Rhinitis medicamentosa

Abstract

Rhinitis medicamentosa (RM) is a condition induced by overuse of nasal decongestants. The term RM, also called rebound or chemical rhinitis, is also used to describe the adverse nasal congestion that develops after using medications other than topical decongestants. Such medications include oral beta-adrenoceptor antagonists, antipsychotics, oral contraceptives, and antihypertensives. However, there are differences in the mechanism through which congestion is caused by topical nasal decongestants and oral medications. Very few prospective studies of RM have been performed and most of the knowledge about the condition comes from case reports and histologic studies. Histologic changes consistent with RM include nasociliary loss, squamous cell metaplasia, epithelial edema, epithelial cell denudation, goblet cell hyperplasia, increased expression of the epidermal growth factor receptor, and inflammatory cell infiltration. Since the cumulative dose of nasal decongestants or time period needed to initiate RM has not been conclusively determined, these medications should only be used for the shortest period necessary. Validated criteria need to be developed for better diagnosis of the condition. Stopping the nasal decongestant is the first-line treatment for RM. If necessary, intranasal glucocorticosteroids should be used to speed recovery.

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J Investig Allergol Clin Immunol 2006; Vol. 16(3): 148-155© 2006 Esmon Publicidad
Review
Rhinitis Medicamentosa
JT Ramey,
1
E Bailen,
2
RF Lockey
1
Resumen. La rinitis medicamentosa (RM) es una enfermedad originada por un uso abusivo de descongestivos
nasales. El término “rinitis medicamentosa”, también denominada rinitis química o de rebote, se utiliza también
para describir la congestión nasal adversa que se desarrolla tras el uso de otros medicamentos que no son
descongestivos tópicos. Estos medicamentos incluyen antagonistas de los receptores ß-adrenérgicos orales,
antipsicóticos, anticonceptivos orales y antihipertensores. Sin embargo, existen diferencias entre el mecanismo de
congestión causado por los descongestivos nasales tópicos y el causado por los medicamentos orales.
Se han realizado muy pocos estudios prospectivos sobre la RM, y la mayor parte de la información conocida sobre
esta enfermedad procede de la observación clínica y de estudios histológicos. Los cambios histológicos
correspondientes a la RM son pérdida nasociliar, metaplasia de células escamosas, edema epitelial, denudación de
células epiteliales, hiperplasia de células caliciformes, aumento del receptor del factor de crecimiento epidérmico
e infiltración de células inflamatorias. No se ha determinado de forma concluyente la dosis acumulada de
descongestivos nasales ni el período de tiempo necesario para el inicio de la RM, por lo que estos medicamentos
sólo deben utilizarse durante un período de tiempo lo más corto posible. Es preciso establecer criterios validados
para un mejor diagnóstico de la enfermedad. La interrupción del descongestivo nasal es el tratamiento de primera
línea para la RM. En caso necesario, deben administrarse glucocorticoesteroides intranasales para acelerar la
recuperación.
Palabras clave: Rinitis medicamentosa. Congestión. Descongestivos. Aminas simpaticomiméticas. Imidazolinas
Abstract. Rhinitis medicamentosa (RM) is a condition induced by overuse of nasal decongestants. The term RM,
also called rebound or chemical rhinitis, is also used to describe the adverse nasal congestion that develops after
using medications other than topical decongestants. Such medications include oral ß-adrenoceptor antagonists,
antipsychotics, oral contraceptives, and antihypertensives. However, there are differences in the mechanism through
which congestion is caused by topical nasal decongestants and oral medications.
Very few prospective studies of RM have been performed and most of the knowledge about the condition comes
from case reports and histologic studies. Histologic changes consistent with RM include nasociliary loss, squamous
cell metaplasia, epithelial edema, epithelial cell denudation, goblet cell hyperplasia, increased expression of the
epidermal growth factor receptor, and inflammatory cell infiltration. Since the cumulative dose of nasal
decongestants or time period needed to initiate RM has not been conclusively determined, these medications
should only be used for the shortest period necessary. Validated criteria need to be developed for better diagnosis
of the condition. Stopping the nasal decongestant is the first-line treatment for RM. If necessary, intranasal
glucocorticosteroids should be used to speed recovery.
Key words: Rhinitis medicamentosa. Congestion. Decongestants. Sympathomimetic amines. Imidazolines
Introduction
This review, based on literature searches in MEDLINE
and the bibliographies of relevant articles, addresses the
most current information on the pathophysiology,
diagnosis, and treatment of rhinitis medicamentosa (RM).
RM is “… a drug-induced, nonallergic form of rhinitis in
which the nasal mucosa is induced or aggravated by the
excessive or improper use of topical decongestants” [1].
Since the first nasal vasoconstrictor was isolated in 1887
from ma-huang, a herb containing ephedrine, these
medications have been used in the nose as inhalants, oils,
sprays, and drops [2]. Fox [3] originally described the
effects of chronic usage of topical decongestants in 1931.
“Rebound congestion” was first mentioned by Feinberg
[4] in 1944 when subjects developed nasal congestion
after using privine hydrochloride, after which Lake [5]
coined the term rhinitis medicamentosa in 1946. Very few
1
Division of Allergy & Clinical Immunology, University of South Florida & James
A. Haley VA Medical Center, Tampa, Florida, USA
2
University of Louisville School of Medicine, Louisville, Kentucky, USA

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JT Ramey, et al
149
prospective studies of RM have been performed, and most
of the knowledge about the condition comes from case
reports and histologic studies [6, 7].
The term RM, also called rebound or chemical rhinitis,
is also used to describe the adverse nasal congestion that
develops after using medications other than topical
decongestants. Such medications include oral ß-
adrenoceptor antagonists, phosphodiesterase type 5
inhibitors, antipsychotics, oral contraceptives, and
antihypertensives (see Table 1) [1, 8-11]. Since a different
mechanism may underlie the congestion caused by topical
nasal decongestants compared with other oral
medications, a term other than RM is preferred to describe
rhinitis associated with oral medications, such as “drug-
induced rhinitis.”
The first criteria for the diagnosis of RM were
proposed in 1952 and included “…(1) history of
prolonged nasal medication, (2) constant nasal
obstruction, and (3) poor shrinkage of nasal mucous
membranes on examination” [12]. Many criteria have
been used since that time to characterize RM, even though
validated criteria do not yet exist. In addition, the results
of studies designed to identify the timing of its onset are
inconclusive. For example, several studies demonstrate
that rebound congestion does not develop with up to
8 weeks of topical decongestant use [13, 14], while others
have suggested that the onset of RM occurs after the use
of topical sympathomimetics for 3 to 10 days [1, 15].
Discontinuation of oxymetazoline is recommended after
3 days of use [16]. This is supported by a study that shows
increased nasal airway resistance after 3 days of daily or
intermittent oxymetazoline [17]. However, several smaller
studies by Graf and Juto [18-20] showed that rebound
congestion does not begin until after 10 days of use in
healthy volunteers. In addition, the congestion continues
to worsen from day 10 to day 30. Those authors also found
that doubling the dose of oxymetazoline in 9 healthy
volunteers for 30 days does not increase rebound
congestion [18]. However, since that was a small study,
further work needs to be done to determine whether
increased dosages of decongestants worsen RM.
Presentation
RM is characterized by nasal congestion without
rhinorrhea, postnasal drip, or sneezing that begins after
using a nasal decongestant for more than 3 days [21].
Nasal decongestants are used to relieve congestion in
patients with allergic rhinitis, nonallergic rhinitis, acute
or chronic sinusitis, nasal polyposis, rhinitis secondary
to pregnancy, or rhinitis due to nasal septal deviation or
obstruction [1, 15]. They are also frequently used by
individuals with viral upper respiratory tract infections,
25% to 50% of whom may develop RM [1].
RM occurs at a similar rate in men and women but is
more common in young and middle-aged adults [1, 22].
The incidence reported in otolaryngology clinics ranges
from 1% to 7% [1, 23, 24]. Out of 500 consecutive patients
with nasal congestion in an allergy clinic, 9% had RM
[1, 25]. In a survey of 119 allergists, 6.7% of the patient
population was reported to have RM [26].
The appearance of the nasal mucosa does not
distinguish RM from infectious or allergic rhinitis. The
nasal mucosa can be “beefy-red” with areas of punctate
bleeding and minimal mucus [1, 12, 27], or edematous
with a profuse, stringy, mucoid discharge [23]. The
mucosa may be pale and edematous or even atrophic and
crusted following continued use of nasal decongestants
[28]. Subjects with RM may snore, have insomnia from
rebound congestion, and mouth-breathe, resulting in dry
mouth and sore throat [8, 10].
The pathologic changes caused by nasal decongestants
can alter normal nasal physiologic functions such as
filtration of particulates and the regulation of temperature
and humidity [23]. RM may also predispose to chronic
sinusitis, otitis media, nasal polyposis, or atrophic rhinitis
Table 1. Medications Associated With Drug-Induced
Rhinitis*
– Antihypertensives:
• Amiloride
• Angiotensin-converting enzyme inhibitors
• ß-blockers
• Doxazosin
• Chlorothiazide
• Clonidine
• Guanethidine
• Hydralazine
• Hydrochlorothiazide
• Methyldopa
• Phentolamine
• Prazosin
• Reserpine
– Phosphodiesterase type 5 inhibitors:
• Sildenafil
• Tadalafil
• Vardenafil
– Hormones:
• Exogenous estrogens
• Oral contraceptives
– Pain relievers:
• Aspirin
• NSAIDs
– Psychotropics:
• Chlordiazepoxide-amitriptyline
• Chlorpromazine
• Risperidone
• Thioridazine
– Miscellaneous:
• Cocaine
• Gabapentin
* NSAID indicates nonsteroidal antiinflammatory drug. Table based on
previously published data [11, 69, 70].

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Rhinitis Medicamentosa
150
[22, 23]. Psychological dependence and an abstinence
syndrome consisting of headaches, restlessness, and
anxiety following discontinuation of nasal decongestants
have been reported, leading some authors to use the word
“addiction” when describing this syndrome [26, 29]. A
case report described a subject with RM who carried
4 gallons of phenylephrine aboard a wartime ship [30],
allegedly because of an addiction to this medication. In
addition, neonatal respiratory distress syndrome has been
associated with the use of topical phenylephrine [31].
Physiology of Nasal Congestion
The nasal mucosa is composed of both resistance and
capacitance blood vessels. The resistance vessels,
comprising small arteries, arterioles, and arteriovenous
anastomoses, drain into the capacitance vessels, which
are made up of venous sinusoids [32]. The venous
sinusoids are richly innervated with sympathetic fibers
and when stimulated these nerves release norepinephrine,
which binds to prejunctional α
2
and postjunctional α
1
and
α
2
receptors. This leads to reduced nasal congestion by
decreasing blood flow and increasing sinus emptying in
the capacitance vessels [32-36].
Other nerves such as parasympathetic, sensory
C-fibers, and nonadrenergic noncholinergic (NANC)
peptidergic nerves also contribute to nasal congestion
[32]. Parasympathetic nerves release both acetylcholine,
which increases nasal secretions, and vasoactive intestinal
peptide (VIP), which causes vasodilation. Sensory C
fibers contain substance P, neurokinin A, and calcitonin
gene-related peptide, all of which downregulate intrinsic
sympathetic vasoconstriction. Stimulation of NANC
nerves causes rhinorrhea, sneezing, and congestion.
Local mediators also affect nasal congestion by
inducing changes in nasal resistance and capacitance
vessels. Mast cells, eosinophils, and basophils contribute
to nasal congestion by the release of histamine, tryptase,
kinins, prostaglandins, and leukotrienes [32]. Exudation
of plasma, which contains albumin, immunoglobulins, and
factors involved in the kinin, complement, coagulation,
and fibrinolytic systems, occurs through the fenestrations
of the superficial capillaries [32]. Goblet cells, which are
increased in RM, are not under autonomic control, but
rather, can cause congestion by releasing mucin after
stimulation from proteases, arachidonic acid metabolites,
histamine, neurotransmitters, cytokines, or nucleotide
triphosphates [32].
Mechanism of Action of Nasal
Decongestants
There are 2 classes of nasal decongestants:
sympathomimetic amines and imidazolines. Sympa-
thomimetic amines include caffeine, benzedrine,
amphetamine, mescaline, phenylpropanolamine (no
longer used in the USA), pseudoephedrine, phenylephrine,
and ephedrine (see Table 2) [1, 33]. Nasal imidazolines
include oxymetazoline, naphazoline, xylometazoline, and
clonidine.
Sympathomimetic amines mimic the actions of the
sympathetic nervous system through the presynaptic
release of norepinephrine in sympathetic nerves.
Norepinephrine then binds postsynaptically to α-receptors
and results in vasoconstriction. They are also mild ß-
receptor agonists and cause rebound vasodilation after
the α-effect has waned. They have no effect on blood
flow [1].
The imidazolines are primarily α
2
-agonists that act
postsynaptically on sympathetic nerves and cause
vasoconstriction [1]. They also lower the production of
endogenous norepinephrine via a negative feedback
mechanism, thus decreasing blood flow and decongesting
the nose.
Pathophysiology of RM
The pathophysiology of RM is unknown. There are
various hypotheses as to why it exists. It may be secondary
to the decreased production of endogenous sympathetic
norepinephrine through a negative feedback mechanism
[1]. With prolonged use or following discontinuation, the
sympathetic nerves may be unable to maintain
vasoconstriction because norepinephrine release is
suppressed.
In a human study by Cauna et al [37], plasma cells
were found surrounding degenerating autonomic and
sensory nerve endings in the nasal mucosa. In rabbits
treated with either oxymetazoline or phenylephrine, acute
purulent maxillary sinusitis developed in 13.3% of the
former group and in 33.3% of the latter group [38]. In
that study, histology of the sinus mucosa revealed ciliary
loss, epithelial cell denudation, inflammatory cell
infiltration, and edema.
Table 2. Decongestants Causing Rhinitis Medicamentosa
– Nasal decongestants:
– Sympathomimetic:
• Amphetamine
• Benzedrine
• Caffeine
• Ephedrine
• Mescaline
• Phenylephrine
• Phenylpropanolamine (no longer available
in the USA)
• Pseudoephedrine
– Imidazolines:
• Clonidine
• Naphazoline
• Oxymetazoline
• Xylometazoline

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Benzalkonium chloride (BKC), a quaternary
ammonium compound used as a preservative to prevent
bacterial contamination in many nasal sprays [1], may
increase the risk of developing RM by inducing mucosal
swelling [39-43]. Therefore, Graf [1] recommends using
BKC-free nasal decongestants, even though there is no
evidence of worsening congestion in subjects who use
nasal glucocorticosteroids containing BKC [44-46].
Histology of RM
Many different changes have been found in histologic
studies of RM (see Table 3). Disruption of nasociliary
function, proposed as early as 1934, was confirmed in an
uncontrolled study in rabbits treated either with 1%
ephedrine with sodium sulfathiazole or naphazoline
4 times a day [47]. The rabbits were found to have ciliary
loss beginning at day 5, epithelial cell damage of the nasal
mucosa in the first week, and edema in the second week.
Edema of the subepithelial layer was followed by fibrosis
and hypertrophy during the third week. Further cellular
damage with accompanying edema and mucus production
occurred during the third and fourth week. Total cellular
disorganization was noted in the fifth week, and the
epithelial cells changed from ciliated columnar to
nonciliated, stratified squamous cells by the eighth week.
Blood vessels were initially dilated but later became
sclerotic and constricted.
Talaat et al [48] used electron microscopy in a rabbit
model to compare normal nasal mucosa with mucosa
treated with 1% ephedrine for 2 and 3 weeks. The rabbits
treated with ephedrine for 2 weeks developed abnormal
microtubules lacking the normal 9+2 structure; instead,
the microtubules adhered together in homogeneous “club-
like” groups. Edema caused the epithelial cells to separate.
Desmosomes, which connect cells in the basal cell layer
near the basal lamina, were decreased. The subepithelial
layer was also edematous and contained irregularly
arranged collagen fibrils. After 3 weeks of medication, a
marked decrease in the number of cilia on the epithelial
surface was noted. Edema was again present in the
epithelium. Vascular dilation and congestion was present
in the tunica venules with increased openings in the
endothelial cell junctions. The basement membrane was
also thickened.
In another study, RM was induced in guinea pigs by
instilling 2 drops of 0.05% naphthazoline nitrate into their
nostrils 3 times a day [50]. The animals were sacrificed
at 2, 4, 6, 8, 12, and 16 weeks, and specimens divided
into 2 groups, 1 for histopathology using light microscopy
and the other for histochemical studies. The number of
goblet cells was found to increase until week 6, after which
time the number decreased. Increased numbers of
lymphocytes, plasma cells, and fibroblasts, squamous
metaplasia, increased vascularity, glandular hyperplasia,
and edema were seen during the study. An increase in the
enzyme cholinesterase was found throughout the entire
study in cholinergic nerve fibers around the glands,
suggesting a decreased parasympathetic response.
Histochemical studies also revealed increased activity of
the enzymes succinic dehydrogenase, alpha esterase,
alkaline phosphatase, and acid phosphatase.
Suh et al [51] evaluated the effect of phenylephrine
and oxymetazoline on 90 healthy rabbits by light and
electron microscopy. The rabbits were divided into 3
groups: topical phenylephrine, oxymetazoline, or saline
administered for 1 week, 2 weeks, or 4 weeks. After 2
weeks of phenylephrine or oxymetazoline, animals had
mucociliary loss, mucosal cell infiltration, primarily of
lymphocytes, and subepithelial edema. The ciliary loss
at the epithelial surface increased at 4 weeks in both the
phenylephrine and oxymetazoline groups compared to
controls. In addition, mitochondrial and endoplasmic
vacuolization and cytoplasmic vesicles were discovered
in the nasal decongestant groups after 2 and 4 weeks.
Acute purulent maxillary sinusitis only occurred in the
phenylephrine group at 4 weeks.
Results in human studies have been inconclusive. For
example, xylometazoline has been reported not to affect
nasal ciliary function [52]. Petruson and Hannson [52,
53] used electron microscopy and posterior
rhinomanometry to study 20 healthy subjects after 6 weeks
of xylometazoline (1 mg/mL), 0.15 mL, 3 times daily.
The nasal mucosa showed no morphological changes in
the intercellular spaces, basement membrane, or tunica
propria after 6 weeks of treatment. Five subjects
developed a viral upper respiratory infection during the
trial. These subjects also did not display decreased
mucociliary transport or reactive congestion after
treatment. Another study showed no development of
rebound congestion in normal subjects after using
xylometazoline for 3 weeks, but RM did develop in
subjects with nonallergic rhinitis [15].
Lin et al [49] used electron microscopy and immuno-
histochemistry to compare the nasal mucosa in control
subjects and individuals with chronic hypertrophic rhinitis
or RM. Subjects with RM had the most prominent goblet
cell hyperplasia and the highest levels of epidermal growth
factor receptor in the basal layers of the hyperplastic
epithelium. The epidermal growth factor receptor is
important in epithelial cell differentiation and cell
Table 3. Pathologic Changes Associated With Rhinitis
Medicamentosa
– Nasociliary loss and changes in nasociliary structure
– Squamous cell metaplasia
– Increased mucus production
– Epithelial cells can change from ciliated columnar to
nonciliated, stratified squamous
– Epithelial cell denudation
– Increase in intercellular widening, vascularity,
fibrosis, edema of the epithelial cell layer
– Goblet cell hyperplasia
– Increase in epidermal growth factor receptor in the
epithelial cell layer
– Increase in lymphocytes, fibroblasts, and plasma cells

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Rhinitis Medicamentosa
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proliferation. It is seen in malignancy and hypersecretory
airway disease but is rarely expressed in normal nasal
tissue [49].
In a study by Graf and Juto [20], no rebound
congestion was observed in 8 healthy volunteers after
10 days of oxymetazoline use. However, subjects were
found to have significant rebound swelling after 30 days
of use. Other studies by Graf and Juto [19, 54] have shown
an increase in histamine sensitivity and subjective nasal
congestion symptom scores in healthy volunteers. The
changes began on day 10 of oxymetazoline treatment and
continued through day 30.
In a study involving 30 human subjects diagnosed with
RM secondary to naphazoline, destruction of the nasal
cilia and epithelial cell mitochondria was demonstrated
[55]. In addition, the nasal epithelium was swollen
secondary to arteriolar dilation, mononuclear infiltration,
and glandular secretion and hyperplasia. Nasal mucus
clearance using saccharin was also prolonged in this
group. Human studies suggest that nasal decongestants
are more likely to cause RM in subjects with previous
nasal congestion, and rebound congestion may develop in
healthy subjects after 10 days of use [15, 19, 20, 52, 54].
Treatment of RM
The first goal in the treatment of RM is the immediate
discontinuation of the nasal decongestant. It has been
suggested that the nasal decongestant should continue to
be used in 1 nostril as much as needed until the congestion
is relieved in the opposite nostril [2]. However, this practice
has never been confirmed in a randomized trial.
Abrupt cessation of the decongestant may result in
rebound swelling and congestion. Several treatments have
been used for this problem. Nasal cromolyn, sedatives/
hypnotics, and saline nasal spray have been suggested in
several review papers, but no prospective trials could be
found to support their use [1,26,56,57]. Oral adenosine
triphosphate, nasal dexamethasone drops, and nasal
triamcinolone drops were used in a Chinese case series
of RM with 100%, 89%, and 100% cure rates, respectively
[55].
An oral antihistamine/decongestant combination (the
specific antihistamine/decongestant was not described in
the study) along with intranasal dexamethasone has also
been recommended [2]. In that study, 22 subjects used an
oral antihistamine/decongestant for 4 weeks in
combination with tapering doses of intranasal
dexamethasone. All subjects stopped their nasal
decongestant within 2 weeks of treatment. Only 1 case
series could be found where oral corticosteroids were used
[59]. In that study, combination treatment with topical
and oral corticosteroids after discontinuing the nasal
decongestant improved nasal congestion in all 20 subjects.
Some studies have suggested beneficial effects of
corticosteroid injections. Mabry [59] recommended
injecting triamcinolone acetonide 20 mg into the anterior
turbinates to reduce interstitial edema in RM, but no
clinical trials or case reports were provided to support
this recommendation. Mowat [60] reported a decrease in
nasal congestion in 3 subjects with RM after injecting
2 mL of 2.5% aqueous prednisolone 25mg/mL into the
inferior turbinates. Despite these case reports, injected
glucocorticosteroids are not recommended for routine
treatment of RM because of the inherent risks of
administrating them into the nasal cavity and the
discomfort associated with their administration. No
randomized controlled trials are available to prove the
usefulness of glucocorticosteroid injections, oral
glucocorticosteroids, or oral antihistamines.
Nasal glucocorticosteroids have been shown in case
reports, animal models, and randomized controlled trials
to be beneficial in the treatment of RM. Intranasal
glucocorticosteroids were first reported to be beneficial
in a case study of 4 subjects [61]. Those subjects were
given 2 sprays of dexamethasone sodium phosphate in
each nostril 3 times daily for 5 days. All 4 subjects were
able to discontinue their nasal decongestants. In another
case series, 10 subjects with RM were able to stop their
nasal decongestants and showed improvement in
objectively measured congestion after 6 weeks of
treatment with budesonide 400 µg daily [58].
Elwany [62] induced RM in 20 guinea pigs with 0.05%
naphazoline nitrite insufflated 3 times a day for 8 weeks
to determine the effects of fluticasone propionate aqueous
nasal spray 50 µg/day. Five animals were sacrificed to
confirm RM by light and electron microscopy. The 15
remaining guinea pigs were treated with fluticasone
propionate aqueous nasal spray (50 µg) once a day for 2
weeks. The animals treated in this manner were found by
light and electron microscopy to have reduced interstitial
edema.
In a study by Tas et al [63], RM was experimentally
induced in 24 guinea pigs with oxymetazoline 0.05%
3 times a day for 8 weeks. Six of the 24 guinea pigs were
sacrificed to confirm the development of RM by light
and electron microscopy. The remaining 18 animals were
divided into 3 groups and received either 0.05% aqueous
mometasone furoate (50 µg) twice a day for 14 days,
saline solution 0.9% twice a day for 14 days, or no
treatment. By the end of the 2 weeks, light and electron
microscopy revealed that the respiratory mucosa of the
mometasone furoate group showed decreased edema,
congestion, and inflammatory cell infiltrates. In contrast,
the groups that received saline or no treatment had
persistent edema, inflammation, and fibrosis.
In a study by Baldwin [2], 22 patients who had been
using a nasal decongestant for at least a month were
treated with an unspecified oral decongestant-
antihistamine and intranasal dexamethasone for 1 month.
The subjects were diagnosed with RM by the investigator,
who determined that the subjects’ nasal congestion was
primarily due to the decongestant. No objective or
histologic studies were done to document RM.
Dexamethasone 0.084 mg was administered as an aerosol
for 4 weeks in decreasing amounts. Patients used 2 puffs
in each nostril 4 times a day during the first week, 3 times

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JT Ramey, et al
a day during the second week, twice a day during the
third week, and once a day during the fourth week. All
subjects were able to discontinue their nasal decongestants
within 2 weeks and at 6 months remained free of nasal
decongestant use.
In a randomized, double-blind study, 20 human
subjects with RM for at least 2 years were randomized to
receive either fluticasone propionate nasal spray 200 µg/
day or placebo aqueous nasal spray [64, 65]. Subjects
stopped their decongestant and administered 2 puffs of
the fluticasone propionate 50 µg or placebo nasal spray
into each nostril every morning for 14 days.
Measurements of the subjects’ nasal mucosa, minimal
cross-sectional area, and peak nasal inspiratory air flow
were documented by rhinostereometry, acoustic
rhinometry, and a Youlten meter on days 0, 7, and 14 of
the study. Both the fluticasone propionate and the placebo
group reported a decrease in nasal congestion; however,
the onset of relief occurred on day 4 in the fluticasone
group versus day 7 in the control group. Nasal mucosal
swelling decreased in both groups after 7 and 14 days of
treatment, but the reduction was significantly greater with
fluticasone propionate. The fluticasone propionate group
also had a reduction in edema and an increase in nasal
sensitivity to histamine after 14 days of treatment. The
control group, however, continued to have interstitial
edema and no changes in histamine sensitivity.
Twenty patients with chronic nasal congestion
secondary to perennial allergic rhinitis were randomized
in a double-blind, placebo-controlled trial to study the
effect of budesonide (32 µg/spray) aqueous nasal spray
on RM [66]. For the first week of the trial, subjects did
not use any nasal sprays. During the second through fourth
weeks, all patients used 2 sprays of 0.05% oxymetazoline
twice a day. At the beginning of the fourth week, subjects
used 2 sprays of either saline or budesonide (32 µg/spray)
aqueous nasal spray in each nostril once a day. During
the fifth week, patients stopped the oxymetazoline and
continued either the saline or the budesonide nasal spray.
In the sixth week, subjects ceased all nasal sprays.
Acoustic rhinometry showed a significant increase in
nasal volume after the addition of budesonide to
oxymetazoline in week 4. This increase in nasal volume
was not found in the placebo group. Both the budesonide
and placebo group had a decrease in nasal volume and
minimal cross sectional area 24 hours after the cessation
of oxymetazoline in week 5. However, a statistically
significant increase in nasal volume and minimal cross
sectional area was shown at the end of week 5 in the
budesonide group, while a decrease in nasal volume and
minimal cross sectional area persisted in the placebo
group. This was further supported by the placebo group,
in which an increase in congestion was seen during weeks
5 and 6 after the cessation of oxymetazoline. The subjects
in the budesonide group reported less congestion than the
placebo group during weeks 5 and 6, and no increase in
congestion after stopping budesonide in week 6.
Nasal corticosteroids have been shown to decrease
nasal edema, inflammation, and congestion associated
with RM in both animal models and several small,
randomized, controlled human trials [2, 59-64, 66, 67].
However, none of the trials had sufficient power and it is
questionable in all the studies whether the subjects
actually had RM [2, 64-66]. Nasal congestion in subjects
with presumed RM may not only be caused by the
implicated nasal decongestant but may instead be caused
or worsened by a concomitant condition such as allergic
rhinitis, nonallergic rhinitis, or other nasal pathology.
It is impossible to confirm a cause for rebound
congestion in subjects with presumed RM, as no standard
accepted definition exists. Validated criteria for this
condition are necessary using both histologic and clinical
features. Adequately powered studies using nasal
glucocorticosteroids are necessary once a validated
definition for RM has been developed.
Further Research
In order to make an accurate diagnosis of RM and
improve research into the condition, validated criteria
using clinical and pathologic characteristics are
necessary. Diagnostic criteria will aid in distinguishing
RM from other nasal diseases such as allergic rhinitis,
nonallergic rhinitis, and viral upper respiratory
infections. In many subjects, RM occurs after they begin
using nasal decongestants to treat one of these other nasal
conditions. It is difficult to determine if the rebound
congestion is secondary to the initial nasal condition,
RM, or both.
Animal studies showed lymphocytic infiltrates on
histologic evaluation [51, 52] Therefore, cytokines may
be involved in the development of RM and research to
study their role may help to generate a better
understanding of this disease. No studies have been
performed to see if other mediators of congestion such as
histamine, tryptase, kinins, prostaglandins, leukotrienes,
and neuropeptides contribute to rebound congestion.
Another area of possible research should address the
factors that increase the number of goblet cells and control
the release of mucin by those cells.
Since nasal glucocorticosteroids appear to be
beneficial in the treatment of RM, the question arises
whether the combination of nasal glucocorticosteroids and
decongestants can be used safely together in the treatment
of allergic and nonallergic rhinitis. Many subjects with
chronic rhinitis continue to have persistent nasal
congestion despite adequate doses of nasal
glucocorticosteroids. The addition of a nasal decongestant
may benefit this patient population.
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John T. Ramey
Division of Allergy & Clinical Immunology
University of South Florida & James A. Haley VA Medical Center
13000 Bruce B. Downs Blvd. (111D), Tampa
FL 33612, USA
Fax: (+1) 813-910-4041
E-mail: jtramey@yahoo.com
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