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Analgesic Use and the Risk of Hearing Loss in Men

      Abstract

      Background

      Hearing loss is a common sensory disorder, yet prospective data on potentially modifiable risk factors are limited. Regularly used analgesics, the most commonly used drugs in the US, may be ototoxic and contribute to hearing loss.

      Methods

      We examined the independent association between self-reported professionally diagnosed hearing loss and regular use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen in 26,917 men aged 40-74 years at baseline in 1986. Study participants completed detailed questionnaires at baseline and every 2 years thereafter. Incident cases of new-onset hearing loss were defined as those diagnosed after 1986. Cox proportional hazards multivariate regression was used to adjust for potential confounding factors.

      Results

      During 369,079 person-years of follow-up, 3488 incident cases of hearing loss were reported. Regular use of each analgesic was independently associated with an increased risk of hearing loss. Multivariate-adjusted hazard ratios of hearing loss in regular users (2+ times/week) compared with men who used the specified analgesic <2 times/week were 1.12 (95% confidence interval [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. For NSAIDs and acetaminophen, the risk increased with longer duration of regular use. The magnitude of the association was substantially higher in younger men. For men younger than age 50 years, the hazard ratio for hearing loss was 1.33 for regular aspirin use, 1.61 for NSAIDs, and 1.99 for acetaminophen.

      Conclusions

      Regular use of aspirin, NSAIDs, or acetaminophen increases the risk of hearing loss in men, and the impact is larger on younger individuals.

      Keywords

      Hearing loss is the most common sensory disorder in the US and afflicts over 36 million people.
      • Pleis J.R.
      • Lethbridge-Cejku M.
      Summary health statistics for U.S. adults: National Health Interview Survey, 2006.
      Data from the National Health and Nutrition Examination Survey (NHANES) demonstrate that not only is hearing loss highly prevalent among the elderly, but approximately one third of those aged 40-49 years already suffer from hearing loss.
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.
      The 5-year incidence of developing hearing loss in adults aged 48 years and older is 21%.
      • Cruickshanks K.J.
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      • Wiley T.L.
      • et al.
      The 5-year incidence and progression of hearing loss: the epidemiology of hearing loss study.
      Even mild hearing loss can compromise the ability to understand speech in the presence of background noise or multiple speakers, leading to social isolation, depression, and poorer quality of life.
      • Gates G.A.
      • Mills J.H.
      Presbycusis.
      • Dalton D.S.
      • Cruickshanks K.J.
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      The impact of hearing loss on quality of life in older adults.
      • Uhlmann R.F.
      • Larson E.B.
      • Rees T.S.
      • et al.
      Relationship of hearing impairment to dementia and cognitive dysfunction in older adults.
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      • Linn R.T.
      • et al.
      Central auditory dysfunction, cognitive dysfunction, and dementia in older people.
      • Hearing loss is the most common sensory disorder in the US and factors other than age and noise might influence the risk of hearing loss.
      • Regular use of aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs, the most commonly used drugs in the US, might increase risk of hearing loss.
      • The increased risk of hearing loss associated with regular analgesic use might be greater among younger men, particularly those below age 60 years.
      Aspirin, acetaminophen, and ibuprofen are the 3 most commonly used drugs in the US.
      • Kaufman D.W.
      • Kelly J.P.
      • Rosenberg L.
      • et al.
      Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey.
      Although 17% of the total population uses aspirin at least weekly, over 28% of men aged 45 years and above are aspirin users. Similarly, acetaminophen is used at least weekly by 23% of the population and ibuprofen is used by 17%.
      • Kaufman D.W.
      • Kelly J.P.
      • Rosenberg L.
      • et al.
      Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey.
      The ototoxic effects of high doses (several grams per day) of salicylates, reversible hearing loss and tinnitus, are well documented.
      • Jung T.T.
      • Rhee C.K.
      • Lee C.S.
      • et al.
      Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
      In contrast, low-dose salicylate has been reported to protect against aminoglycoside
      • Chen Y.
      • Huang W.G.
      • Zha D.J.
      • et al.
      Aspirin attenuates gentamicin ototoxicity: from the laboratory to the clinic.
      and noise-
      • Kopke R.D.
      • Weisskopf P.A.
      • Boone J.L.
      • et al.
      Reduction of noise-induced hearing loss using L-NAC and salicylate in the chinchilla.
      induced hearing loss, possibly through an effect on the outer hair cell motor protein or inhibition of cyclooxygenage.
      • Huang Z.W.
      • Luo Y.
      • Wu Z.
      • et al.
      Paradoxical enhancement of active cochlear mechanics in long-term administration of salicylate.
      High doses of nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to be ototoxic in animals and in human case reports,
      • McKinnon B.J.
      • Lassen L.F.
      Naproxen-associated sudden sensorineural hearing loss.
      potentially through a reduction in cochlear blood flow.
      • Jung T.T.
      • Rhee C.K.
      • Lee C.S.
      • et al.
      Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
      Pre-exposure to salicylates and NSAIDs might potentiate noise-induced hearing loss.
      • McFadden D.
      • Plattsmier H.S.
      Aspirin can potentiate the temporary hearing loss induced by intense sounds.
      • McFadden D.
      • Plattsmier H.S.
      • Pasanen E.G.
      Temporary hearing loss induced by combinations of intense sounds and nonsteroidal anti-inflammatory drugs.
      Acetaminophen might deplete glutathione,
      • Moldeus P.
      • Rahimtula A.
      Metabolism of paracetamol to a glutathione conjugate catalyzed by prostaglandin synthetase.
      which has been shown to protect the cochlea from noise-induced damage.
      • Yamasoba T.
      • Harris C.
      • Shoji F.
      • et al.
      Influence of intense sound exposure on glutathione synthesis in the cochlea.
      • Yamasoba T.
      • Nuttall A.L.
      • Harris C.
      • et al.
      Role of glutathione in protection against noise-induced hearing loss.
      The relation between acetaminophen and hearing loss has not been studied.
      Given that analgesic use might result in pathophysiologic changes in the cochlea and that regular use of these analgesics is so common, the relation of these medications and hearing loss might be an important public health issue. Therefore, we prospectively examined the association between regular analgesic use and risk of hearing loss in over 26,000 men.

      Methods

       Participants

      The Health Professionals Follow-up Study originally enrolled 51,529 male dentists, optometrists, osteopaths, pharmacists, podiatrists, and veterinarians who were 40-75 years of age at baseline in 1986. Study participants filled out detailed questionnaires about diet, medical history, and medication use. These questionnaires have been administered every other year, and the 20-year follow-up exceeds 90%. The 2004 long-form questionnaire included a question about whether the participant had been professionally diagnosed with hearing loss, and if so, the date of diagnosis. Of the 31,496 men who returned the long-form questionnaire, 8291 (26.3%) reported a diagnosis of hearing loss. Those who reported hearing loss diagnosed before 1986 (n=2845) or cancer other than nonmelanoma skin cancer (due to possible exposure to ototoxic chemotherapeutic agents) were excluded from the analysis. Recent data from NHANES demonstrate that 43% of white men aged 60-69 years exhibit low- to mid-frequency hearing loss and 93% exhibit high-frequency hearing loss.
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.
      Thus, because age is such a strong risk factor and the prevalence of hearing loss is so high among the elderly, we also excluded men as they reached age 75 years during follow-up. The number of men included in the analysis was 26,917.

       Ascertainment of Analgesic Use

      On the 1986 questionnaire and every 2 years thereafter, men were asked about regular use, defined as 2 or more times per week, of aspirin, NSAIDs, and acetaminophen. Our primary analyses examined regular analgesic use. If information on analgesic intake was missing for a time period, person-time for that participant was not included for that time period. Analgesic use assessed in this manner has been shown to be associated with a number of important outcomes in this cohort, such as colorectal cancer
      • Chan A.T.
      • Ogino S.
      • Fuchs C.S.
      Aspirin and the risk of colorectal cancer in relation to the expression of COX-2.
      and hypertension.
      • Forman J.P.
      • Rimm E.B.
      • Curhan G.C.
      Frequency of analgesic use and risk of hypertension among men.

       Ascertainment of Outcome

      The primary outcome, self-reported professionally diagnosed hearing loss, was determined based on the response to a hearing loss question on the 2004 long-form questionnaire. The question asked whether the participant had ever had professionally diagnosed hearing loss and the year of first diagnosis.
      We defined incident cases as hearing loss diagnosed after 1986. Although standard pure-tone audiometry is generally considered the gold standard of hearing loss evaluation, due to the cost and logistic limitations of audiometric screening, several survey instruments have been developed to evaluate large populations. Studies that have compared the reliability of self-report to the gold standard of audiometry
      • Sindhusake D.
      • Mitchell P.
      • Smith W.
      • et al.
      Validation of self-reported hearing loss The Blue Mountains Hearing Study.
      • Nondahl D.M.
      • Cruickshanks K.J.
      • Wiley T.L.
      • et al.
      Accuracy of self-reported hearing loss.
      • Valete-Rosalino C.M.
      • Rozenfeld S.
      Auditory screening in the elderly: comparison between self-report and audiometry.
      • Gates G.A.
      • Cooper Jr, J.C.
      • Kannel W.B.
      • Miller N.J.
      Hearing in the elderly: the Framingham cohort, 1983-1985 Part I. Basic audiometric test results.
      demonstrate that self-reported hearing loss is a reasonably reliable measure of hearing loss.
      • Sindhusake D.
      • Mitchell P.
      • Smith W.
      • et al.
      Validation of self-reported hearing loss The Blue Mountains Hearing Study.
      For example, based on NHANES data using the definition of hearing loss to be a pure-tone average (at 500, 1000, 2000, and 4000 kHz) ≥25 dB in both ears, the sensitivity was 65% and the specificity was 83% in a comparison of self-report to audiometry.
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.

       Ascertainment of Covariates

      We selected covariates that have been purported to be risk factors for hearing loss. Covariates considered in the multivariate analysis included: age,
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.
      race,
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.
      body mass index (BMI),
      • Seidman M.D.
      Effects of dietary restriction and antioxidants on presbyacusis.
      alcohol intake,
      • Itoh A.
      • Nakashima T.
      • Arao H.
      • et al.
      Smoking and drinking habits as risk factors for hearing loss in the elderly: epidemiological study of subjects undergoing routine health checks in Aichi, Japan.
      folate intake,
      • Durga J.
      • Verhoef P.
      • Anteunis L.J.
      • et al.
      Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial.
      physical activity,
      • Li Y.
      • Healy E.W.
      • Drane J.W.
      • Zhang J.
      Comorbidity between and risk factors for severe hearing and memory impairment in older Americans.
      smoking,
      • Itoh A.
      • Nakashima T.
      • Arao H.
      • et al.
      Smoking and drinking habits as risk factors for hearing loss in the elderly: epidemiological study of subjects undergoing routine health checks in Aichi, Japan.
      hypertension, diabetes,
      • Bainbridge K.E.
      • Hoffman H.J.
      • Cowie C.C.
      Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004.
      cardiovascular disease,
      • Gates G.A.
      • Cobb J.L.
      • D'Agostino R.B.
      • Wolf P.A.
      The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.
      elevated cholesterol,
      • Gates G.A.
      • Cobb J.L.
      • D'Agostino R.B.
      • Wolf P.A.
      The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.
      and use of furosemide.
      • Rybak L.P.
      • Whitworth C.
      • Scott V.
      Comparative acute ototoxicity of loop diuretic compounds.
      Age and race were obtained from biennial questionnaires. Height and weight were obtained from the baseline questionnaire, with self-reported weight updated every 2 years. BMI was calculated as weight in kilograms divided by the square of height in meters. Information on smoking status and physical activity was updated every 2 years. Intakes of alcohol and folate were calculated from semiquantitative food frequency questionnaires that were mailed to participants every 4 years. Information on other covariates was available from the biennial questionnaires, including diagnoses of hypertension, diabetes mellitus, cardiovascular disease, elevated cholesterol, and use of furosemide.
      Questionnaire-derived information has been validated for many of the covariates by comparison with directly measured values or detailed diaries, with correlations of 0.97 for weight,
      • Rimm E.B.
      • Stampfer M.J.
      • Colditz G.A.
      • et al.
      Validity of self-reported waist and hip circumferences in men and women.
      0.79 for physical activity,
      • Chasan-Taber S.
      • Rimm E.B.
      • Stampfer M.J.
      • et al.
      Reproducibility and validity of a self-administered physical activity questionnaire for male health professionals.
      and 0.9 for alcohol intake.
      • Willett W.C.
      Nutritional Epidemiology.

       Statistical Analysis

      All analyses were prospective, using information on analgesic use that was collected before the diagnosis of hearing loss. For the primary analyses, the frequency of use of a particular analgesic was categorized as regular users (2 or more times per week) or nonregular users (less than twice per week). For each participant, person-time was allocated based on the response to the analgesic questions at the beginning of each follow-up period. Participants were censored at the date of diagnosis of hearing loss or cancer, age 75 years, or the date of death, whichever came first. Age- and multivariable-adjusted hazard ratios (HRs) were calculated using Cox proportional hazards regression models. Multivariable models were adjusted for potential confounders listed above as well as simultaneously for use of the other analgesic types.
      To examine whether the relation between regular analgesic use and hearing loss varied by age, we performed analyses stratified by age <50 years, 50-59 years, and 60 years and older.
      Secondary analyses examined the association between duration of regular analgesic use and hearing loss. Duration of regular aspirin use was categorized according to years of regular use (0, 1-4, 5-8, >8). For NSAIDs and acetaminophen, duration of regular use was categorized similarly; however, the highest categories were collapsed into a category of >4 years of regular use, as too few cases were in the categories of longer duration. We also examined whether the relation between hearing loss and regular analgesic use varied with concomitant regular use of more than one class of analgesic. Analgesic use was categorized as regular use of all 3 classes of analgesics, regular use of aspirin and NSAIDs only, NSAIDs and acetaminophen only, aspirin and acetaminophen only, aspirin only, NSAIDs only, acetaminophen only, or no regular analgesic use.
      For all HRs, we calculated 95% confidence intervals (CIs). All P values are 2-tailed. Statistical tests were performed using SAS statistical software, version 9 (SAS Institute Inc, Cary, NC).

      Results

      Characteristics of participants at baseline according to analgesic use are shown in Table 1. Although updated information was used for the analysis, characteristics are presented from baseline to provide representative values. Regular aspirin and NSAID users were older and acetaminophen users were younger than nonregular users. Hypertension was more common among regular analgesic users. It was common for an individual to use more than one type of analgesic regularly.
      Table 1Characteristics of Men According to Analgesic Use in 1986
      Aspirin Regular UseNSAID Regular UseAcetaminophen Regular Use
      YesNoYesNoYesNo
      Variablen=7217n=19,700n=1311n=25,606n=1439n=25,478
      Age, years52.550.652.051.149.651.2
      Race, %
       African American0.50.90.70.80.50.8
       Asian0.71.80.71.61.01.6
      Body mass index, kg/m225.525.326.025.325.425.3
      Alcohol, g/d131112111111
      Folate, μg/d493469484476497475
      Physical activity, mets/wk212223221822
      Hypertension, %211621172017
      Diabetes, %222212
      Smoking never, %455040494349
      Smoking past, %463752393947
      Smoking current, %888898
      Aspirin use, %39.626.247.325.7
      NSAID use, %7.24.014.04.4
      Acetaminophen use, %9.43.915.34.8
      mets/wk = metabolic equivalent tasks per week; NSAID=nonsteroidal anti-inflammatory drug.
      Regular use is defined as at least 2 times per week.
      Values are means unless otherwise specified.
      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 3 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.
      Table 2Age- and Multivariate-adjusted Hazard Ratios (95% CI) for Analgesic Use and Incident Hearing Loss
      Analgesic MedicationCasesPerson-yearsAge-adjusted Hazard RatioMultivariate Hazard Ratio
      Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      Aspirin
       <2 per week1769213,8311.01.0
       2+ per week1711154,4121.13 (1.06-1.21)1.12 (1.04-1.20)
      NSAIDs
       <2 per week2852320,4671.01.0
       2+ per week63648,6121.38 (1.27-1.50)1.21 (1.11-1.33)
      Acetaminophen
       <2 per week3214347,3621.01.0
       2+ per week27421,7171.32 (1.17-1.50)1.22 (1.07-1.39)
      NSAID=nonsteroidal anti-inflammatory drug.
      low asterisk Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      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% (95% CI, 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 4 or more years were 33% (95% CI, 18-49) more likely to develop hearing loss than those who did not use NSAIDs regularly. The risk of 4 or more years of regular acetaminophen use also was 33% (95% CI, 14-56) higher.
      Table 3Age and Multivariate Adjusted Hazard Ratios (95% CI) for Hearing Loss According to Duration of Analgesic Intake
      Duration of Use (Years)CasesPerson-yearsAge-adjusted Hazard RatioMultivariate Hazard Ratio
      Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      Aspirin
       01042156,1881.01.0
       1-41122108,1771.35 (1.24-1.46)1.28 (1.17-1.40)
       5-868756,4311.34 (1.22-1.48)1.30 (1.17-1.44)
       >863748,2821.26 (1.14-1.40)1.17 (1.04-1.31)
      NSAIDs
       02409284,7061.01.0
       1-472159,7741.30 (1.20-1.42)1.23 (1.12-1.34)
       >435824,6001.41 (1.26-1.57)1.33 (1.18-1.49)
      Acetaminophen
       02897320,8931.01.0
       1-442036,3481.23 (1.11-1.36)1.19 (1.07-1.32)
       >417111,8381.39 (1.19-1.62)1.33 (1.14-1.56)
      NSAID=nonsteroidal anti-inflammatory drug.
      low asterisk Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      The association between hearing loss and regular use of aspirin (P, interaction=.005), NSAIDs (P, interaction=.10), and acetaminophen (P, interaction=.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 <50 years and those aged 50-59 years were 33% more likely to have hearing loss than were nonregular users, but there was no association among men aged 60 years and older. For NSAIDs, regular users aged <50 years were 61% more likely, those aged 50-59 years were 32% more likely, and those aged 60 years and older were 16% more likely to develop hearing loss than nonregular users of NSAIDs. For acetaminophen, regular users aged <50 years were 99% more likely, regular users aged 50-59 years were 38% more likely, and those aged 60 years and older were 16% more likely to have hearing loss than nonregular users of acetaminophen.
      Table 4Analgesic Use and the Age-adjusted and Multivariate
      Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      Hazard Ratios (95% CI) for Incident Hearing Loss Stratified by Age
      AnalgesicAge <50 YearsAge 50-59 YearsAge 60+ Years
      Aspirin
       Age-adjusted1.32 (1.02-1.69)1.36 (1.20-1.54)1.03 (0.94-1.12)
       Multivariate1.33 (1.03-1.72)1.33 (1.17-1.50)1.02 (0.93-1.11)
      NSAIDs
       Age-adjusted1.59 (1.14-2.23)1.35 (1.15-1.58)1.17 (1.04-1.31)
       Multivariate1.61 (1.15-2.26)1.32 (1.13-1.55)1.16 (1.03-1.30)
      Acetaminophen
       Age-adjusted1.91 (1.29-2.82)1.37 (1.09-1.73)1.17 (0.99-1.37)
       Multivariate1.99 (1.34-2.95)1.38 (1.09-1.74)1.16 (0.99-1.37)
      NSAID=nonsteroidal anti-inflammatory drug.
      low asterisk Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, and race, as well as the other analgesics.
      The association between hearing loss and concomitant use of more than one class of analgesic appeared to be approximately additive (Table 5). For the combined use of 2 analgesics, the risk was highest for use of NSAIDs and acetaminophen (HR 1.58 [95% CI, 1.16-2.16]), as compared with those who did not use any of the analgesics regularly. This risk was similar to the impact of regular use of all 3 analgesics (HR 1.60 [95% CI, 1.23-2.09]).
      Table 5Age- and Multivariate-adjusted Hazard Ratios (95% CI) for Concomitant Regular Use of More Than 1 Type of Analgesic and Incident Hearing Loss
      AnalgesicCasesPerson-yearsAge-adjusted Hazard RatioMultivariate Hazard Ratio
      Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, race, and all categories of analgesic use.
      None1378182,3801.01.0
      All 3 analgesics6038091.75 (1.35-2.26)1.60 (1.23-2.09)
      NSAIDs+acetaminophen4330151.72 (1.27-2.32)1.58 (1.16-2.16)
      Aspirin+acetaminophen9777691.44 (1.17-1.76)1.40 (1.13-1.73)
      Aspirin+NSAIDs25019,8321.37 (1.20-1.57)1.25 (1.09-1.44)
      NSAID=nonsteroidal anti-inflammatory drug.
      low asterisk Adjusted for age, body mass index, alcohol, physical activity, folate, smoking, hypertension, diabetes, profession, race, and all categories of analgesic use.

      Discussion

      Regular analgesic use was independently associated with an increased risk of hearing loss. The increased risk of hearing loss seen with regular analgesic use was greatest among younger men, particularly those below age 60 years. In men aged 60 years and above, there was no relation observed between the risk of hearing loss and regular aspirin use, and the relation between regular use of NSAIDs and acetaminophen was attenuated. The risk of hearing loss increased with longer duration of analgesic use for both NSAIDs and acetaminophen.
      The ototoxic effects of high-dose salicylates, reversible hearing loss and tinnitus, are well documented.
      • Jung T.T.
      • Rhee C.K.
      • Lee C.S.
      • et al.
      Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
      In animal models, salicylate administration results in abnormal outer hair cell function and decreased cochlear blood flow.
      • Jung T.T.
      • Rhee C.K.
      • Lee C.S.
      • et al.
      Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
      Salicylates induce biochemical and electrophysiological changes that alter membrane conductance of outer hair cells
      • Stypulkowski P.H.
      Mechanisms of salicylate ototoxicity.
      and vasoconstriction in auditory microvasculature, possibly mediated by antiprostaglandin activity.
      • Brien J.A.
      Ototoxicity associated with salicylates A brief review.
      High doses of NSAIDs also have been reported to be ototoxic in animal studies and in human case reports.
      • McFadden D.
      • Plattsmier H.S.
      • Pasanen E.G.
      Temporary hearing loss induced by combinations of intense sounds and nonsteroidal anti-inflammatory drugs.
      Similar to salicylates, NSAIDs inhibit cyclooxygenase and decrease prostaglandin activity, potentially reducing cochlear blood flow.
      • Jung T.T.
      • Rhee C.K.
      • Lee C.S.
      • et al.
      Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine.
      Histopathologic studies of human temporal bones
      • Nelson E.G.
      • Hinojosa R.
      Presbycusis: a human temporal bone study of individuals with downward sloping audiometric patterns of hearing loss and review of the literature.
      and in animals show degeneration of strial microvasculature.
      • Gratton M.A.
      • Schulte B.A.
      Alterations in microvasculature are associated with atrophy of the stria vascularis in quiet-aged gerbils.
      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 loss
      • Spicer S.S.
      • Schulte B.A.
      Spiral ligament pathology in quiet-aged gerbils.
      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
      • Forman J.P.
      • Rimm E.B.
      • Curhan G.C.
      Frequency of analgesic use and risk of hypertension among men.
      • Forman J.P.
      • Stampfer M.J.
      • Curhan G.C.
      Non-narcotic analgesic dose and risk of incident hypertension in US women.
      • Curhan G.C.
      • Willett W.C.
      • Rosner B.
      • Stampfer M.J.
      Frequency of analgesic use and risk of hypertension in younger women.
      and chronic renal dysfunction.
      • Fored C.M.
      • Ejerblad E.
      • Lindblad P.
      • et al.
      Acetaminophen, aspirin, and chronic renal failure.
      • Curhan G.C.
      • Knight E.L.
      • Rosner B.
      • et al.
      Lifetime nonnarcotic analgesic use and decline in renal function in women.
      Acetaminophen use increases risk of renal function decline, potentially due to depletion of glutathione.
      • Moldeus P.
      • Rahimtula A.
      Metabolism of paracetamol to a glutathione conjugate catalyzed by prostaglandin synthetase.
      Acetaminophen also might deplete endogenous cochlear glutathione, which is present in the cochlea in substantial amounts and protects the cochlea from noise-induced damage.
      • Yamasoba T.
      • Harris C.
      • Shoji F.
      • et al.
      Influence of intense sound exposure on glutathione synthesis in the cochlea.
      • Yamasoba T.
      • Nuttall A.L.
      • Harris C.
      • et al.
      Role of glutathione in protection against noise-induced hearing loss.
      The prevalence of hearing loss increases with age.
      • Cruickshanks K.J.
      • Wiley T.L.
      • Tweed T.S.
      • et al.
      Prevalence of hearing loss in older adults in Beaver Dam, Wisconsin The Epidemiology of Hearing Loss Study.
      After age 60 years, hearing thresholds worsen on average by 1 dB per year,
      • Lee F.S.
      • Matthews L.J.
      • Dubno J.R.
      • Mills J.H.
      Longitudinal study of pure-tone thresholds in older persons.
      and the rate of decline might be even greater in men aged 48-59 years.
      • Wiley T.L.
      • Chappell R.
      • Carmichael L.
      • et al.
      Changes in hearing thresholds over 10 years in older adults.
      The magnitude of the relation between regular analgesic use and hearing loss was greatest in men younger than age 60 years. 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.
      • Bainbridge K.E.
      • Hoffman H.J.
      • Cowie C.C.
      Diabetes and hearing impairment in the United States: audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004.
      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,
      • Agrawal Y.
      • Platz E.A.
      • Niparko J.K.
      Prevalence of hearing loss and differences by demographic characteristics among US adults: data from the National Health and Nutrition Examination Survey, 1999-2004.
      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 might increase the vulnerability to hearing loss related to age
      • Gates G.A.
      • Schmid P.
      • Kujawa S.G.
      • et al.
      Longitudinal threshold changes in older men with audiometric notches.
      • Kujawa S.G.
      • Liberman M.C.
      Acceleration of age-related hearing loss by early noise exposure: evidence of a misspent youth.
      • Erway L.C.
      • Shiau Y.W.
      • Davis R.R.
      • Krieg E.F.
      Genetics of age-related hearing loss in mice III. Susceptibility of inbred and F1 hybrid strains to noise-induced hearing loss.
      or other causes.
      • Brown R.D.
      • Penny J.E.
      • Henley C.M.
      • et al.
      Ototoxic drugs and noise.
      A study of patterns of medication use in the US found that 58% of older men reported that cardiovascular prophylaxis was the most common reason for aspirin use. Other reasons for use of over-the-counter medications, of which acetaminophen, ibuprofen, and aspirin were the most common, included headache and pain.
      • Kaufman D.W.
      • Kelly J.P.
      • Rosenberg L.
      • et al.
      Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey.
      We did not find any published reports relating common headache with hearing loss. Although migraine headaches might be associated with temporary hearing loss,
      • Dash A.K.
      • Panda N.
      • Khandelwal G.
      • et al.
      Migraine and audiovestibular dysfunction: is there a correlation?.
      the prevalence of migraine headaches in men in the US is low (6%),
      • Lipton R.B.
      • Bigal M.E.
      The epidemiology of migraine.
      thus unlikely to explain our findings. Autoimmune diseases, such as rheumatoid arthritis, might cause hearing loss,
      • Ozturk A.
      • Yalcin S.
      • Kaygusuz I.
      • et al.
      High-frequency hearing loss and middle ear involvement in rheumatoid arthritis.
      but these conditions are extremely rare in men and unlikely to have influenced our results. Hypertension might increase the risk of hearing loss due to changes in the cochlear microvasculature,
      • Brant L.J.
      • Gordon-Salant S.
      • Pearson J.D.
      • et al.
      Risk factors related to age-associated hearing loss in the speech frequencies.
      as might cardiovascular disease, such as stroke, coronary heart disease, and intermittent claudication;
      • Gates G.A.
      • Cobb J.L.
      • D'Agostino R.B.
      • Wolf P.A.
      The relation of hearing in the elderly to the presence of cardiovascular disease and cardiovascular risk factors.
      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 might not be generalizable to other racial groups. Although the participants in this cohort might not be representative of the adult population in the US, 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, younger men, and other racial groups.
      Regular use of analgesics, specifically aspirin, NSAIDs, and acetaminophen, might increase the risk of adult hearing loss, particularly in younger individuals. Given the high prevalence of regular analgesic use and health and social implications of hearing impairment, this represents an important public health issue.

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