P. Graf

Effect on the Nasal Mucosa of Long-Term Treatment With Oxymetazoline, Benzalkonium Chloride, and Placebo Nasal Sprays†

A parallel, randomized, double‐blind study was performed in 30 healthy subjects to investigate the effects on the nasal mucosa of a 1‐month treatment with nasal sprays. Ten subjects received oxymetazoline nasal spray; 10 subjects used a nasal spray containing the preservative benzalkonium chloride, and the others were treated with a placebo nasal spray. The three variables that were studied‐nasal mucosal swelling, symptom scores, and nasal reactivity‐were estimated by histamine challenge before and after 28 days of treatment. Rhinostereometry was used to measure nasal mucosal swelling and nasal reactivity.

Benzalkonium chloride in a decongestant nasal spray aggravates rhinitis medicamentosa in healthy volunteers

A randomized double‐blind parallel study with 20 healthy volunteers was performed to research the effect of a preservative in a decongestant nasal spray on the development of rhinitis medicamentosa. Ten subjects received oxymetazoline nasal spray with benzalkonium chloride and the others used oxymetazoline nasal spray without the preservative three times daily for 30 days. Before starting the course of treatment and after its conclusion, recordings of the mucosal surface positions were made with rhinostereometry followed by histamine challenge tests. Symptoms of nasal stuffiness were estimated on visual analogue scales (0–100) in the morning and the evening just before using the nasal spray. After 30 days, rebound swelling and nasal stuffiness were found in both groups. In the group receiving oxymetazoline nasal spray with benzalkonium chloride the mean rebound swelling was 1.1 mm and the estimated mean evening symptom score for nasal stuffiness was 43. In the group without benzalkonium chloride the corresponding variables were significantly less marked, with a mean rebound swelling of 0.5 mm (P<0.05) and a mean evening symptom score of 25 (P<0.05). The increase in histamine sensitivity in both groups was interpreted as a sign of nasal hyperreactivity. A new type of nasal spray bottle was used that has been shown to prevent bacterial contamination. In conclusion, the long‐term use of benzalkonium chloride in oxymetazoline nasal spray accentuates the severity of rhinitis medicamentosa in healthy volunteers.

Rbtis medicamentosa: aspects of pathophysiology and treatment

With modern vasoconstrictors, such as oxy‐ and xylometazoline, the risk of developing rhinitis medicamentosa (RM) has been considered to be small or even nonexistent. However, recent studies have shown that overuse of these drugs may result in rebound congestion, nasal hyperreactivity, tolerance, and histologic changes of the nasal mucosa. Using rhinostereometry, it has also been shown that the long‐term use of the preservative benzalkonium chloride (BKC) in oxymetazoline nasal spray accentuates the severity of rhinitis medicamentosa in healthy volunteers. A nasal decongestant spray composed of a combination of vasoactive substances and BKC has a long‐term adverse effect on the nasal mucosa. BKC alone induces mucosal swelling after 30 days use of the nasal spray in healthy subjects, unlike placebo. According to the author, rhinitis medicamentosa can be defined as a condition of nasal hyperreactivity, mucosal swelling, and tolerance that is induced, or aggravated, by the overuse of topical vasoconstrictors with or without a preservative. An adequate treatment of these patients consists of a combination of vasoconstrictor withdrawal and a topical corticosteroid to alleviate the withdrawal process. The underlying nasal disorder must then be treated. Patients with rhinitis medicamentosa who overuse topical decongestants and are able to stop using such drugs should be careful about taking these drugs again, even for a few days. They must be informed about the rapid onset of rebound congestion upon repeated use in order to avoid the return of the vicious circle of nose‐drop abuse.

Four-week use of oxymetazoline nasal spray (Nezeril®) once daily at night induces rebound swelling and nasal hyperreactivity

A randomized double-blind parallel study with 20 healthy volunteers was performed to examine the effect of oxymetazoline nasal spray on the development of rhinitis medicamentosa. For 30 days, 10 subjects were given oxymetazoline nasal spray once daily at night and placebo in the morning and at noon, while the others used oxymetazoline nasal spray three times daily. Before and after the course of treatment, the mucosal surface positions were determined with rhinostereometry, followed by histamine challenge tests. In the morning and the evening just before use of the nasal spray, symptoms of nasal stuffiness were evaluated on visual analogue scales (0-100). After 30 days, rebound swelling and nasal stuffiness were found in both groups. In the group receiving oxymetazoline nasal spray once daily at night, the mean rebound swelling was 0.8 mm (p < 0.01) and the estimated mean symptom score for nasal stuffiness in the evening was 43 (p < 0.05). In the group receiving the same nasal spray three times daily, the mean rebound swelling was 1.1 mm (p < 0.01) and the mean evening symptom score was 43 (p < 0.05). The finding of an increase in histamine sensitivity in both groups was taken to indicate nasal hyperreactivity. There was no significant difference in the investigated variables between the two groups. It is concluded that the risk of developing rebound swelling and nasal hyperreactivity remains, whether oxymetazoline nasal spray is used once or three times a day for 30 days.

Nasal mucosal swelling and reactivity during a menstrual cycle.

Introduction: Nasal stuffness is a great problem for many women in the later part of pregnancy. Objective: This study was performed to evaluate whether oestrogen causes nasal congestion and/or a hyperreactive reaction of the nasal mucosa. Material and Methods: Ten healthy fertile women were examined during menstruation. Nasal mucosal congestion was studied with rhinostereometry and acoustic rhinometry. The nasal mucosa was challenged with 3 doses of histamine solution to study nasal reactivity. Measurements were made 3 times during menstruation. To find the exact time of ovulation, when oestrogen reaches its peak value, intravaginal ultrasound tests were done and blood samples taken, to determine the oestrogen and progesterone levels. Results: The nasal mucosa became hyperreactive to histamine in connection with ovulation, when the blood level of oestrogen reached its peak. This does not occur during the menstrual or the luteal phase. No significant alteration was found in the baseline position during the menstruation. Conclusion: There is a connection between high oestrogen level and nasal mucosal reactivity.

Fluticasone propionate nasal spray is more effective and has a faster onset of action than placebo in treatment of rhinitis medicamentosa

Background Controversy still exists about the treatment of rhinitis medicamentosa and treatment has never been objectively evaluated.

Decongestion Effect and Rebound Swelling of the Nasal Mucosa during 4-Week Use of Oxymetazoline

The aim of this study was to investigate whether long-term use of oxymetazoline induces a rebound swelling of the nasal mucosa and whether the decongestion effect is altered during medication. Eight healthy volunteers had oxymetazoline nasal spray (0.5 mg/ml; 0.1 ml in each nostril, three times daily) for 30 days and registrations of the mucosal surface positions were made using rhinostereometry. Compared to the registrations before the start of medication, no rebound swelling was registered after 10 days. After 30 days, however, a rebound swelling was registered in all subjects (p < 0.001). All of them, then, also reported nasal stuffiness. The decongested position of the nasal mucosa after one single dose of oxymetazoline was the same in the whole study. It is concluded that rhinitis medicamentosa develops after a relatively short time on oxymetazoline, even in healthy volunteers, and that the swelling probably is due to a vasodilatation rather than an edema. The study supports the recommendation that the drug should not be used over periods > 10 days.

Changes in Nasal Reactivity in Patients with Rhinitis medicamentosa after Treatment with Fluticasone Propionate and Placebo Nasal Spray

Aim of the Study: To study the changes in nasal reactivity in patients with rhinitis medicamentosa during treatment with placebo or fluticasone propionate, in order to better understand the mechanisms of nasal congestion in such patients. Study Design: A parallel, double-blind study. Twenty patients with rhinitis medicamentosa were randomized to either placebo or fluticasone treatment during 14 days. Material and Methods: Nasal mucosa reactivity was studied with a histamine challenge model using three concentrations of histamine to challenge the nasal mucosa (1, 2 and 4 mg histamine/ml). Recordings of the nasal mucosa response were made 5 min after each challenge, using rhinostereometry and acoustic rhinometry, before and after the period of treatment. Results: The fluticasone group had a significantly increased histamine sensitivity after treatment, unlike the placebo group who had an unchanged or slightly decreased histamine sensitivity after treatment. Conclusions: The results of this study support the theory that the nasal obstruction in rhinitis medicamentosa is due to interstitial oedema rather than to vasodilatation. On the first day of vasoconstrictor withdrawal, the inferior concha was congested and oedematous with a limited capacity to respond to histamine challenge. However, after 14 days of treatment with a corticosteroid nasal spray, the oedema was reduced and the increase in histamine sensitivity reflected the persistence of nasal hyperrreactivity. In the placebo group, histamine sensitivity remains unchanged with the measuring technique we used. This probably indicates that oedema was still present after treatment.

One Year Follow-Up of Patients with Rhinitis Medicamentosa After Vasoconstrictor Withdrawal

The aim of the study was to systematically follow-up 10 patients with rhinitis medicamentosa for at least 1 year after vasoconstrictor withdrawal. During withdrawal of the decongestants the patients used budesonide nasal spray, 400 μg/day, for 6 weeks. The thickness of the nasal mucosa, the decongestive effect of oxymetazoline, and the histamine sensitivity were measured with rhinostereometry during the period. The thickness of the nasal mucosa and the symptom scores of nasal stuffiness were reduced considerably 6 and 12 months after vasoconstrictor withdrawal. The histamine sensitivity reflecting nasal hyperreactivity was still increased after 6 months, but not after 1 year. The decongestive effect of oxymetazoline increased after 6 months, indicating reversible tolerance. We conclude that when given adequate treatment and information about nose-drop overuse, all patients were able to stop using the vasoconstrictors and no one relapsed into a daily long-term overuse of vasoconstrictors during the 1-year follow-up period.

Correlation between Objective Nasal Mucosal Swelling and Estimated Stuffiness during Long-Term Use of Vasoconstrictors

The correlation between nasal mucosal swelling and estimated stuffiness was evaluated in 13 healthy volunteers who entered the trial. The nasal mucosa was challenged with increasing concentrations of histamine solutions. The amount of mucosal swelling was recorded using rhinostereometry, and the stuffiness was estimated by the subjects on a visual analogue scale. Then the subjects were randomly chosen to receive either oxy- or xylometazoline nasal spray for 30 days. After 10 days on the drug, the histamine sensitivity was enhanced, and after another 20 days, it had increased further, reflecting the development of rhinitis medicamentosa. Before the subjects started the nasal spray and after 10 days on the drug, a correlation between stuffiness and swelling was seen in the individual subject only when the degree of stuffiness almost obliterated the nasal opening. At the end of the month, no correlation was present. In all histamine provocations throughout the month, a very high correlation was noted between mean mucosal swelling and mean stuffiness. It is concluded that the symptom scores for nasal obstruction are useful for determining nasal mucosal swelling in groups. However, in the individual subjects one can estimate the mucosal swelling only when the amount of swelling almost obliterates the nasal opening. This cannot be done when the mucosa is hyperreactive.