xRead - Nonallergic Rhinitis (September 2025)

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BAROODY ET AL

J ALLERGY CLIN IMMUNOL PRACT JUNE 2024

FIGURE 4. ( A ) Site of endogenous and exogenous molecules that influence TRPV1 activity and selected amino acids in the 6 trans membrane molecule. Note that capsaicin influences 5 different sites. Protein kinase A (PKA), CaM, adenosine triphosphate (ATP), CAM KII, PKC. PIP2, and resiniferatoxin (RTX). ( B ) With acute (transient) desensitization, there is an increase in intracellular calcineurin, which, in turn, decreases CAM KII. There is depletion of PIP2, which is required for ion channel function, and there is conformational change at amino acid tyrosine 671 that reduces the size of the cation influx between the fifth and the sixth transmembrane proteins. ( C ) With repeated activation of capsaicin, there is an increase in intracellular calmodulin that interacts to stabilize activation of the ion channel in a calcium-dependent manner at the C-terminal binding domain and a calcium-independent manner at the N-terminal domain.

controlled trials of NAR. 63-65 Currently, no speci fi c therapies are being developed for NAR. A pharmacological TRPV1 antago nist, SB-705498, did not show clinical ef fi cacy at 1 hour or 24 hours. 66 Surgical Surgical options are considered if medical therapy fails and the patient continues to have signi fi cant symptoms. Clearly, surgical therapy in patients with NAR is targeted at straightening the nasal septum (septoplasty) or other structural problems that are uncovered during the initial physical examination despite maxi mized therapy. Turbinate reduction procedures aim to reduce the volume of the inferior turbinate and increase the space available to air fl ow while preserving the nasal mucosa and its physiological functions. These include microdebrider-assisted submucosal reduction of mucosa, submucosal reduction of bone, lateral bone out-fracture, and the reduction of hypertrophied mucosa by a variety of means including radiofrequency ablation, coblation, laser, cryotherapy, and electrocautery. With the advent of the many modalities that result in turbinate reduction, partial and total turbinectomies have fallen out of favor. A recent systematic review of these techniques yielded 62 studies that investigated turbinectomy, submucosal resection, radiofrequency ablation, microdebrider assisted turbinoplasty, and laser and electrocautery reduction in patients with nasal obstruction related to both AR and nonal lergic rhinitis. 67 The median follow-up in these studies was 6 months, and all techniques resulted in improvements over baseline in visual analog scales of nasal congestion. Rhinorrhea was also assessed by visual analog scales in some studies and showed signi fi cant improvements from baseline. Objective measures of nasal congestion were used in some of the studies and included anterior rhinomanometry, measurement of

For persistent postnasal drainage not responsive to the previ ously discussed preparations, oral anticholinergic agents (eg, fi rst-generation H1-antihistamines such as chlorpheniramine and methscopolamine) have been used in some patients. This recommendation is solely based on expert opinion because there are no adequate clinical trials supporting the use of these agents in this circumstance. Shared decision making with the patient should be exercised after reviewing their bene fi ts and potential risks primarily related to excessive dryness, sedation, and gastrointestinal side effects, and with prolonged use, the potential for cognitive and memory de fi cits. 10,55 Intranasal capsaicin therapy has been demonstrated to be effective in the treatment of NAR by targeting the TRPV1 re ceptor at 5 different sites (Figure 4, A ). 56,57 Acutely, use of capsaicin is reported to engage a transient or acute (also referred to as transient) desensitization of the TRPV1 ion channel, which may work as a control feedback mechanism to regulate this ion channel. There are several intracellular mechanisms that regulate this (Figure 4, B ). 24-26 With repeated stimulation of the TRPV1 ion channel, a state of prolonged desensitization is reported to occur that is dependent on an increase of calmodulin (Figure 4, C ). 58-60 Prolonged desensitization can be reversed in experimental models by the addition of adenosine triphosphate or phosphatidylinositol 4,5-bisphosphate. 61 The concept of prolonged desensitization with capsaicin via changes of subionic activation mechanisms has been challenged by fi ndings that the overexpression of TRPV1 expressing nerve fi bers that is present in NAR is reduced after capsaicin therapy 33 and this clinically correlates with an improvement in symptoms of hypersensitivity to enhanced chemosensation. 62 There are limitations of commercially available capsaicin because they are irritating and have a short half-life, although low-dose (0.01 mM) regular treatment appears to be effective in double-blind placebo