Untitled

Phosphodiesterase Type 5 Inhibitor Use
and Hearing Impairment
Objective: To compare use of phosphodiesterase type
Results: The overall prevalence of self-reported hearing
5 inhibitors (PDE-5i) between participants with and with- impairment and PDE-5i use in each group was 17.9% and out self-reported hearing impairment using logistic 2%, respectively. Men who reported hearing impairment regression, with and without adjustment for potentially were more likely to have also reported the use of any PDE-5i confounding sociodemographic, behavioral, and health- (odds ratio [OR], 2.23; 95% confidence interval [CI], 1.36- 3.66). However, this association was limited to sildenafil(Viagra) (OR, 2.05; 95% CI, 1.23-3.43); no significant as- Design: Cross-sectional.
sociations were observed for tadalafil (Cialis) or vard-enafil (Levitra) (ORs, 1.40 [95% CI, 0.49-4.04] and 0.88 Setting: United States.
Patients: A population-based sample of 11 525 men 40
Conclusions: Current warnings regarding the risk of
years or older (248 217 013 weighted men) in the United hearing loss related to PDE-5i use seems to be justified.
States, selected from the Medical Expenditure Panel Sur- However, the cross-sectional nature of the current study provides only limited insight regarding this relation-ship, and thus additional research is warranted.
Main Outcome Measure: Self-reported hearing
impairment.
Arch Otolaryngol Head Neck Surg. 2010;136(5):488-492 HEARINGLOSS(HL)ISTHE PDE-5iuse.5ThispromptedtheFDAto
require that material associated with these products mention the possibility of HL. De- tails regarding most of the cases reported tors contributing to its etiology. It is esti- were subsequently described in the litera- ence some type of hearing impairment.1 Risk factors include age, sex, occupation, edu- port to the notion that PDE-5i use may in- cation, smoking, diabetes mellitus, and car- diovascular disease.1-3 Genetic risk factors tiple possible susceptibility genes have been help fill this void in the current litera- ture, this study evaluates this relation- inhibitors (PDE-5i), including sildenafil ci-trate (Viagra and Revatio; Pfizer Inc, New York, New York), vardenafil (Levitra; BayerHealthcare Pharmaceuticals, Montville,New Jersey, Schering-Plough, Kenil- DATA SOURCE AND STUDY DESIGN
worth, New Jersey, and GlaxoSmithKline,London, England), and tadalafil (Cialis; Eli The Medical Expenditure Panel Survey (MEPS)is a longitudinal, overlapping panel cohort, with Lilly, Indianapolis, Indiana).5 Following each cohort consisting of approximately 15 000 the published report of a single patient who households, including a subsample of approxi- experienced SSHL after taking sildenafil for Author Affiliation: Department
mately 39 000 individuals chosen from the Na- tional Health Interview Survey using a strati- istration (FDA) identified a total of 29 re- fied and clustered sample with weights that ports of sudden HL potentially related to produce nationally representative estimates.9 (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 136 (NO. 5), MAY 2010 2010 American Medical Association. All rights reserved.
Participants are interviewed 5 times over a 2-year period with cific condition. Medical conditions reported by respondents are respect to demographic, health status, and health care utiliza- coded by professional coders to International Classification of tion, including prescription medication use. For the purposes Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, of this cross-sectional study, data for men 40 years or older from although, to protect respondent confidentiality, nearly all codes the 2003-2006 MEPS Household Component (HC) were com- are available only at the 3-digit level. This information was used bined. These years have a common variance structure neces- to identify the presence of diabetes mellitus and cardiovascu- sary to ensure compatibility and comparability among the lar disease, the latter including coronary heart disease, angina, specific variables and represent the most recent data available.
myocardial infarction, or other heart conditions. Finally, the The institutional review board at the University of Alabama at MEPS collects information related to current and former jobs, including industry and occupation. Industry and occupationcodes are assigned by professional coders at the US Census Bu- VARIABLE DEFINITIONS
reau based on verbatim descriptions provided by respondentsduring the survey interview. The detailed codes are collapsed Hearing Impairment
into broader groups to ensure confidentiality. For the pur-poses of this analysis, individuals were classified as having everworked in any of the following occupational categories: man- The MEPS-HC respondents are asked a series of questions re- agement/business/financial, professional, service, sales, office/ garding HL; these questions are asked of all household mem- administrative, farming/fishing/forestry, construction, produc- bers. Specifically, respondents are asked about the use of a hear- ing aid, any difficulty hearing (with or without the use of ahearing aid), deafness, and the ability to hear most or some ofthings people say. Responses to these questions are summa- STATISTICAL ANALYSIS
rized into a single variable that classifies individuals with re-spect to the extent of their hearing impairment. For the pur- Given the complexity of the MEPS study design, it is neces- poses of this study, individuals classified as having no hearing sary to account for the sampling strategy as well as the longi- difficulty are compared with those with slight, moderate, or ma- tudinal nature of the data collection. To aid in the analysis of jor HL or deafness. This same classification has been used pre- data across several years, the MEPS provides weight and vari- viously to describe the prevalence of HL in the United States.10 ance estimation variables that must be applied when produc-ing national estimates and appropriate estimates of variability PDE-5i Use
for longitudinal analyses. Thus, all analyses conducted as partof this study use these statistical weights.
During each round of the MEPS-HC, all respondents are asked Demographic, environmental, and medical characteristics to supply the name of any prescribed medications they or their were compared between those with and without hearing im- family members purchased or otherwise obtained. For each pairment using t test and ␹2 test for continuous and categori- medication, a variety of information is obtained, including the cal variables, respectively. The association between HL and name(s) of any health problems for which the medicine was PDE-5i use was estimated using logistic regression with and prescribed, frequency of purchase, and the date of first use. For without adjustment for the characteristics given in the “Poten- the purposes of this study, respondents with reported use of tial Confounders” subsection of the “Methods” section. P val- sildenafil, vardenafil, and tadalafil were classified as PDE-5i us- ues of Յ.05 (2-sided) were considered statistically significant.
ers; nonusers were those with no record of having reported useof these medications. Revatio is another PDE-5i used in the treat-ment of pulmonary arterial hypertension; however, no respon- dent reported using it during the study period.
This analysis represents data on a total of 248 217 013 Potential Confounders
(11 525 unweighted) men 40 years or older in the UnitedStates from 2003 through 2006, approximately 62 mil- A number of demographic, environmental, and medical char- lion participants per year. These figures are comparable acteristics have been linked to HL4 and therefore serve as po- with US Census Bureau estimates for the male popula- tential confounders for the relationship between PDE-5i use tion 40 years or older during this same time period. The and hearing impairment. Thus, in addition to sociodemo- overall prevalence of HL was 17.9% and increased with graphic characteristics (ie, age, race, household income), in- age. The prevalence among those in their forties was 7.5%, formation pertaining to current smoking, the use of ototoxicmedications, diabetes mellitus, cardiovascular disease, and job and this increased to 15.0%, 24.4%, 32.9%, and 47.2% characteristics was selected from the MEPS-HC. Information in subsequent decades. Approximately 2% of men re- regarding other potential confounders (eg, alcohol consump- ported having obtained a PDE-5i; use was lowest among tion) is not available in the MEPS, and therefore the confound- those in their forties (0.8%), steadily increased until men ing influence of such characteristics cannot be evaluated. Oto- were in their 60s (3.3%), and then subsequently de- toxic medication use, including antibiotics, diuretics, salicylates, clined to 0.5% for men 80 years or older. Among those and quinine derivatives, was defined using the same informa- reporting PDE-5i use, sildenafil was the most frequently tion source used to define PDE-5i use. Information on acute used (80.3%), followed by vardenafil (20.2%) and tad- and chronic medical conditions in the MEPS-HC is obtained via a number of mechanisms, including the report of a medi- Table 1 presents demographic and health-related
cal event (eg, hospital stay, medication purchase), whether thecondition was responsible for 1 or more disability days, or if characteristics according to HL status. Those classified the condition was reported as “bothering” the person. For cer- as hearing impaired were approximately 10 years older, tain conditions (eg, diabetes mellitus, coronary heart disease) more likely to be white, and had lower household in- respondents are asked explicitly whether they were told by a comes compared with those not classified as such. Those physician or other health care provider that they have a spe- with hearing impairment were less likely to have worked (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 136 (NO. 5), MAY 2010 2010 American Medical Association. All rights reserved.
Table 1. Sociodemographic, Health, and Behavioral Characteristics According to Self-Reported Hearing Impairmenta
Hearing Impairment
Characteristic
(n = 9 125 761)
(n = 239 091 252)
P Value
a Data are given as percentages except where noted.
b Income based on family income relative to the poverty line (based on family size and composition).
Table 2. Prevalence of Hearing Impairment According to Phosphodiesterase Type 5 Inhibitor (PDE-5i) Use and Associated
Odds Ratios (ORs) and 95% Confidence Intervals (CIs)
Hearing Impairment, %
Unadjusted OR
Adjusted OR
PDE-5i Usea
(n = 9 125 761)
(n = 239 091 252)
(95% CI)b
a Manufacturers’ information: Viagra, Pfizer Inc, New York, New York; Cialis, Eli Lilly, Indianapolis, Indiana; and Levitra, Bayer Healthcare Pharmaceuticals, Montville, New Jersey, Schering-Plough, Kenilworth, New Jersey, and GlaxoSmithKline, London, England.
b Adjusted for age, race, household income, smoking, diabetes mellitus, cardiovascular disease, use of ototoxic medications, and occupation.
in the management or business field but more likely to of PDE-5i use compared with those without HL. This as- have worked in the construction industry or have been sociation seemed to be limited to sildenafil use (odds ra- in the military. There was no difference with respect to tio [OR], 2.05; 95% confidence interval [CI], 1.23- current smoking; however, individuals with hearing im- 3.43); there was no significant association for tadalafil pairment were more likely to have diabetes mellitus, car- (OR, 1.40; 95% CI, 0.49-4.04) or vardenafil (OR, 0.88; diovascular disease, or used ototoxic medications com- pared with those without such impairment.
Table 2 presents the overall and medication-
specific prevalence of PDE-5i use among those with and without HL. The use of any PDE-5i was more commonamong those with hearing impairment compared with In 2007, the FDA announced labeling changes for PDE-5i those without (3.0% vs 1.4%); a similar pattern was ob- medications, including sildenafil, vardenafil, and tadala- served for those taking specific PDE-5i medications, al- fil,5 such that the risk of sudden hearing problems is more though the differences were most apparent for those tak- prominently displayed.5 To my knowledge, prior to the ing sildenafil and tadalafil. The adjusted results indicate current study, no epidemiologic studies had evaluated that those with HL had more than 2-fold increased odds this relationship. The current findings suggest that men (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 136 (NO. 5), MAY 2010 2010 American Medical Association. All rights reserved.
40 years or older with self-reported hearing impairment a case report or series that lacks a suitable comparison were more than twice as likely to report PDE-5i use com- group, this is a reasonable concern. Another concern is pared with those not reporting HL. This association per- the fact most cases reported in the literature have been sisted following adjustment for a number of potential of patients found to have unilateral HL. Yet HL attribut- demographic- and health-related confounding charac- able to the toxic effects of PDE-5i use would be ex- teristics. Moreover, this relationship seems to be lim- pected to be bilateral. Finally, for several of the reported ited to sildenafil use, although an elevated, yet not sta- cases there is not a clear temporal relationship between tistically significant, association was also observed for the SSHL and PDE-5i use. Yet, for most (approximately tadalafil. The lower frequency of tadalafil and vardenafil 90%) of the cases reported by Maddox et al,7 HL oc- use may have precluded the identification of similarly in- curred within 24 hours of taking a PDE-5i, and of those, creased risks owing to limited statistical power. The as- most cases occurred within 12 hours. Finally, the lack sociation between PDE-5i use, specifically sildenafil, and of information on potentially confounding characteris- sensory impairment is not novel. In 2005, following a tics has precluded definitive conclusions regarding small case series, the FDA required that PDE-5i users be warned about the risk of sudden-onset blindness or non- The present study compared individuals with self- arteritic ischemic optic neuropathy (NAION).11 A sub- reported hearing impairment with those without such im- sequent case-control study12 reported no significant as- pairment and adjusted for the potentially confounding sociation between NAION and sildenafil and/or tadalafil influence of demographic- and health-related character- use, although an increased risk was observed for those istics. Thus, the concern that previously reported cases with a family history of myocardial infarction. A reanaly- may simply reflect the background incidence of hearing sis of the data from this study revealed that any in- impairment or confounding is diminished, although in- creased risk was limited to sildenafil use (G.M., unpub- formation on certain potential confounders was not avail- able. My results suggest that the previously reported cases Given the dearth of published literature regarding may be over and above the natural incidence and possi- PDE-5i medications and HL, it is difficult to place the bly attributed to PDE-5i use. However, a number of the results of the current study into context. One important concerns mentioned herein could not be resolved in the consideration in evaluating the nature of this relation- current study. First, the study design was cross- ship is the existence of a plausible biological mecha- sectional, and thus I cannot evaluate the temporal rela- nism. It has been hypothesized that PDE-5i might cause tionship between the onset of HL in relation to timing, HL owing to their ability to affect nasal physiologic char- frequency, or duration of PDE-5i use; this is despite the acteristics and thus eustachian tube function. Specifi- longitudinal nature of MEPS. The structure of the ques- cally, PDE-5i use causes congestion of nasal erectile tis- tions regarding HL does not easily lend itself to the iden- sue that results in elevated middle ear pressure.13,14 It has tification of incident hearing problems. Second, I did not also been suggested that PDE-5i may intensify the ef- have information on SSHL but instead focused on self- fects of nitric oxide, which has been implicated in a num- reported hearing impairment. Although those with SSHL ber of otologic diseases, or simulate the effects via acti- are likely to be captured with questions about hearing vated intracellular cyclic guanosine monophosphate impairment in general, it is more than likely that they (cGMP).7,8 The PDE-5i function by blocking the degra- represent the minority of those with self-reported HL.
dation of cGMP, the accumulation of which induces gene Given the observed results, if the association between expression via transcription factors by protein phos- PDE-5i use and SSHL is real, then it is either strong enough phorylation by specific kinases, which themselves have to overcome any misclassification or, and perhaps more been associated with damage to cochlear hair cells.7 To plausibly, PDE-5i use is associated with hearing impair- my knowledge, no study has provided evidence for or ment in general as well as SSHL specifically. That said, against these mechanisms. However, nitric oxide is in- there has been great debate regarding the usefulness of creased following auditory organ injury, and high nitric information regarding self-reported hearing impair- oxide levels are associated with inner ear dysfunction15; ment. It has been suggested that the sensitivity of self- increased nitric oxide production has also been ob- reported HL is low (ie, 41%-65%) compared with audio- served in animals with HL.16-18 In addition, high doses metric measurement,1 and that self-reported prevalence of sildenafil have been observed to induce hearing im- estimates may vary owing to the nature of the question pairment in mice.8 In a study13 of 18 men using PDE-5i being asked.10 However, others have been more optimis- for erectile dysfunction, 4 showed a temporary decrease tic regarding the usefulness of self-reported hearing in hearing threshold, although no permanent deleteri- impairment for documenting prevalence and trends20,21 ous effect was observed. Interestingly, it has been sug- although greater caution is warranted when using self- gested that vardenafil might be useful in the treatment report for etiologic associations.21 Ultimately, in the con- of tinnitus, although research has failed to support this text of the present study the main concern is bias, and there is no reason to expect PDE-5i users to differen- Maddox et al7 expressed several concerns that argue tially report HL; particularly because at the time the data against a causal relationship between PDE-5i use and HL.
used in this study were collected, information regarding These authors suggest that the published case reports of the potential relationship between PDE-5i use and HL SSHL attributed to PDE-5i may simply reflect the natu- was not widespread. Moreover, risk factors for HL dem- ral incidence of this condition rather than excess risk onstrate a high degree of consistency whether impair- posed by the use of these medications. In the context of ment is defined via self-report or audiometry22,23 and have (REPRINTED) ARCH OTOLARYNGOL HEAD NECK SURG/ VOL 136 (NO. 5), MAY 2010 2010 American Medical Association. All rights reserved.
been shown to have equivalent reductions in quality of impairment: contributing environmental and genetic factors. Audiol Neurootol.
life.24 Thus, whether defined based on audiometry or self- 5. FDA announces revisions to labels for Cialis, Levitra and Viagra: potential risk of report, the etiology of HL is likely to be similar.
sudden hearing loss with ED drugs to be displayed more prominently. US Food Based on several case reports, the FDA required the and Drug Administration Web site. http://www.fda.gov/NewsEvents/Newsroom manufacturers of PDE-5i medications to warn users re- /PressAnnouncements/2007/ucm109012.htm. Accessed July 21, 2009.
garding the potential for sudden-onset HL. While case 6. Mukherjee B, Shivakumar T. A case of sensorineural deafness following inges- reports and the hypotheses they generate are often use- tion of sildenafil. J Laryngol Otol. 2007;121(4):395-397.
7. Maddox PT, Saunders J, Chandrasekhar SS. Sudden hearing loss from PDE-5 ful in laying the foundation for future epidemiologic stud- inhibitors: a possible cellular stress etiology. Laryngoscope. 2009;119(8):1586- ies, they provide limited evidence for causality. The re- sults of the current study in conjunction with a plausible 8. Hong BN, Yi TH, Kim SY, Kang TH. High dosage sildenafil induces hearing im- biologic mechanism lend support to the FDA’s decision pairment in mice. Biol Pharm Bull. 2008;31(10):1981-1984.
to warn patients about the potential risk posed by PDE-5i 9. Cohen SB. Design strategies and innovations in the medical expenditure panel survey. Med Care. 2003;41(7)(suppl):III5-III12.
use. However, this support must be tempered in light of 10. Ikeda N, Murray CLJ, Salomon JA. Tracking population health based self- the limitations mentioned herein. The largely irrevers- reported impairments: trends in the prevalence of hearing loss in US adults, ible nature of HL and its impact on quality of life under- 1976-2006. Am J Epidemiol. 2009;170(1):80-87.
score the need for additional research regarding the etio- 11. FDA updates labeling for Viagra, Cialis and Levitra for rare post-marketing re- ports of eye problems. US Food and Drug Administration Web site. http://www logic role of PDE-5i use. In the interim, it is prudent that .fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108458 patients using these medications, specifically sildenafil, be warned about the signs and symptoms of hearing im- 12. McGwin G Jr, Vaphiades MS, Hall TA, Owsley C. Non-arteritic anterior ischaemic pairment and be encouraged to seek immediate medical optic neuropathy and the treatment of erectile dysfunction. Br J Ophthalmol. 2006; attention to potentially forestall permanent damage.
13. Okuyucu S, Guven OE, Akoglu E, Uc¸ar E, Dagli S. The effect of phosphodiester- ase-5 inhibitor on hearing. J Laryngol Otol. 2009;123(7):718-722.
Submitted for Publication: September 1, 2009; final re-
14. Kiroglu AF, Bayrakli H, Yuca K, Cankaya H, Kiris M. Nasal obstruction as a com- vision received November 6, 2009; accepted December mon side-effect of sildenafil citrate. Tohoku J Exp Med. 2006;208(3):251-254.
15. Watanabe K, Hess A, Zumeger C, et al. Changes of the compound action potential Correspondence: Gerald McGwin Jr, MS, PhD, Depart-
(CAP) and the expression of inducible nitric oxide synthase (iNOS/NOS II) in thecochlea under the inflammatory condition. Hear Res. 2000;145(1-2):149-155.
ment of Epidemiology, University of Alabama at Bir- 16. Kopke R, Allen KA, Henderson D, Hoffer M, Frenz D, Van de Water T. A radical mingham, 1922 Seventh Ave S, Ste 120, Birmingham, AL demise: toxins and trauma share common pathways in hair cell death. Ann N Y Financial Disclosure: Dr McGwin has been retained by
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