ARTICLE IN PRESS

Inhaled Corticosteroids and Voice Problems.

What Is New?
*Nikolaos Spantideas, †Eirini Drosou, *Anastasia Bougea, and ‡Dimitrios Assimakopoulos, *†Glyfada and ‡Ioannina,
Greece

Summary: Background. Voice problems are the most common and most annoying local side effect of inhaled cor-
ticosteroids (ICS), affecting not only patients’ treatment compliance but also their quality of life. The literature is very
poor regarding prevalence, mechanism, prevention, and management of voice problems attributed to ICS use and es-
pecially for the new ICS, ciclesonide. Prevalence of dysphonia seems to be less common with the use of ciclesonide
and beclomethasone dipropionate.
Method. We conducted a bibliography review based on recently published data, including data from the recently in-
troduced ICS, ciclesonide, which are lacking in previous reviews.
Results. Very little improvement, based on limited number of new papers published during previous years without
any direct comparison between available ICS, has been made in our understanding of ICS local side effects.
Conclusion. Our understanding concerning basic information of ICS effects on voice still remains poor, and further
investigation is needed to have a better understanding on epidemiology, predisposing factors, mechanisms, prevention,
and treatment of voice problems attributed to ICS.
Key Words: Inhalation–Asthma–Dysphonia–Voice–Hoarseness.

INTRODUCTION Systemic side effects of ICS are mainly attributed to swallow-

Asthma is a chronic inflammatory disorder of the lower airways,
with a worldwide distribution affecting both genders and all ages.
The prevalence of asthma is increasing worldwide.1,2 It is esti-
mated that at least 300 million people currently have asthma,
and it is expected that more than 100 million will have been added
by 2025.3,4 Despite the progress that has been made in the di-
agnosis and treatment of asthma, it continues to be one of the
most underdiagnosed and undertreated diseases, resulting in high
morbidity and disability rates.
Inflammation of the bronchi is the main underlying cause of
airway hyperreactivity and bronchoconstriction and therefore of
asthma symptoms. Corticosteroids are the cornerstone of asthma
management as they are the most potent antiinflammatory agents
currently available. Inhaled corticosteroids (ICS) are recom-
mended, in national and international guidelines, as first-line
therapy at low doses for mild persistent asthma and as the pre-
ferred therapy at medium doses or in combination with a long-
acting b2-agonist for moderate persistent asthma.3,4 Combination
therapy with high doses of ICS is recommended only for pa-
tients with severe persistent asthma.5,6
ICS are preferred to oral administration as they have been as-
sociated with significantly fewer side effects. Systemic side effects
with conventional ICS doses are negligible, but concern is needed
for systemic and local side effects when higher doses are used.
Accepted for publication September 8, 2016.
This paper has not been submitted for publication to any other journal and also has not
been presented in any meeting.
From the *Athens Speech, Language and Swallowing Institute, 10 Lontou Street, Glyfada,
Athens 16675, Greece; †Athens Speech, Language and Swallowing Institute, 37 Oinois
Street, Glyfada, Athens 16674, Greece; and the ‡ENT Department in University Hospital
of Ioannina, Medical School of the University of Ioannina, 51 Napoleontos Zerva Street,
Ioannina 45332, Greece.
Address correspondence and reprint requests to Nikolaos Spantideas, 10 Lontou Street,
Glyfada, Athens 16675, Greece. E-mail: spandideas@gmail.com
Journal of Voice, Vol. ■■, No. ■■, pp. ■■-■■
0892-1997
© 2016 The Voice Foundation. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jvoice.2016.09.002
ing of the topical deposited inhaled ICS.
Voice problems and especially dysphonia continue to remain
the main local side effect of ICS, despite the development of
new ICS molecules and new, sophisticated delivery systems.
The purpose of our study was to review the current litera-
ture by looking for new information that can improve our
understanding in preventing and managing ICS-related voice
problems.
METHODS
A literature search was performed concerning ICS and voice dis-
orders using the following databases: PubMed, EMBASE (from
1980 to October 2015), and Cochrane Library (from 1993 to
2015). The keywords used for the study were “inhaled cortico-
steroids and voice problems,” “treatment and dysphonia,” and
“dysphonia.” Articles, letters, summaries, and dissertations pub-
lished in English were included in our search. Additional
information was gathered from references cited in the identi-
fied publications and products’ package insert. Particular emphasis
was given to original articles and, on a secondary basis, to books
and reviews. One hundred four papers, related to our search, were
identified and reviewed. Only studies reporting appropriate in-
formation on our study design were included for review. Among
these studies, there was one meta-analytic study7 and five
reviews.8–11 Two reviews, one in Spanish and one in German,
were excluded.
RESULTS
Local side effects of ICS
The most common local side effects of ICS are shown in Table 1.
Although local side effects, compared with systemic ones, are
not serious, they can affect the patient’s quality of life, treat-
ment compliance, and most importantly, they can mask symptoms
of a more serious disease. For example, dysphonia and hoarse-
ness are very common local side effects of ICS, but they can
 ARTICLE IN PRESS
2 Journal of Voice, Vol. ■■, No. ■■, 2016
TABLE 1.
Local Side Effects of Inhaled Corticosteroids11–13
Hoarseness or Dysphonia
Cough
Aphonia
Dry, sore throat
Voice misuse or throat clearing
Candidiasis
Pharyngitis
Perioral dermatitis
Tongue hypertrophy
Sensation of thirst
be cardinal symptoms of laryngeal cancer. It is of capital im-
portance in every patient with persistent hoarseness, especially
after cessation of ICS therapy, to perform an in-depth investi-
gation for the exclusion of such a possibility.
Local side effects of ICS are a result of deposition of the active
form of the drug in the pharyngolaryngeal area.
Dysphonia
Whether hoarseness or huskiness and dysphonia are separate
symptoms is a matter of debate. Most of the investigators believe
that the term dysphonia covers all symptoms related to voice prob-
lems as a consequence of ICS use, and from now and on, in this
paper, the term dysphonia will be used to describe the whole
spectrum of voice disturbances related to ICS use.
Incidence of dysphonia
Dysphonia, with or without candidiasis, is by far the most fre-
quent local side effect of ICS. The prevalence of dysphonia varies
significantly among studies, depending on the definition of the
term, the type of the study, and especially the method that was
used to detect dysphonia (questionnaire or inspection).14,15 The
highest prevalence rates are found in studies where symptom-
based questionnaires were used, and the lowest were found in
studies where clinical and laboratory examinations (inspec-
tion) were performed. Generally, the more precise the applied
diagnostic criteria were used, the lower prevalence of dyspho-
nia was observed. For example, recording hoarseness and
dysphonia as different symptoms results in a lower prevalence
of dysphonia. In general, most of the well-organized studies in
which inspection was included among the basic diagnostic cri-
teria estimate the prevalence of dysphonia at 5%–10%.
A number of factors have been recognized as contributing in
the appearance of dysphonia (Table 2).
The prevalence of dysphonia is not the same with different
types of ICS. For reasons related mainly to pharmacological char-
acteristics of each compound, the prevalence of dysphonia varies
significantly among currently available ICS. Table 3 shows the
prevalence of dysphonia of different ICS as it has been re-
ported in their Summary of Product Characteristics or in clinical
trials.
A number of factors influence where and how much drug is
deposited in the airway and upper aerodigestive tract. These
TABLE 2.
Factors Contributing to the Appearance of Dysphonia
1 Active compound of ICS
2 Type of ICS (active drug or prodrug)
3 Potency of ICS
4 Dosage and frequency of ICS use
5 Patient’s compliance and right use of product delivery
device
6 The size of the delivered particles
7 The velocity of the delivered particles
8 The type of the delivery system (DPI, MDI)
9 The use of spacer
include size of particle, type of drug (active or prodrug), veloc-
ity and type of delivery system, and technique of inhalation.
Effect of particle size
The size of the particles is of capital importance for the drug
to reach the final target, which is the lungs and especially the
small airways. The smaller the particle size, the highest depo-
sition on the airways and lungs is observed, and the largest the
particle size, the maximal deposition in the oropharynx and larynx
is. Particles with diameter <5 μm are most likely to be depos-
ited on the small airways, whereas particles with diameter >5 μm
are mainly deposited in the oropharynx and larynx.23 The par-
ticle sizes are related and dependent on the propellant used for
drug dissolution. Chlorofluorocarbons based metered-dose inhaler
(CFC-MDI) devices give larger particles and achieve lung de-
position of approximately 10%–20%,24 whereas hydrofluoroalkane
(HFA)-based devices give smaller particles, achieving 50% lung
deposition.25
Depending on the particle size, oropharyngeal deposition can
be up to 60% of delivered dose.12 The size of the particles varies
significantly among different ICS available for use in today’s
practice, as shown in Table 4.
Effect of type of ICS
The type (active drug or prodrug) of ICS is related to the inci-
dence of dysphonia, as prodrugs that are activated in the lungs
seem to produce less local side effects in the laryngopharynx.
Some ICS, including fluticasone propionate and budesonide, are
inhaled in their pharmacologically active form, whereas others,
like ciclesonide and beclomethasone dipropionate, are inhaled
as inactive compounds and are converted by lung esterases to
TABLE 3.
Prevalence of Dysphonia for Inhaled Corticosteroids Avail-
able Today
Dysphonia
Inhaled Corticosteroid Prevalence (%)
Fluticasone propionate16 3–8
Budesonide17 1–6
Beclomethasone dipropionate18,19 <2
Triamcinolone acetonide20 1–3
Ciclesonide21,22 0–2
 ARTICLE IN PRESS
Nikolaos Spantideas, et al Inhaled Corticosteroids and Voice Problems
TABLE 4.
Particle Size in Currently Available Inhaled
Corticosteroids26–30
Inhaled Corticosteroid Particle Size (μm)
Fluticasone propionate—DPI 6.5
Beclomethasone dipropionate—CFC 3.5
Budesonide—DPI 2.6
Fluticasone propionate—CSF-HFA 2.5
Beclomethasone dipropionate—HFA 1.1
Ciclesonide—HFA 1.1
their active metabolites. For example, ciclesonide is a parent com-
pound that is converted to the active metabolite des-ciclesonide
by the lungs’ esterases. The lack of esterases, practically, in the
area of the laryngopharynx, minimizes the incidence of local side
effects of the product in this area.31,32 This can explain why
ciclesonide and beclomethasone dipropionate are associated with
the lowest dysphonia prevalence (Table 3).
Effect of potency and dosage of ICS
The potency of the administered ICS and the dosage are both
significant factors related to the prevalence of dysphonia. The
potency of different ICS varies, with fluticasone propionate being
the most potent ICS available today. Fluticasone propionate is
nine times more potent than fluocinolone acetonide, two to five
times more potent than budesonide, and two times more potent
than beclomethasone dipropionate. Fluticasone propionate also
has a greater topical potency, longer tissue retention, and longer
elimination half-life.33–35 Clinical reports of dysphonia inci-
dence with fluticasone are limited, and clinical studies have
reported an increased risk of dysphonia with the use of fluticasone
propionate compared with beclomethasone dipropionate and with
pressurized MDIs compared with dry-powder inhalers (DPIs).34–37
A dose-dependent dysphonia has been reported in 34% of pa-
tients under treatment with beclomethasone dipropionate or
budesonide, both administered via pressurized MDI.38,39
In addition, the velocity of the delivered particles plays an im-
portant role in drug deposition. High-velocity systems are
associated with higher steroid deposition in the oropharyngeal
cavity and the larynx than do low velocity systems. Triamcino-
lone acetonide is delivered as a cloud-like spray of low velocity,
whereas beclomethasone dipropionate is delivered in a jet-like
high-velocity spray.40 On the other hand, budesonide in the form
of inhaled powder through a Turbohaler device achieves lung
deposition twice that of MDI.41
Effect of delivery system
The type of delivery system, in conjunction with patient tech-
nique, is another factor that can influence the proportion of an
inhaled dose that is deposited on the oropharynx and larynx, and
hence can influence the prevalence of dysphonia. The dose of
budesonide delivered to the lungs via a DPI was twice the dose
(32%) that reached the lungs when it was delivered via an MDI
(15%),42 and the incidence of local side effects was signifi-
cantly (P = 0.0001) lower when a DPI was used compared with
3
when an MDI was used.37 Both studies suggest lower oropha-
ryngeal deposition with the use of DPI. Unfortunately, this
comparison has been made only between the two delivery systems
(DPI and MDI-CFC) of budesonide, and there are no pub-
lished reports comparing local side effects associated with
different steroid preparations (ie, DPI vs MDI-HFA). Knowing
that HFA-based devices give smaller particles compared with
CFC-based devices, achieving the highest lung deposition and
the lowest dysphonia prevalence, it would be of great interest
to see a comparison between a DPI-based inhaler and an MDI-
HFA based inhaler with ciclesonide or beclomethasone
dipropionate.
The role of spacers in the prevalence of local side effects is
controversial. Oropharyngeal deposition of inhaled isotope-
labeled aerosols is decreased with the use of a spacer, whereas
the intrapulmonary deposition is increased.43 The use of a large-
volume spacer seems to reduce the local side effects and especially
candidiasis by reducing oropharyngeal deposition.44,45 Accord-
ing to other studies, voice problems were either more frequently
observed in patients using a spacer device46,47 or the use of a large-
volume spacing device did not appear to have an effect on the
occurrence of dysphonia.38 Spacer systems can decrease the
amount of oropharyngeal deposition of ICS and, hence, can de-
crease the incidence of candidiasis, but because of the increased
amount of inhalation drug available through the larynx, spacers
can increase the incidence of dysphonia, and this can explain
why they reduce the incidence of oropharyngeal candidiasis but
increase the incidence of dysphonia. The controversial find-
ings regarding the implication of spacer systems in the occurrence
of local side effects can be attributed either to the electrostatic
charge accumulation on the plastic walls of the device, which
may influence the amount of the delivered drug,48 or to poor
patient compliance due to the inconvenient bulk and size of some
spacers.
Inhaler technique is an important factor, because incorrect use
of inhalers is associated with poor asthma control.
Mechanism of dysphonia
Although local side effects are the most frequently described
adverse effects of ICS, their mechanism is poorly studied, con-
trary to the systemic side effects, the mechanisms of which have
been extensively studied and well documented. This is mainly
due to the fact that systemic side effects are considered more
serious than local side effects, thus attracting the interest of most
investigators. It is true that dysphonia is not a serious problem
for most of patients under ICS treatment, but for singers and other
professional voice users, dysphonia could be an unbearable
setback due to voice-regulating difficulties, reduction in pitch
range, and inability to speak or sing loudly.
Dysphonia associated with ICS therapy has been poorly in-
vestigated, and the origins of dysphonia may have multiple
confounding factors. The extent of dysphonia depends on the
vocal stress and the dyskinesia of muscles that control vocal cord
tension.
Most of the publications related to dysphonia have been gen-
erated by pulmonary physicians who may be more concerned
about other issues related to pulmonary functions such as airflow
 ARTICLE IN PRESS
4 Journal of Voice, Vol. ■■, No. ■■, 2016
findings, systemic absorption and, also, may be more aware of
ICS side effects. Few studies have been designed to investigate
voice changes with videostroboscopy or objective acoustic
analysis.15,39,40
Dysphonia can be, per se, a clinical symptom of severe asthma
as a result of inadequate airflow during expiration, and changes
in the quality of voice is the main complaint that prompts pa-
tients with asthma under ICS therapy to seek medical help.
Obstruction and increased resistance, which are more pro-
nounced during the expiration, can lead to ineffective vocal cord
vibration and hence to poor power supply for voice produc-
tion. Increased pause time between speech segments, fewer
syllables per breath, and larger percentage of time spent in non-
speech ventilatory activity have been found in patients with
asthma.49 In patients with inadequately controlled asthma, the
use of ICS can improve lung function and hence improve spe-
cific acoustic measures of voice that are presented as voice
problems.50 The relationship between gastroesophageal reflux and
especially of laryngopharyngeal reflux (LPR) and voice prob-
lems is well known.51 In addition, there is a high prevalence of
gastroesophageal reflux among patients with asthma, and many
cases of asthma episodes have their origin in this pathologic
phenomenon.52,53
It is likely that the steroids and not the constituents of pro-
pellant vehicle are responsible for the local side effects in the
laryngopharynx, although propellants and lubricants of MDIs
have been shown to have a proinflammatory local effect. This
can explain the difference in the incidence of local side effects
between MDIs and high- to medium- to high-resistance DPIs.
Low-resistance DPIs compared with high-resistance DPIs are
associated with higher frequency of local side effects because
of the greater oropharyngeal and larynx drug deposition. DPIs
contrary to MDIs contain lactose, which can trigger local aller-
gic reactions in patients with lactose intolerance, and additionally,
lactose may act as an irritant in the laryngopharyngeal mucosa.
Whatever the role of propellants and lubricants might be in the
appearance of local side effects, their contribution seems to be
minor, and steroids have been proven to play the key causal role
in dysphonia. Patients in therapy with inhaled beclomethasone
were five times more likely to have dysphonia than patients treated
with only the propellant.39 The incidence of hoarseness ranges
from 1% to 9% in patients under therapy with inhaled steroid
preparations compared with 0%–3% of patients receiving non-
steroidal inhalers.7
Although many studies have reported that dysphonia coex-
ists with a candida infection or that dysphonia can be secondary
to oropharyngeal candidiasis, it seems that the two conditions
are separate entities not directly related. In the case where dys-
phonia is secondary to candidiasis, the underlying mechanism
is easily understood, but the mechanism of dysphonia not as-
sociated with candidiasis remains a puzzle.
In the absence of candidiasis, steroid-induced myopathy appears
to be one of the main etiologic factors of ICS-induced dyspho-
nia, but other mechanisms certainly exist particularly with
combination inhalers.
Myopathy is a well-known side effect of both systemic and
local use of steroids. Steroid-induced myopathy affecting vocal
cord muscles may, in some cases, result in a bilateral adductor
fold deformity with bowing of the folds on phonation. Vocal
fold bowing, as characteristic abnormality, was first described
by Williams et al54 and was also confirmed later by other
investigators.55–57 An identical abnormality characterized as “phon-
asthenia” has been described as the cause of dysphonia in
myopathic disorders like myasthenia gravis and dystrophia
myotonica, where the phonatory muscles, the internal tensor
muscle group, are mainly affected.
Although the findings of Williams et al are generally ac-
cepted as a basic theory explaining the cause of dysphonia, it
seems that, at least in some cases, other factors can also be re-
sponsible, or can contribute to the appearance of dysphonia.
Abundant mucus on the vocal folds, preventing closure of the
glottis, has been identified as a cause of transitory dysphonia
as well as small vocal nodules58 and supraglottic hyperfunction.57
DelGaudio59 described a clinical entity characterized as steroid
inhaler laryngitis caused by fluticasone propionate and mani-
fested by dysphonia, throat clearing, voice misuse, and a sensation
of fullness. The laryngoscopic findings of steroid inhaler lar-
yngitis were mucosal edema, erythema, interarytenoid mucosal
thickening, and, in extreme cases, included leukoplakia, gran-
ulation, and candidiasis.
Because dysphonia could be a symptom of other serious dis-
eases, every case of persistent dysphonia has to be thoroughly
investigated for the exclusion of a serious underlying disease.
The possibility of existence or coexistence of LPR has also to
be examined as not only the symptoms are similar to that of LPR,
but also the laryngeal changes of steroid inhaled laryngitis, and
in these cases, the choice of the proper treatment is of signifi-
cant importance. During the examination of the larynx and
especially when functional evaluation of the vocal cords is per-
formed, one should be careful and ensure that anesthetic agents
used for laryngoscopy have not reached the larynx.
Management of ICS-induced dysphonia
For the time being, no evidence-based guidelines or even rec-
ommendations for the prevention or treatment of ICS-induced
dysphonia are available, because no study has been performed
yet to evaluate the value of either preventive measures or spe-
cific therapy. In 1997, the National Asthma Education and
Prevention Program (NAEPP) issued guidelines suggesting certain
clinical interventions to mitigate the risk of or to treat local side
effects.60 For dysphonia, NAEPP suggests (1) the use of a spacer
or holding chamber, (2) temporarily reduced dosage, and (3) rest
of vocal stress.
However, subsequent data from other investigators are con-
trary to what the NAEPP recommended by that time. For example,
dysphonia was more frequent in children using a spacer device.46,47
Practically all measures recommended by the NAEPP or other
investigators are poorly supported by clinical evidence and, in
fact, reflect personal investigators’ views and experience.
Rinsing of the mouth and the oropharynx by gargling with
water immediately after the use of inhaler is the most common
advice given to patients with asthma, aiming to remove, me-
chanically as much as possible, the locally deposited amount of
steroid in the mucosa. It has been shown that 56% of the emitted
 ARTICLE IN PRESS
Nikolaos Spantideas, et al Inhaled Corticosteroids and Voice Problems
aerosol dose is deposited in the oropharynx, and this may persist
in situ for up to 3 hours, and that a mouth rinse promptly can
remove 60% of this residue from the oropharynx.43 These data
provide indirect evidence of the prophylactic role of oral and
oropharyngeal rinse from ICS local side effects, but it remains
unanswered whether the removal of steroid residue from these
areas can also have a positive effect in the larynx, which water
cannot reach.
Practical recommendations to patients to minimize the risk
of dysphonia are listed below:
(1) Instruct patients in the proper use of inhalation
(2) Use the lowest effective dosage of ICS that keeps asthma
under control
(3) Rinse the mouth and oropharynx with water
(4) Use a spacer, wash it with tap water, and allow it to dry
after each use
(5) If dysphonia appears with the use of CFC-MDI, switch
to an HFA-MDI or a DPI
(6) If dysphonia persists, discontinue the use of the ICS.
After discontinuation of the inhaled steroids, dysphonia sub-
sides in a few days for the majority of the patients. For some
patients voice therapy may be valuable to address compensat-
ing voice habits that may have been established during the
dysphonia period and can prove harmful for the functional and
structural integrity of the vocal folds. It takes more time (in some
cases, months) for the larynx to return to its normal appearance.
It must be kept in mind that dysphonia due to laryngeal candi-
diasis will frequently persist despite the reduction or discontinuation
of the ICS, until the candidiasis is treated properly with antifungals.
If dysphonia persists for more than a week without any im-
provement despite ICS discontinuation, the diagnosis of ICS-
related dysphonia should be revised, and the patient should
be assessed thoroughly for an alternative cause of dysphonia,
like candidiasis, vocal fold nodules, and, more importantly,
laryngeal cancer.
CONCLUSIONS
Although ICS are widely used for the treatment of asthma and
chronic obstructive pulmonary disease, our understanding con-
cerning local side effects and especially their effect on voice
remains poor. Recent bibliography including the new ICS
ciclesonide has not improved our knowledge, and further in-
vestigation is needed to better assess the epidemiology,
predisposing factors, mechanisms, prevention, and treatment of
voice problems attributed to ICS use.
Statement
The purpose of our study was to review the current literature
by looking for new information that can improve our under-
standing in the prevention and management of ICS-related voice
problems.
What is already known?
Systemic side effects of ICS have been extensively studied and
are well documented. Local side effects, although can be clin-
5
ically significant, affecting not only patients’ compliance but also
their quality of life, have not attracted the same attention given
to systemic side effects.
Available ICS are not the same in many pharmacological
aspects, and these differences have to be considered when we
prescribe an ICS for a certain patient.
Reviews for local ICS use have been published but are “old”
and do not include recently published data as well as the data
from the newest member of the class ciclesonide.
What questions this paper answers (learning points)
Voice problems and especially dysphonia continue to remain the
main local side effect of ICS, despite the development of new
ICS molecules and new, sophisticated delivery systems.
Data from the most recently introduced ICS ciclesonide, not
available in previous reviews, indicate that ciclesonide has not
reduced the prevalence of ICS-related dysphonia, compared with
older drugs of the category.
Based on clinical data, no guidelines or recommendations are
available for the prevention or treatment of ICS-related dyspho-
nia. Suggestions, in the form of guidelines, issued in 1997 by
the NAEPP, are available only for clinical interventions to mit-
igate the risk of or to treat local side effects.
Although ICS is a well-established treatment for asthma and
chronic obstructive pulmonary disease management, investiga-
tion has to be continued to improve our understanding on
epidemiology, predisposing factors, mechanisms, prevention, and
treatment of voice problems attributed to ICS.
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