Nasal Atropine Sulfate: Efficacy and Safety of 0.050% and 0.075% Solutions for Severe Rhinorrhea

Background  Anticholinergic agents, specifically the quaternary salt of atropine, are currently being recommended for chronic rhinitis and the common cold.

Objective  To evaluate the efficacy and safety of 50- and 75-µg doses of atropine sulfate as a nasal spray in perennial allergic rhinitis.

Methods  A placebo-controlled, double-blind study compared 2 doses of atropine nasal spray given 4 times daily for 2 weeks to 45 patients with perennial allergic rhinitis after a 2-week baseline period.

Results  Both concentrations of atropine nasal spray improved the severity of rhinorrhea and postnasal drip (P<.001) as reported by patients and physicians. The duration of action in reducing rhinorrhea and postnasal drip for atropine was 2 to 3 hours, compared with less than 1 hour for placebo (P<.01). No difference was noted in efficacy between the 2 atropine doses nor in frequency of adverse events with atropine nasal spray and placebo.

Conclusions  Atropine sulfate, 50 or 75 µg 4 times daily, is effective in reducing rhinorrhea and postnasal drip within 2 weeks and may be an alternative therapy for the rhinorrhea component of rhinitis.

REPETITIVE sneezing, profuse rhinorrhea, chronic nasal congestion, and severe postnasal drainage can dramatically affect the lifestyles and daily activities of patients with rhinitis. Treatment of these distressing symptoms includes use of topical medications: sympathomimetics, cromolyn sodium, and/or corticosteroids given intranasally, or alternatively, systemically administered antihistamines, sympathomimetics, corticosteroids, or allergen-specific immunotherapy.¹ Each pharmacological agent has its distinct advantages and disadvantages. In targeting the pharmacotherapy to the symptom of rhinorrhea, the recommendation to use an anticholinergic agent has been proposed to reduce the volume of nasal secretions.²

Atropine sulfate was originally used 100 years ago for nasal coryza (acute rhinitis) and rhinorrhea caused by allergic rhinitis.³ The topical potency of atropine has subsequently been studied as a treatment of obstructive airway diseases.^4-6 Unfortunately, the systemic and drying side effects of atropine have limited its use in asthma even though there is a definite bronchodilator action.

Alternatively, atropine is used as an active ingredient in cough-cold preparations to reduce excessive secretions from the nose and eyes.⁷ Oral doses of 0.2 to 0.3 mg of atropine sulfate are probably safe, but there are insufficient data to establish atropine's effectiveness.⁸ Furthermore, rigorous double-blind, placebo-controlled studies using atropine have not been done in patients with rhinitis symptoms.

This study evaluated the efficacy of 2 doses of atropine sulfate (50 and 75 µg) as a nasal spray given 4 times daily to patients with perennial allergic rhinitis.

This was a double-blind, placebo-controlled randomized study with a 2-week baseline evaluation. Patients signed an informed consent form approved by the Clinical Research Practices Committee of Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.

The subjects were aged 18 to 59 years, were not grossly overweight or underweight, and had normal vital signs and results of general physical examination. All patients had a history of severe rhinorrhea as manifested by runny nose and/or postnasal drainage. To qualify, patients had to have a severity score of 3 or 4 for rhinorrhea and postnasal drip during a 2-week baseline period.

Patients were excluded for serious systemic disorders, or for local nasal obstruction caused by polyps, deviated septum, or structural defects. The following medications were withheld before participation in the study: systemic corticosteroids nonmaintenance immunotherapy for 4 weeks; topical corticosteroids for 2 weeks; concurrent use of antihistamines, sympathomimetics, or cromolyn sodium for 2 weeks; or astemizole for 3 months.

The study design consisted of 3 parallel treatments: 0.050% atropine sulfate (50 µg per spray, 200 µg per dose), 0.075% atropine sulfate (75 µg per spray, 300 µg per dose), and placebo (containing ethylenediaminetetraacetic acid, sodium chloride, sodium citrate, benzalkonium chloride, and water). The treatment regimen was 2 sprays per nostril every 4 hours (4 times daily) for a total daily dose of 800 µg of 0.050% atropine sulfate and 1200 µg of 0.075% atropine sulfate. The duration of treatment was 2 weeks. Patients kept a daily log of rhinitis symptoms by means of a 5-point scale. A global evaluation with a 6-point scale was completed by patients and physician (J.W.G.).

Patients rated the severity of symptoms on a scale of 0 to 4 and the duration as follows: 0, no symptoms returned between treatments of nasal spray; 1, symptoms returned within 3 hours after nasal spray; 2, symptoms returned within 2 hours; 3, symptoms returned within 1 hour; and 4, symptoms returned within one-half hour or less. This scale applies a higher numerical value to the shorter duration of control similar to use of higher scores for severity reflecting worse symptoms. In addition, global evaluations were done at weekly visits by patients and physician with 0 indicating being worse, and 1, no control, to 5, total control or complete relief of symptoms.

Any complaint raised by the subject or the investigator was classified as a possible adverse event. The events were grouped if possible by organ system. In some instances, complaints by the subjects were labeled in their own terms. Differences in frequency of reported adverse events were assessed by P values for the number of subjects and at a power of 80%.

Statistical analysis was done with SAS Version 6.06 (SAS Institute Inc, Cary, NC) with an α level of 5% and 2-tailed tests. Efficacy was compared by analysis of covariance with a test for a common slope for all treatments (P<.05) and a test for the common slope not being equal to zero (P<.10). A 2-sided t test based on pooled estimate of variance was used to test hypothesis. Power was calculated for each efficacy variable by means of the sample size and pooled variance for that variable.

Patient demographic data are presented in Table 1. There was no difference between treatment groups except for mean weight being higher for the 0.050% atropine treatment group compared with 0.075% atropine and placebo.

Adverse events of active treatment are listed in Table 2. There was no difference between placebo and active treatment. The frequency of nasal stinging and irritation was closely monitored for each subject during the 2 weeks of treatment and failed to show any difference between active and placebo treatments (week 1: 0.050% atropine, 0.6; 0.075% atropine, 0.53; placebo, 0.2; week 2: 0.050% atropine, 0.07; 0.075% atropine, 0.53; placebo, 0.33). In analysis for any systemic adverse effects (blurred vision, dizziness, dry mouth, dry or hot skin, tachycardia, or mental status changes), there was no difference between the active treatments and placebo. Only 5 patients reported any unpleasant taste, but this was not significantly different from placebo.

Patients given atropine nasal spray demonstrated a significant reduction in intensity of their postnasal drip compared with the 2-week baseline (Figure 1, left). This decrease was noted after the first week (P<.001) and continued during the second week (power equals 0.76 for sample size). Placebo-treated patients had no substantial change in postnasal drip symptoms during the 2 weeks compared with baseline. In terms of duration of postnasal drip, the symptom reappeared 2 hours after the use of atropine nasal spray compared with 1 hour after the use of placebo nasal spray (P<.01) (Figure 1, right). There was no difference between the 2 atropine doses for severity or duration of postnasal drip.

The rhinorrhea intensity scores with the 2 active treatments were significantly reduced compared with baseline (Figure 2, left). This response was seen within the first week and continued during the second week of treatment (power equals 0.76 for sample size). Again, placebo treatment did not alter the severity of rhinorrhea of patients. In terms of duration of action, both atropine doses had lower scores than placebo, reflecting a longer duration of action (Figure 2, right). The first week showed a significant effect (P=.01) in duration that increased between atropine nasal spray and placebo for the second week of treatment (P=.002). There was no difference in duration of action between the 2 atropine concentrations.

Physician assessments of rhinitis symptom severity concurred with patient assessments for severity of postnasal drip and rhinorrhea (power for postnasal drip, 0.91; for rhinorrhea, 0.99). Global evaluations demonstrate that active atropine nasal spray was preferred by patients and the physician over placebo (P<.05), yet there was no difference between the 2 doses of atropine nasal spray (Figure 3).

This study shows that atropine sulfate nasal spray given as 100 to 150 µg per nostril 4 times a day is highly effective in reducing rhinorrhea and postnasal drip symptoms of perennial rhinitis. The drying effect is evident within the first week of atropine use and continues to reduce symptoms during the second week of treatment. Surprisingly, there is no difference between the 2 concentrations of atropine in terms of clinical benefit.

The adverse event profile of atropine is interesting in that there was no difference between active medication and placebo, indicating that the vehicle is responsible for the majority of complaints. The incidence of nasal stinging, irritation, and dryness to the upper airway was equivalent in the 3 treatments. Furthermore, systemic side effects of topically administered atropine are infrequent. Saline nasal sprays have a beneficial effect on rhinitis symptoms, but this study demonstrates the superiority of active atropine nasal spray in controlling rhinitis symptoms.^9,10

In previous unblinded studies using atropine, the 1-mg/mL solution was shown to be effective in reducing rhinorrhea caused by allergic rhinitis (7 patients) or viral-induced rhinitis (24 patients).⁷ All patients except 1 individual reported a substantial reduction in their nasal secretions. Three of 31 patients had obvious vasoconstriction of nasal blood vessels on nasal examination, whereas none of the subjects reported dry mouth or visual disturbances. The duration of action for atropine was noted to be 3 to 4 hours and longer in 5 patients observed for extended periods. Two studies that used 0.025% nasal solution (400 µg/d for 4 weeks) show no serious adverse effects but little difference from placebo in controlling mild to severe symptoms of rhinorrhea.^11,12

Other studies of anticholinergic agents for rhinitis have focused on the quaternary salt of ipratropium.^11-17 These and other studies have demonstrated efficacy in reducing nasal secretions of both allergic and nonallergic rhinitis, indicating that the cholinergic receptor is important in control of nasal secretions.^18-22 The side effect profile also shows just local adverse drying but no serious systemic side effects compatible with an anticholinergic agent. Surprisingly, these studies have not noted any effect on sneezing, nasal congestion, or itching. This lack of effect suggests that cholinergic receptors have only a minimal role in causing these chronic rhinitis symptoms.

From this clinical trial, atropine sulfate at doses of 100 to 150 µg per nostril 4 times daily is effective in reducing symptoms of runny nose and postnasal drainage. Improvement in symptoms occurs within the first week of atropine treatment, indicating a rapid onset of benefit for the patients. Studies involving long-term use of atropine nasal spray will be needed to assess long-term safety, yet atropine nasal solution may be considered part of the pharmacological treatment of severe rhinorrhea and postnasal drip symptoms of chronic rhinitis.

Accepted for publication December 30, 1997.

This study was supported by a grant from Muro Pharmaceuticals, Tewksburg, Mass.

I thank Jimmy L. Simon, MD, and Jon Shilstone, PhD, for their critical review of the manuscript and Andrea Barker, RN, and Laura Strelka, RN, for their assistance in performing this study.

Reprints: John W. Georgitis, MD, Department of Pediatrics, Bowman Gray School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157 (e-mail: jgeorgit@wfubmc.edu).