Capsaicin in Idiopathic Rhinitis A Hot Topic

In chapter I the currently known causes for nonallergic noninfectious rhinitis and possible treatments are summarised. Also possible pathophysiological mechanisms underlying idiopathic rhinitis (IR) are discussed. In chapter II the aims of the studies are presented. This thesis comprises studies aimed at the therapeutic potential and safety of intranasal capsaicin in IR patients, developing a patient and physician friendly, effective intranasal capsaicin treatment regimen for IR and the histological analysis of the nasal mucosa of IR patients in order to find an explanation for the therapeutic effect of capsaicin and the underlying pathophysiology of IR. In chapter III the efficacy of intranasal capsaicin spray in the treatment of IR patients was studied. Several authors described capsaicin, the pungent substance in red-pepper, as an efficacious therapy for IR. Repeated intranasal capsaicin application induces peptide depletion and specific degeneration of the unmyelinated sensory C-fibers in the nasal mucosa. We performed a double-blind placebo (NaCl 0.9%) controlled study with 25 IR patients. Daily record charts (DRC) and visual analogue scales (VAS) were used for clinical evaluation. Nasal lavages were obtained before, during and after treatment. There was a significant and long-term reduction in the VAS scores in the capsaicin group. No significant difference was found between the placebo and capsaicin treated groups for the mean group concentrations of leukotriene (LT) C4 / D4 / E4 , prostaglandin D2 (PGD2), and tryptase. The levels of mast cell mediators, tryptase and PGD2, and leukotrienes, mediators derived from a variety of inflammatory cells, were low at baseline and comparable with levels observed in nasal lavages obtained from normals. As involvement of inflammation could not be demonstrated, it is not surprising that capsaicin has no effect on inflammatory mediators. This suggests that inflammatory cells do not play a major part in the pathogenesis of IR. In chapter IV we conducted a double-blind double-dummy parallel group trial to determine whether a more practical capsaicin application schedule is equally effective as the one described in chapter III. In daily practice, this application regimen of intranasal capsaicin application once every second or third day for a total of 7 days proved to be impractical because of the large number of visits required in a short period of time. Thirty patients were randomized into two different treatment regimens: one group received capsaicin five times the first day at one-hour intervals. This was followed by a placebo dummy once every second or third day for a total of five treatments 2 weeks after the capsaicin application (group A). The other group (B) received the placebo dummy five times on the first day followed by capsaicin once every second or third day for a total of five treatments 2 weeks after the placebo application. The VAS scores for overall nasal symptoms, rhinorrhea and nasal blockage showed significant decrease after the start of treatment in both groups, with a significantly steeper decrease in group A. A significant reduction in cold dry air dose responsiveness was also found up to 9 months after therapy in both groups, reflecting a decrease in nasal hyperreactivity. No significant changes in safety data (smell, blood pressure, heart rate) were found. We conclude that local capsaicin nasal spray significantly reduces nasal complaints in IR patients and that five treatments of capsaicin on a single day is at least as effective as five treatments of capsaicin in 2 weeks, and even more effective in the reduction of nasal complaints measured with VAS. We also conclude that intranasal capsaicin seems safe to use. In chapter V nasal mucosa inflammatory cell densities of IR patients are studied and compared with normals. Mucosal inflammatory cellular infiltrates are correlated with nasal complaints in symptomatic allergic rhinitis. Some authors suggest inflammation of neurogenic or immunogenic nature as the underlying pathophysiology for IR. We examined whether inflammatory cells are involved in the pathogenesis of IR. Nasal biopsies were taken of 65 patients with significant nasal complaints and 20 controls without nasal complaints. Inflammatory cells were quantified, using monoclonal antibodies directed against lymphocytes, antigen presenting cells, eosinophils, macrophages, monocytes, mast cells and other IgE-positive cells. No significant differences were found, for any cell, between IR patients and controls. We conclude that inflammatory cells do not seem to play an important role in this meticulously characterised group of IR patients. In chapter VI the long term effects of capsaicin spray on the nasal mucosa are studied. Capsaicin has been shown previously to reduce nasal complaints in patients with IR. Proposed pathophysiologic mechanisms for IR include a chronic inflammatory disorder of antigenic or neurogenic nature as well as the possibility of a functional neuronal disorder. We hypothesized that the beneficial effect of capsaicin might be the result of a down regulation of inflammation (by a reduction of inflammatory cells) or through a modulation of neural tissue density. Patients were treated with either a placebo or capsaicin spray solution once every second or third day for a total of seven treatments. Both sides were treated each visit. Biopsies were taken before, 2 weeks after, 3 months after and 9 months after the treatment period. Immunohistochemical staining of the biopsy specimen was performed to ascertain the effect of treatment on immunocompetent cell densities (quantitative) and neural tissue densities (semiquantitative) in the nasal mucosa. Nasal complaints were significantly reduced in the capsaicin treated group (Chapter III). The number of lymphocytes, antigen presenting cells, eosinophils, macrophages, monocytes, mast cells and other IgE-positive cells did not significantly differ between the capsaicin and the placebo group. No significant differences between both groups were found in pan-neurogenic staining of nasal mucosa using neurofilament and synaptophysine. To conclude capsaicin intranasal spray does significantly improve nasal symptomatology in IR patients (shown previously), without affecting cellular homeostasis or overall neurogenic staining upto 9 months after treatment. Immunocompetent cells are not involved in IR. In chapter VII we tried to get more insight into the pathophysiologic mechanism of IR and the direct mode of action of capsaicin on nasal mucosa cell counts and neurogenic staining. To our knowledge data concerning the provocation effect of capsaicin on nasal cellular homeostasis in humans is limited to lavage studies following a single capsaicin application in allergic patients and healthy controls. We performed a double-blind placebo controlled nasal biopsy study in 30 strictly selected and well-defined IR patients challenged with either capsaicin or placebo. Biopsies were taken at baseline 2 weeks before provocation and 15 minutes and 1 hour after a single provocation with capsaicin or placebo. The cell densities of CD3, CD8, CD25, C-Kit, chymase, tryptase, BB1, IgE and BMK 13 and the neuronal staining with synaptophysine, neurofilament and VRL-1 were studied in both layers of the nasal mucosa. No significant difference in nasal mucosa cell counts and neurogenic staining were found 15 minutes and 1 hour after provocation. Only for CD3 in the epithelium 1 hour after provocation a significant higher cell count was found in the capsaicin group using the Mann-Whitney U test. Due to multiple testing this p-value of 0.011 for CD3 could have been easily caused by chance. We conclude that capsaicin, after local anaesthesia of the nasal mucosa, does not affect cellular homeostasis or neurogenic staining 15 minutes and 1 hour after nasal provocation in this double-blind placebo controlled biopsy study. This strengthens us in our idea that inflammatory cells do not play a role in the mode of action of capsaicin and the aetiology of IR.