Ten Days' Use of Oxymetazoline Nasal Spray with Or Without

ORIGINAL ARTICLE Ten Days’ Use of Oxymetazoline Nasal Spray With or Without Benzalkonium Chloride in Patients With Vasomotor Rhinitis

Peter Graf, MD, PhD; Jakob Enerdal, MD; Hans Halle´n, MD, PhD

Context: In most countries, the use of topical nasal de- sectional area were made with rhinostereometry and congestants is limited to a maximum of 10 days because acoustic rhinometry, followed by histamine hydrochlo- of the risk of developing rebound mucosal swelling and ride challenge tests. Symptoms of nasal stuffiness were rhinitis medicamentosa. estimated on visual analog scales (0-100) in the morning and the evening, just before the nasal spray was used. Objective: To determine whether topical nasal decongestants can be safely used for 10 days in patients with Results: No rebound swelling was found after the 10- chronic inflammation of the nasal mucosa. day treatment in the 2 groups with either of the methods or as estimated by symptom scores. In the group re- Design: Double-blind, randomized, controlled, paral- ceiving oxymetazoline containing benzalkonium chloride, lel study. but not in the other group, the histamine sensitivity was significantly reduced after treatment (PϽ.001). Patients: Thirty-five patients with vasomotor rhinitis selected from our outpatient department. Conclusions: It is safe to use topical nasal oxymetazoline with or without benzalkonium chloride for 10 days Intervention: Eighteen patients received oxymetazo- in patients with vasomotor rhinitis. However, this study line hydrochloride (0.5 mg/mL) nasal spray containing indicates that benzalkonium chloride in nasal deconges- the preservative benzalkonium chloride (0.1 mg/mL), and tant sprays affects the nasal mucosa also after short- the other 17 were treated with oxymetazoline nasal spray term use. without benzalkonium chloride. Before and after the treatment, recordings of the nasal mucosa and minimal cross- Arch Otolaryngol Head Neck Surg. 1999;125:1128-1132

HE PRONOUNCED nasal va- tolerance has been considered to be much soconstriction induced by smaller or even nonexistent.2 However, re- topical nasal deconges- cent studies have shown that overuse of tants may be followed by these drugs also results in rebound con- rebound vasodilatation and gestion3,4 and histological changes in the stuffiness.T This is especially likely after nasal mucosa.5 long-term use of these drugs. The patient Most nasal drops and sprays are mul- may then become uncertain as to whether tidose preparations that contain a preser- congestion is still being caused by the na- vative to prevent the growth of microor- sal disease or by rebound congestion. The ganisms. The preservative benzalkonium stuffiness is relieved by additional doses chloride, a quaternary ammonium com- of the vasoconstrictor eventually in larger pound, has a bactericidal effect, since it doses, ie, tolerance. Thus, the patient be- damages the cell wall of the microorgan- comes increasingly dependent on the topi- isms.6 The use of benzalkonium chloride cal decongestant and a vicious circle is es- has been questioned because it is toxic to tablished with long-term daily overuse. the cilia in the nose.7,8 We have shown that This phenomenon is called rhinitis medi- daily use of benzalkonium chloride in oxy- camentosa (RM), a term coined as far back metazoline nasal spray for 30 days in- as 19461 when the topical decongestants duces a more pronounced rebound swell- contained ephedrine hydrochloride and ing in healthy volunteers than does From the Department of RM was a common problem. With mod- oxymetazoline nasal spray used alone for Otorhinolaryngology, Huddinge ern vasoconstrictors, such as oxymetazo- 30 days, indicating that benzalkonium University Hospital, Karolinska line hydrochloride and xylometazoline hy- chloride plays an important role in the Institute, Stockholm, Sweden. drochloride, the risk of developing RM and development of RM.9

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 PATIENTS AND METHODS the outpatient department of the ear, nose, and throat clinic at Huddinge University Hospital or So¨dersjukhuset, Stock- STUDY DESIGN holm, Sweden.

The study was designed as a parallel, randomized, double- MEASURING METHODS blind trial. Thirty-five patients with vasomotor rhinitis (Table) were randomized for treatment with oxymetazo- The nasal mucosal swelling was recorded with rhinostere- line nasal spray either with (18 patients) or without (17 ometry and acoustic rhinometry. Rhinostereometry is an op- patients) benzalkonium chloride in the morning and in the tical, direct, noninvasive method for measuring nasal mu- evening for 10 days. Nasal mucosal swelling and nasal re- cosal swelling with a high degree of accuracy. A surgical activity, as estimated by histamine challenge, were stud- microscope is placed on a micrometer table fixed to a frame. ied with rhinostereometry and acoustic rhinometry be- The microscope is movable in 3 angular directions, estab- fore and after treatment, and symptom scores of nasal lishing a 3-dimensional coordinate system. The subject is fixed stuffiness were estimated throughout the treatment. to the apparatus by a plastic, individually made tooth splint. At noon, after an acclimatization period of 30 min- The eyepiece has a horizontal millimeter scale. The nasal cav- utes, the position of the nasal mucosa of the inferior con- ity is viewed through the eyepiece. Since the microscope has cha in both nasal cavities was recorded repeatedly with rhi- a small depth of focus, changes in the position of the mu- nostereometry, to establish the baseline mucosal position. cosal surface of the medial side of the head of the inferior In the same sitting position, the minimal cross-sectional concha are registered in the plane of focus along the milli- area (MCA 2) was then recorded with acoustic rhinom- meter scale. The accuracy of the method is 0.2 mm.13 etry. Next, the nasal mucosa was challenged with hista- Acoustic rhinometry produces an acoustic pulse that mine hydrochloride, 1, 2, and 4 mg/mL, where 0.14 mL of enters the nose via a tube equipped with a nose adapter the solution was syringed over the inferior concha in 1 side tightly placed in the nostril. Changes in the cross- of the nose. The positions of the mucosal surface and MCA sectional area are digitized by a computer, and numerical 2 were determined 5 minutes after each histamine provo- values of the cross-sectional area are recorded. The mini- cation. The subjects then used their nasal spray. After 10 mal cross-sectional area, MCA 2, is the cross-sectional area days of treatment with the drug, the patients discontinued between the anterior portions of the inferior concha and the spray in the morning. At noon, 14 to 17 hours after the the septum. This method has been described elsewhere,14 last dose on the night before, the mucosal baseline posi- and in previous studies it seems to have been accurate.15 tions and MCA 2 were recorded. Then a histamine provo- The apparatus used in this study was a RHIN 2100 (SR Elec- cation test was done as before. tronics APS, Lynge, Denmark). Throughout the 10 days of medication, each subject filled in a diary card in the morning and the evening, just STUDY DRUGS before using the nasal spray. Nasal stuffiness was estimated on a visual analog scale (0-100). The scale ranged Both groups sprayed 0.1 mL of the substances into each from 0 (nose completely clear) to 100 (nose completely nostril 3 times daily. One group was randomized to treat- blocked). Informed consent was obtained before any pro- ment with oxymetazoline hydrochloride (Nezeril) (0.5 cedure was performed. The study was approved by the lo- mg/mL) nasal spray without benzalkonium chloride, and cal ethics committee and the medical product agency. the other group received oxymetazoline hydrochloride (Ne- zeril) (0.5 mg/mL) nasal spray with benzalkonium chlo- PATIENTS ride (0.1 mg/mL) (Draco La¨kemedel AB, Lund, Sweden). The study drugs were all in a new type of nasal spray bottle Thirty-five patients with vasomotor rhinitis, 26 women and shown to withstand bacterial contamination. 9 men (mean age, 38 years), entered the trial. Most of them had nasal blockage as their main symptom, but, in some STATISTICAL ANALYSES patients, secretions and/or sneezing was the dominating symptom (Table). Eighteen patients had used nasal corti- Trends and spread were analyzed with the use of the means costeroids before entering the trial, but no one was al- and SDs. For further statistical analyses, analysis of vari- lowed to use any medication for nasal symptoms for 1 month ance and paired and unpaired t tests were used. In calculat- before entering the study. On rhinoscopy, no signs of a struc- ing the mucosal swelling, the baseline position recorded on tural basis for the nasal symptoms were noted. A skin test the first day was considered as the reference position and (Soluprick; ALK, Ho¨rsholm, Denmark) performed on all set at 0. The changes in the mucosal positions in each side patients confirmed that no one was allergic. The skin test of the nose, after 10 days of treatment with the nasal sprays, contained the following allergens: birch, hazel, timothy, were added. The presence of mucosal swelling induced by mold (Alternaria, Cladosporium), house dust mite (Derma- histamine challenge was based on data from the challenged tophagoides pteronyss, Dermatophagoides farinae), cat, dog, nasal cavity alone, the baseline values on each day of provo- horse, rabbit, and guinea pig. All patients were selected from cation being used as the reference values.

Opinions vary as to how long topical deconges- mend that present products be used only for “emer- tants can safely be used without risking the develop- gency situations” and for not more than 3 consecutive ment of RM. Some authors claim that the risk of devel- days.11,12 No other drugs are more effective than topical oping RM with oxymetazoline and xylometazoline is very nasal ␣2-agonists for relieving nasal stuffiness. Oxy- small and recommend regular use for at least 2 or 3 weeks, metazoline and xylometazoline produce immediate, pow- without risking adverse effects.10 Other authors recom- erful, long-lasting decongestion, and therefore it is clini-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 regular spraying with oxymetazoline with or without ben- Patient Characteristics* zalkonium chloride in patients with chronic inflammation in their nasal mucosa is safe in this respect. Nasal Symptoms† Previous Use Patient No./ of Topical Sex/Age, y Running Blockage Sneezing Corticosteroid RESULTS Oxymetazoline Hydrochloride With Benzalkonium Chloride 1/F/69 +++ − − No All patients completed the study. However, because of tech- 2/F/43 ++ +++ − Fluticasone nical difficulties, the rhinostereometric baseline values are propionate missing in 4 subjects and the corresponding measurements 3/F/42 +++ ++ +++ No with acoustic rhinometry are missing in 5 other subjects. 4/F/48 + + +++ Budesonide Since all subjects had complete measurements with at least 5/F/22 ++ + ++ No 1 of the objective methods, no patient was excluded. 6/F/29 − +++ − Budesonide 7/F/37 + ++ − No 8/F/19 +++ + − No OXYMETAZOLINE WITH 9/F/51 − + + No BENZALKONIUM CHLORIDE 10/F/35 + ++ − No 11/M/44 − +++ − No Rhinostereometric Measurements 12/M/41 − +++ − Fluticasone propionate 13/F/41 − ++ − Budesonide In the group receiving oxymetazoline with benzalko- 14/M/76 ++ ++ ++ Mometasone nium chloride, the mean mucosal swelling after hista- furoate mine hydrochloride challenge before treatment was 1.4 15/F/51 ++ +++ + Budesonide mm with a dose of 1 mg/mL, 1.8 mm with 2 mg/mL, and 16/F/76 + ++ − Budesonide 2.2 mm with 4 mg/mL. After 10 days of treatment, the 17/F/44 − +++ − No corresponding values for mucosal swelling were 0.5, 0.8, 18/M/25 + ++ − No and 1.1 mm (Figure 1). The reduction in mucosal swell- Oxymetazoline Hydrochloride Without Benzalkonium Chloride ing after histamine challenge was significant at all 3 his- 1/M/32 + ++ − No tamine provocation levels (analysis of variance, PϽ.001). 2/F/30 − +++ − Budesonide 3/M/35 ++ +++ − Budesonide The mean mucosal swelling after 10 days was 0.21 mm, 4/F/32 ++ ++ − No compared with the reference value before starting the 5/M/34 + +++ + No medication (Figure 2). 6/F/22 + +++ − Budesonide 7/F/18 − ++ − Budesonide Acoustic Rhinometric Measurements 8/F/18 − +++ − No 9/F/54 +++ + − No 10/M/32 + +++ − Budesonide The mean MCA 2 after histamine hydrochloride chal- 2 11/M/26 ++ + + No lenge before treatment was −0.09 cm with a dose of 1 12/F/25 + +++ − Budesonide mg/mL, −0.12 cm2 with 2 mg/mL, and −0.20 cm2 with 4 13/F/32 ++ ++ − Budesonide mg/mL. After 10 days of treatment, the corresponding 14/F/26 − ++ − Budesonide MCA 2 values were −0.03, −0.08, and −0.15 cm2 15/F/26 − +++ − Budesonide (Figure 3). The increase in MCA 2 was significant af- 16/F/65 ++ +++ − No 17/F/15 ++ ++ ++ Mometasone ter histamine hydrochloride challenge with 1 mg/mL furoate (analysis of variance, P = .02), but not after challenge with 2 and 4 mg/mL. The mean MCA 2 when both nasal cavi- *Allergy test results were negative in all patients. ties were added before treatment was 0.7 cm2, and the †+ indicates mild; ++, moderate; +++, severe; and −, no symptoms. corresponding MCA 2 after 10 days’ treatment was 0.63 cm2 (paired t test, P = .38) (Figure 4). cally important to establish for how long these drugs may safely be used without risking the development of RM. OXYMETAZOLINE WITHOUT We have previously shown that it is safe to use oxy- BENZALKONIUM CHLORIDE metazoline containing benzalkonium chloride in healthy subjects 3 times daily for 10 days.4 However, A˚ kerlund Rhinostereometric Measurements and Bende3 report that 3 weeks’ regular use of xylometazoline containing benzalkonium chloride induces In the group receiving oxymetazoline without benzal- rebound swelling in patients with vasomotor rhinitis, but konium chloride, the mean mucosal swelling after his- not in healthy subjects. They conclude that predisposed tamine hydrochloride challenge before treatment was 0.6 persons with an underlying inflammatory nasal disease mm with a dose of 1 mg/mL, 0.9 mm with 2 mg/mL, and are more prone to develop RM than healthy subjects with 1.0 mm with 4 mg/mL. After 10 days of treatment, the a normal nasal mucosa. In the present study, we there- corresponding values for mucosal swelling were 0.7, 0.9, fore used patients with chronic untreated rhinitis. and 1.1 mm (Figure 1). The increase in mucosal swell- In most countries, the use of topical nasal decon- ing was not significant at any histamine provocation level gestants is limited to a maximum of 10 days because of (by analysis of variance). The mean mucosal swelling af- the risk of developing rebound mucosal swelling and RM. ter 10 days was 0.17 mm, compared with the reference The aim of this study was to determine whether 10 days’ value before the medication was started (Figure 2).

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 Day 0, With Benzalkonium Chloride Day 0, Without Benzalkonium Chloride Day 0, With Benzalkonium Chloride Day 0, Without Benzalkonium Chloride Day 10, With Benzalkonium Chloride Day 10, Without Benzalkonium Chloride Day 10, With Benzalkonium Chloride Day 10, Without Benzalkonium Chloride

4 0.2 2 0.1 3

0.0 2

–0.1

1 –0.2 Mucosal Swelling, mm

0 –0.3 Change in MCA 2 From Baseline, cm

–1 –0.4 12 4 12 4 12 4 12 4 Histamine, mg/mL Histamine, mg/mL

Figure 1. Mean (± SD) mucosal swelling after histamine hydrochloride Figure 3. Mean (± SD) change in minimal cross-sectional area (MCA 2) from challenge of the nasal mucosa before and after 10 days’ treatment with baseline after histamine hydrochloride challenge of the nasal mucosa before oxymetazoline hydrochloride nasal spray with or without benzalkonium and after 10 days’ treatment with oxymetazoline hydrochloride nasal spray chloride as measured with rhinostereometry. The nasal mucosa was with and without benzalkonium chloride, as measured with acoustic challenged with histamine hydrochloride, 1, 2, and 4 mg/mL, applied to 1 rhinometry. The nasal mucosa was challenged with histamine side of the nose. Recordings were made before and 5 minutes after each hydrochloride,1, 2, and 4 mg/mL, applied to 1 side of the nose. Recordings challenge. were made before and 5 minutes after each challenge.

4 1.25 With Benzalkonium Chloride Without Benzalkonium Chloride

1.00 3

2 0.75

MCA 2, cm 0.50 Mucosal Swelling, mm 1 0.25

0 0 0 10 With Benzalkonium Chloride Without Benzalkonium Chloride Time, d

Figure 2. Mean (± SD) nasal mucosal swelling 10 days after treatment with Figure 4. Mean (± SD) minimal cross-sectional area (MCA 2) before and oxymetazoline hydrochloride nasal spray with or without benzalkonium after treatment with oxymetazoline hydrochloride nasal spray with or without chloride as measured with rhinostereometry. Baseline values were set at 0 benzalkonium chloride, as measured with acou8tic rhinometry. before drug treatment.

Acoustic Rhinometric Measurements reference value before the medication was started. The corresponding mucosal swelling in the group receiving The mean MCA 2 after histamine hydrochloride chal- oxymetazoline without benzalkonium chloride was lenge before treatment was −0.07 cm2 with a dose of 1 0.17 mm (unpaired t test, P = .99). The corresponding mg/mL , −0.14 cm2 with 2 mg/mL, and −0.15 cm2 with 4 MCA 2 figures for both groups also show no significant mg/mL. After 10 days of treatment, the corresponding difference between the groups (unpaired t test). MCA 2 values were −0.06, −0.11, and −0.13 cm2 (Figure In the group receiving oxymetazoline with ben- 3). There were no significant differences in MCA 2 at any zalkonium chloride, the mean symptom score for histamine provocation level. nasal stuffiness was 50 before and 49 after the treat- The mean MCA 2 when values from both nasal cavi- ment. The corresponding figures in the group receiv- ties were added before treatment was 0.67 cm2, and the ing oxymetazoline without benzalkonium chloride corresponding MCA 2 after 10 days of treatment was 0.61 were 48 and 51. cm2 (paired t test, P = .34) (Figure 4). COMMENT COMPARISONS BETWEEN GROUPS This study shows that rebound swelling does not follow The mean mucosal swelling as measured with rhinoste- 10 days’ use of oxymetazoline with or without benzal- reometry after 10 days’ treatment with oxymetazoline with konium chloride 3 times daily in patients with vasomo- benzalkonium chloride was 0.21 mm, compared with the tor rhinitis. This is clinically important, since the rec-

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Downloaded From: https://jamanetwork.com/ on 10/01/2021 ommendation of a 10-day limitation of topical nasal days’ use of these drugs. Therefore, all patients must be decongestants seems adequate. However, our study in- warned about the risk of developing rebound swelling and dicates that oxymetazoline containing benzalkonium chlo- RM after the use of topical nasal decongestants. ride, unlike the vasoconstrictor without benzalkonium chloride, reduces histamine sensitivity already after 10 Accepted for publication June 18, 1999. days’ use in patients with vasomotor rhinitis. This study was supported by Draco La¨kemedel AB, Rhinostereometry and the estimates of symptom Lund, Sweden. scores proved to be useful tools for detecting rebound swell- Reprints: Hans Halleń, MD, PhD, Department of Otorhi- ing in our previous studies.9,16,17 However, in this study nolaryngology, Huddinge University Hospital, 141 86 Hud- we found no rebound mucosal swelling with either of the dinge,Sweden(e-mail:[email protected]). objective rhinometric methods or in symptom scores in any of the investigated groups. The histamine sensitivity in the group that received oxymetazoline containing ben- REFERENCES zalkonium chloride was higher than in the other group before receiving the study drugs. Despite this difference 1. Lake C. Rhinitis medicamentosa. Mayo Clin Proc. 1946;21:367-371. 2. Petruson B. Treatment with xylometazoline (Otrivin) nosedrops over a six-week between the groups, the reduction in histamine sensitiv- period. 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It is possible that benzalkonium chloride may af- sensitive afferent neurons and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis. Br J Pharmacol. 1989;96:693-701. fect the nasal mucosa in a similar way to capsaicin. 20. Wolfe G, Loidolt D, Saria A, Gamse R. A¨nderungen des nasalen Volumsstromes This study supports the current recommendation in nach lokaler applikation des neuropeptides substanz-P und von capsaicin. La- Sweden that oxymetazoline and xylometazoline nasal spray ryngorhinootologie. 1987;66:412-415. 21. Elwany S, Stephanos W. Rhinitis medicamentosa: an experimental histopatho- with or without benzalkonium chloride may safely be used logical and histochemical study. ORL J Otorhinolaryngol Relat Spec. 1983;45: for 10 days in patients with chronic untreated vasomotor 187-194. rhinitis. There is no evidence indicating that this recom- 22. Halleń H, Juto J-E. A test for objective diagnosis of nasal hyperreactivity. Rhi- nology. 1993;31:23-25. mendation should not include other types of rhinitis, such 23. Halleń H, Juto J-E. An objective method to record changes in nasal reactivity dur- as the common cold. However, for safety reasons, pa- ing treatment of non-allergic nasal hyperreactivity. ORL J Otorhinolaryngol Relat Spec. 1994;56:92-95. tients should be instructed to use topical decongestants 24. Stja¨rne P, Lundblad L, A¨ngga˚rd A, Lundberg J. Local capsaicin treatment of the only as long as the common cold produces nasal stuffi- nasal mucosa reduces symptoms in patients with nonallergic nasal hyperreac- ness, which usually lasts not more than 3 to 5 days. Clini- tivity. Am J Rhinol. 1993;4:145-151. 25 25. Morris S, Eccles R, Martez S, Riker D, Witek T. An evaluation of nasal response cal practice and some studies show that certain patients following different treatment regimes of oxymetazoline with reference to re- may develop rebound swelling and RM after only a few bound congestion. 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