-
Journal of Investigational Allergology... 2019Among the constellation of symptoms that characterizes allergic conjunctivitis, many (eg, burning and stinging) can be attributed to chronic neuropathic pain. Cumulative... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Among the constellation of symptoms that characterizes allergic conjunctivitis, many (eg, burning and stinging) can be attributed to chronic neuropathic pain. Cumulative data support that these hallmark symptoms might be linked to the effects of allergen-induced neuromodulation. This review investigates the key characteristics of neuropathic itch and pain in allergic conjunctivitis and their underlying pathogenic mechanisms.
METHODS
A literature review was conducted using a PubMed search focusing on allergic conjunctivitis, neurogenic inflammation, neuropathic itch, and neuropathic pain. Articles were reviewed, and those discussing clinical course, pathophysiology, and neuronal regulation of chronic neuropathic symptoms as related to allergic disease were summarized.
RESULTS
Recent evidence suggests that some symptoms of allergic conjunctivitis may be better represented as a chronic neuropathic disorder. We found that neurogenic mechanisms may have a significant role in chronic ocular surface inflammation from allergic inflammation. Manifestations may be associated with repeated ocular sensory nerve injury leading to an acute-to-chronic transition, which is in turn associated with neuropathologic changes (peripheral and central sensitization), neuronal dysfunction, and spontaneous ocular pain.
CONCLUSION
Current goals in the management of allergic conjunctivitis aim to minimize the inflammatory cascade associated with the allergic response in the initial stages of the pathogenic mechanism. Based on the mechanistic data reviewed herein, the recognition that neuronal inflammation explains many of the symptoms in allergic conjunctivitis opens new frontiers for drug discovery.
Topics: Animals; Anti-Allergic Agents; Biomarkers; Clinical Trials as Topic; Conjunctivitis, Allergic; Disease Management; Disease Susceptibility; Humans; Immunization; Neuralgia; Neuritis; Pruritus; Treatment Outcome
PubMed: 30222114
DOI: 10.18176/jiaci.0320 -
Academic Emergency Medicine : Official... Sep 2014
Topics: Anesthetics, Local; Corneal Injuries; Eye Injuries; Eye Pain; Female; Humans; Male; Tetracaine
PubMed: 25269591
DOI: 10.1111/acem.12468 -
Seminars in Ophthalmology 2016The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing... (Review)
Review
The richly innervated corneal tissue is one of the most powerful pain generators in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache, and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain.
Topics: Cornea; Cytokines; Eye Pain; Humans; Intercellular Signaling Peptides and Proteins; Neuralgia; Ophthalmic Nerve
PubMed: 26959131
DOI: 10.3109/08820538.2015.1114853 -
Journal of Patient-centered Research... 2021Keratoconjunctivitis sicca ("dry eye") is a common (14%-30% of adults over age 48) though difficult to treat condition that causes both discomfort and disability with... (Review)
Review
Keratoconjunctivitis sicca ("dry eye") is a common (14%-30% of adults over age 48) though difficult to treat condition that causes both discomfort and disability with associated dryness, pain, and visual disturbances. Etiology is not clearly understood but is likely varied, with a subset of patients suffering from chronic neuropathic pain referred to as "burning eye syndrome." This review of existing literature summarizes the clinical presentation, natural history, pathophysiology, and treatment modalities of burning eye syndrome. Chronicity of burning eye syndrome is likely secondary to increased nociception from the cornea, decrease in inhibitory signals, and nerve growth factor expression alterations. Treatment centers around symptomatic alleviation and reduction of inflammation. Conservative treatments focus on well-being and perception and include exercise, acupuncture, and cognitive behavioral therapy. Topical treatment consists of the anti-adhesion T-cell antagonist lifitegrast, corticosteroids, and cyclosporine; all have moderate efficacy and good safety. Autologous serum eye drops are a second-line topical that may promote corneal and neural healing on top of symptomatic relief. When these treatments fail, patients may trial neuromodulation with transcranial magnetic stimulation. Despite general treatment safety, more research is needed to develop novel approaches to this condition, possibly focusing more directly on the neurological component.
PubMed: 34322578
DOI: 10.17294/2330-0698.1813 -
Frontiers in Pharmacology 2021Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs,...
Neuropathic ocular pain is a frequent occurrence in medium to severe dry eye disease (DED). Only palliative treatments, such as lubricants and anti-inflammatory drugs, are available to alleviate patients' discomfort. Anesthetic drugs are not indicated, because they may interfere with the neural feedback between the cornea and the lacrimal gland, impairing tear production and lacrimation. Gabapentin (GBT) is a structural analog of gamma-amino butyric acid that has been used by systemic administration to provide pain relief in glaucomatous patients. We have already shown in a rabbit model system that its topic administration as eye drops has anti-inflammatory properties. We now present data on rabbits' eyes showing that indeed GBT given topically as eye drops has analgesic but not anesthetic effects. Therefore, opposite to an anesthetic drug such as oxybuprocaine, GBT does not decrease lacrimation, but-unexpectedly-even stimulates it, apparently through the upregulation of acetylcholine and norepinephrine, and by induction of aquaporin 5 (AQP5) expression in the lacrimal gland. Moreover, data obtained on a primary human corneal epithelial cell line also show direct induction of AQP5 by GBT. This suggests that corneal cells might also contribute to the lacrimal stimulation promoted by GBT and participate with lacrimal glands in the restoration of the tear film, thus reducing friction on the ocular surface, which is a known trigger of ocular pain. In conclusion, GBT is endowed with analgesic, anti-inflammatory and secretagogue properties, all useful to treat neuropathic pain of the ocular surface, especially in case of DED.
PubMed: 34163358
DOI: 10.3389/fphar.2021.671238 -
BMJ Open Ophthalmology 2021Though corneal collagen cross-linking (CXL) is an increasingly available and effective treatment for keratoconus, few reports have considered its impact on pain-related... (Review)
Review
Though corneal collagen cross-linking (CXL) is an increasingly available and effective treatment for keratoconus, few reports have considered its impact on pain-related physiology in depth. This comprehensive narrative review summarises mechanisms underlying pain in CXL and clinical care possibilities, with the goal of future improvement in management of CXL-related pain. Postoperative pain associated with CXL is largely due to primary afferent nerve injury and, to a smaller extent, inflammation. Chronification of pain after CXL has not been reported, even as long-term nerve damage without regeneration following standard CXL treatment is frequently observed. The lack of pain chronification may be due to the minimally invasive nature of the procedure, with its rapidly recovering superficial corneal wound, and to the positive anti-inflammatory changes of the tear film that have been described after CXL. Different CXL approaches have been developed, with the transepithelial epithelial-on technique (epi-on) associated with less postsurgical pain than the gold standard, epithelial-off technique (epi-off). After the first few days, however, the difference in pain scores and need for analgesics between epi-on and epi-off disappear. Patients experience relatively high-intensity pain the first few days post-CXL, and many strategies for acute pain control following CXL have been studied. Currently, no method of pain management is considered superior or universally accepted. Acute pain following CXL is a recognised and clinically significant side effect, but few CXL studies have systematically investigated postoperative pain and its management. This review aims to improve patient pain outcomes following this increasingly common procedure.
PubMed: 34901466
DOI: 10.1136/bmjophth-2021-000878 -
Clinical Ophthalmology (Auckland, N.Z.) 2018Dry eye (DE) is a chronic ocular condition with high prevalence and morbidity. It has a complex pathophysiology and is multifactorial in nature. Chronic ocular surface... (Review)
Review
Dry eye (DE) is a chronic ocular condition with high prevalence and morbidity. It has a complex pathophysiology and is multifactorial in nature. Chronic ocular surface inflammation has emerged as a key component of DE that is capable of perpetuating ocular surface damage and leading to symptoms of ocular pain, discomfort, and visual phenomena. It begins with stress to the ocular surface leading to the production of proinflammatory mediators that induce maturation of resident antigen-presenting cells which then migrate to the lymph nodes to activate CD4 T cells. The specific antigen(s) targeted by these pathogenic CD4 T cells remains unknown. Two emerging theories include self-antigens by autoreactive CD4 T cells or harmless exogenous antigens in the setting of mucosal immunotolerance loss. These CD4 T cells migrate to the ocular surface causing additional inflammation and damage. Lifitegrast is the second topical anti-inflammatory agent to be approved by the US Food and Drug Administration for the treatment of DE and the first to show improvement in DE symptoms. Lifitegrast works by blocking the interaction between intercellular adhesion molecule-1 and lymphocyte functional associated antigen-1, which has been shown to be critical for the migration of antigen-presenting cells to the lymph nodes as well as CD4 T cell activation and migration to the ocular surface. In four large multicenter, randomized controlled trials, lifitegrast has proven to be effective in controlling both the signs and symptoms of DE with minimal side effects. Further research should include comparative and combination studies with other anti-inflammatory therapies used for DE.
PubMed: 29391773
DOI: 10.2147/OPTH.S126668 -
Nature Medicine Aug 2018Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most...
Itch and pain are refractory symptoms of many ocular conditions. Ocular itch is generated mainly in the conjunctiva and is absent from the cornea. In contrast, most ocular pain arises from the cornea. However, the underlying mechanisms remain unknown. Using genetic axonal tracing approaches, we discover distinct sensory innervation patterns between the conjunctiva and cornea. Further genetic and functional analyses in rodent models show that a subset of conjunctival-selective sensory fibers marked by MrgprA3 expression, rather than corneal sensory fibers, mediates ocular itch. Importantly, the actions of both histamine and nonhistamine pruritogens converge onto this unique subset of conjunctiva sensory fibers and enable them to play a key role in mediating itch associated with allergic conjunctivitis. This is distinct from skin itch, in which discrete populations of sensory neurons cooperate to carry itch. Finally, we provide proof of concept that selective silencing of conjunctiva itch-sensing fibers by pruritogen-mediated entry of sodium channel blocker QX-314 is a feasible therapeutic strategy to treat ocular itch in mice. Itch-sensing fibers also innervate the human conjunctiva and allow pharmacological silencing using QX-314. Our results cast new light on the neural mechanisms of ocular itch and open a new avenue for developing therapeutic strategies.
Topics: Animals; Conjunctiva; Cornea; Eye; Humans; Mice, Inbred C57BL; Neurons, Afferent; Pain; Pruritus; Sensory Receptor Cells
PubMed: 29988128
DOI: 10.1038/s41591-018-0083-x -
Eye (London, England) Mar 2015Dry eye has gained recognition as a public health problem given its prevalence, morbidity, and cost implications. Dry eye can have a variety of symptoms including... (Review)
Review
Dry eye has gained recognition as a public health problem given its prevalence, morbidity, and cost implications. Dry eye can have a variety of symptoms including blurred vision, irritation, and ocular pain. Within dry eye-associated ocular pain, some patients report transient pain whereas others complain of chronic pain. In this review, we will summarize the evidence that chronicity is more likely to occur in patients with dysfunction in their ocular sensory apparatus (ie, neuropathic ocular pain). Clinical evidence of dysfunction includes the presence of spontaneous dysesthesias, allodynia, hyperalgesia, and corneal nerve morphologic and functional abnormalities. Both peripheral and central sensitizations likely play a role in generating the noted clinical characteristics. We will further discuss how evaluating for neuropathic ocular pain may affect the treatment of dry eye-associated chronic pain.
Topics: Dry Eye Syndromes; Eye Pain; Humans; Neuralgia
PubMed: 25376119
DOI: 10.1038/eye.2014.263 -
Cornea Apr 2022The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
PURPOSE
The purpose of this study was to characterize rates of opioid prescription for different ulcerative keratitis types.
METHODS
This cohort study included patients diagnosed with ulcerative keratitis according to the University of Michigan electronic health record data between September 1, 2014 and December 22, 2020. Ulcerative keratitis was categorized by etiologic type (bacterial, fungal, viral, acanthamoeba, inflammatory, polymicrobial, or unspecified) using rule-based data classification that accounted for billing diagnosis code, antimicrobial or antiinflammatory medications prescribed, laboratory results, and manual chart review. Opioid prescriptions were converted to morphine milligram equivalent and summed over 90 days from diagnosis. Opioid prescription rate and amount were compared between ulcerative keratitis types.
RESULTS
Of 3322 patients with ulcerative keratitis, 173 (5.2%) were prescribed at least 1 opioid for pain management within 90 days of diagnosis. More patients with acanthamoeba (32.4%), fungal (21.1%), and polymicrobial (25.0%) keratitis were treated with opioids compared with bacterial (6.7%), unspecified (2.9%), or viral (1.8%) keratitis (all Bonferroni adjusted P < 0.05). For the 173 patients who were prescribed opioids, a total of 353 prescriptions were given within 90 days of diagnosis, with half given within the first week after diagnosis. The quantity of opioid prescribed within 90 days from diagnosis was not significantly different between ulcerative keratitis types (P = 0.6559). Morphine milligram equivalent units prescribed ranged from 97.5 for acanthamoeba keratitis to 112.5 for fungal keratitis.
CONCLUSIONS
The type of ulcerative keratitis may influence the opioid prescription rate. Providers can better serve patients needing opioids for pain management through improved characterization of pain and development of more tailored pain management regimens.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Analgesics, Opioid; Child; Child, Preschool; Corneal Ulcer; Drug Prescriptions; Eye Pain; Female; Humans; Infant; Infant, Newborn; Male; Middle Aged; Pain Management; Practice Patterns, Physicians'; Retrospective Studies
PubMed: 34620771
DOI: 10.1097/ICO.0000000000002893