Skip to main content

Randomized Controlled Study to Investigate the Effect of Topical Diquafosol Tetrasodium on Corneal Sensitivity in Short Tear Break-Up Time Dry Eye



Complex mechanisms underlie dry eye (DE) symptom provocation. In particular, corneal hypersensitivity may provoke symptoms in short tear break-up time (BUT) DE characterized by tear film instability. We hypothesized that improved tear film stability may alleviate corneal sensitivity in patients with short tear BUT DE. Therefore, we investigated the effect of topical diquafosol tetrasodium (DQS) on corneal sensitivity in unstable tear film DE.


This prospective, randomized study included 27 subjects (age: 39.1 ± 8.4 years; range: 25–59 years) with short tear BUT DE, defined based on the presence of DE symptoms and tear film instability. Subjects were randomly divided into DQS (3% DQS, 12 subjects) and artificial tear (AT; preservative-free AT, 15 subjects) groups. Subjects applied the medication 6 times a day for 5 weeks. The perception of touch (S-touch) and pain (S-pain) sensitivity was measured using a Cochet—Bonnet esthesiometer. Tear evaluation, corneal sensitivity, and DE symptoms were compared before and after DQS or AT administration. The correlation between the improvement degrees of corneal sensitivity and DE symptoms following medication was analyzed.


DQS significantly improved tear BUT and tear meniscus height (TMH) scores (p < 0.05), while AT significantly improved tear BUT (p < 0.05) but not TMH score. Mean S-pain and DE symptom scores were lower after medication use in the DQS (S-pain and DE symptoms: p  < 0.05) and AT groups (S-pain: p  = 0.05; DE symptoms: p  < 0.05). However, S-touch did not change significantly in either group. A positive correlation was observed between the improvement degrees of S-pain and DE symptoms in the overall subjects studied.


Both DQS and AT alleviate corneal hypersensitivity and DE symptoms in eyes with short tear BUT DE. However, DQS seems to be more effective to adjust tear environment, leading to the normalization of corneal sensitivity and DE symptoms.

Trial Registration

UMIN Clinical Trials Registry Identifier, UMIN000014536

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3


  1. The definition and classification of dry eye disease: report of the definition and classification subcommittee of the international dry eye workshop (2007). Ocul Surf 2007;5:75–92.

  2. Johnson ME. The association between symptoms of discomfort and signs in dry eye. Ocul Surf. 2009;7:199–211.

    Article  PubMed  Google Scholar 

  3. Knop E, Knop N, Millar T, Obata H, Sullivan DA. The international workshop on meibomian gland dysfunction: report of the subcommittee on anatomy, physiology, and pathophysiology of the meibomian gland. Invest Ophthalmol Vis Sci. 2011;52:1938–78.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schaumberg DA, Nichols JJ, Papas EB, Tong L, Uchino M, Nichols KK. The international workshop on meibomian gland dysfunction: report of the subcommittee on the epidemiology of, and associated risk factors for, MGD. Invest Ophthalmol Vis Sci. 2011;52:1994–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shimazaki-Den S, Dogru M, Higa K, Shimazaki J. Symptoms, visual function, and mucin expression of eyes with tear film instability. Cornea. 2013;32:1211–8.

    Article  PubMed  Google Scholar 

  6. Uchino Y, Uchino M, Yokoi N, et al. Alteration of tear mucin 5AC in office workers using visual display terminals: The Osaka Study. JAMA Ophthalmol. 2014;132:985–92.

    Article  PubMed  Google Scholar 

  7. Toda I, Fujishima H, Tsubota K. Ocular fatigue is the major symptom of dry eye. Acta Ophthalmol (Copenh). 1993;71:347–52.

    Article  CAS  Google Scholar 

  8. Yokoi N, Uchino M, Uchino Y, et al. Importance of tear film instability in dry eye disease in office workers using visual display terminals: The Osaka Study. Am J Ophthalmol. 2015;159:748–54.

    Article  PubMed  Google Scholar 

  9. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012;31:472–8.

    Article  PubMed  Google Scholar 

  10. Uchino M, Schaumberg DA, Dogru M, et al. Prevalence of dry eye disease among Japanese visual display terminal users. Ophthalmology. 2008;115:1982–8.

    Article  PubMed  Google Scholar 

  11. Uchino M, Yokoi N, Uchino Y, et al. Prevalence of dry eye disease and its risk factors in visual display terminal users: The Osaka Study. Am J Ophthalmol. 2013;156:759–66.

    Article  PubMed  Google Scholar 

  12. Kaido M, Kawashima M, Yokoi N, et al. Advanced dry eye screening for visual display terminal workers using functional visual acuity measurement: the Moriguchi study. Br J Ophthalmol. 2015;99:1488–92.

    Article  PubMed  Google Scholar 

  13. Rosenthal P, Borsook D. The corneal pain system. Part I: the missing piece of the dry eye puzzle. Ocul Surf. 2012;10:2–14.

    Article  PubMed  Google Scholar 

  14. Rosenthal P, Borsook D. Ocular neuropathic pain. Br J Ophthalmol. 2016;100:128–34.

    Article  PubMed  Google Scholar 

  15. Kaido M, Kawashima M, Ishida R, Tsubota K. Relationship of corneal pain sensitivity with dry eye symptoms in dry eye with short tear break-up time. Invest Ophthalmol Vis Sci. 2016;57:914–9.

    Article  PubMed  Google Scholar 

  16. Fujihara T, Murakami T, Fujita H, Nakamura M, Nakata K. Improvement of corneal barrier function by the P2Y(2) agonist INS365 in a rat dry eye model. Invest Ophthalmol Vis Sci. 2001;42:96–100.

    PubMed  CAS  Google Scholar 

  17. Yokoi N, Kato H, Kinoshita S. Facilitation of tear fluid secretion by 3% diquafosol ophthalmic solution in normal human eyes. Am J Ophthalmol. 2014;157:85–92.

    Article  PubMed  CAS  Google Scholar 

  18. Jumblatt JE, Jumblatt MM. Regulation of ocular mucin secretion by P2Y2 nucleotide receptors in rabbit and human conjunctiva. Exp Eye Res. 1998;67:341–6.

    Article  PubMed  CAS  Google Scholar 

  19. Shigeyasu C, Yamada M, Akune Y, Tsubota K. Diquafosol sodium ophthalmic solution for the treatment of dry eye: clinical evaluation and biochemical analysis of tear composition. Jpn J Ophthalmol. 2015;59:415–20.

    Article  PubMed  CAS  Google Scholar 

  20. Kobashi H, Kamiya K, Igarashi A, Miyake T, Shimizu K. Intraocular scattering after instillation of diquafosol ophthalmic solution. Optom Vis Sci. 2015;92:e303–9.

    Article  PubMed  Google Scholar 

  21. Shimazaki-Den S, Iseda H, Dogru M, Shimazaki J. Effects of diquafosol sodium eye drops on tear film stability in short BUT type of dry eye. Cornea. 2013;32:1120–5.

    Article  PubMed  Google Scholar 

  22. Koh S, Ikeda C, Takai Y, Watanabe H, Maeda N, Nishida K. Long-term results of treatment with diquafosol ophthalmic solution for aqueous-deficient dry eye. Jpn J Ophthalmol. 2013;57:440–6.

    Article  PubMed  CAS  Google Scholar 

  23. Sakane Y, Yamaguchi M, Yokoi N, et al. Development and validation of the dry eye-related quality-of-life score questionnaire. JAMA Ophthalmol. 2013;131:1331–8.

    Article  PubMed  Google Scholar 

  24. van Bijsterveld OP. Diagnostic tests in the Sicca syndrome. Arch Ophthalmol. 1969;82:10–4.

    Article  PubMed  Google Scholar 

  25. Ibrahim OM, Dogru M, Ward SK, et al. The efficacy, sensitivity, and specificity of strip meniscometry in conjunction with tear function tests in the assessment of tear meniscus. Invest Ophthalmol Vis Sci. 2011;52:2194–8.

    Article  PubMed  Google Scholar 

  26. De Paiva CS, Pflugfelder SC. Corneal epitheliopathy of dry eye induces hyperesthesia to mechanical air jet stimulation. Am J Ophthalmol. 2004;137:109–15.

    Article  PubMed  Google Scholar 

  27. Bourcier T, Acosta MC, Borderie V, et al. Decreased corneal sensitivity in patients with dry eye. Invest Ophthalmol Vis Sci. 2005;46:2341–5.

    Article  PubMed  Google Scholar 

  28. Hoşal BM, Ornek N, Zilelioğlu G, Elhan AH. Morphology of corneal nerves and corneal sensation in dry eye: A Preliminary Study. Eye (Lond). 2005;19:1276–9.

    Article  Google Scholar 

  29. Benítez del Castillo JM, Acosta MC, Wassfi MA, et al. Relation between corneal innervation with confocal microscopy and corneal sensitivity with noncontact esthesiometry in patients with dry eye. Invest Ophthalmol Vis Sci. 2007;48:173–81.

    Article  PubMed  Google Scholar 

  30. Situ P, Simpson TL, Jones LW, Fonn D. Conjunctival and corneal hyperesthesia in subjects with dryness symptoms. Optom Vis Sci. 2008;85:867–72.

    Article  PubMed  Google Scholar 

  31. Spierer O, Felix ER, McClellan AL, et al. Corneal mechanical thresholds negatively associate with dry eye and ocular pain symptoms. Invest Ophthalmol Vis Sci. 2016;57:617–25.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Tsubota K, Yokoi N, Shimazaki J, et al. New perspectives on dry eye definition and diagnosis: a consensus report by the Asia Dry Eye Society. Ocul Surf. 2017;15:65–76.

    Article  PubMed  Google Scholar 

  33. Liu H, Begley C, Chen M, et al. A link between tear instability and hyperosmolarity in dry eye. Invest Ophthalmol Vis Sci. 2009;50:3671–9.

    Article  PubMed  Google Scholar 

  34. Belmonte C, Acosta MC, Schmelz M, Gallar J. Measurement of corneal sensitivity to mechanical and chemical stimulation with a CO2 esthesiometer. Invest Ophthalmol Vis Sci. 1999;40:513–9.

    PubMed  CAS  Google Scholar 

Download references



Facility provisions and equipment transport were funded by Santen Pharmaceutical Co., Ltd. The funding organization had no role in data analyses or in the conduct of this research. The article processing charges were funded by the authors.


All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. All authors had full access to all of the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis.

Author Contribution statement

Conception and design of the study: Minako Kaido, Kazuo Tsubota. Analysis and interpretation of results: Minako Kaido. Manuscript preparation: Minako Kaido. Critical review of the article: Motoko Kawashima, Yoshiaki Yamada, Kazuo Tsubota. Data acquisition: Minako Kaido, Yuta Shigeno. Provision of materials, patients, or resources: Minako Kaido, Yoshiaki Yamada. Statistical expertise, literature searches: Minako Kaido. Administrative, technical, or logistic support: Minako Kaido, Kazuo Tsubota

Thanking Patient Participants

We thank all the study participants for their participation in the study.

Data Management

We wish to thank the Biostatistical Research Co. (Tokyo, Japan) for their assistance in data management.


Kazuo Tsubota is a consultant for Santen Pharmaceutical Co., Ltd. (Osaka, Japan). The Department of Ophthalmology, Keio University School of Medicine receives research funds from Santen Pharmaceutical Co., Ltd., and Kazuo Tsubota is a member of Santen’s Speaker’s Bureau. However, Santen Pharmaceutical Co., Ltd. was not involved with the scientific content of the research projects run by the department. Yoshiaki Yamada is an employee at Santen Pharmaceutical Co., Ltd. Minako Kaido, Motoko Kawashima and Yuta Shigeno have nothing to disclose.

Compliance with Ethics Guidelines

This study protocol was reviewed and approved by the Ethics Committee of the Institutional Review Board at the Shinanozaka Clinic. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964, as revised in 2013. Informed consent was obtained from all patients for being included in the study. This study was registered in the University hospital Medical Information Network (UMIN) (Registries No. UMIN000014536).

Data Availability

All data generated or analyzed during this study are included in this published article/as supplementary information files.

Author information

Authors and Affiliations


Corresponding author

Correspondence to Minako Kaido.

Additional information

Enhanced content

To view enhanced content for this article go to

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (XLSX 20 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kaido, M., Kawashima, M., Shigeno, Y. et al. Randomized Controlled Study to Investigate the Effect of Topical Diquafosol Tetrasodium on Corneal Sensitivity in Short Tear Break-Up Time Dry Eye. Adv Ther 35, 697–706 (2018).

Download citation

  • Received:

  • Published:

  • Issue Date:

  • DOI:


  • Corneal sensitivity
  • Diquafosol
  • Dry eye
  • Neuropathic pain
  • Tear film