Understanding chronic ocular surface pain: An unmet need for targeted drug therapy

Chronic ocular surface pain (COSP) may be defined as a feeling of pain, perceived as originating from the ocular surface, that persists for >3 months. COSP is a complex multifactorial condition associated with several risk factors that may significantly interfere with an individual's daily activities, resulting in poor quality of life (QoL). COSP is also likely to have a high burden on patients with substantial implications on global healthcare costs. While patients may use varied terminology to describe symptoms of COSP, any ocular surface damage in the ocular sensory apparatus (nociceptive, neuropathic, inflammatory, or combination thereof) resulting in low tear production, chronic inflammation, or nerve abnormalities (functional and/or morphological), is typically associated with COSP. Considering the heterogeneity of this condition, it is highly recommended that advanced multimodal diagnostic tools are utilized to help discern the nociceptive and neuropathic pain pathways in order to provide targeted treatment and effective clinical management. The current article provides an overview of COSP, including its multifactorial pathophysiology, etiology, prevalence, clinical presentation, impact on QoL, diagnosis, current management, and unmet medical needs.     

Pathogenic Mechanism of Dry Eye–Induced Chronic Ocular Pain and a Mechanism-Based Therapeutic Approach

PurposeDry eye–induced chronic ocular pain is also called ocular neuropathic pain. However, details of the pathogenic mechanism remain unknown. The purpose of this study was to elucidate the pathogenic mechanism of dry eye–induced chronic pain in the anterior eye area and develop a pathophysiology-based therapeutic strategy.MethodsWe used a rat dry eye model with lacrimal gland excision (LGE) to elucidate the pathogenic mechanism of ocular neuropathic pain. Corneal epithelial damage, hypersensitivity, and hyperalgesia were evaluated on the LGE side and compared with the sham surgery side. We analyzed neuronal activity, microglial and astrocytic activity, α₂δ–1 subunit expression, and inhibitory interneurons in the trigeminal nucleus. We also evaluated the therapeutic effects of ophthalmic treatment and chronic pregabalin administration on dry eye–induced ocular neuropathic pain.ResultsDry eye caused hypersensitivity and hyperalgesia on the LGE side. In the trigeminal nucleus of the LGE side, neuronal hyperactivation, transient activation of microglia, persistent activation of astrocytes, α₂δ–1 subunit upregulation, and reduced numbers of inhibitory interneurons were observed. Ophthalmic treatment alone did not improve hyperalgesia. In contrast, continuous treatment with pregabalin effectively ameliorated hypersensitivity and hyperalgesia and normalized neural activity, α₂δ–1 subunit upregulation, and astrocyte activation.ConclusionsThese results suggest that dry eye–induced hypersensitivity and hyperalgesia are caused by central sensitization in the trigeminal nucleus with upregulation of the α₂δ–1 subunit. Here, we showed that pregabalin is effective for treating dry eye–induced ocular neuropathic pain even after chronic pain has been established.     

TFOS DEWS II pain and sensation report

Pain associated with mechanical, chemical, and thermal heat stimulation of the ocular surface is mediated by trigeminal ganglion neurons, while cold thermoreceptors detect wetness and reflexly maintain basal tear production and blinking rate. These neurons project into two regions of the trigeminal brain stem nuclear complex: ViVc, activated by changes in the moisture of the ocular surface and VcC1, mediating sensory-discriminative aspects of ocular pain and reflex blinking. ViVc ocular neurons project to brain regions that control lacrimation and spontaneous blinking and to the sensory thalamus. Secretion of the main lacrimal gland is regulated dominantly by autonomic parasympathetic nerves, reflexly activated by eye surface sensory nerves. These also evoke goblet cell secretion through unidentified efferent fibers. Neural pathways involved in the regulation of meibomian gland secretion or mucin release have not been identified.In dry eye disease, reduced tear secretion leads to inflammation and peripheral nerve damage. Inflammation causes sensitization of polymodal and mechano-nociceptor nerve endings and an abnormal increase in cold thermoreceptor activity, altogether evoking dryness sensations and pain. Long-term inflammation and nerve injury alter gene expression of ion channels and receptors at terminals and cell bodies of trigeminal ganglion and brainstem neurons, changing their excitability, connectivity and impulse firing. Perpetuation of molecular, structural and functional disturbances in ocular sensory pathways ultimately leads to dysestesias and neuropathic pain referred to the eye surface. Pain can be assessed with a variety of questionaires while the status of corneal nerves is evaluated with esthesiometry and with in vivo confocal microscopy.     

Post-LASIK Tear Dysfunction and Dysesthesia

Symptoms of tear dysfunction after laser in situ keratomileusis (LASIK) occur in nearly all patients and resolve in the vast majority. Although dry eye complaints are a leading cause of patient discomfort and dissatisfaction after lasik, the symptoms are not uniform, and the disease is not a single entity. Post-LASIK tear dysfunction syndrome or dry eye is a term used to describe a spectrum of disease encompassing transient or persistent post-operative neurotrophic disease, tear instability, true aqueous tear deficiency, and neuropathic pain states. Neural changes in the cornea and neuropathic causes of ocular surface discomfort may play a separate or synergistic role in the development of symptoms in some patients. Most cases of early post-operative dry eye symptoms resolve with appropriate management, which includes optimizing ocular surface health before and after surgery. Severe symptoms or symptoms persisting after 9 months rarely respond satisfactorily to traditional treatment modalities and require aggressive management. This review covers current theories of post-LASIK dry eye disease, pathophysiology, risk factors, and management options for this disease spectrum of post-LASIK tear dysfunction and neuropathic pain.     

三叉神经痛患者眼表表现及角膜神经的共焦显微镜观察

背景三叉神经眼支是角膜的主要感觉神经和营养神经,三叉神经痛是否会影响患侧眼角膜的功能和形态尚未见报道。共焦显微镜是角膜无创性活体检测的主要手段。目的观察和分析三叉神经痛患者角膜的共焦显微镜下表现及角膜神经在共焦显微镜下形态和密度的改变。方法收集就诊于河南省人民医院疼痛科的33例三叉神经痛患者,对所有受检眼应用角膜知觉敏感度测量计测定角膜知觉,并进行泪液分泌功能测定、泪膜破裂时间（BUT）测定和共焦显微镜观察,对侧眼作为对照组。结果三叉神经痛组角膜知觉测试的纤维长度为（54．348±6．793）mm,正常对照组的角膜知觉平均值为（55．217±6．480）him,差异无统计学意义（t=0．641,P=0．528）;三叉神经痛组SchiemerI试验的滤纸浸湿长度平均值为（9．390±6．583）mm,正常对照组为（9．300±5．295）mm,差异无统计学意义（t=0．070,P=0．945）;2组的BUT平均值分别为（6．09±4．177）S和（6．13±4．799）s,差异无统计学意义（t=-0．085,P=0．933）。角膜鼻侧、颞侧、上方、下方和中央区上皮下神经丛密度与对照组比较,差异均无统计学意义（P=0．840、0．459、0．268、0．120、0．607）。共焦显微镜下三叉神经痛组角膜上皮下神经丛神经纤维数量减少、扭曲;角膜基质中神经丛纤细、盘旋、弯曲;正常对照组上皮下神经纤维分布较密集,平行分布;角膜基质中神经纤维笔直走行,较上皮下神经纤维粗大且分支较多。结论共焦显微镜结果显示三叉神经痛患者患侧眼较正常眼角膜神经扭曲,但眼表功能和角膜神经密度计数无明显改变。     

Herpes zoster ophthalmicus

Introduction : Herpes zoster is a common disease which may cause serious ocular sequelae when it affects the trigeminal nerve. Although involvement of the nasociliary branch of the first division of the trigeminal nerve is well recognised to be associated with serious and direct ocular morbidity, the need for careful long‐term follow‐up of cases of frontal branch involvement is perhaps less well known. Methods : The pathogenesis, epidemiology, risk factors, clinical course and treatment of herpes zoster are discussed with emphasis on trigeminal nerve involvement. A case report is presented which illustrates the importance of continuing management when the frontal branch of the trigeminal nerve is affected. Discussion : Clinical guidelines are suggested for optometric management of these cases in cooperation with medical practitioners.     

The Effect of Stellate Ganglion Block on Prolonged Post-operative Ocular Pain

Japanese Journal of Ophthalmology - There are cases when ocular pain persists long after ocular surgery and cannot be reduced by anti-inflammatory drugs. Our purpose was to evaluate the effect of...     

更昔洛韦联合He-Ne激光治疗眼带状疱疹40例疗效分析

目的 观察更昔洛韦联合He-Ne激光治疗眼带状疱疹的临床疗效.方法 将40例眼带状疱疹患者随机分成两组,治疗组20例给予更昔洛韦静脉输入,VitB1、VitB12服,合并角膜炎、虹膜睫状体炎者加用更昔洛韦滴眼液及散瞳药,同时联合He-Ne激光照射三叉神经相应部位;对照组20例单独给予上述药物治疗.观察患者水疱结痂,疼痛消失及眼并发症消失的时间.结果 治疗组水疱结痂及疼痛消失时间、眼并发症消失时间明显短于对照组.结论 联合He-Ne激光疗法治疗眼带状疱疹疗效明显优于单独药物治疗.     

Topical diclofenac versus dexamethasone after strabismus surgery: a double-blind randomized clinical trial of anti-inflammatory effect and ocular hypertensive response

BACKGROUND: Compared to steroids non-steroidal anti-inflammatory drugs offer comparable anti-inflammatory action without ocular side-effects. AIM: To compare the anti-inflammatory effect and effect on IOP (Goldmann) of topical diclofenac 0.1% with dexamethasone 0.1% after strabismus surgery. DESIGN: Prospective, randomized, double-blind, single-center, clinical trial. MATERIALS AND METHODS: Forty-three cases of constant horizontal strabismus, qualifying for standard uniocular recession-resection surgery on two horizontal rectus muscles were randomized to either the dexamethasone or diclofenac group. They were excluded if they had previous ocular surgery, recently used anti-inflammatory drugs and had a neurological, systemic or an ocular inflammatory condition. In addition all received ciprofloxacin 0.3% four times daily. Assessment was done on the first postoperative day and at two and four weeks. The inflammatory characteristics graded from nil (0) to severe (3) were: discomfort, chemosis, injection, discharge and drop-intolerance. Their sum provided the total inflammatory score (TIS). RESULTS: Dexamethasone group (n=21) was comparable in age, gender, preoperative IOP, strabismus, anesthesia administered and baseline IOP, to diclofenac (n=22). There were no significant differences in the inflammatory characteristics and TIS. The dexamethasone group had IOP significantly higher at two weeks (95% CI 0.17 to 3.25) and four weeks (95% CI 1.09 to 4.24) compared to diclofenac group and the net change of IOP at four weeks (95% CI 0.60 to 3.14). Compared to the baseline IOP. CONCLUSION: Topical diclofenac is comparable to dexamethasone in providing anti-inflammatory and analgesic effect with the advantage of significantly lesser IOP rise and should be preferred after strabismus surgery.     

曲马多控制准分子激光上皮下角膜磨削术后疼痛的临床观察

目的:评价曲马多控制准分子激光上皮下角膜磨削术(laser-assistedsubepithelialkeratomileusisLASEK)术后疼痛的疗效和安全性。方法:采用随机对照实验,对照组术后用典必殊滴眼液4次/d,迪非滴眼液4次/d;实验组除按对照组用药外,加曲马多口服100mg/次,2次/d,共2d。分别于术前、术后第1天、第4天、第7天观察眼痛、畏光、流泪、异物感等症状及眼睑水肿和结膜充血的情况。评分标准为:无痛(0分)、轻度疼痛(1分)、中度疼痛(2分)、重度疼痛(3分)。比较两组在术前、术后第1天、第4天、第7天的评分差异。结果:实验组和对照组术后疼痛评分在术后第1天分别为0.48±0.67和1.70±0.69(P<0.001),第4天分别为0.18±0.39和0.65±0.55(P<0.05),差异有显著性,第7天两组疼痛评分均为0。试验组和对照组术后第1天眼睑水肿和结膜充血发生的比例分别为24.2%和61.3%(P<0.05),第4天的比例分别为6.1%和35.5%(P<0.05),差异有显著性。实验组中有4例出现头晕、恶心症状,停药后自行缓解,未见其它严重并发症和副作用。结论:曲马多对控制LASEK术后疼痛及其它不适反应有效而安全。     

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

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.     

Ocular pain secondary to occipital neuritis.

Sixteen patients whose chief complaint was ocular or periocular pain were diagnosed as having occipital neuritis. All but one had significant relief of pain from one or more injections of an anesthetic in the vicinity of the greater occipital nerve. They were subsequently treated with anti-inflammatory measures. From these cases definitions of significant tenderness and success of treatment were developed. These observations form a basis for a current double-blind study designed to establish a relationship between ocular pain and occipital neuritis.     

Postherpetic ophthalmic neuralgia

Postherpetic ophthalmic neuralgia is the final stage of a varicella zoster infection. Many years after chickenpox infection, patients can develop herpes zoster in one or more specific dermatomal regions. The ophthalmic branch of the trigeminal nerve and the thoracic nerves are most commonly affected. Younger patients are less prone to postherpetic neuralgia than the older. Patients with a depression in cell-mediated immunity are more susceptible to develop postherpetic pain. Postherpetic ophthalmic neuralgia is a neuropathic pain and can be treated by anticonvulsants and tricyclic antidepressants. Neurodestructive procedures are not recommended as they enhance destruction and neuropathic pain. Sympathetic nerve blocks can be helpful. Neurostimulation is the last therapeutic resort.     

Pain in Ophthalmology

The pain, one of the most common and unpleasant symptoms of human experience, is a psychophysiological phenomenon made of physical (elementary) pain and psychological pain. The ocular pain may result from stimulation of trigeminal nerve fibres anywhere within the eye, the surrounding tissues, the deep orbit, and the base of the middle and anterior cranial fossae. An ocular pain which is accompanied by another ocular signs can easily suggest a diagnosis for ophthalmologist, but a deep pain which involves the frontal bone and the deep orbit often asks an interdisciplinary consultation.     

Posttraumatic abducens to oculomotor nerve misdirection.

INTRODUCTION: Paradoxical patterns of extraocular muscle, eyelid, or pupillary movements can occur following injury between divisions of the oculomotor nerve, trigeminal and abducens nerves, and trigeminal and oculomotor nerves. We report three cases of unusual ocular motility and eyelid movements that are a result of aberrant connections between the abducens and oculomotor nerves. METHODS: Three patients with unusual eye movement abnormalities after trauma were studied. A complete ophthalmic examination plus neuroradiologic evaluation were performed. RESULTS: Each patient manifested an aberrant connection between the 6th and 3rd cranial nerves resulting in third nerve function during sixth nerve stimulation. Two patients demonstrated complete third nerve palsies except for adduction on attempted abduction. The third showed improved bilateral ptosis on abduction. CONCLUSIONS: The neuroanatomical abnormalities involve intraorbital structures in one patient and central nervous system pathways in the others. Explanations such as retrograde regeneration, ephaptic transmission, or denervation supersensitivity do not appear to explain these unusual eye movements. The most likely mechanism involves some form of peripheral neuronal misdirection. These rare sixth to third nerve misdirection cases add support to the "neuronal misdirection hypothesis" of aberrant eye movements after trauma.     

Experimental reactivation of ocular herpes simplex in rabbits

Latent herpes simplex virus (HSV) is known to reside in the trigeminal ganglia. Our studies show that the temporay retrobulbar disruption of trigeminal nerve function in chronically infected animals caused a striking decrease in the number of positive HSV cultures obtained during the 20 weeks immediately following surgery. We found that the stereotaxic interruption of intracranial trigeminal nerve function prior to initial HSV infection dramatically reduced the incidence of peripheral recurrence of HSV. Stereotaxic stimulation of the trigeminal ganglion in chronically infected animals produced a significant increase in positive cultures within two days. But, direct neurosurgical stimulation of the trigeminal ganglion proved strikingly effective, producing 83% positive cultures at the eye within 48 hours of operation. These studies further substantiate the premise that the trigeminal ganglion serves as a reservoir for latent ocular HSV in rabbits. They also suggest that the transmission of latent HSV from the trigeminal ganglion to its infectious form in the peripheral ocular tissues somehow involves the trigeminal nerve.     

青光眼睫状体炎综合征的研究进展

青光眼睫状体炎综合征(PSS)是一种较少见、反复发作的自限性前葡萄膜炎，目前发病机制仍不明确，曾认为是前列腺素介导的炎症反应，近年发现与病毒感染、免疫遗传、血管内皮功能障碍等因素相关。临床上多单眼发病，发作时眼压升高，患眼轻度疼痛、视物不清、虹视等，较少引起视神经及视野损害。治疗以局部抗炎、降眼压为主，严重者可全身用药。如果PSS眼压升高药物不可控、发作频繁、病程长造成视神经损害、视野缺损，可进行手术治疗。对PSS早诊断、早治疗可以减少青光眼相关损害。本文将从多个方面论述PSS的研究现状，期望对本病的病因、发病机制及临床诊治方面提供参考。     

Tetracaine versus diclofenac in the treatment of pain following refractive photokeratectomy

PURPOSE: To compare the efficacy and safety of topical diclofenac and tetracaine in reducing ocular pain after photorefractive keratectomy. SETTING: Ophthalmology Department, Minjoz Hospital, Besan?on, France. METHODS: Seventy-four patients were randomized to receive either tetracaine 1% or diclofenac 0.1% after undergoing PRK. Tetracaine was instilled at 30 minute intervals for 24 hours. Diclofenac was instilled four times a day for 3 days. All patients were allowed to use oral Diantalvic (paracetamol-noramidopyrine) as a rescue analgesic if the study medications failed to control the ocular pain. Visual analog pain charts were used to record pain levels every hour for 30 hours after surgery. A subjective questionnaire was to be completed by the patient to evaluate discomfort every day for 3 days. Computer analysis of photography performed at D0, D1, D3, was used to evaluate the rate of epithelial closure. RESULTS: Women had significantly more pain. Patients in the diclofenac group had significantly less pain. No statistically significant difference was seen in the rate of epithelial closure. CONCLUSION: Diclofenac is more effective than tetracaine to reduce ocular pain and functional symptoms.     

干眼与眼部神经病理性疼痛相关性进展

干眼（dry eye，DE）是一种常见的多因子眼表疾病，具有较高的发病率。DE的症状包括视力模糊、刺激和眼部疼痛。研究表明，DE和神经病理性疼痛在流行病学、发病机制和临床表现上有许多相似之处。本文综述了DE与眼部神经病理性疼痛的相似处，重点介绍临床特征、眼部神经性疼痛评估及治疗方法。