Aspirin, acetaminophen and ibuprofen are the three most commonly used drugs in the U.S.⁸ While 17% of the total population uses aspirin at least weekly, over 28% of men aged 45 and above are aspirin users. Similarly, acetaminophen is used at least weekly by 23% of the population and ibuprofen is used by 17%.⁸ The ototoxic effects of high doses (several grams per day) of salicylates, reversible hearing loss and tinnitus, are well documented.⁹ High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be ototoxic in animals and in human case reports,¹⁵ potentially through a reduction in cochlear blood flow.⁹ Pre-exposure to salicylates and NSAIDs may potentiate noise-induced hearing loss.^{10, 11} Acetaminophen may deplete glutathione,¹⁶ which has been shown to protect the cochlea from noise-induced damage.^{17, 18} The relation between acetaminophen and hearing loss has not been studied.

During 369,079 person-years of follow-up, 3488 cases of hearing loss were reported. Regular analgesic use was independently associated with an increased risk of hearing loss for all three types of analgesics (Table 2). After adjusting for age, race, profession, BMI, alcohol intake, folate intake, physical activity, smoking, hypertension, diabetes, and the use of the other classes of analgesics, the multivariate HRs of hearing loss in participants who were regular users compared with participants who used the specified analgesic less than twice per week were 1.12 (95%CI, 1.04–1.20) for aspirin, 1.21 (95% CI, 1.11–1.33) for NSAIDs, and 1.22 (95% CI, 1.07–1.39) for acetaminophen. When further adjusted for history of elevated cholesterol, cardiovascular disease or use of furosemide, or after exclusion of individuals with rheumatoid arthritis or osteoarthritis, the results were materially unchanged.

For NSAIDs and acetaminophen, the risk of hearing loss increased with longer duration of regular use (Table 3). Those who used aspirin regularly for 1–4 years were 28% (17–40%) more likely to develop hearing loss than those who did not use aspirin regularly; the risk did not increase further with longer duration of use. Those who used NSAIDs regularly for four or more years were 33% (18–49%) more likely to develop hearing loss than those who did not use NSAIDs regularly. The risk of four or more years of regular acetaminophen use was also 33% (14–56%) higher.

The association between hearing loss and regular use of aspirin (p, interaction=0.005), NSAIDs (p, interaction=0.10), and acetaminophen (p, interaction=0.09) varied by age (Table 4). For each class of analgesic, the magnitude of the association tended to decrease with advancing age. For aspirin, regular users aged less than 50 and those aged 50–59 were 33% more likely to have hearing loss than were non-regular users, but there was no association among men aged 60 and older. For NSAIDs, regular users aged less than 50 were 61% more likely, those aged 50–59 were 32% more likely, and those aged 60 and older were 16% more likely to develop hearing loss than non-regular users of NSAIDs. For acetaminophen, regular users aged less than 50 were 99% more likely, regular users aged 50–59 were 38% more likely, and those aged 60 and older were 16% more likely to have hearing loss than non-regular users of acetaminophen.

The ototoxic effects of high dose salicylates, reversible hearing loss and tinnitus, are well documented.⁹ In animal models, salicylate administration results in abnormal outer hair cell function and decreased cochlear blood flow.⁹ Salicylates induce biochemical and electrophysiological changes that alter membrane conductance of outer hair cells³⁵ and vasoconstriction in auditory microvasculature, possibly mediated by antiprostaglandin activity.³⁶

High doses of NSAIDs have also been reported to be ototoxic in animal studies and in human case reports.¹⁵ Similar to salicylates, NSAIDs inhibit cyclooxygenase and decrease prostaglandin activity, potentially reducing cochlear blood flow.⁹

Histopathologic studies of human temporal bones³⁷ and in animals show degeneration of strial microvasculature.³⁸ These studies suggest that vascular compromise, such as that which may result from salicylate or NSAID use, contributes to strial degeneration. Degeneration of the stria vascularis, a highly vascularized and metabolically active region of the cochlea, is a notable pathophysiologic change characteristic of age-related hearing loss³⁹ that may reduce the endolymphatic potential and the function of the cochlear amplifier.

The relation between acetaminophen and hearing loss has not been studied previously. Frequent use of acetaminophen has been associated with hypertension^{20, 40, 41} and chronic renal dysfunction.^{42, 43} Acetaminophen use increases risk of renal function decline, potentially due to depletion of glutathione.¹⁶ Acetaminophen may also deplete endogenous cochlear glutathione, which is present in the cochlea in substantial amounts and protects the cochlea from noise-induced damage.^{17, 18}

The prevalence of hearing loss increases with age.⁴⁴ After age 60, hearing thresholds worsen on average by 1 dB per year⁴⁵ and the rate of decline may be even greater in men aged 48–59 years.⁴⁶ The magnitude of the relation between regular analgesic use and hearing loss was greatest in men younger than age 60. Possibly, the relative contribution of regular analgesic use to hearing loss may be greater in younger individuals before the cumulative effects of age and other factors have accrued. A similar impact of age on the relative contribution of diabetes to hearing loss was seen by Bainbridge et al.²⁹

The risk of hearing loss increased with longer duration of regular use of NSAIDs and acetaminophen, but not of aspirin. However, years of use were counted from the 1986 baseline questionnaire when the mean age of participants was 51 years. Thus, those who reported 11 or more years of aspirin use were older. As the relation between analgesic use and hearing loss diminished with increasing age, this likely explains the lack of association between longer duration of aspirin use and hearing loss.

The impact of regular use of multiple analgesics appeared to be additive. This raises the possibility that the different classes of analgesics may impair auditory function through different mechanisms.

Our study has limitations. Assessment of hearing loss was based on self-report of professionally diagnosed hearing loss and individuals who did not report hearing loss were considered not to be hearing impaired. Although standard pure-tone audiometry is generally considered the gold standard of hearing loss evaluation, self-reported hearing loss has been demonstrated to be a reliable assessment. Moreover, participants were specifically queried as to whether they had been “professionally diagnosed” with hearing loss, a more objective measure than the frequently used single question, “Do you feel you have a hearing loss?” Nevertheless, given the high prevalence of hearing loss in men of this age group,² there may have been misclassification of outcome.

We also did not have information on lifetime noise exposure or reasons for analgesic use. Noise is a common cause of hearing loss, and its targets overlap with those that may be compromised by analgesics. Moreover, noise exposure may increase the vulnerability to hearing loss related to age^47–49 or other causes.⁵⁰ A study of patterns of medication use in the US found that 58% of older men reported cardiovascular prophylaxis was the most common reason for aspirin use. Other reasons for use of OTC medications, of which acetaminophen, ibuprofen, and aspirin were the most common, included headache and pain.⁸ We did not find any published reports relating common headache with hearing loss. Although migraine headaches may be associated with temporary hearing loss,⁵¹ the prevalence of migraine headaches in men in the US is low (6%),⁵² thus unlikely to explain our findings. Autoimmune diseases, such as rheumatoid arthritis, may cause hearing loss,⁵³ but these conditions are extremely rare in men and unlikely to have influenced our results. Hypertension may increase the risk of hearing loss due to changes in the cochlear microvasculature,⁵⁴ as may cardiovascular disease, such as stroke, coronary heart disease and intermittent claudication,³⁰ however, we adjusted for these in our analyses and our results were not materially changed.

The present study was carried out in a population of predominantly white men, thus the results may not be generalizable to other racial groups. Although the participants in this cohort may not be representative of the adult population in the U.S., follow-up rates are high and information provided is reliable. The observed associations are likely to apply to other groups inasmuch as the underlying biologic and pharmacologic mechanisms are likely to be similar. However, additional studies are needed to examine these associations in women and younger men.