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Molecular Pain 2017Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a... (Review)
Review
Recent data suggest that corneal somatosensory dysfunction may be the underlying cause of severe dry eye symptoms in the absence of ocular surface pathology seen in a subset of patients diagnosed with “dry eye syndrome.” This subset of patients tends to demonstrate a unique constellation of symptoms that are persistent, more severe, and generally respond poorly to current dry eye therapies targeting inadequate or dysfunctional tears. A growing body of literature suggests that symptoms in these patients may be better characterized as neuropathic ocular pain rather than dry eye. In these patients, dry eye symptoms are often associated with numerous comorbid pain conditions and evidence of central pain processing abnormalities, where eye pain is just one of multiple overlapping peripheral manifestations. In this review, we discuss the concept and potential mechanisms of chronic overlapping pain conditions as well as evidence for considering neuropathic ocular pain as one of these overlapping pain conditions.
Topics: Animals; Chronic Disease; Chronic Pain; Cornea; Dry Eye Syndromes; Eye Pain; Humans; Neuralgia; Pain Measurement
PubMed: 28814146
DOI: 10.1177/1744806917729306 -
Experimental Eye Research Jun 2022The purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE)...
The purpose of this study was to analyze inflammation- and pain-related molecules in tears of patients suffering from chronic ocular pain associated with dry eye (DE) and/or a previous corneal refractive surgery (RS). Based on history, symptomatology, and clinical signs, the subjects (n = 180, 51.0 ± 14.7 years, 118 females, 62 males) in this cross-sectional study were assigned to one of five groups: DE and chronic ocular pain after RS (P/DE-RS, n = 52); asymptomatic subjects, i.e., without DE and chronic ocular pain, after RS (A-RS, n = 30); DE and chronic ocular pain without previous RS (P/DE-nonRS, n = 31); DE, no pain, and no previous RS (DE-nonRS, n = 35); and asymptomatic subjects with no previous RS (controls, n = 32). The tear concentrations of 20 cytokines and substance P (SP) were analyzed by immunobead-based assay and enzyme-linked immunosorbent assay, respectively. We found that tear levels of interleukin (IL)-10 and SP were increased in the RS groups. There were significant differences in IL-8/CXCL8 among the five groups. Nerve growth factor (NGF) tear levels were significantly higher in P/DE-RS than in DE-nonRS and controls. IL-9 had the highest percentage of detection in the P/DE-RS and P/DE-nonRS groups, while macrophage inflammatory protein (MIP)-1α, IL-2, and interferon (IFN)-γ were higher in the P/DE-RS, A-RS, and P/DE-nonRS groups. IL-17A was detected only in the A-RS group. Moderate correlations were observed in the A-RS, P/DE-nonRS, DE-nonRS and controls groups. A positive correlation was obtained between growth related oncogene concentration and tear break-up time (rho = 0.550; p = 0.012), while negative correlation was found between monocyte chemoattractant protein-3/CCL7 and conjunctival staining (rho = -0.560; p = 0.001), both in the A-RS group. IL-10 correlated positively with ocular pain intensity (rho = 0.513; p = 0.003) in the P/DE-nonRS group. Regulated on Activation Normal T Cell Expressed and Secreted/CCL5 correlated negatively with conjunctival staining (rho = -0.545; p = 0.001) in the DE-nonRS group. SP correlated negatively with corneal staining (rho = -0.559; p = 0.001) in the controls. In conclusion, chronic ocular pain was associated with higher IL-9 tear levels. IL-10, SP, MIP-1α/CCL3, IL-2, and IFN-γ were associated with previous RS. Higher levels of IL-8/CXCL8, MIP-1α/CCL3, IL-2, and IFN-γ were associated with DE-related inflammation, while NGF levels were related to chronic ocular pain and DE in RS patients. These findings suggest that improved knowledge of tear cytokines and neuromodulators will lead to a more nuanced understanding of how these molecules can serve as biomarkers of chronic ocular pain, leading to better therapeutic and disease management decisions.
Topics: Chemokine CCL3; Conjunctiva; Cross-Sectional Studies; Cytokines; Dry Eye Syndromes; Female; Graft vs Host Disease; Humans; Inflammation; Interleukin-10; Interleukin-2; Interleukin-8; Interleukin-9; Male; Nerve Growth Factor; Pain; Tears
PubMed: 35358536
DOI: 10.1016/j.exer.2022.109057 -
Translational Vision Science &... Mar 2023Evaluation of safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
Evaluation of safety and efficacy of topical ocular SAF312 (Libvatrep) in post-photorefractive keratectomy (PRK) pain.
METHODS
In this placebo (vehicle)-controlled, participant- and investigator-masked study, 40 participants were randomized (1:1) to two treatment sequences in a bilateral PRK crossover design (SAF312 2.5% followed by vehicle [or vice versa], one eye drop, four times daily for 72 hours after PRK). Primary endpoints were visual analog scale (VAS) pain scores at 6 hours after first drop of study drug and average VAS scores over 0 to 12 hours postoperatively. Secondary endpoints included postoperative oral rescue medication (ORM) use and adverse events (AEs).
RESULTS
All 40 participants completed the study. Both primary endpoints were met; mean difference in VAS pain scores between SAF312- and vehicle-treated eyes was -11.13 (P = 0.005, -25%) at 6 hours postoperatively and -8.56 (P = 0.017, -22%) over 0 to 12 hours. Mean VAS pain scores with SAF312 were consistently lower than with vehicle from 1 hour postoperatively up to 30 hours (P ≤ 0.10 observed in 8/11 time points). Less ORM was taken with SAF312 up to 0 to 72 hours postoperatively, with a trend of fewer participants taking ORM at 0 to 24 hours postoperatively with SAF312 versus vehicle. No serious AEs were reported. All ocular AEs were mild and transient, and none were drug related. SAF312-treated eyes showed no delay in wound healing and had a lower grade 4 conjunctival hyperemia 24 hours postoperatively versus vehicle-treated eyes.
CONCLUSIONS
SAF312 was well tolerated and effective in reducing ocular pain post-PRK.
TRANSLATIONAL RELEVANCE
Topical SAF312 presents a new therapeutic option for patients undergoing PRK.
Topics: Humans; Photorefractive Keratectomy; Pain, Postoperative; Wound Healing; TRPV Cation Channels
PubMed: 36917119
DOI: 10.1167/tvst.12.3.7 -
Transactions of the American... Aug 2017To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs.
PURPOSE
To evaluate associations between sensations of ocular itch and dry eye (DE) symptoms, including ocular pain, and DE signs.
METHODS
A cross-sectional study of 324 patients seen in the Miami Veterans Affairs eye clinic was performed. The evaluation consisted of questionnaires regarding ocular itch, DE symptoms, descriptors of neuropathic-like ocular pain (NOP), and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Analyses were performed to examine for differences between those with and without subjective complaints of ocular itch.
RESULTS
The mean age was 62 years with 92% being male. Symptoms of DE and NOP were more frequent in patients with moderate-severe ocular itch compared to those with no or mild ocular itch symptoms. With the exception of ocular surface inflammation (abnormal matrix metalloproteinase 9 testing) which was less common in those with moderate-severe ocular itch symptoms, DE signs were not related to ocular itch. Individuals with moderate-severe ocular itch also demonstrated greater sensitivity to evoked pain on the forearm and had higher non-ocular pain, depression, and post-traumatic stress disorders scores, compared to those with no or mild itch symptoms.
CONCLUSIONS
Subjects with moderate-severe ocular itch symptoms have more severe symptoms of DE, NOP, non-ocular pain and demonstrate abnormal somatosensory testing in the form of increased sensitivity to evoked pain at a site remote from the eye, consistent with generalized hypersensitivity.
Topics: Cornea; Cross-Sectional Studies; Dry Eye Syndromes; Eye Diseases; Eye Pain; Female; Humans; Male; Middle Aged; Ophthalmology; Pain Measurement; Pruritus; Quality of Life; Skin Physiological Phenomena; Societies, Medical; Surveys and Questionnaires; Tears; United States; Veterans
PubMed: 29391860
DOI: No ID Found -
Australian Journal of General Practice Aug 2019Ocular dysfunction, including eye movement defects, has been documented in up to 69% of patients with concussion. However, standard sports-related concussion assessment...
BACKGROUND
Ocular dysfunction, including eye movement defects, has been documented in up to 69% of patients with concussion. However, standard sports-related concussion assessment protocols do not typically include any clinical examination of the ocular system.
OBJECTIVE
The aim of this article is to inform general practitioners (GPs) about ocular defects associated with concussion, identify test procedures and highlight the important role of GPs within the concussion paradigm.
DISCUSSION
Ocular dysfunction that commonly occurs with concussion includes abnormalities of accommodation, convergence, saccades and smooth pursuits. This may cause blurred vision, double vision, ocular pain and difficulty with close work. Symptoms can severely affect daily work, school or play activities. Patients complaining of extended ocular symptoms following concussion should be referred to an ophthalmologist for a complete ocular assessment.
Topics: Accommodation, Ocular; Brain Concussion; Humans; Oculomotor Muscles; Physical Examination; Saccades; Vision Disorders
PubMed: 31370123
DOI: 10.31128/AJGP-03-19-4876 -
Ophthalmology Science 2024To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP...
PURPOSE
To conduct a genome-wide association study (GWAS) of individuals with neuropathic ocular pain (NOP) symptoms to identify genomic variants that may predispose to NOP development.
DESIGN
Prospective study of individuals with NOP.
PARTICIPANTS
Three hundred twenty-nine patients recruited from the Miami Veterans Affairs eye clinic.
METHODS
The Neuropathic Pain Symptom Inventory modified for the eye (NPSI-Eye) was completed to calculate a NPSI-Eye-Sub-Score (summed ratings of burning and wind sensitivity) as an indicator of NOP severity. A GWAS was performed for the NPSI-Eye-Sub-Score with a significance threshold of < 5 × 10. A gene-based analysis was performed using the multimarker analysis of genomic annotation software (in the functional mapping and annotation of GWAS online platform). The 13 865 778 single nucleotide polymorphisms (SNPs) from our GWAS analysis were mapped to 10 834 protein coding genes, and significant genes were run through gene set enrichment analysis.
MAIN OUTCOME MEASURES
Identification of SNPs and protein products that may be associated with the development of NOP.
RESULTS
One hundred seventy-one SNPs reached a threshold of < 10, of which 10 SNPs reached the suggestive level of significance of < 5 × 10 and 1 SNP met our genome-wide significance threshold of < 5 × 10. This lead SNP, rs140293404 ( = 1.23 × 10), is an intronic variant found within gene ENSG00000287251 coding for transcript ENST00000662732.1. Rs140293404 is in linkage disequilibrium with exon variant rs7926353 (r2 > 0.8) within ENSG00000279046 coding for transcript ENST00000624288.1. The most significant genes from gene-based tests were matrix metalloproteinase-19 ( ( = 1.12 × 10), zinc finger RNA-binding motif and serine/arginine rich-1 ( ( = 1.48 × 10), ( = 1.79 × 10), receptor expression-enhancing protein-5 ( ( = 2.36 × 10), and signal recognition particle-19 ( ( = 2.56 × 10). From gene set enrichment analysis, the sensory perception (false discovery rate = 6.57 × 10) and olfactory signaling (false discovery rate = 1.63 × 10) pathways were enriched with the most significant genes.
CONCLUSIONS
Our GWAS revealed genes with protein products that may impact sensory perception, lending biological plausibility to a role for SNPs identified by our GWAS in the development of NOP. A better understanding of the biological relevance of these genes and pathways in the pathophysiology associated with NOP may facilitate future novel mechanism-based treatments.
FINANCIAL DISCLOSURES
Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
PubMed: 37868788
DOI: 10.1016/j.xops.2023.100384 -
Journal of Ophthalmology 2022Since quantification and communication of ocular pain is important for a healthier patient follow-up and postoperative guidance, reliable measures like the Ophthalmic...
PURPOSE
Since quantification and communication of ocular pain is important for a healthier patient follow-up and postoperative guidance, reliable measures like the Ophthalmic Pain Assessment Survey (OPAS) are needed to assess the outcome and management of different operations. To address that need, we carried out the adaptation of OPAS into Turkish to reach different age groups and backgrounds, widening the use of OPAS on patients who underwent an ophthalmic operation.
METHODS
We used back-translation method and achieved cultural adaptation through content validity scoring by 5 independent ophthalmologists. The survey is then administered three times: preoperatively, postoperatively within 24 hours, and finally a week later in the follow-up visit. Validity is measured in comparison to Visual Analog Scale using Spearman's correlation coefficient and reliability is measured using Cronbach's alpha. Factor analysis is performed by principal component analysis and rotation is performed using Varimax method when necessary.
RESULTS
We reached a total of 132 patients with a mean age of 64.2 years. Most of them underwent phacoemulsification ( = 83), followed by PRK ( = 37). Overall, the T-OPAS demonstrated good reliability (mean C. alpha: 0.830) and its correlation with the VAS was especially high (S. coeff. >0.5) in the first three sections in all three surveys. Factor analysis yielded 5 subscales, allowing us to shape the final form of T-OPAS.
CONCLUSION
Through this adaptation of OPAS into a foreign language, we present a reliable and valid tool for postoperative pain quantification, allowing objective measurement of pain in different populations such as the elderly.
PubMed: 36276918
DOI: 10.1155/2022/3116913 -
Journal of Neuroinflammation May 2021Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient...
BACKGROUND
Dry eye disease (DED) is a multifactorial disease of the ocular surface accompanied by neurosensory abnormalities. Here, we evaluated the effectiveness of transient receptor potential vanilloid-1 (TRPV1) blockade to alleviate ocular pain, neuroinflammation, and anxiety-like behavior associated with severe DED.
METHODS
Chronic DED was induced by unilateral excision of the Harderian and extraorbital lacrimal glands of adult male mice. Investigations were conducted at 21 days after surgery. The mRNA levels of TRPV1, transient receptor potential ankyrin-1 (TRPA1), and acid-sensing ion channels 1 and 3 (ASIC1 and ASIC3) in the trigeminal ganglion (TG) were evaluated by RNAscope in situ hybridization. Multi-unit extracellular recording of ciliary nerve fiber activity was used to monitor spontaneous and stimulated (cold, heat, and acid) corneal nerve responsiveness in ex vivo eye preparations. DED mice received topical instillations of the TRPV1 antagonist (capsazepine) twice a day for 2 weeks from d7 to d21 after surgery. The expression of genes involved in neuropathic and inflammatory pain was evaluated in the TG using a global genomic approach. Chemical and mechanical corneal nociception and spontaneous ocular pain were monitored. Finally, anxiety-like behaviors were assessed by elevated plus maze and black and white box tests.
RESULTS
First, in situ hybridization showed DED to trigger upregulation of TRPV1, TRPA1, ASIC1, and ASIC3 mRNA in the ophthalmic branch of the TG. DED also induced overexpression of genes involved in neuropathic and inflammatory pain in the TG. Repeated instillations of capsazepine reduced corneal polymodal responsiveness to heat, cold, and acidic stimulation in ex vivo eye preparations. Consistent with these findings, chronic capsazepine instillation inhibited the upregulation of genes involved in neuropathic and inflammatory pain in the TG of DED animals and reduced the sensation of ocular pain, as well as anxiety-like behaviors associated with severe DED.
CONCLUSION
These data provide novel insights on the effectiveness of TRPV1 antagonist instillation in alleviating abnormal corneal neurosensory symptoms induced by severe DED, opening an avenue for the repositioning of this molecule as a potential analgesic treatment for patients suffering from chronic DED.
Topics: Animals; Capsaicin; Cornea; Dry Eye Syndromes; Male; Mice; Mice, Inbred C57BL; Pain; Syndrome; TRPV Cation Channels
PubMed: 33975636
DOI: 10.1186/s12974-021-02162-7 -
Ophthalmology and Therapy Mar 2024Chronic ocular pain, particularly prevalent in patients with dry eye disease and post-femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) surgery,...
INTRODUCTION
Chronic ocular pain, particularly prevalent in patients with dry eye disease and post-femtosecond laser-assisted laser in situ keratomileusis (FS-LASIK) surgery, presents with unclear clinical characteristics and an undefined pathogenesis. In this study, we aimed to compare clinical characteristics and tear neuropeptide concentrations in patients with dry eye disease (DED) with and without chronic ocular pain following FS-LASIK, and investigate correlations between ocular pain, clinical characteristics, and tear neuropeptide levels.
METHODS
Thirty-eight post-FS-LASIK patients with DED were assigned to two groups: those with chronic ocular pain and those without chronic ocular pain. Dry eye, ocular pain, and mental health-related parameters were evaluated using specific questionnaires and tests. The morphology of corneal nerves and dendritic cells (DCs) was evaluated by in vivo confocal microscopy. Function of corneal innervation was evaluated by corneal sensitivity. Concentrations of tear cytokines (interleukin [IL]-6, IL-23, IL-17A, and interferon-γ) and neuropeptides (α-melanocyte-stimulating hormone, neurotensin, β-endorphin, oxytocin, and substance P [SP]) were measured using the Luminex assay.
RESULTS
Most patients with chronic ocular pain experienced mild to moderate pain; the most common types included stimulated pain (provoked by wind and light), burning pain, and pressure sensation. More severe dry eye (P < 0.001), anxiety symptoms (P = 0.026), lower Schirmer I test values (P = 0.035), lower corneal nerve density (P = 0.043), and more activated DCs (P = 0.041) were observed in patients with ocular pain. Tear concentrations of SP and oxytocin were significantly higher in patients with ocular pain (P = 0.001, P = 0.021, respectively). Furthermore, significant correlations were observed among ocular pain severity, SP, and anxiety levels.
CONCLUSIONS
Patients with DED after FS-LASIK who have chronic ocular pain show more severe ocular and psychological discomfort and higher tear levels of neuropeptides. Furthermore, ocular pain severity is correlated with tear SP levels.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT05600985.
PubMed: 38190027
DOI: 10.1007/s40123-023-00861-3 -
Scientific Reports Oct 2020Lacrimal gland excision (LGE) induced dry eye produces more severe corneal damage in female mice, yet signs of LGE-induced ocular pain and anxiety in male and female...
Lacrimal gland excision (LGE) induced dry eye produces more severe corneal damage in female mice, yet signs of LGE-induced ocular pain and anxiety in male and female mice have not been characterized. Excision of either the extraorbital gland (single LGE), or both the extraorbital and intraorbital glands (double LGE) was performed in male and female C57BL/6J mice to induce moderate and severe dry eye. Ongoing pain was assessed by quantifying palpebral opening and evoked nociceptive responses after corneal application of capsaicin and menthol. The open-field and plus maze were used to assess anxiety. Single LGE caused a reduction in palpebral opening and an increase in capsaicin and menthol-evoked responses only in female mice. Furthermore, single LGE produced signs of increased anxiety in female but not male mice. Overall, female mice appear more susceptible to signs of ocular pain, irritation, and anxiety in response to aqueous tear deficiency.
Topics: Animals; Anxiety; Capsaicin; Dry Eye Syndromes; Eye Pain; Female; Lacrimal Apparatus; Male; Menthol; Mice, Inbred C57BL; Pain Measurement; Sex Characteristics
PubMed: 33057056
DOI: 10.1038/s41598-020-73945-w