Evidence that dry eye is a comorbid pain condition in a U.S. veteran population.

Many women with vulvodynia also suffer from other chronic co-morbid pain conditions. Alone, these pain conditions are associated with feeling invalidated by others and feeling socially isolated. It is unclear, however, how the presence of additional pain co-morbidities are associated with the psychosocial wellbeing of women with vulvodynia. We used data from a survey administered by the National Vulvodynia Association. Women reported clinician-diagnosed vulvodynia, presence of co-morbid pain, and how often they felt that they felt no one believed their pain existed (invalidated) and isolated. Analyses determined prevalence of feeling invalidated or isolated, and the difference in prevalence when co-morbidities existed. Forty-five percent of these 1847 women with vulvodynia reported having at least one of the following five chronic pain conditions, chronic fatigue syndrome, endometriosis, fibromyalgia, interstitial cystitis, or irritable bowel syndrome. Adjusted baseline prevalence among all women of feeling invalidated was 9% and of feeling isolated was 14%. Having a co-morbid condition with vulvodynia, as well as having an increasing number of co-morbid conditions with vulvodynia, was significantly associated with the presence of feeling both invalidated and isolated. Chronic fatigue syndrome was the co-morbidity most strongly associated with feelings invalidation and isolation. One or more co-morbid pain conditions in addition to vulvodynia were significantly associated with psychosocial wellbeing. However, the temporality of the association could not be elucidated and therefore we cannot conclude that these pain conditions cause poor psychosocial wellbeing. Despite this, future studies should explore the utility of promoting validation of women's pain conditions and reducing social isolation for women with chronic pain.

A Comparative study of tear film dysfunction after Small incision cataract surgery (SICS) and Phacoemulsification. Aims: To study tear film dysfunction after Small Incision Cataract Surgery (SICS) and Phacoemulsification. Settings and Design: Prospective Observational and Comparative study.Materials and Methods: 164 patients that met the inclusion and exclusion criteria were enrolled into the study at the Department of Ophthalmology, Dhiraj Hospital Piparia, Waghodia, Vadodara, after getting approval from Ethics committee.82 patients underwent SICS and other 82 underwent Phacoemulsification surgery.The dry eye parameters were evaluated preoperatively and thereafter on four follow ups: first post-operative day, seventh post-operative day , 1 Month and 3 Months to study the effect of cataract surgery on tear film.The data obtained was compiled and statistically analysed.Results: Tear film dysfunction was most significant on first postoperative day and gradually came back to near normal values towards the last visit.At the end of 3 months, 21.95% and 8.54% of the patients in SICS and Phaco groups respectively had dry eye on the basis of Shirmer's -I test.Shirmer's II showed persistent dry eyes in 24.39% of the patients in SICS and 13.41% of the patients in the Phaco group.On the last visit, TBUT values in all 82 patients undergoing phaco were normal, Whereas TBUT remained abnormal in 2.44% of the patients in SICS group.TMH values were ineffective in determining tear film function. Conclusion:Our study shows that tear film dysfunction occurs more after SICS than Phacoemulsification surgery.Modifying the risk factors associated with the surgical procedure and initiation of topical lubricating agents in the early postoperative period can minimize the incidence and duration of recovery of dry eye after cataract surgery.

Dry eye disease (DED) has increasingly been linked to oxidative stress; however, the specific redox mechanisms underlying different clinical phenotypes remain incompletely understood. This study aimed to evaluate tear film oxidative stress profiles in patients with primary DED and sarcoidosis-associated DED (S-DED) by assessing lipid peroxidation, antioxidant enzyme activity, and total tear protein content, and to explore their relationship with clinical tear film dysfunction. Tear samples were analyzed for superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, as well as for malondialdehyde (MDA) and total protein levels, alongside standard clinical tests of tear film stability and secretion. Both DED groups exhibited significant oxidative alterations compared to controls, but with distinct redox signatures. Primary DED was characterized by markedly increased tear MDA levels, indicating predominant lipid peroxidation, whereas S-DED showed a more pronounced impairment of antioxidant defense, reflected by preserved or increased SOD activity in the context of significantly reduced GPx activity. Total tear protein levels were reduced in both groups, with evidence suggesting qualitative protein alterations in S-DED. The tear collection method significantly influenced the measured levels of several oxidative stress markers, underscoring the importance of sampling technique when interpreting tear-based redox profiles. Oxidative stress markers correlated with clinical measures of tear film dysfunction, supporting their physiological relevance. These findings demonstrate that DED encompasses heterogeneous oxidative stress mechanisms and that sarcoidosis acts as a modifier of ocular surface redox homeostasis. Distinct tear-based redox profiles differentiate primary from sarcoidosis-associated dry eye, highlighting the potential value of oxidative biomarkers for phenotyping DED beyond tear deficiency alone.

Self-Report of Severity of Ocular Pain Due to Light as a Predictor of Altered Central Nociceptive System Processing in Individuals With Symptoms of Dry Eye Disease

To quantify the severity and frequency of ocular pain in Tibetan plateau patients with dry eye, and to evaluate the related factors affecting ocular pain. A retrospective study included 160 cases of dry eye disease (DED) patients who were treated from July 2022 to June 2023. Age, gender, occupation, illness course, anxiety, plateau duration, plateau protection, ocular surface disease index scale (OSDI), break-up time (BUT), Schirmer I test (SIT), conjunctivitis, history of ophthalmic medication, autoimmune disease, the workload of daily near vision range, smoking and overnight stay were obtained via comprehensive ophthalmic assessment, and their duration was followed up. Logistic regression analysis was used to determine the related factors affecting ocular pain. Totally 77.5% (124/160) of DED patients had ocular pain, of which the severity of ocular pain was mild, moderate, and severe in 30.0%, 36.3%, and 11.3% of patients, respectively. Frequency of ocular pain was reported occasional, half the time, frequent, and persistent pain in 19.4%, 36.9%, 16.9%, and 4.4%. OSDI score was 19.67±5.70 (13 to 36), and the level of pain was lowly correlated with OSDI (rs =0.316, P<0.001). Logistic regression showed that in plateau DED patients, increased anxiety led to increased severity and frequency of ocular pain [odds ratio (OR)=3.662, 5.613, 2.387, and 4.870; all P<0.05], professional eye protection and improvement of daily sleep quantity decreased pain (OR=0.307, 0.572, 0.418, and 0.789; all P<0.05), while smoking and general protection of plateau did not affect the severity and frequency of ocular pain (all P>0.05). Ocular pain is a common complaint in high-altitude DED patients during the pandemic. Anxiety, eye protection, and adequate sleep during the epidemic period are significantly associated with the severity and frequency of ocular pain in patients with plateau DED, while symptoms of DED have relatively little influence on them.

The autonomic nervous system plays a crucial role in the maintenance of homeostasis. Neurogenic inflammation due to decreased stability of tear film may induce changes in autonomic nerve activity, which could be associated with symptom expression.This study aimed to measure biological parameters that represent autonomic nerve activity in dry eye (DE)s caused by tear film dysfunction and investigate their relationship with symptom intensity. This prospective, cross-sectional, comparative study evaluated 34 eyes of 34 participants (mean age: 52.5 ± 13.4 years; range: 20–81 years) without keratoconjunctival damage. Nineteen eyes in the DE group showed DE symptoms and tear break-up time (TBUT) of ≤5 seconds (short TBUT DE); the 15 eyes in the non-DE group showed no DE symptoms. Autonomic nerve activity was measured for 10 minutes—starting and ending 5 minutes before and after instilling ophthalmic solution—and evaluated using the low-frequency component (LF) to the high-frequency component (HF) ratio of heart rate variability (autonomic balance). The pre-ophthalmic solution administration LF/HF ratio was not significantly different (P = 0.59) between the two groups, however, the standard deviation of the LF/HF ratio (LF/HF-SD) tended to be higher in the DE group than that in the non-DE group (P = 0.086). The DE symptom intensity was significantly related to LF/HF-SD (P = 0.005), which significantly decreased after ophthalmic solution administration in the DE group (P = 0.04). The large fluctuations in autonomic balance may be key for the understanding of the mechanism underlying DE symptoms.

A Clinically Relevant Animal Model of Temporomandibular Disorder and Irritable Bowel Syndrome Comorbidity

ObjectiveThis research investigates the associations between Dry Eye Disease (DED), pain perception, and mental health, focusing on how neuropathic pain influences treatment efficacy and patients' quality of life.Methods and ResultsThe study delves into the complexity of DED by assessing the correlation between ocular pain, depression, PTSD, and systemic pain conditions. It highlights the role of chronic neuropathic pain in DED and the nociceptive hypothesis, which suggests that psychological stress can exacerbate DED symptoms. Additionally, it explores diagnostic and management strategies for DED, emphasizing the importance of considering psychological aspects to improve patient care.ConclusionsThe intricate nature of DED, closely linked to mental health issues, requires a comprehensive diagnostic and therapeutic approach. Addressing neuropathic pain and psychological factors is crucial for effective DED management. Future efforts should focus on developing specific interventions targeting DED's physical and emotional impacts to enhance overall patient well-being.

The aims of the study were to define the heterogeneity of vulvodynia by determining data-driven subgroups within the vulvodynia diagnosis using exploratory cluster analysis and to characterize the subgroups identified. Included were participants in the longitudinal population-based study of vulvodynia in southeast Michigan who screened positive for vulvodynia at least once during the study. A cluster analysis using variables reflecting vulvar pain characteristics and comorbid pain conditions was conducted. Variables reflecting best separation of clusters were used to assign participants to subgroup categories. Demographic, psychiatric, general health, and other vulvar pain characteristics were summarized for each subgroup, followed by multinomial regression and pairwise comparisons of subgroups on these factors. Of 441 women screening positive for vulvodynia during the course of the study, 393 were eligible on the basis of data requirements. Cluster analysis suggested that best subgroup separation was based on the following 2 variables: (1) presence or absence of spontaneous vulvar pain and (2) presence or absence of other comorbid pain conditions. Subgroups did not differ by age or ethnicity. The subgroup having spontaneous pain and other comorbid conditions demonstrated greatest morbidity in general health measures, psychiatric disorders, and other vulvar pain measures. Primary versus secondary vulvodynia did not vary between subgroups and did not assist in subgroup separation in the cluster analysis. Subgroups based on exploratory cluster analysis demonstrated that presence of spontaneous pain and the presence of comorbid pain conditions resulted in best separation of groups. Presence of both spontaneous pain and other comorbid pain conditions identified the group with greatest morbidity.

Dry eye disease (DED) is a common chronic condition with multifactorial etiologies that is increasing in prevalence worldwide, up to 20% in the elderly. The economic burden and impact of DED on vision, quality of life, work productivity, psychological and physical impact of pain, are considerable. Chronic ocular pain is the most common symptom of DED and there is currently no topical ocular analgesic therapy available to treat this debilitating disease. Eye pain can be perceived as itch, irritation, dryness, grittiness, burning, aching, and light sensitivity. Ocular pain is triggered by corneal nociceptors (cornea being the most sensory innervated tissue of the body). It was clearly established that repeated direct damage to ocular surface and per se corneal nerves can cause peripheral and central sensitization mechanisms explaining the ocular pain in some patients with DED. However, the brain regions and the neuronal pathways associated with ocular pain are still unclear. Thus, a better characterization of chronic ocular pain and an understanding of the peripheral and central molecular and cellular mechanisms involved are crucial issues for developing effective management and therapeutic strategy to alleviate ocular pain. In this review, we first describe the nociceptive corneal nerve pathways and the classification and the neurochemistry of primary afferents innervating the cornea. Then, an update of the fundamental and clinical studies related to the inflammatory processes linked to ocular pain is detailed. The last part of the review presents the diagnostic tools used in clinic for evaluating corneal sensitivity and corneal inflammation.

Background/Objectives: Post-coronavirus syndrome (long-COVID) refers to a multi-systemic range of symptoms that follows acute SARS-CoV-3 infection. Long-COVID has been linked with autonomic neuropathy as well as dry-eye disease (DED), an umbrella term that includes a variety of ocular symptoms and signs. Despite these associations, little is known about the co-occurrence of DED and dysautonomia symptoms in individuals with long-COVID. This study aims to examine relationships between dysautonomia and ocular symptoms in a long-COVID patient population. Methods: Cross-sectional study of 162 veterans with long-COVID. The Composite Autonomic Symptom Score-31 (COMPASS-31) assessed dysautonomia symptoms, and the NASA lean test and heart-rate variability metrics captured dysautonomia signs. Dry-eye disease (DED) symptoms were measured with the 5-Item Dry-Eye Questionnaire (DEQ5) and the Ocular Surface Disease Index (OSDI), while ocular pain intensity and neuropathic pain descriptors were evaluated using a Numerical Rating Scale (NRS) and select questions from the Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-Eye), respectively. Results: Most participants (78%) reported DED symptoms (DEQ5 ≥ 6). Nearly all COMPASS-31 domains were associated with DED symptoms, with the strongest correlation observed between the OSDI and pupillomotor scores (r = 0.67, p < 0.001). Among the autonomic signs, the strongest associations were observed between the change in systolic and diastolic blood pressure from baseline to 8 min and ocular pain triggered by temperature (r = -0.44 and r = -0.48, respectively, p < 0.01 for both). On linear regression analyses, pupillomotor and secretomotor symptoms remained positively associated with DED symptoms, while autonomic signs were most closely related to ocular pain metrics, with fluctuating blood pressure changes during orthostasis relating to neuropathic symptoms. Conclusions: DED symptoms, including ocular pain intensity, relate to autonomic symptoms in a long-COVID cohort. While associations with autonomic signs were less consistent, these data suggest that subtle autonomic variability relates to ocular pain in the long-COVID setting.

PurposePatients with dry eye disease (DED) sometimes complain of ocular pain. DED-related ocular pain has many similarities with neuropathic pain. Mirogabalin, a novel ligand for the α2δ subunit of voltage-gated calcium channels, is approved for treating neuropathic pain in Japan. This study aimed to investigate the effect of mirogabalin on hyperalgesia and chronic ocular pain in a rat DED model.MethodsDED was induced in female Sprague Dawley rats by unilaterally excising the external lacrimal gland (ELG) and Harderian gland (HG). After 4 weeks of ELG and HG removal, tear production (pH threads) and corneal epithelial damage (fluorescein staining) were evaluated. Corneal hyperalgesia and chronic pain were analyzed, respectively, by measuring capsaicin-induced eye-wiping behavior and c-Fos expression in the trigeminal nucleus. Mirogabalin (10 or 3 mg/kg) was evaluated for effects on DED-induced hyperalgesia and chronic ocular pain.ResultsTear production was significantly lower in DED-induced eyes than in control eyes. Corneal damage was significantly higher in DED eyes than in control eyes. Hyperalgesia and chronic ocular pain were detected 4 weeks after ELG and HG removal. Five days of mirogabalin administration significantly suppressed capsaicin-induced eye-wiping behavior, which indicated the suppression of ocular hyperalgesia. Administration of 10 mg/kg mirogabalin significantly reduced c-Fos expression in the trigeminal nucleus, which indicated the amelioration of chronic ocular pain.ConclusionsMirogabalin suppressed DED-induced hyperalgesia and chronic ocular pain in a rat DED model. Our findings suggested that mirogabalin might effectively alleviate chronic ocular pain in patients with DED.

Background/Objectives: The purpose of this study was to clinically characterize the lacrimal functional unit (LFU) of patients with chronic ocular pain associated with dry eye disease (DED). Methods: Ninety-three participants were included in this cross-sectional study: 28 patients with chronic ocular pain associated with DED (pain-DED), 35 patients with DED but no pain (no pain-DED), and 30 subjects without DED or ocular pain (controls). The following examinations were performed: symptom questionnaires, visual function assessment, tear meniscus, ocular surface evaluation, meibography, corneal sensitivity, Schirmer test, and in vivo corneal confocal microscopy. Results: Both DED groups presented increased DED-related symptoms (p < 0.001), corneal staining (p < 0.001), Meibomian gland loss (p < 0.010), and dendritic cell density (p < 0.001) compared with controls. Comparing both DED groups, the pain-DED group showed higher DED-related symptoms (p < 0.002) and increased microneuroma density (p < 0.001). Additionally, significant positive correlations were observed between symptom questionnaires and corneal staining (vs. OSDI: r = 0.514, p < 0.001; vs. m-SIDEQ: r = 0.504, p < 0.001; vs. NRS: r = 0.361, p < 0.001; vs. WBFPRS: r = 0.317, p = 0.002), dendritic cell density (vs. OSDI: r = 0.429, p < 0.001; vs. m-SIDEQ: r = 0.440, p < 0.001), and microneuroma density (vs. NRS: r = 0.405, p < 0.001; vs. WBFPRS: r = 0.416, p < 0.001). Conclusions: Differences in the LFU, especially in the morphology of sub-basal corneal nerves, are related to the presence of DED and chronic ocular pain and, along with ocular clinical questionnaires, can help phenotype these patients.

PurposeTo evaluate the safety and efficacy of topical TOP1630, a novel nonsystemic kinase inhibitor, in dry eye disease (DED).Patients and methodsA randomized, double-masked, parallel-group trial of 0.1% TOP1630 ophthalmic solution TID or placebo (vehicle without active drug) was conducted in DED subjects (n=61). Key eligibility criteria consistent with enrolling a moderate to severe DED population included >6 months DED history; OSDI© score ≥18; Schirmer’s test score ≤10 and ≥1 mm/5 minutes; tear film break-up time >1 and <7 seconds; and dry eye exacerbation in corneal staining and ocular discomfort in a Controlled Adverse Environment (CAE®). After a 7-day run-in period with placebo TID, eligible subjects were randomized to TOP1630 or placebo for 28 days. No supplemental artificial tears or rescue medication were allowed.ResultsTOP1630 was safe, well-tolerated, and efficacious in treating DED symptoms and signs. No serious adverse events (AEs) or withdrawals due to treatment emergent AEs occurred. Drop comfort scores showed TOP1630 to be comfortable and comparable with placebo. Significant symptom improvements were seen for TOP1630 vs placebo for ocular discomfort (P=0.02 post-CAE), grittiness/foreign body sensation (on four independent assessment scales, each P<0.05), worst DED symptom (diary, P=0.06), and ocular pain (VAS, P=0.03). Sign improvements were seen for total ocular surface (all regions), corneal sum, and conjunctival sum staining with TOP1630 compared with placebo (each P<0.05).ConclusionTOP1630 had placebo-like tolerability and produced improvements in multiple symptom and sign endpoints in both environmental and challenge settings. The emergent TOP1630 benefit–risk profile for DED treatment is highly favorable and supports further development.

The total tenderness score (TTS) is commonly used in headache practice and contributes valuable information. To assess muscle tenderness scores in patients diagnosed with Temporomandibular disorders (TMD) and analyse their associations with various demographic and clinical parameters. Masticatory (MTS), cervical (CTS) and TTSs were analysed in this case-control study among 192 TMD patients and 99 controls. The study included a questionnaire and a clinical examination following RDC/TMD guidelines. Data were analysed using: Pearson's chi-square, analysis of variance, t test and Bonferroni post hoc. To examine the factors associated with MTS score in a multivariate manner, a conceptual hierarchical multiple regression model was adopted. Masticatory and TTS differed between TMD sub-groups and controls. Muscle tenderness was positively associated with: female sex, whiplash history, parafunction, co-morbid pains such as headaches and body pain, pain intensity, onset, frequency and duration. In the conceptual hierarchical multiple regression model, pain onset, frequency and duration, co-morbid pains were mediators in the relationship between TMD diagnosis and MTS. Muscle tenderness scores were positively associated with TMD disease characteristics and co-morbid pain conditions, which may reflect associations with disease severity. MTS differed between TMD populations and may be used in routine patient workup, to assess MMD severity and changes over time as well as treatments response and as a research tool. MTS can be used as a common methodology to describe both headaches and masticatory muscle disorders and to facilitate interprofessional research and crosstalk between a headache and oro-facial pain practitioners.