Increased Risk of Dry Eye Disease in Patients with Chronic Pain Conditions: Insights from a Large Retrospective Cohort Study

Highlight

– Patients with chronic pain conditions (CPCs) have a notably higher risk of developing incident dry eye disease (DED) over a 3-year follow-up.
– CPCs are associated with increased incidence of prescription-requiring DED, indicating more severe or symptomatic cases.
– Large-scale retrospective cohort analysis demonstrates a robust independent association validated in a secondary cohort.
– Findings support considering CPCs as significant risk factors for DED in clinical evaluation and management strategies.

Study Background and Disease Burden

Dry eye disease (DED) is a common, multifactorial ocular surface disorder characterized by tear film instability and inflammation, leading to symptoms such as dryness, irritation, and visual disturbance. Its prevalence increases with age and it significantly impacts quality of life and productivity. Despite advances in understanding ocular surface physiology, the pathogenesis of DED often involves systemic factors beyond local ocular causes.

Chronic pain conditions (CPCs) affect a substantial portion of the adult population and are characterized by persistent pain with or without overt tissue injury. Neural mechanisms including central sensitization may contribute to widespread symptoms including abnormalities in pain processing and sensory perception.

The intersection of chronic pain and dry eye disease suggests shared pathophysiological pathways related to neural dysregulation and inflammation. However, large-scale population-based evidence delineating the risk of incident DED among patients with CPCs was lacking prior to this study.

Study Design

This study was a retrospective cohort analysis leveraging the TriNetX Analytics Network, encompassing electronic health records from 2005 to 2025. Adults aged 18 years or older who had a qualifying ophthalmology examination and no prior record of DED were included. The exposure cohort consisted of patients with at least one documented chronic pain condition diagnosis before the index ophthalmology visit, whereas controls were patients without any CPC diagnosis before or after the index date.

Propensity score matching was employed at a 1:1 ratio to balance demographics and comorbid conditions, resulting in 538,364 patients in each cohort. Additionally, a validation cohort restricted to patients with age-related cataract (506,763 matched patients per group) was analyzed to confirm findings.

Chronic pain conditions and dry eye disease were identified using standard diagnostic codes (ICD-10-CM, SNOMED) and CPT procedure codes. Outcomes were assessed at 1-year, 2-year, and 3-year intervals following the index visit. Two primary endpoints were evaluated: incident DED defined by new clinical diagnoses of dry eye syndrome or keratoconjunctivitis sicca excluding Sjögren’s syndrome, and prescription-requiring DED defined by initiation of topical immunomodulatory agents cyclosporine or lifitegrast.

Key Findings

Patients with chronic pain conditions had a significantly increased risk of developing incident dry eye disease at all measured time points. At 1 year, the incidence of new DED diagnosis was 3.34% in the CPC cohort versus 0.72% in controls, corresponding to a risk ratio (RR) of 4.64 (95% CI, 4.49–4.81; p<0.0001). The cumulative incidence increased over time, reaching 7.16% versus 1.50% at 3 years (RR 4.78; 95% CI, 4.66–4.89; p<0.0001).

Importantly, prescription-requiring DED—reflecting more symptomatic or treatment-refractory disease—was also significantly more frequent in the CPC group (0.79% vs 0.30% at 3 years; RR 2.60; 95% CI, 2.45–2.75). Kaplan-Meier survival curves demonstrated a consistent time-dependent elevation in DED incidence in patients with CPCs.

Multivariable Cox proportional hazards modeling, adjusted for demographics and confounders, confirmed that presence of CPCs was independently associated with nearly a fivefold increase in hazard of incident DED (hazard ratio 4.85; 95% CI, 4.76–4.94; p<0.0001). These findings were replicated in the validation cohort limited to patients with cataract, underscoring robustness and generalizability.

Expert Commentary

This study compellingly establishes chronic pain conditions as strong risk factors for incident dry eye disease and more severe forms requiring pharmacologic treatment. The large sample size and rigorous methodology, including propensity score matching and use of a validation cohort, strengthen the validity of these results.

From a mechanistic perspective, the data support the hypothesis that neural sensitization and aberrant pain processing pathways intrinsic to chronic pain disorders may contribute to ocular surface dysregulation and symptom generation in DED. This extends understanding of DED pathogenesis beyond traditional factors such as tear deficiency or local inflammation.

Clinically, these findings argue for increased vigilance among ophthalmologists and primary care providers to screen for dry eye symptoms in patients with chronic pain. Early identification could facilitate timely therapeutic intervention potentially improving both ocular and systemic symptom burden.

Limitations include the retrospective design and reliance on diagnosis codes, which may be prone to misclassification. Furthermore, unmeasured confounding including medication use or lifestyle factors could contribute. Prospective studies and mechanistic investigations would be valuable to confirm causality and explore targeted management strategies.

Conclusion

The presence of chronic pain conditions confers a significantly increased risk of developing dry eye disease, including cases severe enough to require prescription immunomodulatory treatment. This highlights an important systemic dimension to DED pathophysiology and underscores the need for integrated multidisciplinary care approaches.

Consideration of CPCs as risk factors should become part of standard dry eye screening and evaluation protocols, and research is warranted to elucidate underlying mechanisms and optimize management for this patient subset.

Funding and Disclosures

This study was published in the American Journal of Ophthalmology on July 17, 2026 (PMID: 42468897). Specific funding sources were not detailed in the abstract. The authors have not disclosed conflicts of interest in the summarized content.

References

Berzack S, Shmushkevich SB, Zhang C, Felix ER, De Lott LB, Galor A. Risk of Incident Dry Eye Disease Among Patients with Chronic Pain Conditions. Am J Ophthalmol. 2026 Jul 17. PMID: 42468897.
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Galor A, Levitt RC, Felix ER, et al. Neuropathic Pain and Dry Eye. Ocul Surf. 2018;16(1):31-44.
Vehof J, Smith SE, Barabino S, Dry Eye Epidemiology. Cornea. 2019;38 Suppl 1:S53-S59.