Treat Respir Med 2005; 4 (1): 21-29 1176-3450/05/0001-0021/$34.95/0

REVIEW ARTICLE

 2005 Adis Data Information BV. All rights reserved.

Rhinitis Medicamentosa A Review of Causes and Treatment Peter Graf Karolinksa University Hospital, Stockholm, Sweden

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 1. Presentation and Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2. Epidemiology and Risk Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 3. Histology and Physiology of the Nasal Mucosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 4. Pathophysiology and Origins of Rhinitis Medicamentosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.1 Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.2 Pharmacological Basis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 4.3 Benzalkonium Chloride (BKC) as a Preservative . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24 4.4 BKC and Rhinitis Medicamentosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5. Treatment of Rhinitis and Rhinitis Medicamentosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.1 Nasal Decongestants in Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 5.2 Anticholinergics in Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 5.3 Nasal Corticosteroids in Rhinitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 5.4 Nasal Corticosteroids in Rhinitis Medicamentosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26 6. Prevention of Rhinitis Medicamentosa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 6.1 Importance of Education . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Abstract

Rhinitis medicamentosa (RM) is a drug-induced, nonallergic form of rhinitis that is associated with prolonged use of topical vasoconstrictors, i.e. local decongestants. Symptoms are exacerbated by the preservative benzalkonium chloride (BKC) in the nasal preparations. Nasal stuffiness is caused by rebound swelling of the mucosa when the decongestive effect of the drug has disappeared. To alleviate this symptom, patients gradually start using larger doses of the vasoconstrictor more frequently. In many cases, the patient is unaware of the condition, thus entering a vicious circle of self-treatment. Careful questioning is required during consultation to establish diagnosis. The pathophysiology of the condition is unclear; however, vasodilatation and intravascular edema have both been implicated. Management of RM requires withdrawal of topical decongestants to allow the damaged nasal mucosa to recover, followed by treatment of the underlying nasal disease. Topical corticosteroids such as budesonide and fluticasone propionate should be used to alleviate rebound swelling of the nasal mucosa. Where possible, avoiding exposure to BKC is recommended.

Rhinitis is a common inflammatory disease of the nasal mucous membranes that is estimated to affect approximately 20% of the population of the Western world.[1] Traditionally, topical decongestants are used to alleviate the symptoms of rhinitis, despite the fact that nasal corticosteroids and oral antihistamines are indicated as first-line therapy. Prolonged or repeated use of topical decon-

gestants can cause problems, leading to the development of rhinitis medicamentosa (RM). Recognized as a distinct medical phenomenon as early as 1946,[2] RM is also sometimes referred to as rebound or chemical rhinitis.[3] It is a drug-induced, nonallergic form of rhinitis in which inflammation of the nasal mucosa is induced or aggravated by the excessive or improper use of topical

22

Graf

decongestants. Occurring typically after more than 10 days of use of the topical decongestant, RM is associated with rebound congestion when the decongestive effect of the drug disappears. Histological changes of the mucosa, including ciliary loss, epithelial ulceration, and inflammatory cell infiltration, can occur.[4] Topical nasal vasoconstrictive medications, such as sympathomimetic amines and imidazoline derivatives, are thought to be the main causative agents of RM. RM also refers to nasal stuffiness as an adverse effect associated with drugs such as oral β-adrenoceptor antagonists used for prolonged periods, antidepressants, antipsychotics, oral contraceptives and antihypertensives.[5] Patients with some underlying chronic nasal obstruction such as allergic and vasomotor rhinitis, nasal polyposis, and septal deviation run a greater risk of developing RM, but most patients without previous nasal disease are thought to overuse nasal vasoconstrictors because of a common cold and/or sinusitis. Recent reports, to be discussed in this review, have also suggested that there is a specific link between the incidence of RM and the use of topical nasal decongestants that contain the preservative benzalkonium chloride (BKC). This article reviews current knowledge of RM induced by the use of topical decongestants, its prevalence, etiology, and presentation and available treatment options. 1. Presentation and Diagnosis Patients with RM present with inflamed nasal mucosae, which often appear ‘beefy-red’ with areas of punctate bleeding and scant mucus.[6] In the later stages, nasal mucosae may look pale and edematous. The condition is characterized by nasal blockage without discharge and is associated with a history of topical vasoconstrictor abuse.[7-9] Diagnosis is characterized by persistent prominent nasal congestion following the use of intranasal decongestants on a daily basis for more than 1 week.[6] Differential diagnosis between RM and allergic or vasomotor rhinitis, however, can be difficult because the medical history, symptoms of nasal blockage, and use of topical decongestants are similar in both diseases. It is important, therefore, that physicians question patients specifically about their use of topical decongestants to differentiate between RM and allergic or vasomotor rhinitis. The clinical implications of misdiagnosis are clear. Nasal hyperreactivity in patients with RM is more resistant to treatment than vasomotor rhinitis.[10] If undertreated, severe nasal blockage can lead to oral breathing and a dry, sore throat, which may in turn cause insomnia, snoring, and disturbed sleep.[5] Furthermore, some authors claim that complications of unmanaged RM may lead to chronic ethmoiditis, nasal polyposis, and atrophic rhinitis.[11,12]  2005 Adis Data Information BV. All rights reserved.

However, this has not been proven in any published studies and it is my opinion that these complications are extremely rare. 2. Epidemiology and Risk Factors RM is more common in young and middle-aged adults than in children and elderly patients, but there appears to be no difference in sex predisposition.[12,13] In general, the condition appears to be more common in Northern Europe and North America than other regions of the world. Although allergy is often considered to be a predisposing factor, there has been no evidence that the incidence of RM is greater in areas with high ragweed growth.[14] Reported incidences of RM range from 1% to 7% in specialist ear, nose and throat (ENT) practices.[9,12,14] In a group of 500 patients who presented consecutively with nasal obstruction at a private allergy clinic in the US, the incidence of RM was 9.2%.[15] The true incidence of the disease is likely to be much greater than these retrospective estimates, however, because patients with RM are often unaware of the origin of their nasal congestion and, unless specific questions on vasoconstrictor use are asked during consultation, diagnosis is frequently overlooked. Patients with RM represent a diverse group of individuals united in their overuse/misuse of vasoconstrictive medication. Many patients start overusing topical vasoconstrictors because of some underlying chronic nasal obstruction, such as a deviated nasal septum, nasal polyposis, or vasomotor/allergic rhinitis. However, it has been suggested that RM frequently occurs in the absence of an underlying nasal disorder; for example, between 25% and 50% of patients with RM are estimated to start overusing nasal decongestants after an upper respiratory infection.[8,12] Rhinitis during pregnancy is also a predisposing factor.[16] Although patients affected by RM may continue to use nasal decongestants to relieve stuffiness, the dose and frequency of application usually remain relatively constant, suggesting habituation rather than addiction.[17,18] However, it has been shown that the effect of the topical decongestant is reduced after prolonged use[19] and, indeed, there are patients who are known to use a topical decongestant 5–10 times daily for many years. In some patients, psychological dependence has been reported[14,20] and an abstinence syndrome that includes headache, restlessness, anxiety, and dysphoria has been observed on cessation of medication.[8,14] 3. Histology and Physiology of the Nasal Mucosa Histological changes to the nasal mucosa have been reported with overuse of oxymetazoline and xylometazoline vasoconstrictors.[4,18] These changes are caused by mucosal swelling due to pooling of blood in venous sinusoids within the connective tissue underlying the epithelium. These changes involve the surface Treat Respir Med 2005; 4 (1)

Intranasal Corticosteroids in Rhinitis Medicamentosa

epithelium as well as the underlying connective tissue and include disruption of desmosomes and wide separation of epithelial cells due to edema, congested capillaries surrounded by edema fluid, and an increased population of goblet cells (figure 1).[21] 4. Pathophysiology and Origins of Rhinitis Medicamentosa

4.1 Pathophysiology

The pathophysiology of rebound swelling in RM is unclear, although vasodilation and intravascular edema have both been implicated. Swelling has also been ascribed to alterations in vasomotor tone with increased parasympathetic activity, followed by vascular permeability and edema formation.[22,23] Interstitial edema was observed as the main pathological change in a guinea-pig model in which animals were treated with naphazoline for 4 months.[21] Furthermore, edema appeared to be the cause of congestion of the inferior concha, in patients with rhinitis medicamentosa, on the first day after withdrawal of vasoconstrictors.[24] In the latter clinical study, the edema diminished and patients’ histamine sensitivity increased following 14 days of treatment with fluticasone propionate nasal spray. Given that fluticasone

a

c

b

d

Fig. 1. Photomicrographs of guinea-pig nasal mucosa showing pathological changes due to rhinitis medicamentosa (reproduced from Elwany and Abdel-Salaam,[21] with permission from Springer-Verlag). (a) Light microscope section of nasal mucosa 8 weeks after administration of naphazoline, showing increased goblet cell population (arrowhead) and subepithelial edema (*) [×400]. (b) Transmission electron microscopy (TEM) of the respiratory nasal mucosa 8 weeks after administration of naphazoline, showing wide separation of endothelial cells (E) due to accumulation of edema fluid (*); desmosomes (arrowheads) widely separated (×4600). (c) Light microscope section of nasal mucosa 8 weeks after administration of naphthazoline nitrate, showing congested blood capillary (arrow) surrounded by edema fluid (×400). (d) TEM of the respiratory nasal mucosa 8 weeks after administration of naphazoline, showing slightly dilated blood capillary (C) surrounded by edema fluid (*) [×5600].  2005 Adis Data Information BV. All rights reserved.

23

propionate has no vasoconstrictive effect, these results support the theory that rebound swelling is caused by edema. 4.2 Pharmacological Basis

Topical decongestants typically act as agonists on α-adrenoceptors in the nasal mucosa, either directly or indirectly. In general, α-adrenoceptor stimulation causes vasoconstriction while β-receptor stimulation causes vasodilation.[25,26] The imidazoline derivatives oxymetazoline and xylometazoline are selective α2-agonists resembling noradrenaline (norepinephrine); they mainly act postsynaptically and directly constrict nasal arteries and arterioles, reducing blood flow. The sympathomimetic amine phenylpropanolamine (PPA), however, acts indirectly by causing the presynaptic release of noradrenaline;[27] PPA has no blood flow-reducing effect on the nasal mucosa.[28] PPA also has some βadrenoceptor activity which, although not as pronounced as the αeffect, is prolonged and may cause rebound swelling after the αeffect has waned.[13] PPA is no longer available in the US because of an association with stroke in young women.[29,30] Long-term treatment with α2-adrenoceptor agonists, such as oxymetazoline and xylometazoline, can reduce the production of endogenous noradrenaline as a result of stimulation of a presynaptic negative feedback mechanism.[31] Thus, the α-adrenergic tone persists only as long as the topical agonist is used, with rebound swelling on cessation of therapy. Although the earliest decongestants, based on ephedrine, were associated with nasal stuffiness and tolerance,[7] PPA and imidazolines were thought to be associated with reduced risk of rebound swelling.[32] However, studies have shown rebound congestion[18,33] and changes in the nasal mucosa[4,34] with their longterm use. Although rebound swelling appears to occur only if oxymetazoline, with or without preservative, is used for more than 10 days, histamine sensitivity may be reduced in patients using oxymetazoline plus the preservative BKC for less than 10 days.[35] The reduction is probably due to BKC, since this same study showed that the use of oxymetazoline nasal spray alone increases histamine sensitivity. Thus, as also shown by others,[36] oxymetazoline nasal spray containing BKC affects the nasal mucosa after short-term use. Long-term use of oxy- and xylometazoline nasal spray containing BKC will probably, therefore, induce RM in all patients.[18,34,37,38] This may also be true for xylo- and oxymetazoline nasal sprays without BKC. Clinical evidence indicates that 3–4 weeks’ use of oxymetazoline 0.5 mg/mL should be avoided, and even oxymetazoline 0.5 mg/mL with BKC once daily at night for 4 weeks induced RM in healthy individuals.[37] Thus, overuse of topical vasoconstrictors can lead to nasal stuffiness due to rebound when the decongestive effect wears off; Treat Respir Med 2005; 4 (1)

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Table I. Toxic effects of benzalkonium chloride (BKC) in vitro and in animal and human models Model

Effect

References

In vitro

Reduces beat frequency of nasal cilia over a range of concentrations (including concentrations ordinarily used in nasal drops and sprays)

42,48-53

In vitro

Can inhibit granulocyte chemotaxis and phagocytosis, and defensive functions of neutrophils

46,47,54,55

Frog skeletal muscle cells

In vitro cell damage by inducing irreversible depolarization of membranes

56

Rabbit

Two-minute exposure to BKC caused damage to corneal epithelium by cellular destruction

57

Rat

Toxic effects shown in nasal mucosa in vivo; inclusion of BKC in corticosteroidal nasal sprays linked to squamous cell metaplasia with reduced epithelial cell height, epithelial cell pleomorphism, fewer cilia, and reduced number of goblet cells leading to loss of mucus covering to epithelia

58

Rat

Associated with development of nasal lesions

59

Patients with asthma

Induction of bronchoconstriction on inhalation

60-62

Patients with chronic external otitis

BKC induced contact allergy

63

Humans

Associated with contact dermatitis

64

Patients with open-angle glaucoma or ocular hypertension

Ophthalmic mucositis

65

stuffiness can be relieved by additional decongestant, often in larger doses, leading to drug habituation.[39] Individuals with nasal blockage and hyperreactivity induced or aggravated by long-term use of nasal decongestants show reduction in decongestant response. This tolerance may show up as decreased effectiveness of the same dose of the drug and as decreased duration of effect.[19] Additional factors that may influence the origin and severity of RM include any underlying nasal disease, the period of use of decongestants, the number of daily doses, the concentration of the decongestant and the presence of preservatives in the preparation.[5] This last point is particularly significant, since many nasal decongestant sprays contain BKC as a preservative, and use of this material has been associated with increases in the incidence of RM. Since 1981, it has been possible to purchase single-dose preparations of oxymetazoline nasal drops over the counter in Sweden. This increased the sales, particularly after 1989 when multi-dose preparations of oxymetazoline and xylometazoline nasal sprays also became available.[40] Unlike single-dose preparations, all multi-dose preparations on the Swedish market at that time contained BKC. Simultaneously, reports of patients experiencing RM had increased and the role of vasoconstrictors and BKC in this regard was discussed.[41] 4.3 Benzalkonium Chloride (BKC) as a Preservative

Given that a large variety of microorganisms have been found in the nasal mucosa of healthy volunteers, there is a clear risk of 1

bacterial contamination in multi-dose pharmaceutical preparations that do not contain preservatives. Contamination can reduce the durability of a preparation and may even induce nasal infections.[42] BKC, a quaternary ammonium compound, was first approved by the US FDA in 1982 as an ‘inactive ingredient’ for prescription drugs [43] and is used as a preservative in many multidose pharmaceutical preparations. Although not the only potentially harmful preservative in use, BKC is one of the most common, being found in many over-the-counter preparations such as nasal decongestants and glucocorticosteroids.[44] While xylometazoline and oxymetazoline decongestive nose drops and sprays are mostly preserved with BKC, these nasal sprays are now available without BKC. Similarly, while topical nasal corticosteroid preparations such as beclomethasone dipropionate, fluticasone propionate, mometasone furoate, and flunisolide contain BKC, some BKC-free alternatives exist, including budesonide (Rhinocort Aqua)1, which contains potassium sorbate as a preservative. The bactericidal effect of BKC is attributed to the hydrophobic and cationic nature of the detergent. This makes it capable of damaging the cell walls of a wide variety of Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa, even at the concentrations (typically 100 or 200 mg/L) in nasal solutions.[45-47] Some reports have suggested that the presence of BKC in nasal sprays may be associated with adverse effects, such as reduced mucociliary transport, RM, and neutrophil dysfunction. In fact,

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Treat Respir Med 2005; 4 (1)

Intranasal Corticosteroids in Rhinitis Medicamentosa

4.4 BKC and Rhinitis Medicamentosa

BKC has been shown to aggravate RM, having long-lasting effects on the nasal mucosa.[34,38] BKC appears to act as an irritant, stimulating non-myelinated afferent nerve cells in the nose and inducing nasal blockage.[71] Long-term exposure seems to increase parasympathetic activity in the nasal reflex pathway, resulting in vascular dilation, increased permeability, edema, and nasal blockage.[23] The development of rebound swelling and nasal hyperreactivity has been investigated in healthy volunteers undergoing long-term treatment with oxymetazoline spray with and without BKC.[34,38,72] In the first of three studies, rebound swelling and nasal stuffiness occurred in volunteers randomized to either treatment after 30 *

Mucosal swelling (mm)

2.0

With BKC Without BKC

1.5

75

Symptom score

toxic effects have been observed in a number of animal and human models (table I). It is postulated that the cationic surfactant properties of BKC promote strong binding to nasal tissue, thereby increasing the viscoelastic nature of the mucus gel with attendant toxicity. Diverse adverse reactions have been reported in humans using BKC-containing vasoconstrictors, including RM in patients using nasal decongestants, bronchoconstriction in patients with asthma using inhaled medications, and alteration of corneal permeability in individuals treated with eyedrops (reviewed by McMahon et al.[66]). BKC-induced contact allergy has also been reported in patients with chronic otitis media.[63] Although a series of in vivo animal and human studies failed to detect adverse effects with BKC in nasal sprays,[67,68] the clinical relevance of these results has been questioned.[69] Indeed, the upsurge in sales of multi-dose oxymetazoline and xylometazoline nasal sprays containing BKC in Sweden following their availability without prescription in 1989 and the increase in cases of RM in Sweden during the 1990s[70] raises the concern that there may be a possible link between the use of these medications and RM.

25

*

With BKC Without BKC

50

25

0 1

2 3 Treatment (weeks)

4

Fig. 3. Evening nasal stuffiness following 30 days’ treatment with oxymetazoline nasal spray with or without benzalkonium chloride (BKC) [reproduced from Graf et al.[72] with permission from Blackwell Publishing]. * p < 0.05.

days; however, both parameters were significantly greater in volunteers using oxymetazoline plus BKC than oxymetazoline without BKC (p < 0.05) [figure 2 and figure 3].[72] In a 10-day followup study conducted 3 months later in the same volunteers, only those receiving oxymetazoline plus BKC had significantly increased nasal stuffiness and mucosal swelling, illustrating the long-term adverse effects of BKC on the nasal mucosa using both subjective (figure 4) and objective (figure 5) measures.[38] In a third study, 30 healthy volunteers were treated with oxymetazoline alone, BKC alone, or placebo.[34] After 30 days, oxymetazoline had induced pronounced nasal hyperreactivity and a significantly greater sensation of nasal stuffiness than placebo. Individuals receiving BKC alone experienced significantly more mucosal swelling (figure 6)[34] but did not report nasal stuffiness. Thus, the combined effects of oxymetazoline and BKC on mucosal swelling may account for the prolonged use of nasal decongestant sprays and the development of RM. Moreover, since BKC alone can induce mucosal swelling,[34] its inclusion in a decongestant spray may aggravate RM. To date, there has been no published evidence of a deleterious effect in vivo of BKC when used as a preservative in intranasal corticosteroid preparations. However, given these results, caution should be exercised in the use of nasal products that contain BKC. Moreover, since nowadays it is possible to safely administer all nasal drugs without the preservative BKC, topical nasal drugs without BKC should be preferred in routine medication. 5. Treatment of Rhinitis and Rhinitis Medicamentosa

1.0 0.5

5.1 Nasal Decongestants in Rhinitis

0.0 Treatment (30 days)

Fig. 2. Mucosal swelling following 30 days’ treatment with oxymetazoline nasal spray with or without benzalkonium chloride (BKC) [reproduced from Graf et al.,[72] with permission from Blackwell Publishing]. * p < 0.05.  2005 Adis Data Information BV. All rights reserved.

Topical nasal decongestants are commonly used to treat the symptoms of allergic rhinitis, most acting to constrict nasal blood flow. The characteristics of an ideal nasal decongestant should be fast onset of action, long duration of effect, no decrease in potency Treat Respir Med 2005; 4 (1)

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am with BKC am without BKC pm with BKC pm without BKC

50

*

45 * **

35 30 **

25 20

** **

15 10 5

*

0 1

2

3

4

5

6

7

8

9

10

Day

Fig. 4. The long-term adverse effects of benzalkonium chloride (BKC) on nasal stuffiness 3 months after treatment with oxymetazoline with or without BKC in healthy volunteers. Mean symptom scores were estimated by the volunteers on a visual analog scale in the morning (am) and evening ´ (pm) just prior to administration of the nasal spray (reproduced from Hallen and Graf,[38] with permission from Blackwell Publishing). * p < 0.05, ** p < 0.01 for between treatment differences.

on repeated use, no rebound swelling after long-term use, no adverse effect on the mucociliary apparatus of the nose, and no systemic adverse effects.[73,74] The most desirable effects include only a symptomatic effect on blockage, no effect on itch/sneezing, and no impaired sense of smell. Imidazolines, for example, have a decongestive effect over 7–9 hours and a rapid onset of action; they achieve their maximum decongestive effect after about 30–60 minutes with minimal systemic effects.[75] However, after approximately 30 days’ use, their decongestive effect disappears after about 5 hours, indicating tolerance;[76] if overused and certainly in association with BKC, imidazolines can induce RM.[38] 5.2 Anticholinergics in Rhinitis

Ipratropium bromide nasal spray or aerosol is usually effective within 1 hour and is especially useful at reducing rhinorrhea in patients with rhinitis.[77] Since rhinorrhea can lead to the dilution of other drugs, ipratropium bromide given in combination allows other drugs to be given at a reduced dosage.[78] However, intranasal anticholinergics have no effect on nasal symptoms other than rhinorrhea.[6] 5.3 Nasal Corticosteroids in Rhinitis

In addition to allergen avoidance, new global treatment guidelines recommend that all patients with allergic rhinitis, other than those with mild or occasional symptoms, should be treated with nasal corticosteroids, with other treatments being added as necessary.[79] Although nasal corticosteroids may take up to 2 weeks to  2005 Adis Data Information BV. All rights reserved.

5.4 Nasal Corticosteroids in Rhinitis Medicamentosa

The various treatments of RM all have the same goals. The patient must stop using topical decongestants in order to allow the damaged nasal mucosa to recover,[14] while an abrupt cessation of topical decongestant use induces marked nasal blockage because of rebound congestion. The pronounced nasal obstruction is hard to endure and therefore patients often start using the decongestants again after only a few days of withdrawal. This is why treatment of RM often fails. However, use of topical nasal corticosteroids has been shown to make the process of vasoconstrictor withdrawal more effective. In one clinical study, ten patients treated with budesonide nasal spray 400 µg/day for 6 weeks after vasoconstrictor withdrawal showed considerable reduction in thickness of the nasal mucosa within 14 days and 100% success at 7-week follow-up.[76] Interestingly, since budesonide has no vasoconstrictor effect on the nasal mucosa,[41] this study again emphasizes the importance of edema rather than vasodilatation in the pathogenesis of RM. In the absence of decongestants, topical corticosteroids will usually reduce the worst symptoms of nasal stuffiness within 7 days. However, the introduction of a corticosteroid nasal spray simultaneously with cessation of nasal decongestant resulted in faster resolution (after 4 days) of nasal stuffiness compared with Oxymetazoline with BKC Oxymetazoline without BKC * Mucosal swelling (mm)

Symptom scores

40

provide maximal symptomatic relief,[77] effects are noted within 24 hours of the first dose. Corticosteroids are an optimal treatment if used regularly for the treatment of all but mild intermittent symptoms of allergic rhinitis.[6,79,80] They exert an anti-edematous effect via an influence on β-adrenergic receptors, inhibit the endothelial adherence of leukocytes and the activation of prostaglandin synthesis, and reduce the sensitivity of irritant receptors.[21] There is currently no evidence of deleterious effects on nasal mucosal histology with long-term nasal corticosteroid use.[81,82]

1.5 *** 1.0 0.5 0.0

Fig. 5. The long-term adverse effects of benzalkonium chloride (BKC) on mean mucosal swelling (SD) in healthy volunteers after 10 days’ treatment ´ and with oxymetazoline with or without BKC (reproduced from Hallen Graf,[38] with permission from Blackwell Publishing). * p < 0.05 vs without BKC; *** p < 0.001 vs before treatment. Treat Respir Med 2005; 4 (1)

Intranasal Corticosteroids in Rhinitis Medicamentosa

Mucosal swelling (mm)

2.0 1.5

*

BKC Oxymetazoline Placebo

1.0 0.5 0.0

Fig. 6. Mean increases in nasal mucosal swelling (± SD) in healthy volunteers after treatment with placebo, oxymetazoline nasal spray and benzalkonium chloride (BKC) for a period of 1 month (reproduced from ´ [34] with permission from Lippincott Williams and Wilkins). Graf and Hallen, * p < 0.05 vs before treatment.

placebo, using both subjective and objective measures.[83] In another study, 20 patients with perennial rhinitis with nasal obstruction received twice-daily oxymetazoline for 2 weeks, and were then randomized to 2 additional weeks of concomitant budesonide nasal spray or placebo.[84] The rebound congestion was reduced by concomitant budesonide nasal spray, supporting the common clinical practice of nasal corticosteroid sprays to ameliorate rebound congestion concomitant with and after cessation of topical decongestant sprays. The use of a topical corticosteroid before withdrawal of decongestant could, therefore, be recommended in all cases of RM regardless of the underlying condition. For maximum effect, corticosteroid treatment should persist for 4–6 weeks, followed by a physician visit to address the underlying disease.[76] There is no clinical evidence indicating that there is a difference in efficacy between the different topical corticosteroids in the treatment of RM. 6. Prevention of Rhinitis Medicamentosa It should be pointed out to patients that nasal decongestants have no curative effect in the treatment of sinusitis, otitis media, or the common cold. If used at all, nasal decongestants should be for short-term symptomatic relief only. It is recommended that patients with idiopathic rhinitis use nasal decongestants for no more than 10 days and, preferably, only at the lowest concentration (e.g. with oxymetazole, 0.1 mg/mL) and when nasal stuffiness is most bothersome (e.g. at night). After this, the use of nasal topical decongestants should be stopped completely. If RM has developed, a combination of topical and oral corticosteroids, systemic decongestants, and/or antihistamines can be used[76] to ease withdrawal nasal blockage. These tactics have had a success rate of 72–100% after short-term follow-up.[14] An alternative strategy suggested to prevent RM, however, is to not use decongestants at all to control rhinitis.[80]  2005 Adis Data Information BV. All rights reserved.

27

6.1 Importance of Education

In addition to appropriate symptomatic treatment and nasal examination, patients need to be informed about the importance of not overusing vasoconstrictors again after successful treatment of RM.[76] Patients successfully treated may otherwise return months or years after treatment with a new episode of RM this time induced after only a few days of use of topical decongestants. When patients with rhinitis medicamentosa who were given adequate information about decongestant overuse in addition to a corticosteroid nasal spray (budesonide nasal spray 400 µg/day for 6 weeks) were monitored for 1 year after vasoconstrictor withdrawal, there were no cases of relapse into daily long-term overuse of vasoconstrictors.[85] 7. Summary RM is drug-induced rhinitis that follows the long-term use of topical nasal vasoconstrictors, particularly those containing the preservative BKC. If used at all, topical nasal decongestants should be taken only for symptomatic relief in rhinitis. There is no evidence that nose drops have any curative effect in the common cold, sinusitis, or otitis media, and preparations should be used only for a short time, at a low concentration, and preferably only at night when nasal stuffiness is most bothersome. Decongestants without preservatives should be used in preference to those containing, for example, BKC. BKC is a substance with proven negative effects, in vitro and in vivo, on the nasal mucosa and has no essential role in topical nasal preparations, either pharmacologically or for the delivery of the product. With incidences of rhinitis apparently increasing, it is a paradox that such a substance is included in so many preparations aimed at reducing symptoms. It is, therefore, advised that products containing BKC should be avoided. Patients with RM need to seek professional help and should be educated as to the most likely cause of their condition. Topical nasal corticosteroids reduce edema and the worst symptoms of stuffiness, enabling patients to withdraw from decongestants by reducing rebound congestion and allowing the nasal mucosa to recover. Nasal corticosteroids may need to be used for at least 6 weeks after decongestants are discontinued, and patients need to be advised about the importance of not reverting to decongestants; again, it is advised that products containing BKC be avoided. Acknowledgment No sources of funding were used to assist in the preparation of this review. The author has no conflicts of interest that are directly relevant to the content of this review. Treat Respir Med 2005; 4 (1)

28

Graf

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Correspondence and offprints: Peter Graf, Karolinska University Hospital, Solna, 171 76 Stockholm, Sweden. E-mail: [email protected]

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