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Original Research
Published: 07 February 2022
Longitudinal Study of Analgesic Use and Risk of Incident Persistent

Tinnitus
Sharon G. Curhan MD, ScM ORCID: orcid.org/0000-0003-0282-08221,2,
Jordan Glicksman MD, MPH3,
Molin Wang PhD1,4,5,
…
Roland D. Eavey MD, SM6 &
Gary C. Curhan MD, ScD1,2,5,7
Show authors
Journal of General Internal Medicine (2022)Cite this article
82 Accesses
654 Altmetric
https://link.springer.com/article/10.1007/s11606-021-07349-5 Page 1 of 24
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Abstract
Background
Persistent tinnitus is common, disabling, and difficult to treat. High-dose aspirin may precipitate tinnitus, but
longitudinal data on typical dose aspirin and other analgesics are scarce.
Objective
To investigate independent associations of aspirin, NSAIDs, and acetaminophen and risk of incident persistent
tinnitus.
Design
Longitudinal cohort study.
Setting
Nurses’ Health Study II (1995–2017).
Participants
A total of 69,455 women, age 31–48 years, without tinnitus at baseline.
Main Measures
Information on analgesic use and tinnitus obtained by biennial questionnaires.
Key Results
After 1,120,936 person-years of follow-up, 10,452 cases of incident persistent tinnitus were reported. For low-
dose aspirin, the risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users.
For moderate dose aspirin, frequent use was associated with higher risk of tinnitus among women aged < 60
years, but not among older women (p-interactionage = 0.003). Compared with women aged < 60 using
moderate-dose aspirin < 1 day/week, the multivariable-adjusted hazard ratio (MVHR, 95% CI) among women
using moderate-dose aspirin 6–7 days per week was 1.16 (1.03, 1.32). Among all women, frequent non-aspirin
non-steroidal anti-inflammatory drug (NSAID) or acetaminophen use was associated with higher risk.
Compared with women using NSAIDs <1 day/week, the MVHR for use 4–5days/week was 1.17 (1.08, 1.28)
and for 6–7days/week was 1.07 (1.00, 1.16) (p-trend=0.001). For acetaminophen, compared with use <1
day/week, the MVHR for use 6–7days/week was 1.18 (1.07, 1.29) (p-trend=0.002).
Limitations
Information on tinnitus and analgesic use was self-reported. Information on indications for analgesic use was
not available. Studies in non-White women and men are needed.
Conclusion
The risk of developing persistent tinnitus was not elevated among frequent low-dose aspirin users. Among
younger women, frequent moderate-dose aspirin use was associated with higher risk. Frequent NSAID use and
frequent acetaminophen use were associated with higher risk of incident persistent tinnitus among all women,
and the magnitude of the risks tended to be greater with increasing frequency of use. Our results suggest
analgesic users are at higher risk for developing tinnitus and may provide insight into the precipitants of this
challenging disorder, but additional investigation to determine whether there is a causal association is needed.
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US women. Hypertension 2005;46:500-7.
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tinnitus. Am J Med 2014;127:739-43.
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tinnitus prevalence and severity. Hear Res 2016;337:70-9.
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Acknowledgements
We would like to thank Elaine Coughlin-Gifford for her programming help on this project.
Funding
This research was supported by grants U01 DC010811, R01 DC017717, and UO1 CA176726 from the National
Institutes of Health.
Author information
Affiliations
1. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital,
Boston, MA, USA
Sharon G. Curhan MD, ScM, Molin Wang PhD & Gary C. Curhan MD, ScD
2. Harvard Medical School, Boston, MA, USA
Sharon G. Curhan MD, ScM & Gary C. Curhan MD, ScD
3. Massachusetts Eye and Ear, Boston, MA, USA
Jordan Glicksman MD, MPH
4. Department of Biostatistics, Harvard School of Public Health, Boston, MA, USA
Molin Wang PhD
5. Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA
Molin Wang PhD & Gary C. Curhan MD, ScD
6. Vanderbilt Bill Wilkerson Center for Otolaryngology and Communication Sciences and the Department
of Otolaryngology, Vanderbilt University Medical Center, Nashville, TN, USA
Roland D. Eavey MD, SM
7. Renal Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
Gary C. Curhan MD, ScD
Authors
1. Sharon G. Curhan MD, ScM

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2. Jordan Glicksman MD, MPH

3. Molin Wang PhD

4. Roland D. Eavey MD, SM

5. Gary C. Curhan MD, ScD

Contributions
Dr. S. Curhan led this investigation. Dr. S. Curhan formulated the study question and design, contributed to
directing its implementation, performed the statistical analyses, contributed to the acquisition of the data,
conducted the analysis and interpretation of the data, conducted the literature review, and wrote the first draft of
the manuscript. Dr. Glicksman contributed to the formulation of the study question, data analysis, and the
interpretation of the results. Dr. Wang contributed to the data acquisition and analysis. Dr. Eavey contributed to
the study conception and design. Dr. G. Curhan contributed to the study conception and design, supervision of
its implementation, data acquisition and analysis, and interpretation of the results. All authors contributed to the
critical revision of the manuscript, approved the final version, and made the decision to submit the manuscript
for publication.
Corresponding author
Correspondence to Sharon G. Curhan MD, ScM.
Ethics declarations
Conflict of Interest
Dr. S. Curhan serves as a consultant to Decibel Therapeutics. Dr. G. Curhan serves as a consultant to Decibel
Therapeutics, AstraZeneca, Shire, RenalGuard, Allena Pharmaceuticals, OrfanBiotech, OM1, and Merck. He
receives royalties from UpToDate for being an author and Section Editor. The other authors declare no conflicts
of interest. All authors had access to the data and participated in the preparation of the manuscript.
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Curhan, S.G., Glicksman, J., Wang, M. et al. Longitudinal Study of Analgesic Use and Risk of Incident
Persistent Tinnitus. J GEN INTERN MED (2022). https://doi.org/10.1007/s11606-021-07349-5
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Received: 13 August 2021
Accepted: 15 December 2021
Published: 07 February 2022
DOI: https://doi.org/10.1007/s11606-021-07349-5
KEY WORDS
tinnitus
analgesics
acetaminophen
non-steroidal anti-inflammatory drug (NSAID)
cohort study
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1. Baguley D, McFerran D, Hall D. Tinnitus. Lancet

2013;382:1600-7.
2. Nondahl DM, Cruickshanks KJ, Dalton DS, et al.

The impact of tinnitus on quality of life in older
adults. J Am Acad Audiol 2007;18:257-66.
3. Shargorodsky J, Curhan GC, Farwell WR.

Prevalence and characteristics of tinnitus among US
adults. Am J Med 2010;123:711-8.
4. Nondahl DM, Cruickshanks KJ, Wiley TL, Klein

R, Klein BE, Tweed TS. Prevalence and 5-year
incidence of tinnitus among older adults: the
epidemiology of hearing loss study. J Am Acad
Audiol 2002;13:323-31.
5. Martinez C, Wallenhorst C, McFerran D, Hall DA.

Incidence rates of clinically significant tinnitus: 10-
year trend from a cohort study in England. Ear Hear
2015;36:e69-75.
6. Hoare DJ, Kowalkowski VL, Kang S, Hall DA.

Systematic review and meta-analyses of randomized
controlled trials examining tinnitus management.
Laryngoscope 2011;121:1555-64.
7. Dale O, Borchgrevink PC, Fredheim OM, Mahic

M, Romundstad P, Skurtveit S. Prevalence of use of
non-prescription analgesics in the Norwegian HUNT3
population: Impact of gender, age, exercise and
prescription of opioids. BMC Public Health
2015;15:461.
8. Kaufman DW, Kelly JP, Rosenberg L, Anderson

TE, Mitchell AA. Recent patterns of medication use
in the ambulatory adult population of the United
States: the Slone survey. JAMA 2002;287:337-44.
9. Patterns of medication use in the United States 2006:

A report from the Slone survey. 2006. (Accessed
5/6/2021, at
http://www.bu.edu/slone/files/2012/11/SloneSurveyReport2006.pdf.)
10. Bennett K, Teeling M, Feely J. "Selective" switching

from non-selective to selective non-steroidal anti-
inflammatory drugs. Eur J Clin Pharmacol
2003;59:645-9.
11. Chan FK, Hung LC, Suen BY, et al. Celecoxib

versus diclofenac and omeprazole in reducing the risk
of recurrent ulcer bleeding in patients with arthritis. N
Engl J Med 2002;347:2104-10.
12. Hoshino T, Tabuchi K, Hara A. Effects of NSAIDs

on the Inner Ear: Possible Involvement in Cochlear
Protection. Pharmaceuticals (Basel) 2010;3:1286-95.
CAS Google Scholar
13. Someya S, Kim MJ. Cochlear detoxification: Role of

alpha class glutathione transferases in protection
against oxidative lipid damage, ototoxicity, and
cochlear aging. Hear Res 2021;402:108002.
14. Salvi R, Auerbach BD, Lau C, et al. Functional

Neuroanatomy of Salicylate- and Noise-Induced
Tinnitus and Hyperacusis. Curr Top Behav Neurosci
2021;51:133-160.
15. Salvi R, Radziwon K, Manohar S, et al. Review:

Neural Mechanisms of Tinnitus and Hyperacusis in
Acute Drug-Induced Ototoxicity. Am J Audiol
2021:1-15.
16. Jung TT, Rhee CK, Lee CS, Park YS, Choi DC.
Ototoxicity of salicylate, nonsteroidal
antiinflammatory drugs, and quinine. Otolaryngol
Clin North Am 1993;26:791-810.
17. Curhan SG, Eavey R, Shargorodsky J, Curhan

GC. Analgesic use and the risk of hearing loss in
men. Am J Med. 2010;123:231-7.
18. Curhan SG, Shargorodsky J, Eavey R, Curhan

GC. Analgesic use and the risk of hearing loss in
19. Lin BM, Curhan SG, Wang M, Eavey R, Stankovic

KM, Curhan GC. Duration of Analgesic Use and
Risk of Hearing Loss in Women. Am J Epidemiol
2017;185:40-7.
20. Cazals Y. Auditory sensori-neural alterations induced

by salicylate. Prog Neurobiol 2000;62:583-631.
21. Bao Y, Bertoia ML, Lenart EB, et al. Origin,

Methods, and Evolution of the Three Nurses' Health
Studies. Am J Public Health 2016;106:1573-81.
22. Forman JP, Stampfer MJ, Curhan GC.Non-

narcotic analgesic dose and risk of incident
hypertension in US women. Hypertension
2005;46:500-7.
23. Cho E, Curhan G, Hankinson S, et al. Prospective

evaluation of analgesic use and risk of renal cell
cancer. Arch Intern Med 2011;171:1487-93.
24. Gao X, Chen H, Schwarzschild MA, Ascherio A.

Use of ibuprofen and risk of Parkinson disease.
Neurology 2011;76:863-9.
25. Curhan SG, Halpin C, Wang M, Eavey RD,

Curhan GC. Tinnitus and 3-Year Change in
Audiometric Hearing Thresholds. Ear Hear
2021;42:886-95.
26. Glicksman JT, Curhan SG, Curhan GC. A

prospective study of caffeine intake and risk of
incident tinnitus. Am J Med 2014;127:739-43.
27. McCormack A, Edmondson-Jones M, Somerset S,

Hall D. A systematic review of the reporting of
tinnitus prevalence and severity. Hear Res
2016;337:70-9.
28. Chiuve SE, Fung TT, Rimm EB, et al. Alternative

dietary indices both strongly predict risk of chronic
disease. J Nutr 2012;142:1009-18.
29. Burgess PM, Mazzocco L, Campbell

IM.Discriminant validity of the Crown-Crisp
Experiential Index. Br J Med Psychol 1987;60 ( Pt
1):61-9.
30. Trudel-Fitzgerald C, Chen Y, Singh A, Okereke

OI, Kubzansky LD. Psychiatric, Psychological, and
Social Determinants of Health in the Nurses' Health
Study Cohorts. Am J Public Health 2016;106:1644-9.
31. Salvini S, Hunter DJ, Sampson L, et al.Food-based

validation of a dietary questionnaire: the effects of
week-to-week variation in food consumption. Int J
Epidemiol 1989;18:858-67.
32. Wolf AM, Hunter DJ, Colditz GA, et al.

Reproducibility and validity of a self-administered
physical activity questionnaire. Int J Epidemiol
1994;23:991-9.
33. Colditz GA, Martin P, Stampfer MJ, et al.

Validation of questionnaire information on risk factors
and disease outcomes in a prospective cohort study of
34. Rimm EB, Stampfer MJ, Colditz GA, Chute CG,

Litin LB, Willett WC. Validity of self-reported waist
and hip circumferences in men and women.
Epidemiology 1990;1:466-73.
35. Therneau TM. Extending the Cox model. 2nd ed.

New York: Springer Verlag; 1997.
Google Scholar
36. Bhatt JM, Lin HW, Bhattacharyya N. Prevalence,

Severity, Exposures, and Treatment Patterns of
Tinnitus in the United States. JAMA Otolaryngol
Head Neck Surg 2016;142(10):959-965.
37. Altissimi G, Colizza A, Cianfrone G, et al. Drugs

inducing hearing loss, tinnitus, dizziness and vertigo:
an updated guide. Eur Rev Med Pharmacol Sci
2020;24:7946-52.
38. Sheppard A, Hayes SH, Chen GD, Ralli M, Salvi

R. Review of salicylate-induced hearing loss,
neurotoxicity, tinnitus and neuropathophysiology.
Acta Otorhinolaryngol Ital 2014;34:79-93.
39. Zheng SL, Roddick AJ.Meta-analysis of Aspirin for

Primary Prevention of Cardiovascular Events-Reply.
JAMA 2019;321:2244-5.
40. Chan AT, Manson JE, Albert CM, et al.

Nonsteroidal antiinflammatory drugs, acetaminophen,
and the risk of cardiovascular events. Circulation
2006;113:1578-87.
41. Pillinger MH, Capodici C, Rosenthal P, et al.

Modes of action of aspirin-like drugs: salicylates
inhibit erk activation and integrin-dependent

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