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Adverse Effects of benzalkonium chloride on the nasal mucosa: Allergic rhinitis and rhinitis medicamentosa
CLINlCALTHERAPEUTICS”NOL.
21, NO. 10, 1999
Commentary Adverse Effects of Benzalkonium Chloride on the Nasal Mucosa: Allergic Rhinitis and Rhinitis Medicamentosa Peter Graf, MD, PhD Department of OtorhinolarvngoloRy, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden
ABSTRACT Prolonged, repeated use of nasal decongestants for symptomatic relief of allergic rhinitis often results in rhinitis medicamentosa (RM), a condition involving “rebound swelling” and additional congestion. Most decongestant sprays contain the preservative benzalkonium chloride (BKC), which causes toxic reactions in the nose, eyes, ears, and lungs, and may exacerbate the symptoms of allergic rhinitis. Recent studies demonstrate the effects of nasal sprays containing BKC or the decongestant oxymetazoline (OXY) in the development of RM. Using rhinostereometry, a technique that measures nasal mucosal swelling and nasal reactivity (with histamine challenge tests), prolonged use of OXY has been shown to induce nasal mucosal swelling and hyperreactivity. Sustained use of BKC alone induces nasal mucosal swelling and, in combination with OXY, BKC appears to have a long-term adverse effect on nasal mucosa. Its presAccepted for publication August 23, 1999. Printed in the USA. Reproduction in whole or part is not permitted
0149.2918/99/$19.00
ence may also contribute to the RM resulting from overuse of decongestant sprays. Additional research is needed to confirm the deleterious effects of BKC in nasal products. However, these potential effects may be points of clinical differentiation in the treatment of allergic rhinitis and prevention of RM. Key words: allergic rhinitis, benzalkonium chloride, oxymetazoline, preservatives, rhinitis medicamentosa, topical nasal decongestants. INTRODUCTION Allergic rhinitis (seasonal or perennial) is generally considered the most common hypersensitivity disorder in the United States. In 1994, the Centers for Disease Control and Prevention estimated that 26 million (10%) Americans had allergic rhinitis.’ In earlier studies (1960 to 1970) of various communities across the nation, the prevalence of allergic rhinitis ranged from -4% to 26%,2 while a nationwide survey of physician diagnoses recorded in 1988 under the International Clas$cation of Diseases, Ninth Revision, found that allergic rhinitis (code 477) represented 9.3% of all diagnoses.-7 1749
CLINICAL
More recently, a nationwide mail survey2 of residents in 15,000 randomly selected, representative US households estimated the prevalence of allergic rhinitis by self-diagnosis at -14.2% (corresponding to 35.9 million people). This is similar to the estimated prevalence based on physician diagnoses of seasonal or perennial rhinitis in survey responders.2 However, because rhinitic nasal/ocular symptoms can be caused by a variety of conditions and because there are no standardized criteria for the diagnosis of allergic rhinitis, the true prevalence of the disorder is difficult to determine. Medical historians have observed that allergic rhinitis was much less prevalent before the industrial revolution and have hypothesized that urban pollution has contributed significantly to increased immunoglobuiin E production and immunologic responses such as allergic rhinitis.* The prevalence of allergic rhinitis may still be rising at the end of the 20th century-the number of physician consultations for hay fever in England and incidence of allergic rhinitis in Swedish army recruits between 1971 and 198 I have almost doubled .2 A 1994 US study of physician-diagnosed allergic rhinitis in children suggests that the prevalence of allergic rhinitis may be increasing in the United States as well: Indeed, a 23-year follow-up study of American college students in 1984 predicted that the frequency of allergic rhinitis and asthma would increase with the aging of the US population.5 TOPICAL NASAL DECONGESTANTS The use of topical nasal decongestants in the treatment of allergic rhinitis is as wide1750
THERAPEUTICS”
spread as the disease itself. This is surprising because allergic rhinitis should not be treated primarily with decongestants, but with nasal steroids and oral antihistamines. Topical nasal decongestants are sympathomimetic drugs that cause vasoconstriction and decrease mucosal swelling by stimulating alpha-adrenergic receptors. With prolonged or repeated use of these decongestants, patients become tolerant to these therapies; that is, more frequent applications and a greater dose often result in rebound swelling and congestion, or rhinitis medicamentosa (RM).h The development and use of topical nasal decongestants have been previously reviewed.6-9 The earliest products were mainly derived from ephedrine, and some investigators reported that rebound swelling occurred after protracted use of these topical vasoconstrictors. The use of modem vasoconstricting substances, such as the imidazoline derivatives oxymetazoline (OXY) or xylometazoline, in lieu of ephedrine or phenylpropanolamine in topical nasal decongestants, has been perceived to be associated with a decreased or nonexistent risk of developing rebound swelling. However, although some studies’” have shown no rebound swelling in healthy volunteers after the long-term use of these vasoconstrictors, other studies7q8 have shown that overuse of these drugs results in rebound congestion and histologic changes of the nasal mucosa. Since 198 I, the use of over-the-counter nasal vasoconstrictors has increased in Sweden. This is especially due to the availability, since 1989, of multidose nasal sprays containing OXY or xylometazoline that do not require a physician’s prescription. Unlike single-dose preparations, most decongestant sprays on the Swedish market contain the preservative benzalko-
P. GRAF
nium chloride (BKC). Since the early 1990s the number of patients in Sweden with RM has increased, causing concern about the overuse of these products and the role BKC might play in complicating the treatment of allergic rhinitis?
BENZALKONIUM CHLORIDE AS A PRESERVATIVE BKC is a quaternary ammonium compound used as a preservative in many pharmaceutical preparations. The bactericidal activity of BKC damages the cell wall of microorganisms, thereby inhibiting their growth and maintaining product sterility. Since 1982, BKC has been approved by the US Food and Drug Administration as an “inactive ingredient” for prescription drugs. It has been widely used in the United States and other countries as a common preservative in several topical nasal drops and sprays, as well as in metered-dose bronchodilator inha1ers.t’ %I2 There are numerous reports13-15of systemic and local toxic reactions to BKC, involving not only the nose but also the eyes, ears, and lungs. In a recent review, McMahon et ait2 cited reports of adverse reactions in human subjects to locally applied BKC in nose drops, bronchoconstriction caused by antiasthmatic inhalants, and alteration of cornea1 permeability by BKC in eyedrops. In addition, BKC-induced contact allergy has been reported in patients with chronic external otitis.16 Because of the “paradoxical” bronchospasm that develops in some children with asthma after they inhale BKC-containing medications, the American Academy of Pediatrics notes that BKC-free preparations may offer improved efficacy and significant benefit to severely ill patients.” In England, the addition of BKC to nebulizer
solutions for inhalation generally has been abandoned because of the bronchoconstrictive effects of the preservative.‘” Despite the frequent use of BKC in nasal drops and sprays, the effects of the preservative on the protective function of mucociliary clearance in the nose are still unclear. In vitro studies have shown that BKC does have a toxic (ciliostatic) effect on animal and human nasal mucosa,‘s and that nasal decongestants containing BKC can have deleterious effects on chemotaxis and phagocytosis via human granulocytes, as well as on important defensive functions of neutrophils. l4 However, similar effects on the nasal mucosa have not been found by others,‘* and further studies are needed to clarify these inconsistent observations.
RHINITIS MEDICAMENTOSA The classic definition of RM, also known as “chemical rhinitis,” is a “chronic inflammatory condition of the nasal mucous membranes secondary to the prolonged use of topical vasoconstrictive agents .“9 Accordingly, a compensatory vasodilatation remains after the vasoconstrictive effect of a nasal decongestant has disappeared. As a result, patients use the agent repeatedly, and with each cycle, tolerance to the drug and the nasal congestion increases. Individuals with an underlying chronic nasal obstruction are at increased risk of developing RM. Patients who have deviated nasal septa, upper respiratory infections, or allergic rhinitis frequently resort to and, subsequently, overuse topical decongestants for symptomatic relief.Y Over time, the only way to relieve the rebound swelling is to stop using the decongestant. The precise pathophysiologic condition underlying the rebound swelling characteristic of RM is unknown. The theories 1751
CLINICAL
postulate that various neuropharmacologic mechanisms are involved, including (1) alpha- and beta-adrenergic receptor activity and vasopressor “fatigue”; (2) tissue hypoxia and reactive hyperemia9; (3) alpha-2 receptor activity and presynaptic negative feedback, resulting in reduction of endogenous noradrenaline17; and (4) alteration in vasomotor tone with increased parasympathetic activity, vascular permeability, and edema formation. ‘* Clinically, it is difficult to distinguish between RM and allergic or vasomotor rhinitis. Nasal blockage, particularly without discharge, is the main symptom in patients with RM. Patients who have both nasal blockage and rhinorrhea often have allergic or vasomotor rhinitis as an underlying nasal disease. Patients who have RM often are unaware of the origin of their stuffiness, which may be related to the use of topical vasoconstrictors for chronic nasal obstruction. Severe nasal blockage may lead to oral breathing and a dry, sore throat, as well as to insomnia, snoring, and disturbed sleep with excessive sweating.” The diagnosis of RM is established by a history of prolonged use of nasal decongestants, constant nasal obstruction, and the presence of nasal mucosal swelling on visual examination. The symptoms of RM have been likened to an addiction, since the long-term use of topical decongestants induces drug tolerance, abstinence syndrome, and psychologic dependence. If unrecognized and unmanaged, the complications of RM can lead to chronic ethmoiditis and atrophic rhinitis.’ Assessment of Rhinitis Medicamentosa Determining whether nasal mucosal swelling is due to RM or vasomotor rhinitis is often difficult because the medical 1752
THERAPEUTIC9
history, nasal blockage, and use of topical decongestants in patients with both diseases are similar. It is therefore important to ask all patients with nasal obstruction about their use of topical decongestants. First described in 1982, rhinostereometry is an optical, direct method for accurately measuring nasal mucosal swelling in patients. This noninvasive technique uses a surgical microscope that is placed on a micrometer table fixed to a frame and is movable in 3 angular directions; topographic measurements can then be made without manipulation of the nasal structures.19 In addition to measuring nasal mucosal swelling, rhinostereometry is used to estimate nasal mucosal reactivity by employing a histamine provocation model. With this challenge test, it is possible to distinguish between healthy subjects and patients with vasomotor (perennial nonallergic) rhinitis who have an increased sensitivity to histamine.20 Role of Benzalkonium Chloride in Rhinitis Medicamentosa Using rhinostereometry, the development of rebound swelling and increased histamine sensitivity (nasal hyperreactivity) was tracked in healthy subjects who had used a decongestant nasal spray (OXY plus BKC) for 30 days.’ The duration of decongestive response during treatment was reduced, indicative of the tolerance characteristic of RM. Two days after patients stopped taking the medication, the rebound swelling disappeared. A series of more recent double-blind studies has demonstrated the effects of BKC and OXY nasal sprays a - in the development of RM in healthy subjects. The study variables included symptoms of nasal stuffiness (using visual analog scales),
P. GRAF
ness occurred in both groups. However, both variables were significantly reduced in the group using OXY without BKC (Figures 1 and 2), suggesting that BKC potentiates the effect of OXY. In a follow-up study22 performed 3 months later, the same methods and sub-
nasal mucosal swelling (using rhinostereometry), and nasal mucosa reactivity (using histamine challenge tests). In the fiit study?t 10 subjects used OXY with BKC nasal spray 3 times daily, and IO subjects used OXY without the preservative. After 30 days, rebound swelling and nasal stuffrz
2.0
1
n With BKC 0 Without BKC
T
Treatment
(30 days)
Figure I. Mucosal swelling of both inferior turbinates after 30 days of using oxymetazoline nasal spray with and without benzalkonium chloride (BKC), respectively. Values are given as mean + SD. Baseline values were set at zero before starting treatment. The mean increase in mucosal swelling was significant (P < 0.01). Reprinted, with permission, from Graf et al?’ n With BKC 0 Without BKC
T
T
2
Treatment
T
1
3
(weeks)
Figure 2. Evening nasal stuffiness during 4 weeks of treatment with oxymetazoline nasal spray with and without benzalkonium chloride (BKC), respectively, using a visual analog scale (0 to 10 cm). Values are given as mean f SD. The increases in evening nasal stuffiness were significant from the second week of treatment (P < 0.05). Reprinted, with permission, from Graf et al? 1753
CLINICAL THERAPEUTICS@’
jects were used; however, the study lasted only 10 days. After treatment, only the subjects who received OXY with BKC had significantly increased nasal stuffiness and nasal mucosal swelling. Thus the presence of BKC in a decongestant nasal spray appears to have a long-term (3-month) adverse effect on nasal mucosa. Because there were no significant differences in histamine reactivities in either study, the nasal mucosal congestion observed was probably due to vasodilatation. In a third study,’ groups of 10 healthy subjects were treated with OXY alone, BKC alone, or placebo nasal sprays. After 30 days of treatment, only OXY alone induced pronounced nasal hyperreactivity and a significantly greater sense of nasal stuffiness (evaluated using symptom scores reported by subjects during treatment). Subjects who received only BKC experienced significantly more mucosal swelling but did not report nasal stuffiness. The combined effects of OXY on nasal stuffiness and BKC on mucosal swelling may account for the prolonged use of decongestant nasal sprays and the development of RM. Moreover. the presence of BKC as a preservative may exacerbate the RM that often results from the long-term use of decongestant products.
CONCLUSIONS The increase in the prevalence of allergic rhinitis and the use of intranasal preparations to relieve congestive symptoms are significant concerns, particularly since patients tend to use these products repeatedly and for prolonged periods, contributing to the development of RM. Although the adverse effects of BKC on nasal mucosa have been demonstrated in decongestant nasal sprays. they have not been 1754
well studied in other nasal products. The potential deleterious effects of the preservative may prove to be a point of clinical differentiation in the prevention and treatment of RM.
ACKNOWLEDGMENT This research was supported by an educational grant from Astra Zeneca USA, Wayne, Pennsylvania.
Address correspondence to: Peter Graf, MD, PhD, Department of Otorhinolaryngology, Huddinge University Hospital, S-141 86 Huddinge. Sweden. REFERENCES Adams PF, Marano MA. Current
Estimates ,fiam the National Health Interview Survey, 1994: Vital and Health Statistics.
Hyattsville, Md: National Center for Health Statistics; 1995. US Departmentof Health and Human Services Publication (PHS) 96-1521, Series 10, No. 193. Nathan RA, Meltzer EO, Selner JC. Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immu&. 1997;99(Suppl):SXOg-5814. McMenamin P. Costs of hay fever in the United Statesin 1990.Ann Allergy. 1994; 731:3.5-39. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 1994;94: 895-90 1.
Settipane RJ, Hagy GW. Settipane GA. Long-term risk factors for developing asthmaand allergic rhinitis: A 23-year follow-up of college students.Allergy Proc. 1984;15:21-25.
P. GRAF
6 Yoo JK, Seikaly
H, Calhoun KH. Extended use of topical nasal decongestants. Luryngoscope.
1997;107:40-43.
7. Graf P, Hallen H. Effect on the nasal mu-
cosa of long-term treatment with oxymetazoline, benzalkonium chloride, and placebo 1996;106: nasal sprays. Laryngoscope. 605-609. 8 Suh SH, Chon K, Min Y-G, et al. Effects of topical nasal decongestants on histology of nasal respiratory mucosa in rabbits. Actu Otolaryngol (Stockh). 1995; 115:664-671.
9. Graf P. Rhinitis medicamentosa: Aspects of pathophysiology and treatment. Allergy. 1997;52(Suppl 40):28-34. IO. Petruson B, Hansson H-A. Function and structure of the nasal mucosa after 6 weeks’ use of nose-drops. Acto Otolaryngo1 (Stockh).
C, Martin G, Bond S. The effect of some preservatives used in nasal preparations on mucociliary clearance. J Pharm Pharmacol. 1989;41: 1X-159.
16. F&i J, Kalimo K, Tuohimaa P,Aantaa G. Contact allergy to various components of topical preparations for treatment of ex(Stockh). ternal otitis. Acta Otolaryngol 1985;100:414-418, I7 Lacroix JS. Adrenergic and non-adrenergic mechanisms in sympathetic vascular control of the nasal mucosa. Acta Phy.sio/ Stand. 1989;581(Suppl): l-63. I8 Elwany SS, Stephanos WM. Rhinitis medicamentosa. An experimental histopathological and histochemical study. ORL. 1983;4:187-194.
1982;94:563-569.
Il. American Academy of Pediatrics Committee on Drugs. “Inactive” ingredients in pharmaceutical products: Update. Pediatrics.
IS. Batts A, Marriot
19. Juto J, Lundberg C. An optical method for determining changes in mucosal congestion in the nose in man. Acts Otolatyngol (Stockh). 1982;94:149-156.
1997;99:268-278.
20. Hallen H. Nusal 12. McMahon C, Darby Y, Ryan R, Scadding G. Immediate and short-term effects of benzalkonium chloride on the human nasal mucosa in vivo. Clin Otoluryngol. 1997; 22:3 1X-322.
Mucoscr Reactivity in Healthy Subjects, in Patients with Nonallergic Nasal Hyperreactivity. and in Patients with Nasal Polyps. Stockholm:
Karolinska Institute; 1994. Thesis.
13. Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. Br J Clin Phhurmacol. I988;25: 157-l 63
21. Graf P, Hallen H, Juto J-E. Benzalkonium chloride in a decongestant nasal spmy aggravates rhinitis medicamentosa in healthy volunteers. Clin Exp Aller~~y. 1995;25: 395400.
14. Bjerknes R. SteinsvSg K. Inhibition of human neutrophil actin polymerization, phagocytosis and oxidative burst by components of decongestive nosedrops. Phar-
22 Hallen H, Graf P. Benzalkonium chloride in nasal decongestive sprays has a longlasting adverse effect on the nasal mucosa of healthy volunteers. Clin Exp Allergy. 1995;25:4011105.
nzatd
To.~icol. 1993;73:4 l-45.
1755
21, NO. 10, 1999
Commentary Adverse Effects of Benzalkonium Chloride on the Nasal Mucosa: Allergic Rhinitis and Rhinitis Medicamentosa Peter Graf, MD, PhD Department of OtorhinolarvngoloRy, Huddinge University Hospital, Karolinska Institute, Huddinge, Sweden
ABSTRACT Prolonged, repeated use of nasal decongestants for symptomatic relief of allergic rhinitis often results in rhinitis medicamentosa (RM), a condition involving “rebound swelling” and additional congestion. Most decongestant sprays contain the preservative benzalkonium chloride (BKC), which causes toxic reactions in the nose, eyes, ears, and lungs, and may exacerbate the symptoms of allergic rhinitis. Recent studies demonstrate the effects of nasal sprays containing BKC or the decongestant oxymetazoline (OXY) in the development of RM. Using rhinostereometry, a technique that measures nasal mucosal swelling and nasal reactivity (with histamine challenge tests), prolonged use of OXY has been shown to induce nasal mucosal swelling and hyperreactivity. Sustained use of BKC alone induces nasal mucosal swelling and, in combination with OXY, BKC appears to have a long-term adverse effect on nasal mucosa. Its presAccepted for publication August 23, 1999. Printed in the USA. Reproduction in whole or part is not permitted
0149.2918/99/$19.00
ence may also contribute to the RM resulting from overuse of decongestant sprays. Additional research is needed to confirm the deleterious effects of BKC in nasal products. However, these potential effects may be points of clinical differentiation in the treatment of allergic rhinitis and prevention of RM. Key words: allergic rhinitis, benzalkonium chloride, oxymetazoline, preservatives, rhinitis medicamentosa, topical nasal decongestants. INTRODUCTION Allergic rhinitis (seasonal or perennial) is generally considered the most common hypersensitivity disorder in the United States. In 1994, the Centers for Disease Control and Prevention estimated that 26 million (10%) Americans had allergic rhinitis.’ In earlier studies (1960 to 1970) of various communities across the nation, the prevalence of allergic rhinitis ranged from -4% to 26%,2 while a nationwide survey of physician diagnoses recorded in 1988 under the International Clas$cation of Diseases, Ninth Revision, found that allergic rhinitis (code 477) represented 9.3% of all diagnoses.-7 1749
CLINICAL
More recently, a nationwide mail survey2 of residents in 15,000 randomly selected, representative US households estimated the prevalence of allergic rhinitis by self-diagnosis at -14.2% (corresponding to 35.9 million people). This is similar to the estimated prevalence based on physician diagnoses of seasonal or perennial rhinitis in survey responders.2 However, because rhinitic nasal/ocular symptoms can be caused by a variety of conditions and because there are no standardized criteria for the diagnosis of allergic rhinitis, the true prevalence of the disorder is difficult to determine. Medical historians have observed that allergic rhinitis was much less prevalent before the industrial revolution and have hypothesized that urban pollution has contributed significantly to increased immunoglobuiin E production and immunologic responses such as allergic rhinitis.* The prevalence of allergic rhinitis may still be rising at the end of the 20th century-the number of physician consultations for hay fever in England and incidence of allergic rhinitis in Swedish army recruits between 1971 and 198 I have almost doubled .2 A 1994 US study of physician-diagnosed allergic rhinitis in children suggests that the prevalence of allergic rhinitis may be increasing in the United States as well: Indeed, a 23-year follow-up study of American college students in 1984 predicted that the frequency of allergic rhinitis and asthma would increase with the aging of the US population.5 TOPICAL NASAL DECONGESTANTS The use of topical nasal decongestants in the treatment of allergic rhinitis is as wide1750
THERAPEUTICS”
spread as the disease itself. This is surprising because allergic rhinitis should not be treated primarily with decongestants, but with nasal steroids and oral antihistamines. Topical nasal decongestants are sympathomimetic drugs that cause vasoconstriction and decrease mucosal swelling by stimulating alpha-adrenergic receptors. With prolonged or repeated use of these decongestants, patients become tolerant to these therapies; that is, more frequent applications and a greater dose often result in rebound swelling and congestion, or rhinitis medicamentosa (RM).h The development and use of topical nasal decongestants have been previously reviewed.6-9 The earliest products were mainly derived from ephedrine, and some investigators reported that rebound swelling occurred after protracted use of these topical vasoconstrictors. The use of modem vasoconstricting substances, such as the imidazoline derivatives oxymetazoline (OXY) or xylometazoline, in lieu of ephedrine or phenylpropanolamine in topical nasal decongestants, has been perceived to be associated with a decreased or nonexistent risk of developing rebound swelling. However, although some studies’” have shown no rebound swelling in healthy volunteers after the long-term use of these vasoconstrictors, other studies7q8 have shown that overuse of these drugs results in rebound congestion and histologic changes of the nasal mucosa. Since 198 I, the use of over-the-counter nasal vasoconstrictors has increased in Sweden. This is especially due to the availability, since 1989, of multidose nasal sprays containing OXY or xylometazoline that do not require a physician’s prescription. Unlike single-dose preparations, most decongestant sprays on the Swedish market contain the preservative benzalko-
P. GRAF
nium chloride (BKC). Since the early 1990s the number of patients in Sweden with RM has increased, causing concern about the overuse of these products and the role BKC might play in complicating the treatment of allergic rhinitis?
BENZALKONIUM CHLORIDE AS A PRESERVATIVE BKC is a quaternary ammonium compound used as a preservative in many pharmaceutical preparations. The bactericidal activity of BKC damages the cell wall of microorganisms, thereby inhibiting their growth and maintaining product sterility. Since 1982, BKC has been approved by the US Food and Drug Administration as an “inactive ingredient” for prescription drugs. It has been widely used in the United States and other countries as a common preservative in several topical nasal drops and sprays, as well as in metered-dose bronchodilator inha1ers.t’ %I2 There are numerous reports13-15of systemic and local toxic reactions to BKC, involving not only the nose but also the eyes, ears, and lungs. In a recent review, McMahon et ait2 cited reports of adverse reactions in human subjects to locally applied BKC in nose drops, bronchoconstriction caused by antiasthmatic inhalants, and alteration of cornea1 permeability by BKC in eyedrops. In addition, BKC-induced contact allergy has been reported in patients with chronic external otitis.16 Because of the “paradoxical” bronchospasm that develops in some children with asthma after they inhale BKC-containing medications, the American Academy of Pediatrics notes that BKC-free preparations may offer improved efficacy and significant benefit to severely ill patients.” In England, the addition of BKC to nebulizer
solutions for inhalation generally has been abandoned because of the bronchoconstrictive effects of the preservative.‘” Despite the frequent use of BKC in nasal drops and sprays, the effects of the preservative on the protective function of mucociliary clearance in the nose are still unclear. In vitro studies have shown that BKC does have a toxic (ciliostatic) effect on animal and human nasal mucosa,‘s and that nasal decongestants containing BKC can have deleterious effects on chemotaxis and phagocytosis via human granulocytes, as well as on important defensive functions of neutrophils. l4 However, similar effects on the nasal mucosa have not been found by others,‘* and further studies are needed to clarify these inconsistent observations.
RHINITIS MEDICAMENTOSA The classic definition of RM, also known as “chemical rhinitis,” is a “chronic inflammatory condition of the nasal mucous membranes secondary to the prolonged use of topical vasoconstrictive agents .“9 Accordingly, a compensatory vasodilatation remains after the vasoconstrictive effect of a nasal decongestant has disappeared. As a result, patients use the agent repeatedly, and with each cycle, tolerance to the drug and the nasal congestion increases. Individuals with an underlying chronic nasal obstruction are at increased risk of developing RM. Patients who have deviated nasal septa, upper respiratory infections, or allergic rhinitis frequently resort to and, subsequently, overuse topical decongestants for symptomatic relief.Y Over time, the only way to relieve the rebound swelling is to stop using the decongestant. The precise pathophysiologic condition underlying the rebound swelling characteristic of RM is unknown. The theories 1751
CLINICAL
postulate that various neuropharmacologic mechanisms are involved, including (1) alpha- and beta-adrenergic receptor activity and vasopressor “fatigue”; (2) tissue hypoxia and reactive hyperemia9; (3) alpha-2 receptor activity and presynaptic negative feedback, resulting in reduction of endogenous noradrenaline17; and (4) alteration in vasomotor tone with increased parasympathetic activity, vascular permeability, and edema formation. ‘* Clinically, it is difficult to distinguish between RM and allergic or vasomotor rhinitis. Nasal blockage, particularly without discharge, is the main symptom in patients with RM. Patients who have both nasal blockage and rhinorrhea often have allergic or vasomotor rhinitis as an underlying nasal disease. Patients who have RM often are unaware of the origin of their stuffiness, which may be related to the use of topical vasoconstrictors for chronic nasal obstruction. Severe nasal blockage may lead to oral breathing and a dry, sore throat, as well as to insomnia, snoring, and disturbed sleep with excessive sweating.” The diagnosis of RM is established by a history of prolonged use of nasal decongestants, constant nasal obstruction, and the presence of nasal mucosal swelling on visual examination. The symptoms of RM have been likened to an addiction, since the long-term use of topical decongestants induces drug tolerance, abstinence syndrome, and psychologic dependence. If unrecognized and unmanaged, the complications of RM can lead to chronic ethmoiditis and atrophic rhinitis.’ Assessment of Rhinitis Medicamentosa Determining whether nasal mucosal swelling is due to RM or vasomotor rhinitis is often difficult because the medical 1752
THERAPEUTIC9
history, nasal blockage, and use of topical decongestants in patients with both diseases are similar. It is therefore important to ask all patients with nasal obstruction about their use of topical decongestants. First described in 1982, rhinostereometry is an optical, direct method for accurately measuring nasal mucosal swelling in patients. This noninvasive technique uses a surgical microscope that is placed on a micrometer table fixed to a frame and is movable in 3 angular directions; topographic measurements can then be made without manipulation of the nasal structures.19 In addition to measuring nasal mucosal swelling, rhinostereometry is used to estimate nasal mucosal reactivity by employing a histamine provocation model. With this challenge test, it is possible to distinguish between healthy subjects and patients with vasomotor (perennial nonallergic) rhinitis who have an increased sensitivity to histamine.20 Role of Benzalkonium Chloride in Rhinitis Medicamentosa Using rhinostereometry, the development of rebound swelling and increased histamine sensitivity (nasal hyperreactivity) was tracked in healthy subjects who had used a decongestant nasal spray (OXY plus BKC) for 30 days.’ The duration of decongestive response during treatment was reduced, indicative of the tolerance characteristic of RM. Two days after patients stopped taking the medication, the rebound swelling disappeared. A series of more recent double-blind studies has demonstrated the effects of BKC and OXY nasal sprays a - in the development of RM in healthy subjects. The study variables included symptoms of nasal stuffiness (using visual analog scales),
P. GRAF
ness occurred in both groups. However, both variables were significantly reduced in the group using OXY without BKC (Figures 1 and 2), suggesting that BKC potentiates the effect of OXY. In a follow-up study22 performed 3 months later, the same methods and sub-
nasal mucosal swelling (using rhinostereometry), and nasal mucosa reactivity (using histamine challenge tests). In the fiit study?t 10 subjects used OXY with BKC nasal spray 3 times daily, and IO subjects used OXY without the preservative. After 30 days, rebound swelling and nasal stuffrz
2.0
1
n With BKC 0 Without BKC
T
Treatment
(30 days)
Figure I. Mucosal swelling of both inferior turbinates after 30 days of using oxymetazoline nasal spray with and without benzalkonium chloride (BKC), respectively. Values are given as mean + SD. Baseline values were set at zero before starting treatment. The mean increase in mucosal swelling was significant (P < 0.01). Reprinted, with permission, from Graf et al?’ n With BKC 0 Without BKC
T
T
2
Treatment
T
1
3
(weeks)
Figure 2. Evening nasal stuffiness during 4 weeks of treatment with oxymetazoline nasal spray with and without benzalkonium chloride (BKC), respectively, using a visual analog scale (0 to 10 cm). Values are given as mean f SD. The increases in evening nasal stuffiness were significant from the second week of treatment (P < 0.05). Reprinted, with permission, from Graf et al? 1753
CLINICAL THERAPEUTICS@’
jects were used; however, the study lasted only 10 days. After treatment, only the subjects who received OXY with BKC had significantly increased nasal stuffiness and nasal mucosal swelling. Thus the presence of BKC in a decongestant nasal spray appears to have a long-term (3-month) adverse effect on nasal mucosa. Because there were no significant differences in histamine reactivities in either study, the nasal mucosal congestion observed was probably due to vasodilatation. In a third study,’ groups of 10 healthy subjects were treated with OXY alone, BKC alone, or placebo nasal sprays. After 30 days of treatment, only OXY alone induced pronounced nasal hyperreactivity and a significantly greater sense of nasal stuffiness (evaluated using symptom scores reported by subjects during treatment). Subjects who received only BKC experienced significantly more mucosal swelling but did not report nasal stuffiness. The combined effects of OXY on nasal stuffiness and BKC on mucosal swelling may account for the prolonged use of decongestant nasal sprays and the development of RM. Moreover. the presence of BKC as a preservative may exacerbate the RM that often results from the long-term use of decongestant products.
CONCLUSIONS The increase in the prevalence of allergic rhinitis and the use of intranasal preparations to relieve congestive symptoms are significant concerns, particularly since patients tend to use these products repeatedly and for prolonged periods, contributing to the development of RM. Although the adverse effects of BKC on nasal mucosa have been demonstrated in decongestant nasal sprays. they have not been 1754
well studied in other nasal products. The potential deleterious effects of the preservative may prove to be a point of clinical differentiation in the prevention and treatment of RM.
ACKNOWLEDGMENT This research was supported by an educational grant from Astra Zeneca USA, Wayne, Pennsylvania.
Address correspondence to: Peter Graf, MD, PhD, Department of Otorhinolaryngology, Huddinge University Hospital, S-141 86 Huddinge. Sweden. REFERENCES Adams PF, Marano MA. Current
Estimates ,fiam the National Health Interview Survey, 1994: Vital and Health Statistics.
Hyattsville, Md: National Center for Health Statistics; 1995. US Departmentof Health and Human Services Publication (PHS) 96-1521, Series 10, No. 193. Nathan RA, Meltzer EO, Selner JC. Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immu&. 1997;99(Suppl):SXOg-5814. McMenamin P. Costs of hay fever in the United Statesin 1990.Ann Allergy. 1994; 731:3.5-39. Wright AL, Holberg CJ, Martinez FD, et al. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 1994;94: 895-90 1.
Settipane RJ, Hagy GW. Settipane GA. Long-term risk factors for developing asthmaand allergic rhinitis: A 23-year follow-up of college students.Allergy Proc. 1984;15:21-25.
P. GRAF
6 Yoo JK, Seikaly
H, Calhoun KH. Extended use of topical nasal decongestants. Luryngoscope.
1997;107:40-43.
7. Graf P, Hallen H. Effect on the nasal mu-
cosa of long-term treatment with oxymetazoline, benzalkonium chloride, and placebo 1996;106: nasal sprays. Laryngoscope. 605-609. 8 Suh SH, Chon K, Min Y-G, et al. Effects of topical nasal decongestants on histology of nasal respiratory mucosa in rabbits. Actu Otolaryngol (Stockh). 1995; 115:664-671.
9. Graf P. Rhinitis medicamentosa: Aspects of pathophysiology and treatment. Allergy. 1997;52(Suppl 40):28-34. IO. Petruson B, Hansson H-A. Function and structure of the nasal mucosa after 6 weeks’ use of nose-drops. Acto Otolaryngo1 (Stockh).
C, Martin G, Bond S. The effect of some preservatives used in nasal preparations on mucociliary clearance. J Pharm Pharmacol. 1989;41: 1X-159.
16. F&i J, Kalimo K, Tuohimaa P,Aantaa G. Contact allergy to various components of topical preparations for treatment of ex(Stockh). ternal otitis. Acta Otolaryngol 1985;100:414-418, I7 Lacroix JS. Adrenergic and non-adrenergic mechanisms in sympathetic vascular control of the nasal mucosa. Acta Phy.sio/ Stand. 1989;581(Suppl): l-63. I8 Elwany SS, Stephanos WM. Rhinitis medicamentosa. An experimental histopathological and histochemical study. ORL. 1983;4:187-194.
1982;94:563-569.
Il. American Academy of Pediatrics Committee on Drugs. “Inactive” ingredients in pharmaceutical products: Update. Pediatrics.
IS. Batts A, Marriot
19. Juto J, Lundberg C. An optical method for determining changes in mucosal congestion in the nose in man. Acts Otolatyngol (Stockh). 1982;94:149-156.
1997;99:268-278.
20. Hallen H. Nusal 12. McMahon C, Darby Y, Ryan R, Scadding G. Immediate and short-term effects of benzalkonium chloride on the human nasal mucosa in vivo. Clin Otoluryngol. 1997; 22:3 1X-322.
Mucoscr Reactivity in Healthy Subjects, in Patients with Nonallergic Nasal Hyperreactivity. and in Patients with Nasal Polyps. Stockholm:
Karolinska Institute; 1994. Thesis.
13. Miszkiel KA, Beasley R, Rafferty P, Holgate ST. The contribution of histamine release to bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. Br J Clin Phhurmacol. I988;25: 157-l 63
21. Graf P, Hallen H, Juto J-E. Benzalkonium chloride in a decongestant nasal spmy aggravates rhinitis medicamentosa in healthy volunteers. Clin Exp Aller~~y. 1995;25: 395400.
14. Bjerknes R. SteinsvSg K. Inhibition of human neutrophil actin polymerization, phagocytosis and oxidative burst by components of decongestive nosedrops. Phar-
22 Hallen H, Graf P. Benzalkonium chloride in nasal decongestive sprays has a longlasting adverse effect on the nasal mucosa of healthy volunteers. Clin Exp Allergy. 1995;25:4011105.
nzatd
To.~icol. 1993;73:4 l-45.
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