A significant proportion (25%-30%) of patients suffering from persistent rhinitis have nasal symptoms without clinical evidence of endonasal infection or systemic signs of sensitization to aeroallergens, a condition often referred to as nonallergic rhinitis.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (137) Google Scholar Up to 50% of patients with nonallergic rhinitis are classified as having idiopathic rhinitis (IR) after exclusion of occupational, elderly, gustatory, hormonal, and drug-induced rhinitis.1Hellings P.W. Klimek L. Cingi C. Agache I. Akdis C. Bachert C. et al.Non-allergic rhinitis: position paper of the European Academy of Allergy and Clinical Immunology.Allergy. 2017; 72: 1657-1665Crossref PubMed Scopus (137) Google Scholar IR remains a therapeutic challenge because of the inefficacy of intranasal corticosteroids.2Blom H.M. Godthelp T. Fokkens W.J. KleinJan A. Mulder P.G. Rijntjes E. The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis.J Allergy Clin Immunol. 1997; 100: 739-747Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar Intranasal administration of capsaicin at a high dose (0.1 mM) is currently the best medical therapeutic option for IR.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar However, this treatment has limitations because it is uncomfortable for patients owing to the need for prior local anesthesia, time-consuming (5 consecutive applications at 1-hour intervals), and incompletely understood in terms of its working mechanism.4Van Rijswijk J.B. Boeke E.L. Keizer J.M. Mulder P.G.H. Blom H.M. Fokkens W.J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study.Allergy. 2003; 58: 754-761Crossref PubMed Scopus (93) Google Scholar Thus, research for better capsaicin treatment formulations and protocols is warranted. To this aim, we conducted a randomized, double-blind, placebo-controlled trial in which we compared the effect of 2 lower-dose capsaicin nasal sprays (0.01 mM and 0.001 mM) that could be self-administered with the current capsaicin treatment (0.1 mM) in suppressing nasal symptoms. Additionally, because of the implication of substance P (SP) in IR,5Baraniuk J.N. Lundgren J.D. Okayama M. Goff J. Mullol J. Merida M. et al.Substance P and neurokinin A in human nasal mucosa.Am J Respir Cell Mol Biol. 1991; 4: 228-236Crossref PubMed Scopus (149) Google Scholar, 6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar we evaluated how nasal levels of SP are affected by capsaicin treatment to better understand the underlying working mechanism. The study was approved by the medical ethical committee of the University Hospitals of Leuven and registered at ClinicalTrials.gov (NCT02288156). A total of 68 well-characterized patients with IR (see Table E1 in this article’s Online Repository at www.jacionline.org) were randomized to 4 treatment arms (ie, Placebo/Placebo; Placebo/Capsaicin 0.001 mM; Placebo/Capsaicin 0.01 mM; and Capsaicin 0.1 mM/Placebo). Patients received 5 intranasal applications (2 puffs per nostril [0.4 mL per puff]) of either placebo or capsaicin, 0.1 mM, on a single day at 1-hour intervals. After the treatment visit, patients who had received the current capsaicin treatment (capsaicin, 0.1 mM) were sent home with a nasal spray containing placebo for daily use (the Capsaicin 0.1 mM/Placebo arm). Patients who were treated with placebo at the treatment visit received either a nasal spray containing placebo (the Placebo/Placebo arm); capsaicin, 0.001 mM (the Placebo/Capsaicin 0.001 mM); or capsaicin, 0.01 mM (the Placebo/Capsaicin 0.01 mM arm) (Fig 1 and see also Fig E1 in this article’s Online Repository at www.jacionline.org). All patients were asked to stop their treatment after 4 weeks and to score their major and individual nasal symptoms on a visual analogue scale (VAS) at screening, follow-up visit 1 (FU1), follow-up visit 2 (FU2), and follow-up visit 3 (FU3). The therapeutic response evaluation (TRE) was assessed at FU1, FU2, and FU3. SP levels were determined in nasal secretions collected at screening, FU1, and FU2. More details on patient selection and methodology are provided in the Online Repository (at www.jacionline.org). At FU1 and FU2, the VAS score for major symptom was significantly reduced in the Capsaicin 0.1 mM/Placebo and the Placebo/Capsaicin 0.01 mM groups compared with in the Placebo/Placebo group (Fig 2, A). Similarly, the VAS score for nasal obstruction was significantly decreased for both groups at FU2 (Fig 2, B). Nasal symptoms were not altered in the Placebo/Capsaicin 0.001 group versus the Placebo/Placebo group. At FU1, TRE showed an 82% improvement in the Placebo/Capsaicin 0.01 group, which was higher than the TRE of the Capsaicin 0.1/Placebo group (71%) (Fig 2, C). At FU2, a TRE of 73% was still observed for the Placebo/Capsaicin 0.01 group versus for the Placebo/Placebo group (Fig 2, D). At FU3, no significant improvement could be observed in any of the arms (data not shown). Previously, we reported increased SP concentrations in the nasal secretions of patients with IR compared with the nasal secretions of healthy controls.7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar Here, we found that the nasal SP levels of patients in the Placebo/Capsaicin 0.01 and Capsaicin 0.1/Placebo groups were significantly decreased compared with the levels of patients in the Placebo/Placebo group at FU2 (Fig 2, E). No significant difference in nasal SP levels between the Placebo/Capsaicin 0.001 and Placebo/Placebo groups was observed. Interestingly, SP positively correlated with the VAS score for major symptom (r = 0.34; P < .05) (Fig 2, F) and VAS score for nasal obstruction (see Fig E2 in this article’s Online Repository at www.jacionline.org). No correlation between SP and other VAS scores were found at FU1 and FU2 in any of the arms (data not shown). Given that only 70% to 80% of patients with IR will benefit from capsaicin treatment, we studied whether SP could serve as a biomarker to predict therapeutic response. Patients reporting therapeutic improvement at FU1 had a clear reduction in nasal SP levels, which was not observed in patients without therapeutic improvement (Fig 2, G). A decline in nasal SP of more than 7.08 ng/mL had a sensitivity of 72% and specificity of 75% to predict therapeutic continuation/effect (Fig 2, H). Until now, capsaicin has not been routinely used in clinical practice, although symptom reduction is observed in 70% to 80% of patients with IR.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar,4Van Rijswijk J.B. Boeke E.L. Keizer J.M. Mulder P.G.H. Blom H.M. Fokkens W.J. Intranasal capsaicin reduces nasal hyperreactivity in idiopathic rhinitis: a double-blind randomized application regimen study.Allergy. 2003; 58: 754-761Crossref PubMed Scopus (93) Google Scholar,6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar, 7Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Google Scholar, 8Lacroix J.S. Buvelot J.M. Polla B.S. Lundberg J.M. Improvement of symptoms of non-allergic chronic rhinitis by local treatment with capsaicin.Clin Exp Allergy. 1991; 21: 595-600Crossref PubMed Scopus (138) Google Scholar Therefore, the present study was designed to compare novel low-dose capsaicin treatment with the current therapy in improving nasal symptoms and to evaluate the role of SP in the pathology of IR. Daily nasal administration of low-dose capsaicin was well tolerated and similarly reduced nasal symptoms as the current capsaicin treatment at FU1 and FU2, which adds novel information to a recent Cochrane review on the use of capsaicin in the management of nonallergic rhinitis.3Gevorgyan A. Segboer C. Gorissen R. van Drunen C.M. Fokkens W. Capsaicin for non-allergic rhinitis.Cochrane Database Syst Rev. 2015; 7CD010591Google Scholar Furthermore, capsaicin in a concentration of 0.01 mM improved therapeutic response at FU1 and FU2. Interestingly, 23% of patients receiving placebo treatment reported therapeutic improvement, which might be due to daily nasal rinsing. Second, we further explored the role of SP in the pathophysiology of IR. Self-administration of capsaicin in a concentration of 0.01 mM reduced SP levels at FU2. Additionally, we found a positive correlation between SP and nasal obstruction, suggesting that IR symptoms result from abnormally increased SP levels. As SP increases mucus secretion, suppressing SP might represent a novel therapeutic approach, at least in IR.5Baraniuk J.N. Lundgren J.D. Okayama M. Goff J. Mullol J. Merida M. et al.Substance P and neurokinin A in human nasal mucosa.Am J Respir Cell Mol Biol. 1991; 4: 228-236Crossref PubMed Scopus (149) Google Scholar Finally, we investigated whether SP might serve as a biomarker to predict the therapeutic response to capsaicin. A decrease in SP of 7.08 ng/mL at FU1 had a sensitivity of 72% and a specificity of 75% to predict response to therapy. The strength of this study lies in the meticulous patient selection and characterization and the well-executed study design, with 4 groups (including a placebo and a current standard treatment group). In the past, the recruitment of patients with ill-defined nonallergic rhinitis resulted in confusing and contradictory data, such as data on the effect of corticosteroids in nonallergic rhinitis.2Blom H.M. Godthelp T. Fokkens W.J. KleinJan A. Mulder P.G. Rijntjes E. The effect of nasal steroid aqueous spray on nasal complaint scores and cellular infiltrates in the nasal mucosa of patients with nonallergic, noninfectious perennial rhinitis.J Allergy Clin Immunol. 1997; 100: 739-747Abstract Full Text Full Text PDF PubMed Scopus (61) Google Scholar,9Lundblad L. Sipilä P. Farstad T. Drozdziewicz D. Mometasone furoate nasal spray in the treatment of perennial non-allergic rhinitis: a Nordic, multicenter, randomized, double-blind, placebo-controlled study.Acta Otolaryngol (Stockh). 2001; 121: 505-509Crossref PubMed Scopus (39) Google Scholar The major limitation of our clinical trial, however, is the relatively low number of patients, which resulted from the strict inclusion and exclusion criteria. Furthermore, no objective parameter to evaluate therapeutic response was utilized, and no specific question on adverse effects was being considered, which is warranted for follow-up studies. In conclusion, capsaicin in a concentration of 0.01 mM is equally effective in suppressing nasal symptoms as the current capsaicin treatment and therefore might be a good, novel therapeutic option for patients with IR. The authors would like to thank Steffen Fieuws for providing support for the statistical analyses. We also would like to thank Mrs Emily Dekimpe for helping with the clinical trial. Finally, we thank all the patients for participating in this study. A total of 80 patients with IR were recruited via the outpatient clinic of the Otorhinolaryngology Department of the University Hospitals of Leuven, Belgium, between May 2015 and July 2017. Patients with IR were defined as nonsmoking patients experiencing at least 2 of the following complaints for more than 1 hour a day and for more than 1 year: nasal obstruction, rhinorrhea, sneezing, and itch. These patients had negative skin prick test results, no clinical signs of infection (ie, no discolored secretions), and no anatomic nasal abnormalities responsible for nasal symptoms. To be included, patients had to have IR, be between 18 and 65 years old, have signed the informed consent, and have reported inefficacy of intranasal corticosteroid treatment at the recommended dose (mometasone furoate, 50 μg per spray administered at a rate of 2 sprays twice daily, or fluticasone furoate, 50 μg per spray at a rate of 2 sprays twice daily) for at least 4 weeks. In our experience, patients with local allergic rhinitis do benefit from intranasal corticosteroids because the underlying pathophysiology is mainly IgE-mediated and thus responsive to the classic anti-inflammatory treatment. By including patients with nonallergic rhinitis who are nonresponsive to intranasal corticosteroids, patients with local allergic rhinitis were effectively excluded. The exclusion criteria were a positive skin prick test result for the 18 most frequently inhaled allergens in Belgium (house dust mite; pollen of timothy grass, smooth meadow grass, orchard grass, nettle, plantago, oxeye daisy, mugwort, alder, birch, and hazel; horse; cat; dog; rabbit; and spores of Alternaria, Aspergillus and Cladosporium [HAL Allergy, Leiden, The Netherlands]); pregnancy or lactation; systemic disorders or malignancies; use of medication affecting nasal function; use of local and/or systemic corticosteroids 4 weeks before the study; and history of prolonged use or abuse of decongestant nasal spray such as xylomethazoline. Patients with colored secretions and/or inflammation at the level of the osteomeatal complex were excluded after nasal endoscopy. Nasal medication was prohibited throughout the entire duration of the study. The study was approved by the Medical Ethical Committee on Clinical Investigations of the University Hospitals of Leuven and registered at ClinicalTrials.gov (NCT02288156). The patients with IR were invited for an outpatient visit to the Department of Otorhinolaryngology of the University Hospitals of Leuven on 5 occasions (Figs 1 and E1). This study was performed in a randomized, double-blind, placebo-controlled way. Patients were seen at a screening visit to check inclusion and exclusion criteria. During the treatment visit, patients were randomized to 4 arms in a 1:4 ratio as follows: arm 1, Placebo/Placebo; arm 2, Placebo/Capsaicin 0.001 mM; arm 3, Placebo/Capsaicin 0.01 mM; and arm 4, Capsaicin 0.1 mM/Placebo. In brief, patients received 5 intranasal applications (2 puffs in each nostril, 0.4 mL/puff, per application) of either placebo or capsaicin 0.1 mM on a single day at 1-hour intervals. The nasal mucosa was anesthetized before the first 2 applications by application of a cocaine 5% nasal spray (same volume per spray as already mentioned). To ensure effective local anesthesia, an interval of 15 minutes was maintained between the application of the cocaine and blinded nasal spray. After the treatment visit, patients who had received the current standard treatment with capsaicin, 0.1 mM, were sent home with a nasal spray that contained placebo (Capsaicin 0.1/Placeboarm) for daily use. The other patients who were treated with placebo during the treatment visit, received a nasal spray containing placebo (Placebo/Placebo arm), capsaicin 0.001 mM (Placebo/Capsaicin 0.001 arm), or capsaicin 0.01 mM (Placebo/Capsaicin 0.01 arm) (Fig 1). All patients were asked to stop their treatment after 4 weeks. All patients were invited for a follow-up visit after 4, 12, and 24 weeks. Capsaicin and placebo solutions were prepared at the Center for Clinical Pharmacology at the University Hospitals of Leuven, and the solutions were blinded. The placebo solution contained the same buffer but lacked pelargonic acid vanillylamide. The sample size was calculated to have at least 80% power to detect a significant difference in change in VAS score for major symptom between baseline and week 12 (FU2). Previously, we showed a clear reduction in VAS score for major symptom after capsaicin treatment compared with the score after placebo at week 12.E1Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar,E2Van Gerven L. Alpizar Y.A. Wouters M.M. Hox V. Hauben E. Jorissen M. et al.Capsaicin treatment reduces nasal hyperreactivity and transient receptor potential cation channel subfamily V, receptor 1 (TRPV1) overexpression in patients with idiopathic rhinitis.J Allergy Clin Immunol. 2014; 133: 1332-1339.e3Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Assuming a 50% reduction in VAS score for major symptom at week 12 and α set at 0.0125 (application of Bonferroni correction for the 4 groups) and with an unequal group size (three-fourths of patients received capsaicin and one-fourth received placebo) and a 2-sample t test, 16 patients were needed to detect a ratio of geometric means equal to 2 (ie, with the VAS score for major symptom being 2-fold higher in placebo group). When a dropout rate of 20% was taken into account, 76 patients in total were needed (19 patients per group). All participants were asked to rate the typical nasal symptoms of IR (ie, rhinorrhea, nasal obstruction, itch, and sneezing) on a VAS of 0 to 10 at the screening visit (visit 1) and at FU1 (at week 4), FU2 (at week 12), and FU3 (at week 24). The symptom was considered relevant only if the VAS score was more than 2. The major nasal symptom was selected on the basis of the highest VAS score at screening. At FU1, FU2, and FU3, a TRE was performed. Patients with IR were asked to score the overall improvement in their symptoms compared with baseline (with 0 indicating no reduction of symptoms and 1 indicating reduction of symptoms). At the screening visit, FU1, and FU2, nasal secretions were collected before the Cold Dry Air provocation as described earlier.6Van Gerven L. Alpizar Y.A. Steelant B. Callebaut I. Kortekaas Krohn I. Wouters M. et al.Enhanced chemosensory sensitivity in patients with idiopathic rhinitis and its reversal by nasal capsaicin treatment.J Allergy Clin Immunol. 2017; 140: 437-446.e2Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar For the collection of nasal secretions, a nasal sponge (Ivalon Surgical Products, San Diego, Calif) was weighed and inserted in each nostril for 5 minutes. Afterward, the sponge was removed and weighed again. A volume of saline was added depending on the weight of the collected sponge (1:5 dilution). The sponge was then squeezed and centrifuged at 1500 g and 4°C for 5 minutes. The supernatant was stored at –20°C for further analysis. In nasal secretions, SP was determined with ELISA according to the manufacturer’s guidelines (Cayman Chemicals, Ann Arbor, Mich).Fig E2Correlation between SP and nasal obstruction at FU1. Spearman correlation r = 0.32; P < .05.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Table E1Patient characteristics at screeningCharacteristicPlacebo/placeboPlacebo/capsaicin (0.001 mM)Placebo/capsaicin (0.01 mM)Capsaicin (0.1mM)/placeboN18181616Age (y), mean ± SD45 ± 1548 ± 1445 ± 1050 ± 14Sex (male/female)8/109/99/77/9Nasal symptom (%)Nasal obstruction (56%)Rhinorrea (39%)Sneezing (5%)Itch (0%)Nasal obstruction (50%)Rhinorrea (28%)Sneezing (11%)Itch (11%)Nasal obstruction (44%)Rhinorrea (44%)Sneezing (0%)Itch (12%)Nasal obstruction (31%)Rhinorrea (44%)Sneezing (25%)Itch (0%)Allergy (positive SPT result)0%0%0%0%Responders to INCS0%0%0%0%Smokers0%0%0%0%INCS, Intranasal corticosteroid; SPT, skin prick test. Open table in a new tab INCS, Intranasal corticosteroid; SPT, skin prick test.