Neuropathic pain and itch: mechanisms in allergic conjunctivitis.

PURPOSE OF REVIEW: Allergic conjunctivitis is highly prevalent and affects up to one third of the general population. The current understanding of the pathophysiology and therapeutic strategies center around the type 2 inflammatory pathway. However, there is an increasing body of evidence that suggests neurogenic mechanisms also play a role in allergic inflammation, with a substantial proportion of allergic conjunctivitis patients experiencing both ocular itch and pain. RECENT FINDINGS: Unmyelinated C fibres on the ocular surface transmit histaminergic itch and can be directly activated by mast cell mediators. The conjunctival mucosa also contains TRPV1+ (histamine-dependent) and TRPA1+ (histamine-independent) neurons that enhance ocular pain and itch in allergic conjunctivitis. Allergen-complexed IgE also binds directly to FcεRI expressed on peripheral neurons. Environmental aeroallergens can also directly stimulate neuronal nociceptors to release inflammatory substances. Allergic inflammation thus stimulates nerve terminals to release vasoactive and inflammatory neuropeptides, leading to a cyclical neuronal dysregulation that augments mast cell activity. These repetitive cycles lead to both peripheral and central sensitization and neuronal plasticity, resulting in decreased itch/pain thresholds and a heightened itch/pain response. SUMMARY: Neurogenic mechanisms including peripheral and central sensitization may drive chronic ocular itch and pain secondary to allergic inflammation. Research into these pathways may help to identify therapeutic targets in allergic conjunctivitis patients with refractory symptoms.

Percutaneous electric nerve field stimulation alters cortical thickness in a pilot study of veterans with fibromyalgia.

Objective: To evaluate changes in cortical thickness and right posterior insula (r-pIns) gamma-aminobutyric acid (GABA) concentrations in veterans with fibromyalgia treated with auricular percutaneous electric nerve field stimulation (PENFS). Materials & methods: This was a randomized, controlled, open label investigation conducted in a government hospital. Twenty-one veterans with fibromyalgia were randomized to receive either standard therapy (ST; i.e., 4 weekly visits with a pain practitioner) or ST with auricular PENFS (ST + PENFS). Neuroimaging data was collected at baseline (i.e. before the first treatment session) and again within 2 weeks post-treatment.​ Clinical pain and physical function were also assessed at these timepoints. Single-voxel magnetic resonance spectroscopy was carried out in r-pIns to assess changes in r-pIns GABA concentrations and high-resolution T1-weighted images were collected to assess changes in regional gray matter volume using cortical thickness. Results: Both the ST + PENFS and ST groups reported a decrease in pain with treatment. Volumetric: Cortical thickness significantly decreased in the left middle posterior cingulate (p = 0.018) and increased in the left cuneus (p = 0.014) following ST + PENFS treatment. These findings were significant following FDR correction for multiple comparisons. ST group right hemisphere insula cortical thickness increased post-treatment and was significantly (p = 0.02) inversely correlated with pain scores. ST + PENFS group right hemisphere posterior dorsal cingulate size significantly (p = 0.044) positively correlated with pain scores. GABA: There were no significant correlations with GABA, though a trend was noted towards increased GABA following treatment in both groups (p = 0.083) using a linear mixed effects model. Conclusions: Results suggest a novel effect of PENFS reflected by differential volumetric changes compared to ST. The changes in GABA that occur in both groups are more likely related to ST. Insular GABA and cortical thickness in key regions of interest may be developed as potential biomarkers for evaluating chronic pain pathology and treatment outcomes.

Approach to Perioperative Anaphylaxis in 2020: Updates in Diagnosis and Management.

PURPOSE OF REVIEW: The goal of the paper is to review the epidemiology, pathogenesis, diagnosis, and manifestations of perioperative anaphylaxis (POA). We seek to review the most common culprits of POA and different diagnostic modalities for evaluation. RECENT FINDINGS: Specific IgE testing has a limited role in POA evaluation due to lack of widespread availability and low sensitivity. Basophil activation testing is complementary to skin tests and can assist NMBA sensitivity diagnosis in complex cases. In the past years, there has been an exponential increase in suspected teicoplanin allergic reactions in the European Union. Chlorhexidine is also being increasingly implicated as a culprit in POA. Multiple classes of perioperative medications cause POA. Diagnostic modalities available include skin testing with nonirritating concentrations, basophil activation tests, specific IgE, and drug provocation testing. An accurate record and critical analysis of perioperative events is more important than isolated test results. Future studies evaluating the pathophysiology of these reactions and other therapeutic strategies, such as targeting the MRGPRX2 receptor, are needed.

Feasibility of Auricular Field Stimulation in Fibromyalgia: Evaluation by Functional Magnetic Resonance Imaging, Randomized Trial.

OBJECTIVE: To evaluate the feasibility of recruitment, preliminary efficacy, and acceptability of auricular percutaneous electrical nerve field stimulation (PENFS) for the treatment of fibromyalgia in veterans, using neuroimaging as an outcome measure and a biomarker of treatment response. DESIGN: Randomized, controlled, single-blind. SETTING: Government hospital. SUBJECTS: Twenty-one veterans with fibromyalgia were randomized to standard therapy (ST) control or ST with auricular PENFS treatment. METHODS: Participants received weekly visits with a pain practitioner over 4 weeks. The PENFS group received reapplication of PENFS at each weekly visit. Resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) data were collected within 2 weeks prior to initiating treatment and 2 weeks following the final treatment. Analysis of rs-fcMRI used a right posterior insula seed. Pain and function were assessed at baseline and at 2, 6, and 12 weeks post-treatment. RESULTS: At 12 weeks post-treatment, there was a nonsignificant trend toward improved pain scores and significant improvements in pain interference with sleep among the PENFS treatment group as compared with the ST controls. Neuroimaging data displayed increased connectivity to areas of the cerebellum and executive control networks in the PENFS group as compared with the ST control group following treatment. CONCLUSIONS: There was a trend toward improved pain and function among veterans with fibromyalgia in the ST + PENFS group as compared with the ST control group. Pain and functional outcomes correlated with altered rs-fcMRI network connectivity. Neuroimaging results differed between groups, suggesting an alternative underlying mechanism for PENFS analgesia.

Absence of Iodinated Contrast Hypersensitivity and Characterization of Gadolinium Utilization in an Interventional Pain Population.

BACKGROUND: Iodinated contrast media (ICM) allergy labels pose a unique clinical problem for the interventional pain physician due to the drawbacks of gadolinium for enhancement during pain procedures, as well as the reluctance to add to the cumulative steroid burden with steroid premedication. However, the risks of ICM hypersensitivity specific to this setting have not been previously described. METHODS: We aimed to describe the incidence of ICM-induced hypersensitivity during the performance of epidural injections in a large healthcare system. We also sought to characterize preexisting ICM allergy labels and how these affected consequent gadolinium utilizations in this population. RESULTS: 6,471 epidural pain procedures requiring contrast enhancement were performed during the 18-month study period. There were no reported contrast-induced hypersensitivity reactions in this time. 108 patients (1.6%) had a preexisting ICM allergy; a shellfish/seafood allergy was recorded in 118 patients (1.82%), and 51 charts (0.78%) were labeled with "iodine" allergy. 183 individuals received gadolinium for enhancement during epidural steroid injections. 96.7% of gadolinium utilization occurred in the context of preexisting allergy labels in the electronic medical record. Of note, 20 patients (18.5%) with ICM allergy labels also received iodinated contrast, and this was uneventful in all cases. CONCLUSION: Our results suggest that ICM-associated hypersensitivity is very rare during epidural procedures and the incidence is significantly lower than expected based on reaction rates during intravascular administration. This may be related to both dose as well as route of administration. The establishment of a protocol for safe workup of ICM allergy labels would be useful in optimizing pain procedures.

Case Series: Cancer-Related Facial Pain Treated with Stellate Ganglion Block.

Stellate ganglion block (SGB) is believed to modify the pathologic sympathetic pain response and has been commonly used to treat complex regional pain syndrome. We report successful treatment of cancer-related facial pain with SGB in three patients, suggesting a possible sympathetic pain-related mechanism. All patients exhibited clinically significant improvement of pain 12 weeks following the procedure. SGB should be considered a palliative pain treatment option in cancer-related facial pain.

Clinical Manifestations and Diagnostic Evaluation of Opioid Allergy Labels - A Review.

While opioids represent one of the most common medication allergy labels, these labels are often unsubstantiated in clinical practice. The removal of erroneous opioid allergy labels has a unique importance in the population with acute or chronic pain. The current approach to patients with pseudo-allergy to opioids is switching to an alternative opioid with less histamine release. Thus, allergy labels to relatively lower potency opioids such as codeine may be feasibly result in the prescription of stronger medications like fentanyl that would otherwise not be indicated.This narrative review provides an overview of the epidemiology and clinical manifestations of opioid allergy labels commonly encountered by pain management practitioners along with recommendations for evaluation and management.A literature search of PubMed was performed using the comprehensive MeSH term, "Opioid Allergy".In recent years, it has become apparent that a substantial proportion of patients labeled as opioid allergic are found to be tolerant of these agents. Opioid skin testing and IgE assays are of limited application. DPT is the yet underutilized gold standard for diagnosis. There is also an increasing call for studies evaluating basophil activation testing in opiate allergy.Opioid allergy labels require a closer look especially in view of the current opioid epidemic. The low likelihood of true reactivity, combined with the conceivable clinical relevance of an opioid allergy label, calls for further characterization of this label in populations with acute or chronic pain diagnoses. Future directions should include larger prospective studies with systematic evaluation and classification of opioid allergy labels to determine future viability of opioid use.AbbreviationsEHRelectronic health recordNMBAneuromuscular blocking agentIgEimmunoglobulin EMCmast cellGPCRG-protein coupled receptorMRGPRX2mas-related G-protein receptorQAIquaternary ammonium ionsSCARsevere cutaneous adverse reactionAGEPacute generalized exanthematous pustulosisSDRIFEsymmetrical drug-related intertriginous and flexural exanthemaBATbasophil activation testingDPTdrug provocation testing.

Neuropathic Pain and Itch Mechanisms Underlying Allergic Conjunctivitis.

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.

Characteristics of Ocular Pain Complaints in Patients With Idiopathic Dry Eye Symptoms.

OBJECTIVE: The purpose of this study was to examine the severity and quality of ocular pain complaints in patients with dry eye symptoms. METHODS: Subjects with clinically relevant dry eye symptoms (dryness, discomfort, tearing) of unknown origin seen in the Miami Veterans Affairs eye clinic were administered questionnaires for dry eye symptoms and ocular pain and underwent a standardized ocular examination. Qualities and severity ratings of ocular pain in subjects with idiopathic dry eye were compared with similar measures from published data in other chronic pain populations. RESULTS: The study sample consisted of 154 subjects, of which 91% were men and ranged in age from 27 to 89 (mean age=61). Fifty-three percent of participants reported an average ocular pain of at least moderate intensity (numerical rating scale≥4), with specific characteristics (i.e., "burning" spontaneous pain) reported at frequencies comparable to prevalent chronic neuropathic pain syndromes as reported in the literature. Significant correlations were found between ocular pain metrics and dry eye symptom severity scores (r=0.57-0.66). Dry eye signs, however, did not generally correlate with ocular pain severity. CONCLUSIONS: A significant proportion of subjects with idiopathic dry eye symptoms reported moderate or greater ocular pain intensity, with most endorsing descriptors commonly used by patients with nonocular neuropathic pain conditions. Identifying subgroups of dry eye patients based on the presence and characteristics of ocular pain complaints may improve dry eye subclassification and better individualize treatment strategies.

Assessment of Somatosensory Function in Patients With Idiopathic Dry Eye Symptoms.

IMPORTANCE: Somatosensory dysfunction likely underlies dry eye (DE) symptoms in many individuals yet remains an understudied component of the disease. Its presence has important diagnostic and therapeutic implications. OBJECTIVE: To assess the integrity of nociceptive system processes in persons with DE and ocular pain using quantitative sensory testing (QST) techniques applied at a site remote from the eye. DESIGN, SETTING, AND PARTICIPANTS: A cross-sectional study conducted at Miami Veterans Affairs Hospital included 118 individuals with a wide variety of DE symptoms and signs. The study was conducted from October 31, 2013, to January 28, 2016. INTERVENTIONS: Individuals completed questionnaires regarding ocular symptoms (5-Item Dry Eye Questionnaire [DEQ5], Ocular Surface Disease Index [OSDI], and Neuropathic Pain Symptom Inventory modified for the eye [NPSI-E]), psychological status, and medication use and underwent an ocular surface examination. The QST metrics included measures of vibratory and thermal thresholds and cold and hot pain temporal summation (surrogate measures of central sensitization) on the forearm. MAIN OUTCOMES AND MEASURES: Correlations among DE and ocular pain symptom severity with QST metrics measured on the forearm. The OSDI score ranges from 0 to 100, with 100 indicating the most severe DE symptoms. The DEQ5 score ranges from 0 to 22, with the highest score indicating the most severe symptoms, and the NPSI-E score ranges from 0 to 100, with the highest score indicating the most severe symptoms. Psychological state was measured with the 9-item Patient Health Questionnaire, the PTSD Checklist-Military Version for PTSD, and the Symptom Checklist-90 for anxiety. RESULTS: Of the 118 patients who participated in the study, 105 (88.9%) were men (mean [SD] age, 60 [10] years), and a mean of 41% had PTSD, 10% depression, and 0.93% anxiety. Using stepwise linear regression analyses, significant associations were identified between overall DE symptom severity and posttraumatic stress disorder scores and tear breakup time (DEQ5 model: R = 0.54; OSDI model: R = 0.61, P < .001). All other variables (ie, demographics, comorbidities, medications, tear film factors, and QST metrics) dropped out of these models. When specifically considering neuropathic-like qualities of DE pain, however, anxiety and hot pain temporal summation at the forearm explained 17% of the variability in ocular burning (R = 0.41; P < .001), and PTSD score, tear breakup time, and hot pain temporal summation at the forearm explained 25% of the variability in sensitivity to wind (R = 0.50; P < .001) and 30% of the variability in total NPSI-E scores (R = 0.55; P < .001). CONCLUSIONS AND RELEVANCE: Our findings demonstrate that neuropathic-like DE pain symptom severity correlates with quantitative measures of pain sensitivity at a site remote from the eye. This result provides additional evidence that DE symptoms are not only manifestations of a local disorder but also involve somatosensory dysfunction beyond the trigeminal system.

Burning Eye Syndrome: Do Neuropathic Pain Mechanisms Underlie Chronic Dry Eye?

OBJECTIVE: 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." METHODS: 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. RESULTS: 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. CONCLUSION: 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."

Neuropathic Ocular Pain due to Dry Eye is Associated with Multiple Comorbid Chronic Pain Syndromes.

UNLABELLED: Recent data show that dry eye (DE) susceptibility and other chronic pain syndromes (CPS) such as chronic widespread pain, irritable bowel syndrome, and pelvic pain, might share common heritable factors. Previously, we showed that DE patients described more severe symptoms and tended to report features of neuropathic ocular pain (NOP). We hypothesized that patients with a greater number of CPS would have a different DE phenotype compared with those with fewer CPS. We recruited a cohort of 154 DE patients from the Miami Veterans Affairs Hospital and defined high and low CPS groups using cluster analysis. In addition to worse nonocular pain complaints and higher post-traumatic stress disorder and depression scores (P < .01), we found that the high CPS group reported more severe neuropathic type DE symptoms compared with the low CPS group, including worse ocular pain assessed via 3 different pain scales (P < .05), with similar objective corneal DE signs. To our knowledge, this was the first study to show that DE patients who manifest a greater number of comorbid CPS reported more severe DE symptoms and features of NOP. These findings provided further evidence that NOP might represent a central pain disorder, and that shared mechanistic factors might underlie vulnerability to some forms of DE and other comorbid CPS. PERSPECTIVE: DE patients reported more frequent CPS (high CPS group) and reported worse DE symptoms and ocular and nonocular pain scores. The high CPS group reported symptoms of NOP that share causal genetic factors with comorbid CPS. These results imply that an NOP evaluation and treatment should be considered for DE patients.

A reconstituted telomerase-immortalized human corneal epithelium in vivo: a pilot study.

PURPOSE: Telomerase-immortalized human corneal epithelial cells have been reported to stratify and differentiate in vitro similar to native tissue. The purpose of this study was to assess the ability of a telomerase-immortalized human corneal epithelial cell line to generate a full thickness epithelium in vivo in athymic mice. METHODS: Telomerized corneal epithelial cells were transduced with a retroviral vector encoding the herpes simplex thymidine kinase gene. Efficacy of the thymidine kinase suicide gene was confirmed using a live/dead assay. The epithelium was mechanically removed from athymic nude mice and remaining cells were treated with mitomycin C to prevent re-epithelialization. Telomerized corneal epithelial cells were seeded onto the denuded cornea and allowed to adhere for 4 and 24 hours. Cellular attachment was assessed using a fluorescent cell tracker. Stratification and differentiation were assessed after 7 days using phalloidin and a mouse monoclonal antibody to K3. RESULTS: Telomerized corneal epithelial cells were visualized across the denuded stromal surface at 4 and 24 hours, with multi-layering evident at the latter time point. No epithelium was present in the non-treated eye. After 7 days post-transplantation cells stratified into a multilayered epithelium, with positive K3 expression in basal and suprabasal cells. Treatment with ganciclovir induced significant loss of viability in vitro. CONCLUSIONS: The findings in this pilot study demonstrate that telomerized corneal epithelial cells possess the capacity to reconstitute a stratified corneal epithelium in vivo. The introduction of thymidine kinase allowed for the successful induction of cell death in proliferating cells in vitro. Collectively, these data suggest that a telomerase-immortalized corneal epithelial cell line transduced with thymidine kinase represents a potential model for studying differentiation and epithelial-niche interactions in vivo with potential applications in tissue engineering.