Spotting Long-Term LASIK Pain Through Protein Patterns in Tears

In the United States, around 64% of adults now require prescription glasses or contacts.¹ And each year, more than 800,000 people decide they would rather not be part of this spectacle (pun very much intended), opting instead for laser eye surgery—with laser in situ keratomileusis (LASIK) and photorefractive keratectomy (PRK) being the most common types.² While it is unsurprising that applying a laser to your eyeball might cause some discomfort in the immediate post-surgical period, up to 40% of people experience chronic pain and eye symptoms long after surgery.^3,4 Studies show tear film abnormalities in people who continue to experience pain, as well as dysfunctional corneal nerve sensations suggestive of both nociceptive and neuropathic pain signaling.^5,6

Now, a new study in the Journal of Proteome Research reports that changes in tear proteins could be linked to whether people experience long-lasting pain after surgery. Crucially, this could provide clinicians with a biomarker that could help to predict those at risk of long-term adverse outcomes.⁷

For this study, 120 volunteers who received LASIK or PKK from two clinics in the United States had their tears collected three months after surgery. Participants rated their eye pain using a numerical rating scale at baseline, and then at the three-month mark. The researchers then used an untargeted proteomic analysis to compare any measurable proteins in tears from patients with pain after their surgery to those without.

Of 2,748 proteins analyzed, about 3% were found to be associated with pain three months after surgery—with models using three or four proteins delivering better classification performance than just one. Interestingly, many of the proteins that were altered in participants with persistent postoperative pain are known to be involved in injury, inflammation, and immune function. This chimes with proteome data from other ocular conditions—for example, 190 proteins have been found to be significantly expressed in people suffering from dry eye, and many are also inflammatory-related proteins and metabolites.⁸

Previous work from the same team has also shown that some individual and clinical features such as tear volume or contact lens use can alter tear proteins.⁹ In fact, researchers have been looking into this for a long time. In work published in 2004, tears collected from 21 patients scheduled for surgery to remove an ocular surface neoplasm verified that three human α-defensins were significantly up-regulated after surgery, with levels returning to normal when healing was complete around the one-month mark.¹⁰

Future studies will be needed to determine exactly how these biomarkers could be used for an accurate diagnosis or prediction of persistent symptoms after eye surgery. However, the authors note that biomarkers for pain may not be confined to molecular signatures, and may include other physical measures or quantifiable and personal assessments, leading to the emerging concept of biosignatures for pain or other states of interest.^11,12

In fact, the eye seems to be emerging as a window into not only our souls, but also our health, and has been suggested as a suitable environment for non-invasive monitoring of diseases via smart contact lens sensors.¹³ As well as eye-specific monitoring, biomarkers correlate strongly with their concentration in blood, so could be used for measure glucose concentrations, for example. And of course, we can’t come back to the topic of tears without reminding you that proteomic analysis was used to isolate tear proteins from Dracula's 15th century letters that revealed the infamous prince could have suffered from a rare condition called haemolacria.¹⁴

As the understanding of pain pathophysiology evolves, integrating these biomarker insights with emerging biosignature concepts could transform postoperative care. With ongoing research, clinicians may soon have powerful tools to predict and manage persistent pain, enhancing outcomes for countless individuals seeking clear vision without the burden of glasses or contacts.

References

1. Share of adult consumers wearing prescription (Rx) eyeglasses in the United States from 2013 to 2016. Statista 2024.
2. Joffe, S. N. The 25th Anniversary of Laser Vision Correction in the United States. Clin. Ophthalmol. 2021, 15, 1163–1172.
3. Eydelman M, et al. Symptoms and Satisfaction of Patients in the Patient-Reported Outcomes With Laser In Situ Keratomileusis (PROWL) Studies. JAMA Ophthalmol. 2017, 135 (1), 13–22.
4. Gaeckle, H. C. Early clinical outcomes and comparison between trans-PRK and PRK, regarding refractive outcome, wound healing, pain intensity and visual recovery time in a real-world setup. BMC Ophthalmol. 2021, 21 (1), 181.
5. Singh, S. et al. Study of tear function before and after laser-assisted in-situ keratomileusis. Indian J. Ophthalmol. 2023, 71 (4), 1503–1507.
6. Galor, A. et al. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye 2015, 29 (3), 301–312.
7. Harkness, B. M. et al. Tear Proteins Altered in Patients with Persistent Eye Pain after Refractive Surgery: Biomarker Candidate Discovery. J. Proteome Res. 2024, 23, 7, 2629–2640.
8. Chen, X. et al. Integrated Tear Proteome and Metabolome Reveal Panels of Inflammatory-Related Molecules via Key Regulatory Pathways in Dry Eye Syndrome. J. Proteome Res. 2019, 18, 5, 2321–2330.
9. Harkness, B. M. et al. Experimental design considerations for studies of human tear proteins. Ocul. Surf. 2023, 28, 58–78.
10. Zhou, L. et al. Proteomic Analysis of Human Tears: Defensin Expression after Ocular Surface Surgery. J. Proteome Res. 2004, 3, 3, 410–416.
11. Shirvalkar, P. et al. First-in-human prediction of chronic pain state using intracranial neural biomarkers. Nat. Neurosci. 2023, 26 (6), 1090–1099.
12. Sluka, K. A. et al. Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures. Pain 2023, 164 (9), 1912–1926.
13. Liu, X. et al. Smart Contact Lenses for Healthcare Monitoring and Therapy. ACS Nano 2024, 18, 9, 6817–6844.
14. Pittalà, M. G. G. et al. Count Dracula Resurrected: Proteomic Analysis of Vlad III the Impaler’s Documents by EVA Technology and Mass Spectrometry. Anal. Chem. 2023, 95, 34, 12732–12744.