-Jun N-terminal (JNKs) and the p38 isoforms once monthly then 15 cases of SSHL would occur within have been shown to be involved in the cellular stress 24 hours of Sildenafil ingestion. However, this extrapola- response.24,25 The JNK proteins in particular have been tion is entirely speculative and based on assumptions shown to be activated within cochlear hair cells during about the true incidence of SSHL and PDE-5 inhibitor cellular stress in vitro. Yilkoski et al.26 (2002) conducted usage, both of which are poorly understood and recog- experiments in guinea pigs by injecting one group with nized. Also, adverse drug reactions are frequently gentamicin and another with gentamicin and CEP-1347, unrecognized and underreported. A recent systemic a nonprotein inhibitor of the JNK pathway. They found review estimated underreporting rates as high as 94%.31 that CEP-1347 inhibition of JNK attenuated aminoglyco- Another important consideration is that although side induced cochlear hair cell damage. Wang et al.27 the original case reported by Mukherjee et al.5 was of (2003) reproduced these results with D-JNK-1, another bilateral SSHL, 96% of subsequent cases of suspected inhibitor of JNKs, injected into guinea pig cochlear cell PDE-5 inhibitor-induced SSHL have been unilateral. It cultures. Once again, JNK inhibition provided an otopro- is counterintuitive that a drug that has a systemic dis- tective effect against neomycin and noise-induced hair tribution should affect hearing asymmetrically. However, cell toxicity. Wei et al.28 (2005) used minocycline, an inhib- gentamicin, an established ototoxic drug, has been itor of MAP kinase p38, on rat cochlear explants treated shown to induce unilateral and asymmetrical bilateral with gentamicin. It was shown that p38 inhibition was hearing loss.28 Furthermore, in the only prospective otoprotective against cochlear hair cell death.
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