Treat Respir Med 2005; 4 (1): 21-29

REVIEW ARTICLE 1176-3450/05/0001-0021/$34.95/0

© 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 decon-
gestants 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 phenome-
non 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
decongestants. Occurring typically after more than 10 days of use
of the topical decongestant, RM is associated with rebound con-
gestion when the decongestive effect of the drug disappears.
Histological changes of the mucosa, including ciliary loss, epithe-
lial ulceration, and inflammatory cell infiltration, can occur.[4]
Topical nasal vasoconstrictive medications, such as sympatho-
mimetic 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-adrenocep-
tor antagonists used for prolonged periods, antidepressants, antip-
sychotics, 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 be-
cause 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 presen-
tation 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 with-
out discharge and is associated with a history of topical vasocon-
strictor abuse.[7-9] Diagnosis is characterized by persistent promi-
nent nasal congestion following the use of intranasal deconges-
tants on a daily basis for more than 1 week.[6] Differential
diagnosis between RM and allergic or vasomotor rhinitis, howev-
er, 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 pa-
tients 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.
Graf
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] Rhi-
nitis 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 habitua-
tion 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 vasoconstric-
tors.[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 vaso-
motor tone with increased parasympathetic activity, followed by
vascular permeability and edema formation.[22,23] Interstitial ede-
ma 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 con-
gestion of the inferior concha, in patients with rhinitis medica-
mentosa, 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
Fig. 1. Photomicrographs of guinea-pig nasal mucosa showing pathologi-
cal changes due to rhinitis medicamentosa (reproduced from Elwany and
Abdel-Salaam,[21] with permission from Springer-Verlag). (a) Light micro-
scope 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 ac-
cumulation 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 dilat-
ed 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-adre-
noceptors 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 β-
adrenoceptor activity which, although not as pronounced as the α-
effect, is prolonged and may cause rebound swelling after the α-
effect 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 con-
gestion[18,33] and changes in the nasal mucosa[4,34] with their long-
term 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] oxymeta-
zoline 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 ox-
ymetazoline nasal sprays without BKC. Clinical evidence indi-
cates 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)
24 Graf

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 42,48-53
concentrations ordinarily used in nasal drops and sprays)
In vitro Can inhibit granulocyte chemotaxis and phagocytosis, and defensive functions of 46,47,54,55
neutrophils
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 57
destruction
Rat Toxic effects shown in nasal mucosa in vivo; inclusion of BKC in corticosteroidal 58
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
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 Ophthalmic mucositis 65
ocular hypertension

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 re-
sponse. 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 prepara-
tion.[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 na-
sal sprays also became available.[40] Unlike single-dose prepara-
tions, all multi-dose preparations on the Swedish market at that
time contained BKC. Simultaneously, reports of patients exper-
iencing 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
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 infec-
tions.[42] BKC, a quaternary ammonium compound, was first ap-
proved by the US FDA in 1982 as an ‘inactive ingredient’ for
prescription drugs [43] and is used as a preservative in many multi-
dose pharmaceutical preparations. Although not the only poten-
tially harmful preservative in use, BKC is one of the most com-
mon, being found in many over-the-counter preparations such as
nasal decongestants and glucocorticosteroids.[44] While xylometa-
zoline 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 prepa-
rations such as beclomethasone dipropionate, fluticasone propion-
ate, 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 solu-
tions.[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,

1 The use of trade names is for product identification purposes only and does not imply endorsement.

© 2005 Adis Data Information BV. All rights reserved. Treat Respir Med 2005; 4 (1)
Intranasal Corticosteroids in Rhinitis Medicamentosa
toxic effects have been observed in a number of animal and human
models (table I). It is postulated that the cationic surfactant proper-
ties 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.
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 block-
age.[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
*
With BKC
Without BKC
2.0
Mucosal swelling (mm)
1.5
1.0
0.5
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.
25
75 With BKC
*
Without BKC
Symptom score
50
25
0
1 2 3 4
Treatment (weeks)
Fig. 3. Evening nasal stuffiness following 30 days’ treatment with ox-
ymetazoline nasal spray with or without benzalkonium chloride (BKC) [re-
produced from Graf et al.[72] with permission from Blackwell Publishing]. * p
< 0.05.
days; however, both parameters were significantly greater in vol-
unteers using oxymetazoline plus BKC than oxymetazoline with-
out BKC (p < 0.05) [figure 2 and figure 3].[72] In a 10-day follow-
up study conducted 3 months later in the same volunteers, only
those receiving oxymetazoline plus BKC had significantly in-
creased 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
5.1 Nasal Decongestants in Rhinitis
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)
26
50
45
40 * symptoms of allergic rhinitis.[6,79,80] They exert an anti-edematous
35 **
Symptom scores
30
25 **
20 **
15 **
10
5 *
0 5.4 Nasal Corticosteroids in Rhinitis Medicamentosa
1 2 3 4 5 6 7 8
Day
Fig. 4. The long-term adverse effects of benzalkonium chloride (BKC) on
nasal stuffiness 3 months after treatment with oxymetazoline with or with-
out 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 Hallén
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 approxi-
mately 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, in-
tranasal 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 guide-
lines 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 neces-
sary.[79] Although nasal corticosteroids may take up to 2 weeks to
© 2005 Adis Data Information BV. All rights reserved.
Graf
am with BKC
am without BKC provide maximal symptomatic relief,[77] effects are noted within
pm with BKC 24 hours of the first dose. Corticosteroids are an optimal treatment
pm without BKC
*
if used regularly for the treatment of all but mild intermittent
effect via an influence on β-adrenergic receptors, inhibit the
endothelial adherence of leukocytes and the activation of pros-
taglandin synthesis, and reduce the sensitivity of irritant recep-
tors.[21]
There is currently no evidence of deleterious effects on nasal
mucosal histology with long-term nasal corticosteroid use.[81,82]
9 10
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] Interest-
ingly, 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
*
1.5
Mucosal swelling (mm)
***
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
with oxymetazoline with or without BKC (reproduced from Hallén and
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
2.0 BKC
Oxymetazoline
Mucosal swelling (mm)
Placebo
1.5 *
1.0
0.5
0.0
Fig. 6. Mean increases in nasal mucosal swelling (± SD) in healthy volun-
teers after treatment with placebo, oxymetazoline nasal spray and
benzalkonium chloride (BKC) for a period of 1 month (reproduced from
Graf and Hallén,[34] with permission from Lippincott Williams and Wilkins).
* p < 0.05 vs before treatment.
placebo, using both subjective and objective measures.[83] In an-
other study, 20 patients with perennial rhinitis with nasal obstruc-
tion 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 re-
bound congestion concomitant with and after cessation of topical
decongestant sprays.
The use of a topical corticosteroid before withdrawal of decon-
gestant could, therefore, be recommended in all cases of RM
regardless of the underlying condition. For maximum effect, corti-
costeroid 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 pa-
tients 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 devel-
oped, a combination of topical and oral corticosteroids, systemic
decongestants, and/or antihistamines can be used[76] to ease with-
drawal 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 ade-
quate 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 with-
drawal, 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 con-
taining, 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
References
1. Lundback B. Epidemiology of rhinitis and asthma. Clin Exp Allergy 1998; 28
Suppl. 2: 3-10
2. Lake C. Rhinitis medicamentosa. Mayo Clinic Proc 1946; 21: 367-71
3. Stephens A, Boggs P. Intranasal dexamethasone: an adjunct in the treatment of
chemical rhinitis. Ann Allergy 1968; 26: 612-3
4. Suh SH, Chon KM, Min YG, et al. Effects of topical nasal decongestants on
histology of nasal respiratory mucosa in rabbits. Acta Otolaryngol 1995; 115:
664-71
5. Graf P. Rhinitis medicamentosa: aspects of pathophysiology and treatment. Aller-
gy 1997; 52 Suppl. 40: 28-34
6. Dykewicz MS, Fineman S, Skoner DP, et al. Diagnosis and management of
rhinitis: complete guidelines of the Joint Task Force on Practice Parameters in
Allergy, Asthma and Immunology. Ann Allergy Asthma Immunol 1998; 81:
478-518
7. Kully BM. The use and abuse of nasal vasoconstrictor medication. JAMA 1945;
127: 307-10
8. Walker J. Rhinitis medicamentosa. J Allergy 1952; 23: 183-6
9. Stride R. Nasal decongestant therapy. Br J Clin Pract 1967; 21: 541-8
10. Hallén H, Juto J-E. An objective method to record changes in nasal reactivity
during treatment of non-allergic nasal hyperactivity. ORL J Otorhinolaryngol
Relat Spec 1994; 56: 92-5
11. Black M, Remsen K. Rhinitis medicamentosa. CMAJ 1980; 122: 881-4
12. Toohill R, Lehman R, Grossman T, et al. Rhinitis medicamentosa. Laryngoscope
1981; 91: 1614-21
13. Baldwin R. Rhinitis medicamentosa (an approach to treatment). J Med Assoc State
Ala 1977; 47: 33-5
14. Fleece L, Mizes JS, Jolly PA, et al. Rhinitis medicamentosa: conceptualisation,
incidence and treatment. Ala J Med Sci 1984; 21: 205-8
15. Feinberg A, Feinberg S. The “nose drop nose” due to oxymetazoline (Afrin) and
other topical vasoconstrictors. IMJ Ill Med J 1971; 140: 50-2
16. Silva AL, Silva AB, Stankiewicz AB. Nasal obstruction in pregnancy. Prim Care
Update Ob Gyns 1995; 2: 37-44
17. Rijntjes E. Nose-drop abuse, a functional and morphological study [thesis]. Leiden:
University of Leiden, 1985
18. Åkerlund A, Bende M. Sustained use of xylometazoline nose drops aggravates
vasomotor rhinitis. Am J Rhinol 1991; 5: 157-60
19. Graf P, Juto J-E. Sustained use of xylometazoline nasal spray shortens the decon-
gestive response and induces rebound swelling. Rhinology 1995; 33: 14-7
20. Snow S, Logan T, Hollender M. Nasal spray “addiction” and psychosis. Br J
Psychiatry 1980; 136: 297-9
21. Elwany S, Abdel-Salaam S. Treatment of rhinitis medicamentosa with fluticasone
propionate: an experimental study. Eur Arch Otorhinolaryngol 2001; 258:
116-9
22. Talaat M, Belal A, Aziz T, et al. Rhinitis medicamentosa: electron microscopic
study. J Laryngol Otol 1981; 95 (2): 125-31
23. Elwany SS, Stephanos WM. Rhinitis medicamentosa: an experimental histopatho-
logical and histochemical study. ORL J Otorhinolaryngol Relat Spec 1983; 45:
187-94
24. Graf PM, Hallén H. Changes in nasal reactivity in patients with rhinitis medica-
mentosa after treatment with fluticasone propionate and placebo nasal spray.
ORL J Otorhinolaryngol Relat Spec 1998; 60: 334-8
25. Hall L, Jackson R. Effects of alpha and beta adrenergic agonists on nasal blood
flow. Ann Otol Rhinol Laryngol 1968; 77: 1120-31
26. McGrath A. Vascular adrenergic receptors. In: Canoutte P, Leusen I, editors.
Vasodilatation. New York: Raven Press, 1981: 97-106
27. Starke K. α-Adrenoreceptor subclassification. Rev Physiol Biochem Pharmacol
1981; 88: 199-236
28. Bende M, Andersson KE, Johansson CJ, et al. Dose-response relationship of a
topical nasal decongestant: phenylpropanolamine. Acta Otolaryngol 1984; 98:
543-7
29. Glick R, Hoying J, Cerullo L, et al. Phenylpropanolamine: an over-the-counter
drug causing central nervous system vasculitis and intracerebral hemorrhage:
case report and review. Neurosurgery 1987; 20: 969-74
© 2005 Adis Data Information BV. All rights reserved.
Graf
30. Lake CR, Zaloga G, Bray J, et al. Transient hypertension after two phenylpropano-
lamine diet aids and the effects of caffeine: a placebo-controlled follow-up
study. Am J Med 1989; 86: 427-32
31. Lacroix J. Adrenergic and non-adrenergic mechanisms in sympathetic vascular
control of the nasal mucosa. Acta Physiol Scand Suppl 1989; 581: 1-63
32. Petruson B, Hansson HA. Function and structure of the nasal mucosa after 6
weeks’ use of nose-drops. Acta Otolaryngol 1982; 94: 563-9
33. Graf P, Juto J-E. Decongestion effect and rebound swelling of the nasal mucosa
during four-week use of oxymetazoline. ORL J Otorhinolaryngol Relat Spec
1994; 56: 131-4
34. Graf P, Hallén H. Effect on the nasal mucosa of long-term treatment with
oxymetazoline, benzalkonium chloride, and placebo nasal sprays. Laryngo-
scope 1996; 106: 605-9
35. Graf P, Enerdal J, Hallén H. Ten days’ use of oxymetazoline nasal spray with or
without benzalkonium chloride in patients with vasomotor rhinitis. Arch Oto-
laryngol Head Neck Surg 1999; 125: 1128-32
36. Morris S, Eccles R, Martez SJ, et al. An evaluation of nasal response following
different treatment regimes of oxymetazoline with reference to rebound conges-
tion. Am J Rhinol 1997; 11: 109-15
37. Graf P, Hallén H, Juto J-E. Four-week use of oxymetazoline nasal spray (Nezeril®)
once daily at night induces rebound swelling and nasal hyperreactivity. Acta
Otolaryngol 1995; 115: 71-5
38. Hallén H, Graf P. Benzalkonium chloride in nasal decongestive sprays has a long-
lasting adverse effect on the nasal mucosa of healthy volunteers. Clin Exp
Allergy 1995; 25 (5): 401-5
39. Yoo JK, Seikaly H, Calhoun KH. Extended use of topical nasal decongestants.
Laryngoscope 1997; 107: 40-3
40. Apoteksbolaget. Swedish drug statistics. Svensk läkemedelsstatistik 1991, 172-4
41. Kumlien J. Rhinitis medicamentosa, a resurrected disease? [letter]. Läkartidningen
1991; 88: 4117
42. van de Donk HJM, Muller-Plantema IP, Zuidema J, et al. The effects of preserva-
tives on the ciliary heat frequency of the chicken embryo trachea. Rhinology
1980; 18: 119-33
43. American Academy of Pediatrics Committee on Drugs. “Inactive” ingredients in
pharmaceutical products: update. Pediatrics 1997; 99: 268-78
44. Bernstein IL. Is the use of benzalkonium chloride as a preservative for nasal
formulations a safety concern? A cautionary note based on compromised
mucociliary transport. J Allergy Clin Immunol 2000; 105: 39-44
45. Richards R, Cavill R. Electron microscopic study of benzalkonium chloride and
edeate disodium on the cell envelope of Pseudomonas aeruginosa. J Pharm Sci
1976; 65: 76-80
46. Håkansson B, Forsgren A, Tegner H, et al. Inhibitory effects of nasal drop
components on granulocyte chemotaxis. Pharmacol Toxicol 1989; 64: 321-3
47. Håkansson B, Linder C, Ohlsson K, et al. The inhibition of granulocyte phagocyto-
sis by various components of nasal drops. Pharmacol Toxicol 1989; 65: 89-91
48. van de Donk HJM, Zuidema J, Merkus FW. The effects of nasal drops on the
ciliary beat frequency of chicken embryo tracheas. Rhinology 1981; 19: 215-30
49. van de Donk HJM, van den Heuvel AG, Zuidema J, et al. The effects of nasal drips
and their additives on human nasal mucociliary clearance. Rhinology 1982; 20:
127-37
50. Stanley PJ, Griffin WM, Wilson R, et al. Effect of betamethasone and
betamethasone with neomycin nasal drops on human nasal mucociliary clear-
ance and ciliary beat frequency. Thorax 1985; 40: 607-12
51. Batts AH, Marriott C, Martin GP, et al. The effect of some preservatives used in
nasal preparations on mucociliary clearance. J Pharm Pharmacol 1989; 41:
156-9
52. Joki S, Saano V, Nuutinen J, et al. Effects of some preservative agents on rat and
guinea pig tracheal and human nasal ciliary beat frequency. Am J Rhinol 1996;
10: 181-6
53. Hofmann T, Wolf G, Koidl B. Effect of topical corticosteroids and topical
antihistamines on ciliary epithelium of human nasal mucosa in vitro. HNO
1998; 46: 146-51
54. Bjerknes R, Steinsvag SK. Inhibition of human neutrophil actin polymerization,
phagocytosis and oxidative burst by components of decongestive nose drops.
Pharmacol Toxicol 1993; 73: 41-5
Treat Respir Med 2005; 4 (1)
Intranasal Corticosteroids in Rhinitis Medicamentosa
55. Steinsvåg SK, Bjerknes R, Berg ØH. The effect of topical nasal steroids on human
respiratory mucosa and human granulocytes in vitro. Acta Otolaryngol 1996;
116: 868-75
56. Bonciocat C. The action of benzalkonium chloride on the activation of contraction
in frog skeletal muscle. Physiologie 1975; 12: 215-20
57. Tonjum AM. Permeability of rabbit corneal epithelium to horseradish peroxidase
after the influence of benzalkonium chloride. Acta Ophthalmol 1975; 53:
335-47
58. Berg OH, Lie K, Steinsvag SK. The effects of topical nasal steroids on rat
respiratory mucosa in vivo, with special reference to benzalkonium chloride.
Allergy 1997; 52: 627-32
59. Kuboyama Y, Suzuki K, Hara T. Nasal lesions induced by intranasal administra-
tion of benzalkonium chloride in rats. J Toxicol Sci 1997; 22: 153-60
60. Miszkiel K, Beasley R, Holgate ST. The influence of ipratropium bromide and
sodium cromoglycate on benzalkonium chloride-induced bronchoconstriction
in asthma. Br J Clin Pharmacol 1988; 26: 295-301
61. Miszkiel K, Beasley R, Rafferty P, et al. The contribution of histamine release to
bronchoconstriction provoked by inhaled benzalkonium chloride in asthma. Br
J Clin Pharmacol 1988; 25: 157-63
62. Beasley R, Fishwick D, Miles JF, et al. Preservatives in nebulizer solutions: risks
without benefit. Pharmacotherapy 1998; 18: 130-9
63. Fraki J, Kalimo K, Tuohimaa P, et al. Contact allergy to various components of
topical preparations for treatment of external otitis. Acta Otolaryngol 1985;
100: 414-8
64. Klein GF, Sepp N, Fritsch P. Allergic reactions to benzalkonium chloride? Do the
use test! Contact Dermatitis 1991; 25: 269-70
65. de Jong C, Stolwijk T, Kuppens E, et al. Topical timolol with and without
benzalkonium chloride: epithelial permeability and autofluorescence of the
cornea in glaucoma. Graefes Arch Clin Exp Ophthalmol 1994; 232: 221-4
66. McMahon C, Darby Y, Ryan R, et al. Immediate and short-term effects of
benzalkonium chloride on the human nasal mucosa in vivo. Clin Otolaryngol
1997; 22: 318-22
67. Ainge G, Bowles JAK, McCormick SG, et al. Lack of deleterious effects of
corticosteroid sprays containing BKC on nasal ciliated epithelium: in vivo
results in laboratory animals. Drug Invest 1994; 8: 127-33
68. Braat JP, Ainge G, Bowles JA, et al. The lack of effect of benzalkonium chloride on
the cilia of the nasal mucosa in patients with perennial allergic rhinitis: a
combined functional, light scanning and transmission electron microscopy
study. Clin Exp Allergy 1995; 25: 957-65
69. Graf P. Benzalkonium chloride as a preservative in nasal solutions: re-examining
the data. Respir Med 2001; 95: 728-33
70. Graf P. Adverse effects of benzalkonium chloride on the nasal mucosa: allergic
rhinitis and rhinitis medicamentosa. Clin Ther 1999; 21: 1749-55
© 2005 Adis Data Information BV. All rights reserved.
29
71. Wolfe G, Loidolt D, Saria A, et al. Anderungen des nasalen Volumsstromes nach
lokaler Application des Neuropeptides Subtanz-P und von Capsacin.
Laryngorhinootologie 1987; 66: 412-5
72. Graf P, Hallén H, Juto J-E. Benzalkonium chloride in a decongestant nasal spray
aggravates rhinitis medicamentosa in healthy volunteers. Clin Exp Allergy
1995; 25: 395-400
73. Mayer P. A prolonged acting topical nasal decongestant for various rhinitides. IMJ
Ill Med J 1966; 129: 230-2
74. Young JR. A new decongestant in otolaryngology. Eye Ear Nose Throat Mon
1967; 46: 51-3
75. von Knothe J, Rietshek M. Vergleichende Untersuchungen zum therapeutischen
Effect overschiedener Antirhinitika. Dtsche Gesundheitsw 1976; 31: 569-73
76. Graf P, Hallén H, Juto J-E. The pathophysiology and treatment of rhinitis medica-
mentosa. Clin Otolaryngol 1995; 20: 224-9
77. Ferguson BJ, Bensimhon D. What’s causing your patient’s rhinosinusitis? J Respir
Dis 1997; 18: 321-34
78. Naclerio RM. Optimizing treatment options. Clin Exp Allergy 1998; 28 Suppl. 6:
54-9
79. van Cauwenberge P, Bachert C, Passalacqua G, et al. Consensus statement on the
treatment of allergic rhinitis: European Academy of Allergology and Clinical
Immunology. Allergy 2000; 55: 116-34
80. Bousquet J, van Cauwenberge P, Khaltaev N. Allergic rhinitis and its impact on
asthma (ARIA), in collaboration with the World Health Organization (WHO). J
Allergy Clin Immunol 2001; 108: S147-336
81. Lindqvist N, Balle VH, Karma P, et al. Long-term safety and efficacy of budeso-
nide nasal aerosol in perennial rhinitis: a 12-month multicentre study. Allergy
1986; 41: 179-86
82. Pipkorn U, Pukander J, Suonpää J, et al. Long-term safety of budesonide nasal
aerosol: a 5.5-year follow-up study. Clin Allergy 1988; 18: 253-9
83. Lindqvist N, Holmberg K, Pipkorn U. Intranasally administered budesonide, a
glucocorticoid, does not exert its clinical effect through vasoconstriction. Clin
Otolaryngol 1988; 14: 519-23
84. Ferguson BJ, Paramaesvaran S, Rubinstein E. A study of the effect of nasal steroid
sprays in perennial allergic rhinitis patients with rhinitis medicamentosa. Oto-
laryngol Head Neck Surg 2001; 125: 253-60
85. Graf PM, Hallén H. One year follow-up of patients with rhinitis medicamentosa
after vasoconstrictor withdrawal. Am J Rhinol 1997; 11: 67-72
Correspondence and offprints: Peter Graf, Karolinska University Hospital,
Solna, 171 76 Stockholm, Sweden.
E-mail: peter.graf@karolinska.se
Treat Respir Med 2005; 4 (1)