Understanding chronic ocular pain

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.

Dry eye disease (DED) is a prevalent condition characterized by ocular surface inflammation and pain. This study evaluated the long-term progression of DED by analyzing clinical and molecular status, considering the impact of chronic ocular pain. Patients with DED were evaluated at two visits (V1 and V2) separated by at least two years. Evaluations included validated symptom questionnaires alongside slit-lamp examination, corneal sensitivity testing, and sub-basal nerve plexus analysis. Basal tear samples were collected for multiplex quantification of 20 cytokines and substance P (SP), and conjunctival cells were obtained to analyze 25 genes and 12 microRNAs (miRNA). Based on the presence or absence of chronic ocular pain, patients were then divided into two groups. Patients improved in DED-related symptoms, with no changes observed in ocular surface signs. Corneal dendritic cell density decreased, along with epidermal growth factor (EGF), fractalkine, and monocyte chemoattractant protein (MCP-1) tear levels, whereas interleukin (IL)-10 and SP tear levels increased. Neurotrophic tyrosine kinase, receptor, type (NTRK)1 gene expression was significantly downregulated, especially in patients without chronic ocular pain. miR-665 expression decreased significantly in DED patients. Monitoring corneal dendritic cells, tear cytokines, and gene/miRNA expression offers promising tools for tracking DED progression. Distinguishing the presence of chronic ocular pain as a separate symptom is crucial to optimizing therapeutic strategies and DED progression.

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.

PurposeChronic ocular pain is poorly understood and difficult to manage. We developed a murine model of corneal surface injury (CSI)–induced chronic ocular neuropathic pain. The study focuses on changes in corneal nerve morphology and associated short- and long-term pain-like behavior after CSI.MethodsCSI was induced in mice by local application of an alkali solution (0.75 N NaOH). Corneal nerve architecture, morphology, density, and length were studied. Eye-wiping was evaluated before and after CSI in response to hypertonic saline (2 M NaCl). Naltrexone (NTX) or Naloxone-methiodide (NLX-me), opioid receptor antagonists, were given subcutaneously (s.c., 3 mg/kg) or topically (eye drop, 100 μM), and then an eye-wiping test was performed.ResultsCSI caused partial corneal deinnervation followed by gradual reinnervation. Regenerated nerves displayed increased tortuosity, beading, and branching. CSI enhanced hypertonic saline-induced eye-wiping behavior compared to baseline or sham-injury (P < 0.01). This hypersensitivity peaked at 10 days and subsided 14 days after CSI. Administration of NTX, or NLX-me, a selective peripheral opioid antagonist, reinstated eye-wiping behavior in the injury group, but not in the sham groups (P < 0.05).ConclusionsThis study introduces a model of chronic ocular pain and corneal neuropathy following CSI. CSI induces central and peripheral opioid receptor-dependent latent sensitization (LS) that is unmasked by systemic or topical administration of opioid antagonists.Translational RelevanceThis model of chronic ocular pain establishes LS as a new inhibitory mechanism in the oculotrigeminal system and may be used for potential diagnostic and therapeutic interventions for ocular neuropathy.

The aim of this real-world registry study was to evaluate the quality-of-life (QoL) impact of dry eye disease (DED). The specific objectives were to determine factors affecting QoL in DED, and to evaluate the psychometric properties of the Ocular Surface Disease Index (OSDI), Ocular Comfort Index (OCI), and Patient Health Questionnaire (PHQ) in a real-world DED population using modern psychometric methods. This descriptive cross-sectional study included 368 DED patients (mean 54.7±16.6 years; 80.2% female) who completed one or more of the three questionnaires (OSDI, OCI and PHQ). Psychometric analysis of the QoL data was carried out with Andrich's Rating Scale Model of Rasch analysis. The original OSDI and OCI had disordered categories. The Rasch-optimised final QoL scales (OSDI - Overall, OSDI - Symptoms [SY], OSDI - Activity limitation [AL], OSDI - Environmental trigger [EN], OCI Overall, OCI - Frequency [FR], OCI - Intensity [IN], and PHQ) had satisfactory psychometric properties. Patients diagnosed with a mixed aqueous/evaporative DED subtype had worse mean OSDI-Overall and OSDI-AL scores than individuals with evaporative DED (p=0.012 and 0.001 respectively). Patients with corneal neuropathic pain had worse QoL scores (OSDI-Overall, OSDI-AL, OSDI-SY, OSDI-EN, OCI-Overall, OCI-FR, OCI-IN, and PHQ; all p<0.05) than those without. Patients who reported undergoing prior treatment or procedure for DED had worse QoL scores than those who did not (all p<0.05 except for PHQ). The associations between DED signs (tear breakup time and staining) and symptoms were weak or not significant. In this real-world setting, diagnoses of mixed DED, corneal neuropathic pain, and history of DED treatment/procedures were associated with worse dry eye symptoms, activity limitation, and/or QoL.

Dry eye is a multi-factorial disorder that manifests with painful ocular symptoms and visual disturbances, which can only be partly attributed to tear dysfunction. This disorder may also involve neuroplasticity in response to neuronal injury. This review will emphasize the key characteristics of dry eye pain and its pathologic mechanisms, making the argument that a subset of dry eye represents a neuropathic pain disorder of the eye, more appropriately called "burning eye syndrome." A literature review was conducted using a PubMed search focusing on dry eye, corneal nociception, and neuropathic pain. Articles were reviewed and those discussing clinical course, pathophysiology, and neuronal regulation of chronic ocular pain as related to dry eye were summarized. We found that there is a discordance between ocular pain and dryness on the ocular surface. Although tear dysfunction may be one of the initial insults, its persistence may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic pain transition associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain. Dry eye is becoming a major health concern due to its increasing incidence, significant morbidity, and economic burden. Recent evidence suggests that a subset of dry eye may be better represented as a chronic neuropathic pain disorder due to its features of dysesthesia, spontaneous pain, allodynia, and hyperalgesia. Future therapies targeted at the underlying neuroplasticity may yield improved efficacy for patients with this subset of dry eye, which we term "burning eye syndrome."

Ocular pain is a common complaint, and anything that stimulates the sensory nerve terminals innervating the eye, the peripheral axons of neurons located in the trigeminal ganglion, can cause it. An undetected ocular foreign body sometimes masquerades as a common condition such as dry eye or other frequencies, which can misguide both the doctor and the patient into an endless cycle of ineffective therapies and incomplete diagnoses. In recent years, as the concept of neuropathic pain has become more widely recognized, cases of idiopathic ocular pain in which the actual cause of the discomfort is a foreign body seem to be increasingly misdiagnosed as neuropathy. This report reviews cases in which hidden foreign bodies were responsible for unresolved, long-lasting chronic ocular pain. All records referencing the phrase “foreign body removal” were extracted from the outpatient clinic notes recorded by the author (H.T.) between 2016 and 2018 at Ashikaga Red Cross Hospital using the search engine of the computerized record system. There were 3 cases that were very difficult to diagnose: (1) a very minute iron shard in a 72-year-old female cataract surgery patient, (2) a deeply hidden eyelash in a 60-year-old female with varicella-zoster virus-related keratoconjunctivitis, and (3) an extremely small grain of sand in an 83-year-old female diagnosed with dry eye. In all cases, the foreign body was detected in an area of the upper palpebral conjunctiva without typical pathognomonic signs. Removing the foreign bodies led to immediate and dramatic relief of long-lasting, previously unresolved chronic ocular pain.

Recent evidence suggests that dry eye (DE) may be comorbid with other chronic pain conditions. To evaluate DE as a comorbid condition in the U.S. veteran population. Retrospective review of veterans seen in the Veterans Administration Healthcare System (Veteran Affairs) between January 1, 2010, and December 31, 2014. Dry eye and nonocular pain disorders were ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes. Dry eye was further separated into ICD-9 codes representing tear film dysfunction or ocular pain. χ2 and logistic regression analyses were used to examine frequency and risk of DE, ocular pain, and tear film dysfunction by pain disorders. Of 3,265,894 veterans, 959,881 had a DE diagnosis (29.4%). Dry eye frequency increased with the number of pain conditions reported (P < 0.0005). Ocular pain was most strongly associated with headache (odds ratio [OR] 2.98; 95% confidence interval [CI] 2.95-3.01), tension headache (OR 2.64; 95% CI 2.58-2.71), migraine (OR 2.58; 95% CI 2.54-2.61), temporomandibular joint dysfunction (OR 2.39; 95% CI 2.34-2.44), pelvic pain (OR 2.30; 95% CI 2.24-2.37), central pain syndrome (OR 2.24; 95% CI 1.94-2.60), and fibromyalgia/muscle pain (OR 2.23; 95% CI 2.20-2.26), all P < 0.0005. Tear film dysfunction was most closely associated with osteoarthritis (OR 1.97; 95% CI 1.96-1.98) and postherpetic neuralgia (OR 1.95; 95% CI 1.90-2.00), both P < 0.0005. Dry eye, including both ocular pain and tear film dysfunction, is comorbid with pain conditions in this nationwide population, implying common mechanisms.

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.

Dry eye symptoms are one of the leading complaints in ophthalmology. They include visual disturbance, various types of symptoms and variable intensity of pain and discomfort that may become chronic or permanent and thus affect significantly the quality of life of patients. Nevertheless, the pathophysiological mechanisms of ocular surface pain remain largely unknown. A better clinical characterization of chronic ocular pain and an understanding of the 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 of corneal sensitive receptors neurons. The second part of this review gives an update of the preclinical and clinical data related to the inflammatory processes linked to inflammatory ocular pain. The last section describes the various diagnostic tools used in the clinic to evaluate corneal sensitivity and corneal inflammation.

IntroductionThe factors that mediate the expression of ocular pain and the mechanisms that promote chronic ocular pain symptoms are poorly understood. Central nervous system involvement has been postulated based on observations of pain out of proportion to nociceptive stimuli in some individuals. This investigation focused on understanding functional connectivity between brain regions implicated in chronic pain in persons reporting ocular pain symptoms.MethodsWe recruited a total of 53 persons divided into two cohorts: persons who reported no ocular pain, and persons who reported chronic ocular pain, irrespective of ocular surface findings. We performed a resting state fMRI investigation that was focused on subcortical brain structures including the trigeminal nucleus and performed a brief battery of ophthalmological examinations.ResultsPersons in the pain cohort reported higher levels of pain symptoms relating to neuropathic pain and ocular surface disease, as well as more abnormal tear metrics (stability and tear production). Functional connectivity analysis between groups evinced multiple connections exemplifying both increases and decreases in connectivity including regions such as the trigeminal nucleus, amygdala, and sub-regions of the thalamus. Exploratory analysis of the pain cohort integrating clinical and brain function metrics highlighted subpopulations that showed unique phenotypes providing insight into pain mechanisms.DiscussionStudy findings support centralized involvement in those reporting ocular-based pain and allude to mechanisms through which pain treatment services may be directed in future research.

The Ocular Pain Assessment Survey (OPAS) has been used to quantify chronic ocular pain and quality of life (QOL). We aim to investigate the psychometric properties of individual OPAS items with the Rasch analysis in an Asian population of dry eye disease and neuropathic corneal pain (NCP). Question responses were obtained from 196 patients; 138 with dry eye disease (DED) and 58 with NCP, at the Singapore National Eye Centre. Item hierarchy, item fit statistics, item separation, reliability indices, and Yen's Q3 values were calculated. Individual dimensions that quantify eye pain levels in the past 24hours and QOL showed good discriminative ability according to their person separation index values. However, individual dimensions that measured eye pain in the past 2weeks, non-eye pain, as well as aggravating and associated factors showed suboptimal person separation index values. Significant correlations were found between the individual item pairs of the aggravating factors dimension as well as between some of the items in the QOL and associated factors dimensions. Two dimensions of the OPAS questionnaire were validated with the Rasch analysis. Based on these findings, we shorten the number of questions in some dimensions to improve the performance of the tool in similar Asian populations. Our study provides insights to improve the existing OPAS for real-world clinical applications and clinical trials.

Abstract: PURPOSE: Dry eye disease (DED) significantly impacts patients’ quality of life and career performance, being the most prevalent chronic ocular condition in ophthalmic clinics. This study aimed to assess the prevalence and risk factors of DED among adults in Saudi Arabia. METHODS: A cross-sectional study involving 5768 adult participants across various demographics in Saudi Arabia was conducted. Data were collected on participants’ demographics, occupational status, smoking habits, and symptoms of DED. The prevalence of symptoms was evaluated, and diagnosed cases were identified to determine the overall impact of DED on this population. RESULTS: The study revealed that the majority of participants were middle-aged females with high educational levels, predominantly not working, and infrequently reporting smoking. More than half of the participants exhibited symptoms of DED but remained undiagnosed (59.8%), whereas approximately one-fourth were diagnosed with the condition (24.9%). The analysis identified significant risk factors associated with DED, including older age, Rheumatoid Arthritis, systemic lupus erythematosus, ulcerative colitis, and seasonal variations, particularly in the summer. CONCLUSION: The current study highlights a concerning prevalence of DED among adults in Saudi Arabia, with a significant proportion of individuals being symptomatic yet undiagnosed. Key predictors of DED include older age, chronic health issues, and seasonal factors. There is an urgent need for health education initiatives aimed at raising awareness about DED and promoting healthier lifestyle choices to mitigate associated risk factors. We recommend providing routine DED screening in high-risk groups, workplace adjustments for digital screen users, and public health guidelines on eye strain prevention.

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 analyse the occurrence and cost of dry eye disease in Spain in the recent years. A cross-sectional analysis based on anonymised data from an insurance claims database that includes data from 1997 to 2015 from public and private hospitals and healthcare centres; 36,081 patients were eligible for the study after duplicate elimination. Five ICD9 codes associated with dry eye were used for patient selection, including vitamin A deficiency with xerophthalmic scars of cornea, xerophthalmia due to vitamin A deficiency, keratoconjunctivitis sicca not specified as Sjögren's, dry eye syndrome and keratoconjunctivitis sicca Sjögren's disease. Over 88% of the patients were female, and the mean age was 66 years. Patients with keratoconjunctivitis sicca Sjögren's disease represented more than 89% of all patients and had the highest percentage of women. Both the annual number of patients and the number of admissions have increased exponentially since 1997 raising from 1079 to 3097 and from 1344 to 5938, respectively. The in-hospital length of stay was 9.6 (standard deviation = 11.6) days where more than 65% of the admissions were due to emergencies. Total costs were found to increase from €4.9 to €30.3 million during the study period; in parallel, there was an increase in the mean annual cost per patient, which was on average €7379. Disease incidence is likely to increase due to the influence of modern-day workplace, and it is important to take into account the high economic burden and the large decrease in quality of life in regards to Spanish society and health policies.