SE Ten Days’ Use of Oxym etazoline Nasal Spray With or Without Benzalkonium Chloride in Patients With Vasomotor Rhinitis Peter Graf, MD, PhD; Jakob Enerdal, MD; Hans Hallén, MD, PhD Context: In most countries, the use of topical nasal de- ‘congestanis is limited to a maximum of 10 days because of the risk of developing rebound mucosal swelling and rhinitis medicamentosa, Objectives To determine whether topical nasal decon- jgestants can be safely used for 10 days in patients with chronic inflammation of the nasal mucosa Design: Double-blind, randomized, controlled, paral- lel study. Patients: Thirty-five patients with vasomotor rhinitis selected from our outpatient department jervention: Eightcen patients received oxymetazo- line hydrochloride (0.5 mg/mL) nasal spray containing the preservative benzalkonium chloride (0.1 mg/mL), and the other 17 were treated with oxymetazoline nasal spray without benzallkonium chloride, Before and alter the treat- ment, recordings of the nasal mucosa and minimal cross- sectional area were made with hinostereometry and acoustic rhinometry, followed by histamine hydrochlo- ride challenge tests, Symptoms of nasal stuffiness were estimated on visual analog scales (0-100) in the morn- ing and the evening, just before the nasal spray was used. Results: No rchound swelling was found after the 10- day treatment in the 2 groups with either of the meth- ods or as estimated by symptom scores. In the group re- ceiving oxymetazoline containing benzalkonium chloride, but not in the other group, the histamine sensitivity was, significantly reduced after treatment (P<.001), Conelustons: It is sale 10 use topical nasal oxymetazo- line with or without benzalkoniuim chloride for 10 days patients with vasomotor thinitis. However, this study cates that benzalkoniu chloride in nasal deconge tant sprays alfects the nasal mucosa also alter short- “Arch Otolaryngol Head Neck Surg, 1999;125:1 128-1132 From the Department of ‘Otorhinlaryngology. Huddinge University Hospital, Karolinska Institute, Stockholm, Sweden. HE PRONOUNCED nasal va- soconstriction induced by topical nasal deconges- tants may be followed by rebound vasodilatation and stuffiness. This is especially likely after long-term use of these drugs. The patient ‘may then become uncertain as to whether congestion is sill being caused by the na- sal disease or by rebound congestion. The stuffiness is relieved by additional doses of the vasoconstrictor eventually in larger doses, ie, tolerance. Thus, the patient be- comes increasingly dependent on the top! cal decongestant and a vicious circle is es- tablished with long-term daily overuse. This phenomenon is called rhinitis medi- camentosa (RM), a term coined as far back. as 1946! when the topical decongestants contained ephedrine hydrochloride and RM was a common problem, With mod- ern vasoconstrictors, such as oxymetazo- line hydrochloride and xylometazoline hy- drochloride, the risk of developing RM and Downloaded From: http:/jamanetwork.com/ on 12/07/2016 tolerance has been considered to be much smaller or even nonexistent? However, re- es have shown that overuse of these drugs also results in rebound con- gestion™* and histological changes in the nasal mucosa.” Most nasal drops and sprays are mul- Lidose preparations that contain a preser- valive to prevent the growth of microor- ganisms, The preservative benzalkoniuin chloride, a quaternary ammonium com- pound, has a bactericidal effect, since it damages the cell wall of the microorgan- sms." The use of benzalkonium chloride hhas been questioned because its toxic to the cilia inthe nose." We have shown that daily use of benzalkonium chloride in oxy- metazoline nasal spray for 30 days in- duces a more pronounced rebound swell- ing in healthy volunteers than does oxymetazoline nasal spray used alone for 30 days, indicating that benzalkonium chloride plays an important role in the development of RM.”PATIENTS AND METHODS STUDY DESIGN ‘The study was designed a parallel, randomized, double- blind tial Thirty-five patients with vasomotor shits (fable) were randomized fr treatment with oxymetazo- Hine nse spray ether with (18 patients) of without (17 patients) benalkonium chloride inthe morning and inthe Evening fr 10 days, Nasal mucosl swelling aid nasal re- scvity as estimated by histamine challenge, were stud- ted wilh thinstereomeuy nn couse rasomery be fore and afer teatment, nd symptom scores of nasal Sullines were estimated throughott the teatenk ‘Atnoon, afer an acclimateaion period of 30 min- utes, the postion ofthe nasal mucosa of the inferior con- chain both nasal caves was recorded repeatedly with hi postereometry. to establish the baseline mucosal position, In the same sting poston, the minimal crose-sectional sea QCA 2) was then recorded with acoustic rhinom- city. Nex, the nasal mucosa was challenged with hist tnine hydrochloride, 2, and 4 mg/m, where 0.14 mL of thesoltion was yringed over the inferior conchain I side ofthe nose. The postions of the mucosal surface and MCA S were determined 3 minutes afer cach histamine provo- cation The subjects then used their nasal spray. After 10 dlysof teatment with the drug, the patent discontinued thespray inthe morning At noon, 13 to 17 hours after the last dose on the night before, the mucosal baseline post tions and MCA 2 were recorded. Then a histamine provo- Cation test was done as before. “Throughout the 10 days of medication, each subject, filled in diary card un the morning and the evening, just before using the nasal spray. Nasal stulfiness was est tated om a vista analog scale (0-100) The scale ranged from o (nose completely clear) to 100 (nose completely blocked). Informed consent was obiined before any pro- cedure was performed. The study was approve bythe l- Cal ethics committe and the medial product agency PATIENTS ‘Thirty-five patients with vasomotor thintis, 26 women and. ‘9 men (mean age, 38 years), entered the trial. Most of them hhad nasal blockage ae their main symptom, but, in some patients, secretions and/or sneezing was the dominating Symptom (Table). Eighteen patients had used nasal cor costeroids before entering the tral, but no one was al- lowed tose any medication for nasal symptoms for I month before entering the study. On rhinoscopy,nosigns ofastruc- tural basis for the nasal symplome were noted. Askin test, (Goluprick; ALK, Horsholm, Denmark) performed on all, ptients confirmed that no one was allergic. The skin test contained the following allergens: birch, hazel, timothy, mold (Aliemaria, Cladosporium), house dust mite (Derma tophagoides pteronyss, Dermatephagoides farinae), at. dog, horse, rabbit, and guinea pig, All patients were selected from the outpatient eparmentof the ext nose, and throat clinic 4 Halinge University Hospital or Sadersjukhset, Sock: itm, Sweden MEASURING METHODS ‘The nasa mucosl swelling was recorded with hinoster- metry and acoustic rhinometr. Rhinostercometry sano tial iret, noninvasive method for mescuring aca ma Cenal swelling with «high degree of accuracy” A surgical tiiroscope ts placed ona micrometer ble ted to frame ‘The microscope is movable in 3 angular directions, extab- Ishings > dimencional coordnatesystem, The subjects xed tothe apparatus y a plasti, indvidvally made tooth spin ‘Theeyeplee has ahorizontal illineter sale, The nasal cay iy levewed through the eyepiece. Since the lcrscope has 2 oll depth of focus, changes in the poston ofthe mu Cevsl surface ofthe medal sie of the ead ofthe inferior Concha ae registered inthe plane of focus along the mili tmeter scale. The accuracy ofthe method ts 0.2 mm. ‘Acouslerhinomelry produces an acoustic pulse that enters the nose via «tube equipped with nose adapter tightly place inthe mos Change i the cs Sectional area are digized by a computer, and numerical talus of the cross-sectional area are recorded, The mint thal rows sectional ares, MCA isthe cos-sclonal area between the anterior portions of the inferior concha a the septum, This method has been described clewhere, ‘nd in previous studies seems to have been accurate ‘The apparatus used in thisstudy asa RIN 2100 (SR Elec twonles APS, Lynge, Dena) sTuby DRUGS Both groups sprayed 0.1 ml. of the substances into exch, nostril 3 times daily. One group was randomized to treal- ment with oxymetazoline hydrochloride (Nezeril) (05 g/mL) nasal spray without benzalkonium chloride, and the other group received exymetazoline hydrochloride (Ne- zeril) (0.5 mg/mL) nasal spray with benzalkonium chlo- ride (0.1 mg/mL) (Draco Lakemedel AB, Lund, Sweden) ‘The study drugs wereall in a new type of nasal spray botle shown to withstand bacterial contamination, STATISTICAL ANALYSES ‘Trends and spread were analyze with the use ofthe means and SDs. For further statistical analyses analysis of vari ance and paired and unpaired teste Were used. In calcula ing the mucosal welling the baseline postion recorded on the first day was considered asthe reference poston and selatO, The changes in the micosl postions in cach side othe nose, lier 16 days of treatment with he nasal sprays, twere added. The presence of mucosal swelling induced by Histamine challenge was based on data from the challenged nasal cavity alone, the baseline valueson each day of provo- Catton being used a the reference values. ‘Opinions vary as to how long topical deconges- tants can safely be used without risking the develop- ment of KM. Some authors claim that the risk of devel- ‘oping RM with oxymetazoline and xylometazoline is very stnall and recommend regular use fort least 2 or 3 weeks, without risking adverse ellects.° Other authors recom- Downloaded From: http:/jamanetwork.com/ on 12/07/2016 mend that present products be used only for “emer- gency situations” and for not more than 3 consecutive days." No other drugs are more effective than topical nasal «,-agonists for relieving nasal stulfiness. Oxy- metazoline and xylometazoline produce immediate, pow- erful, long-lasting decongestion, and therefore its linPalient Characteristics” ‘asal symploms Patent no Sexige.y ‘Oxymelavalin Hyrocior ih Berzakonlum cherie “oe ai Blosage Sneezing DFS = Flosone propionate M2 tenet re * To Budesonide Sree oe + tN wrap a T esoide Tar + ” = Nie ern = Ne ost H + SNe as * 2 We swe > “ = Ne yemat = ae = Flosone propionate sara # = Buteroide ME s+ Mometasane tures ASRS + Budeeonide wees ” Budo vias > a naa “ = Bdesoide “ = Budo ” Budesonide “ = Nie = Ne a = esoide + No a = esoide ” = Buderoide # = Buderoide “ Budesonide “ = Ne 7 Se Mometasane frost ‘Alergy test results were negate ial patents. ‘elndates mids, moderate, ster and, 0 symtoms. cally important io establish for how long these drugs may Safely be used without risking the development of RM. We have previously shown that i is sale to use ony- mmeuizoline containing bnzallonium chloride in heathy subjects 3 times daily for 10 days * However, Akeelund and Bende’ report that 3 weeks regular use of xylo- tnetazoline containing benzalkoniunn chloride induces rebound swellings patients with vasomotor thiits, but notin healthy subjects. They conclude that predisposed persons with an underlying inflammatory nasal disease re more prone to develop RM than healthy subjects with 2 normal nasal mucosa, In the present study, we the fore used patients with chronic untreated thinks Tn most countries, the se of topical nasal decon- estan is limited ta maxiimutn of 10 days because of theriskof developing rebound mucosal swelling and RM. The aim of this study was to determine whether 10 days! Downloaded From: http:/jamanetwork.com/ on 12/07/2016 regular spraying with oxymetazoline with or without ben- zalkoniim chloride in patients with chronic inflamma- on in their nasal mucosa is safe in this respect. ES} Allpatients completed the study. However, because oftech- nical difficulties, the rhinostercometric baseline values are ‘missing in 4 subjects and the corresponding measurements withacoustic rhinometry are missing in 5 other subjects Since all subjectshad complete measurements with t least 1 of the objective methods, no patient was excluded OXYMETAZOLINE WITH. BENZALKONIUM CHLORIDE Rhinostereometric Measurements In the group receiving oxymetazoline with benzalko- nium chloride, the mean mucosal swelling alter hista- mine hydrochloride challenge before treatment was 14 mm witha dose of | mg/mL, 1.8 mm with 2 mg/mL, and 2.2 mm with 4 mg/mL. Alter 10 days of treatment, the corresponding values for mucosal swelling were 0.5, 0.8, and 1.1 mm (Figure 1). The reduction in mucosal swel walter histamine challenge was significant at all 3 hi tamine provocation levels (analysis of variance, P<.001). The mean mucosal swelling after 10 days was 0.21 mm, compared with the reference value before starting the medication (Figure 2) Acoustic Rhinometric Measurements The mean MCA 2 after histamine hydrochloride chal- lenge before treatment was 0.09 em? with a dose of 1 mg/mL. -0.12 em? with 2 mg/mL. and -0.20 em* with 4 mg/ml. After 10 days of treatment, the corresponding, MCA 2 values were -0.03, ~0.08, and -0.15 em* (Figure 3). The increase in MCA 2 was significant af- ter histamine hydrochloride challenge with 1 mg/ml. (analysis of variance, P=.02), but not alter challenge with 2and 4 mg/mL. The mean MCA 2 when both nasal eavi- jes were added before treatment was 0.7 cm, and the corresponding MCA 2 alter 10 days treatment was 0.63 tem (paired (test, P=.38) (Figure 4). OXYMETAZOLINE WITHOUT BENZALKONIUM CHLORIDE. Rhinostereometric Measurements In the group receiving oxymetazoline without benzal- koniumn chloride, the mean mucosal swelling after his tamine hydrochloride challenge before treatment was 0.6 mm witha dose of 1 mg/mL, 0.9 mm with 2 mg/mL, and 10 mm with 4 mg/mL. Alter 10 days of treatment, the corresponding values for mucosal swelling were 0.7, 0.9, and 1-1 mm (Figure 1). The increase in mucosal swell- {ng was not significant at any histamine provocation level (by analysis of variance). The mean mucosal swelling af- ter 10 days was 0.17 mm, compared with the reference value before the medication was started (Figure 2).: fe ot am I i Ba WN. La : i B “Tt T T T ay 7 T T Teal fn Figure 1. Mean < 80) mucosal syeling afte ianine hydrochloride tllnge a te asl cosa Defoe an afer 10 days eaten ot Daymetazoin hyarohlride asl sry wth or without enzaltanm ‘onde as measured with hinostereomety. The nasal mucosa was legs eine rachoie 2 ard mg ape 1 Side ofthe nose Recordings were mae befor and minutes afer each halenge. gure 3. Mean 2 0) change in minimal cross-sectional area (MGA 2) rom biselne ater histamine yaoi halengeof he nasal cose before and afte 10 ays teatment wi oxyetazae yah nasal spray ‘th and without Berzaionum ere as measred with acoustic ‘minameny The nas mucosa vas changed wih Bitamine Iycrochvide 1, 2 and 4 mgin. apa ideo the nase. Recorngs wore made bela and § minutes afer ecb chlnge. * i Ban [Ean sae 10 » é Pee MS 2 2 i Bow. 1 ws, x o. ° 7 Witesnn hie” Wet saan Tian Figure 2. Men c SO) masal mucosal seling 10 days afer teatmen wih aymetione hyevochlride asl sry wih or wou enzaltnim tone as measred with hinotereomeny. Basle vales wer se at before aru reament Acoustic Rhinometric Measurements The mean MCA 2 after histamine hydrochloride chal- lenge before treatment was -0.07 em? with a dose of 1 mg/mL. -0.14 em? with 2 mg/mL, and -0.15 ems with 4 mg/mL. Afler 10 days of treatment, the corresponding MCA 2 values were -0.06, -0.11, and -0.13 em" (Figure 3). There were no significant differences in MCA 2at any histamine provocation level The mean MCA 2 when values from both nasal eavi- lies were added before treatment was 0.67 cm?, and the corresponding MCA 2aller 10 days of reatment was 0.61 ‘em’ (paired t test, P= 34) (Figure 4). COMPARISONS BETWEEN GROUPS The mean mucosal swelling as measured with rhinoste- reometry alter 10 days treatment with oxymetazoline with benzalkonium chloride was 0.21 mm, compared with the Downloaded From: http:/jamanetwork.com/ on 12/07/2016 Figure 4. Mean z 0) minimal cass-sctnal area (HCA2) before and afer eatment it xymetazone hyaotore asal spray wor witout benzalonum clone, as measured with acoudtle minomety reference value before the medication was started. The corresponding mucosal swelling in the group receiving, oxymetazoline without benzalkonium chloride was 0.17 mm (unpaired { test, P=.99). The corresponding. MCA 2 figures for both groups also show no significant lft ence between the groups (unpaired (st). In the group receiving oxymetazoline with ben- zalkonium chloride, the mean symptom score [or nasal stulliness was 50 before and 49 after the treat ment. The corresponding figures in the group recetv- ing oxymetazoline without benzalkonium chloride were 48 and 51 ee} This study shows that rebound swelling does not follow 10 days’ use of oxymetazoline with or without benzal- onium chloride 3 umes daily in patients with vasomo- tor rhinitis. This is clinically important, since the rec-‘ommendation of a 10-day limitation of topical nasal decongestants seems adequate, However, our study in- dicates that oxymetazoline containing benzalkonium chlo- ride, unlike the vasoconstrictor without benzalkonium chloride, reduces histamine sensitivity already alter 10 days’ use in patients with vasomotor rhinitis, Rhinostereometry and the estimates of symptom. scores proved to be useful tools for detecting rebound swell- ing in our previous studies.""*"” However, in this study ‘we found no rebound mucosal swelling with either of the ‘objective ehinometric methods or in symptom scores in any of the investigated groups. The histamine sensitivity in the group that received oxymetazoline containing bet zalkoniuin chloride was higher than in the other group before receiving the study deugs, Despite this difference between the groups, the reduction in histamine sensitiv ity is probably caused by benzalkonium chloride, since we previous showed that the we of xpmetaolne sal pny We previously reported that the long-term use of ben- zalkoniuim chloride in oxymetazoline nasal spray wors- ‘ens RM in healthy volunteers.” Moreover, a nasal decon- _gestant spray composed of a combination of vasoactive substance and benzalkoniuim chloride has long-term ad- verse effect on the nasal mucosa, unlike the vasoactive sub- stance without benzalkonium ehlorie."* The nose has a reflex pathway, consisting ofaflerent unmyelinated Che thers and ellerent parasympathetic nerves, and activa: ton of nonmyeinated ters ndces asl blockage Long-term exposure to iritants may cause alterations in vasomotor tone, with increased parasympathetic activ ‘which results in vascular dilatation, inreased permesbil ity, edema, and nasal blockage." Benzalkoniumm chloride say be sich an iztant, since it has been shown to induce mucosal swelling alter 30days' use of benzalkonium chlo- side nasal spray alone in healthy subjects" Thisstudy shows that shortterm use of oxymetazoline containing benzal- keoniunn chloride also affects the nasal mucosa of patients ‘with vasomotor shinitis by reducing nasal reactivity. Pax Uients with vasomotor rhinitis have an increased sensitiv- ity to histamine compared with healthy subjects, and 14 days treatment with topical nasal corticosteroids reduces nasal reactivity and symptoms.” Likewise, Same and co- workers" treated therapy-resistant patients with vasomo- tor rhinitis with capsaicin, «substance known to acivate unmyelinated € bers, witha depletion of vasoactive sub- stances, These patients reported a positive ellect om nasal symptoms for up to 6 months before nasal symptorns re ‘curred. Itis possible that benzalkoniuim chloride may al feet the nasal mucosa ina simular way to capsaicin This study supports the curzent recommendation in sweden that oxymetazoline and xylometazoline nasal pray ‘with or without benzalkonium chloride may safely be used for 10 days in patients with chronie untreated vasomotor rhinitis, There is no evidence indicating that this recom ‘mendation should not nclade other types of rhinitis, such as the common cold. However, for safety reasons, pa- Uients should be instructed to use topical decongestants ‘only as long as the common cold produces nasal stl ness, which usally lasts not more than 3105 days. Clini- ‘al practice and some studies show that certain patients may develop rebound swelling and RM alter only «few Downloaded From: http:/jamanetwork.com/ on 12/07/2016 days’ use of these drugs. Therefore, all patients must be warned about the risk of developing rebound swelling and RM aller the use of topical nasal decongestants Accepted for publication June 18, 1999. This study was supported by Draco Lilkemedel AB, Lund, Sweden Reprints: Hans Hallén, MD, PhD, Department of Otorhi- nolaryngology, Huddinge University Hospital, 141 86 dling, Sweden (e-mail: hans hallen@stockholm.mail.telia.com) ES} 4, Late. ins mseanetosa. Myo in Pa. 184621367371. 2 Parson Treatment wth maaan (On maodrops ve asi-wesk fea Rng 6.1 67-72 toruid A Sete M Susie use of nfomatine nose dps aggro, \asamotr ht Ap iol 190597160. 4 GaP, ao Dsconastn ete nahn sualing fe esa mucosa Sung tnekuse of ena, ORL J Orinotryga Re pee 10 sense 5. Suh SH. Con Kin ¥.6 ong CH, Hong fers of apical nas ongestrtsanhislogy ana espa muzosin bbs At Oak fa Sac) Tons. see 6. Reads. Ca Escon mcscopic sy of te ttf bream ‘Horde and EDTA dsogum ont cal onelpe of Pseudbmanas aagosa ‘Phan Sl 1765 768, 1 Bats Aaa © Main 6 fond. 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