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Evaluation and treatment of subacute and chronic
cough in adults
AUTHORS: Steven E Weinberger, MD, MACP, FRCP, Kai Saukkonen, MD
SECTION EDITORS: Peter J Barnes, DM, DSc, FRCP, FRS, Talmadge E King, Jr, MD
DEPUTY EDITOR: Paul Dieffenbach, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2024.
This topic last updated: Dec 01, 2023.
INTRODUCTION
Prolonged cough can be a particularly bothersome symptom that precipitates many
outpatient visits to the clinician for treatment. Three categories of cough that are
distinguished based upon duration help with the approach to diagnosis and treatment
[1,2]:
● Acute cough, lasting less than three weeks
● Subacute cough, lasting between three and eight weeks
● Chronic cough, lasting more than eight weeks
Specific therapy for the most common causes of subacute and chronic cough and
nonspecific suppressive therapy for refractory cough will be reviewed here. The causes and
complications of subacute and chronic cough are discussed separately. (See "Causes and
epidemiology of subacute and chronic cough in adults".)
INITIAL EVALUATION
Algorithmic approach — There is general agreement that the initial approach to a patient
with subacute or chronic cough should follow a systematic algorithmic or tiered approach
to evaluation (
algorithm 1) [1-3]. If initial investigations fail to reveal the underlying
cause of chronic cough, several physician specialists (including internist or geriatrician,
otorhinolaryngologist, pulmonologist, allergist, and/or gastroenterologist) may need to be
involved to ensure effective diagnosis and therapy [4].
Exclude serious underlying processes — The initial evaluation (detailed history and
physical examination) should identify any danger signs that may indicate a diagnosis that
needs urgent attention [5]. Important danger signs that will need further evaluation with a
chest radiograph and possibly laboratory testing and computed tomography (CT) include
the following.
● Fevers, night sweats, or weight loss raises suspicion for chronic infection (eg,
tuberculosis, lung abscess) or rheumatic disease.
● Purulent sputum warrants evaluation for pulmonary and possibly sinus infection,
followed by treatment of identified infections.
● Hemoptysis can be an indicator of infection (eg, bronchiectasis, lung abscess,
tuberculosis), cancer (eg, lung, bronchus, or larynx), rheumatologic diseases, heart
failure, or foreign body inhalation.
● Dyspnea can be a clue to airway obstruction (laryngeal, tracheal, bronchial,
bronchiolar) or lung parenchymal disease. Other features such as waxing and waning
versus progressively worsening symptoms, particular triggers, associated
hoarseness, and focal abnormalities on examination can help focus the investigation.
Pulmonary function testing, including pre- and postbronchodilator testing, is
important to characterize the potential problem causing both dyspnea and cough.
● Immunosuppression can be a risk factor for infections such as tuberculosis and
should prompt a diligent and rapid evaluation for infection.
Initial steps — The most common causes of subacute cough are postinfectious cough and
exacerbation of underlying diseases such as asthma, chronic obstructive pulmonary
disease (COPD), and upper airway cough syndrome (UACS, commonly referred to as postnasal drip); the most common causes of chronic cough are asthma, gastroesophageal
reflux, UACS due to rhinosinus conditions, nonasthmatic eosinophilic bronchitis, and
combinations of these [2]. (See "Causes and epidemiology of subacute and chronic cough
in adults".)
● Clinical evaluation – The characteristics of cough should be determined: duration,
productive or nonproductive, associated symptoms (eg, rhinorrhea, nasal congestion,
sneeze, fever, sputum production, hemoptysis, dyspnea, weight loss, dysphonia,
dysphagia, peripheral edema), and prior episodes. Patients should be asked about
personal or family history of allergic rhinoconjunctivitis, tobacco use, vaping (eg,
electronic cigarettes), occupational exposures, and travel-related exposures.
Patients with prolonged cough after pertussis infection often report paroxysmal
cough, posttussive vomiting, inspiratory whooping, and absence of fever [6,7]. The
choice of further diagnostic tests (culture, polymerase chain reaction, serology)
depends upon the duration of cough, as discussed separately. (See "Pertussis
infection in adolescents and adults: Clinical manifestations and diagnosis" and
"Pertussis infection in adolescents and adults: Treatment and prevention".)
Physical examination should make note of nasal congestion, pharyngeal erythema,
tonsillar swelling, hoarseness, stridor, wheeze (particularly focal wheeze), crackles,
and other adventitious sounds (ie, rub).
● Tobacco use – Tobacco smoking is an irritant that can contribute to cough in addition
to being a risk factor for chronic bronchitis and lung cancer. A chest CT may be
needed to identify cancers missed by a chest radiograph. Smoking cessation should
be encouraged. Cough due to cigarette smoking will often improve with smoking
cessation, particularly in patients with early COPD. (See "Benefits and consequences
of smoking cessation", section on 'Pulmonary disease'.)
● Chest radiograph – Most adults with a cough >8 weeks in duration should have a
chest radiograph. Possible exceptions include patients in whom UACS or asthma
seems likely who can initially receive empiric therapy for the suspected diagnosis
[1,2]. Chest CT should not be obtained routinely for patients with a normal chest
examination and chest radiograph but may be required for further evaluation of
abnormalities on chest radiograph or potential suspected diagnoses that may be
missed on plain radiography (eg, bronchiectasis) [1]. The threshold to obtain a chest
CT for chronic cough may be lower in those patients with increased risk for lung
cancer, such as heavy smoking history.
● Pulmonary function testing – Spirometry pre- and postbronchodilator is commonly
obtained to evaluate possible asthma or COPD.
● Review medication list for potential culprit medications – Patients taking an
angiotensin-converting enzyme inhibitor should have a trial of medication
discontinuation for at least four weeks before extensive other testing for a cause of
chronic cough. Other medications that have been associated with chronic cough
include medications that worsen pre-existing gastroesophageal reflux, such as
calcium channel blockers and bisphosphonates. (See 'Angiotensin-converting enzyme
inhibitors' below and "Causes and epidemiology of subacute and chronic cough in
adults", section on 'ACE inhibitors and other medications'.)
EMPIRIC THERAPY FOR COMMON CAUSES
The most common causes of subacute and chronic cough should be addressed in an
organized fashion (
algorithm 1). Using a sequential, empiric approach to therapy has
diagnostic as well as therapeutic utility. It is usually best to follow one avenue of treatment
at a time rather than several branches of treatment simultaneously. If there is partial but
incomplete resolution of the cough with one line of therapy, then it is reasonable to add
therapy for the next most likely diagnostic possibility. (See "Causes and epidemiology of
subacute and chronic cough in adults", section on 'Causes of chronic cough'.)
On the other hand, some patients have more than one cause for chronic cough,
particularly those seen in a referral clinic. Among such individuals, cough only resolves
when all causes are successfully treated at the same time [8]. When more than one etiology
is suspected at the time of the initial evaluation and the cough is particularly disabling,
empiric treatment or evaluation of likely causes can be pursued simultaneously. Once
cough has resolved, treatments can be stopped sequentially, starting with the least likely to
have been helpful, observing the patient for any return of cough.
Asthma — Asthma is the cause of cough in approximately 25 to 30 percent of adult
nonsmokers with chronic cough [9-11]. Associated symptoms such as dyspnea and wheeze
are common, but cough can be present in isolation (so-called "cough variant asthma").
Evaluation should include spirometry pre- and postbronchodilator. If spirometry does not
demonstrate reversible airflow obstruction, but cough variant asthma is still suspected, it is
reasonable to pursue a trial of therapy or proceed to bronchoprovocation challenge (eg,
methacholine challenge test). Confirmation that cough is due to asthma requires a
beneficial response to therapy for asthma, as patients with asthma can also have cough
due to other causes [12]. (See "Causes and epidemiology of subacute and chronic cough in
adults", section on 'Asthma' and "Bronchoprovocation testing".)
Therapy for chronic cough as a unique symptom of asthma follows the same general
principles as initial therapy for asthma. While robust studies support a stepwise approach
to asthma treatment, studies of cough due to asthma are more limited. (See "An overview
of asthma management".)
● Inhaled glucocorticoids – Similar to therapy for mild persistent or moderate asthma,
inhaled glucocorticoids (GCs) are the mainstay of therapy for cough due to asthma
[9]. We typically start with a low or medium dose of inhaled GC (
table 1). If the
cough is unimproved after three to four weeks, we increase the dose of inhaled GC or
add a leukotriene receptor antagonist.
Blood and sputum eosinophil cell counts and fractional exhaled nitric oxide (FENO)
measurement have been used in patients with asthma as measures of airway
inflammation [9,13-15]. This has led some to suggest that such tests can be used by
the clinician in evaluating whether patients with a suboptimal response to therapy for
cough variant asthma would benefit from an escalation in their anti-inflammatory
asthma treatment [1,16]. Further study of this approach is needed before widespread
implementation. (See "Exhaled nitric oxide analysis and applications".)
Inhaled GCs have well-documented benefit in asthma, although studies often do not
include cough as an outcome. A systematic review identified four randomized trials
(277 participants; study duration 4 to 52 weeks) that demonstrated a reduction in
cough score with inhaled GC [17].
● Leukotriene receptor antagonists (LTRAs) – The LTRAs are an alternative initial
therapy for patients who wish to avoid GCs or for patients who have not responded to
GCs and need add-on therapy. The LTRAs improve cough due to asthma compared
with placebo based on limited data [9,18]. Addition of an LTRA to inhaled GC has been
compared with continuing the inhaled GC in a small, randomized trial of patients with
cough variant asthma (22 participants) who were refractory to treatment with inhaled
bronchodilators and inhaled GCs; therapy with an LTRA for two or four weeks resulted
in decreased cough scores compared with placebo [19]. (See "Antileukotriene agents
in the management of asthma".)
● Combination inhaled GC and long-acting beta-agonist (LABA) – While combination
inhaled GC-LABA has a well-established place in the treatment of asthma, clinical trials
to assess the role in chronic cough due to asthma are lacking (
table 2) [9].
● Oral glucocorticoids for disabling cough – For patients who are disabled by their
cough, a short (one to two week) course of oral prednisone can be given, generally
with excellent results [17,20]. Once the patient has improved, prednisone is
discontinued and maintenance therapy with inhaled GCs is continued.
Nonasthmatic eosinophilic bronchitis — Nonasthmatic eosinophilic bronchitis (NAEB)
accounts for approximately 10 to 30 percent of patients with chronic cough referred for
specialist evaluation [9,21]. Cough may be productive or nonproductive [22]. NAEB should
be suspected in patients with atopy, eosinophilic airway inflammation, and when cough
improves with inhaled GC, but in the absence of variable airway obstruction or airway
hyperresponsiveness [9]. Exposure to potential occupational allergens (eg, isocyanates,
flour) may be an additional clue [9,23,24]. The role of measurement of FENO in the
diagnosis of NAEB remains unclear [14,25,26]. (See "Causes and epidemiology of subacute
and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)
For patients with suspected NAEB, we suggest treatment with inhaled GCs based on
observational data and guideline recommendations [9,27,28]. In a systematic review, three
randomized trials (56 participants) found improvement in the cough visual analog scale or
cough frequency score with inhaled GC compared with placebo [9,29]. Severity of cough
and sensitivity to capsaicin-induced cough both improved. The optimal dose and duration
of therapy have not been determined. We typically start with a low-to-medium dose inhaled
GC, such as budesonide 180 to 360 mcg or fluticasone 44 to 110 mcg twice a day. Limited
data support continuing inhaled GC for at least two months to reduce the risk of relapse
[29].
Small randomized, open-label trials have examined addition of montelukast in NAEB for
patients with insufficient improvement in cough with low- or medium-dose inhaled GC
[9,30,31]. Addition of montelukast improved cough relative to continuing budesonide 400
mcg/day [31] and had a similar improvement in cough compared with doubling the dose of
budesonide from 400 mcg/day to 800 mcg/day [30].
Rarely, oral GCs are needed for refractory symptoms. When an inciting agent (eg, inhaled
or occupational allergen) is identified, further exposure should be avoided [9,23,24].
NAEB usually has a benign course and resolves with inhaled GC. A subgroup of patients will
have relapses, and among these some will develop small airways dysfunction.
Evidence in favor of the use of inhaled corticosteroids in patients with chronic cough and
without asthma includes the following:
● In a systematic review (eight studies, 570 participants), inhaled GC treatment led to a
significant reduction in cough score, but the heterogeneity of the studies precluded a
meta-analysis [32].
● In a randomized trial, 44 patients with chronic cough (average duration 20 weeks)
were treated with high-dose beclomethasone (1500 mcg/day), while 20 received
placebo [33]. After two weeks, 82 percent of the beclomethasone group and 12
percent of the placebo group had complete resolution of cough. Response to
beclomethasone did not correlate with atopy or bronchial hyperresponsiveness.
● In one study, for example, there was a suggestion that more patients with chronic
cough responded to inhaled GCs (beclomethasone 2000 mcg/day) than to placebo,
although overall mean daily cough scores were not significantly different in the two
groups [34].
A potential reason for variable responses to inhaled GCs may be related to the dose used.
One study that showed no benefit to inhaled GCs in patients with chronic nonasthmatic
cough used a low-dose of inhaled GC (beclomethasone 400 mcg/day) [35]. Another
potential reason for inconsistent results may reflect variable numbers of patients with
nonasthmatic eosinophilic bronchitis in the study population.
Upper airway cough syndrome — Upper airway cough syndrome (UACS; previously
known as postnasal drip syndrome but revised to include all upper airway abnormalities
associated with cough) has a number of different etiologies, including allergic, nonallergic,
and vasomotor rhinitis; acute nasopharyngitis; and sinusitis [36]. However, the mechanism
by which UACS would cause chronic cough remains unclear. One possibility is that UACS
acts as a trigger for cough in patients with cough hypersensitivity [1].
Practice parameters for the diagnosis and management of rhinitis have been published
[37]. These guidelines describe high-quality evidence that intranasal GCs are the most
effective therapy for symptoms of allergic rhinitis (
table 3). In addition, intranasal GCs
are effective for several types of nonallergic rhinitis, including nonallergic rhinitis with
eosinophilia and vasomotor rhinitis. For patients with cough due to allergic rhinitis,
intranasal GCs are generally effective in reducing cough within the first few days but may
take up to two weeks to achieve maximal effect. If the patient responds, therapy is
continued until pollen or ambient allergen counts are low and/or exposure to possible
inciting antigens is minimized [38]. When an environmental precipitant for allergic rhinitis
can be identified, exposure to this precipitant should be eliminated if possible. (See
"Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis".)
Only a few trials have evaluated the effect of oral nonsedating antihistamines on cough
associated with seasonal allergic rhinitis, asthma, or atopy, and results are mixed [39].
Additional therapies for allergic and nonallergic rhinitis and chronic rhinosinusitis are
reviewed in detail separately. (See "Pharmacotherapy of allergic rhinitis" and "Chronic
nonallergic rhinitis" and "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations
and diagnosis" and "Chronic rhinosinusitis without nasal polyposis: Management and
prognosis" and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
For patients with suspected nonallergic UACS, we suggest a trial of therapy with intranasal
administration of one or more of the following: azelastine, glucocorticoid, or ipratropium
[37]. However, azelastine may cause somnolence even with intranasal use. Intranasal
ipratropium significantly reduces the rhinorrhea associated with perennial nonallergic
rhinitis and has few side effects [40]. (See "Chronic nonallergic rhinitis", section on 'Efficacy
of antihistamine sprays' and "Chronic nonallergic rhinitis", section on 'Prominent
rhinorrhea without other symptoms'.)
Lack of improvement in cough after one to two weeks of empiric therapy for UACS is
evidence that UACS due to allergic or nonallergic rhinitis is not the cause of the cough.
However, in the presence of nasal symptoms or signs, a sinus CT scan could be performed
before completely excluding the possibility of UACS as a cause of cough.
The four cardinal symptoms of chronic rhinosinusitis are anterior and/or posterior nasal
mucopurulent drainage, nasal obstruction/nasal blockage/congestion, facial pain and/or
fullness, and reduced or absent sense of smell. A sinus CT scan or nasal endoscopy is
needed to confirm the diagnosis. The treatment of chronic rhinosinusitis is discussed
separately. (See "Chronic rhinosinusitis without nasal polyposis: Management and
prognosis" and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis".)
Gastroesophageal reflux — Cough due to gastroesophageal reflux disease (GERD)
generally responds to a regimen that includes lifestyle modifications and acid suppression
medication [12,41-43]:
Lifestyle modifications — The evidence in favor of lifestyle modifications to reduce or
prevent GERD and thereby treat cough is limited [12,41]. The following interventions are
based on the lifestyle modifications that are suggested for the routine management of
GERD:
● Weight loss for patients who are overweight
● Elevation of the head of the bed (eg, place six- to eight-inch blocks under the legs at
the head of the bed or a Styrofoam wedge under the mattress)
● Cessation of smoking
● Avoidance of reflux-inducing foods (eg, fatty foods, chocolate, alcohol, caffeinated
beverages)
● Avoidance of very acidic beverages (eg, carbonated beverages, red wine, orange juice)
● Avoidance of meals for two to three hours before lying down (except for medications)
Lifestyle modification in the management of GERD is discussed separately. (See "Medical
management of gastroesophageal reflux disease in adults", section on 'Lifestyle and
dietary modification'.)
Acid-suppression medication — For patients with chronic cough and symptoms of reflux
(eg, heartburn, regurgitation), we suggest a trial of acid suppression medication combined
with lifestyle modifications [12]. However, regimens proven effective in the management of
GERD may not necessarily be the optimum regimens for cough due to GERD. A metaanalysis of randomized trials of medical GERD interventions for cough showed that while
such therapy indeed has some effect in adults, the frequency is less universal than often
suggested in consensus guidelines [44]. A possible explanation for failure to improve
despite acid suppression is that of nonacidic reflux [12].
We suggest using an empiric trial of a proton pump inhibitor (PPI) at a moderate dose (eg,
omeprazole 40 mg once daily in the morning). This is based on the evidence that therapy
with a PPI is more effective than H2 antagonist treatment [45]. In addition, as it may take
up to eight weeks, and sometimes several months, to yield optimal improvement in cough,
it seems reasonable to start with the more effective choice [12,41].
For patients whose cough does not improve after one to two months of empiric therapy,
we proceed to 24-hour esophageal pH probe monitoring. Results that suggest cough due
to GERD include an abnormal amount of time with an esophageal pH less than four and
cough occurring within a few minutes of reflux events. Multichannel intraluminal
impedance (MII) monitoring, which is increasingly available, may help identify patients with
cough from nonacidic reflux. Due to its higher availability in some practice locations, a
barium esophagram may be a helpful alternative in selected patients, especially if there is
concern for hiatal hernia, esophageal stricture, or esophageal dysmotility. (See "Clinical
manifestations and diagnosis of gastroesophageal reflux in adults" and "Esophageal
multichannel intraluminal impedance testing".)
Other therapies — Other therapies are less well validated:
● Prokinetic therapy – The addition of prokinetic therapy such as metoclopramide may
be beneficial in patients with nonacidic reflux or may add to the effectiveness of acid
suppression therapy in cough due to acidic reflux. However, supportive data are weak,
and patients placed on metoclopramide should be followed for the possible
development of extrapyramidal side effects (eg, rigidity, bradykinesia, tremor, and
restlessness).
● Antireflux surgery – The role of antireflux surgery to relieve extraesophageal
symptoms related to GERD is unclear [46-48]. We reserve laparoscopic or open Nissen
fundoplication for the small number of patients with chronic cough who have
objectively documented gastroesophageal or laryngopharyngeal reflux disease that is
refractory to medical measures. In a meta-analysis of 25 studies, a variable proportion
of patients (15 to 95 percent) experienced improvement in extraesophageal
symptoms (including but not limited to cough) after surgical fundoplication [48]. The
studies were all nonrandomized and used variable selection criteria. In a subsequent
observational study of 16 patients with nonacid reflux by MII, antireflux surgical
procedures resulted in cough resolution in 13 and cough improvement in 3 patients
[47]. A meta-analysis of the results of antireflux surgery in GERD with respiratory
symptoms found that different surgical techniques or a combination of them led to
cough relief in 83.4 percent of patients [49]. Nissen fundoplication has been reported
to result in complete resolution of chronic cough in approximately three-fourths of
patients [50,51]. (See "Medical management of gastroesophageal reflux disease in
adults" and "Surgical treatment of gastroesophageal reflux in adults".)
Persistent cough after upper respiratory tract infection — Cough following an upper
respiratory tract infection may be due to postnasal drip or a direct effect of the viral
infection to increase bronchial reactivity or cough receptor sensitivity. For patients in whom
postnasal drip (ie, UACS) seems to be contributing to the prolonged cough following a viral
upper respiratory tract infection, the treatment follows that for nonallergic UACS, as
described above [52]. (See 'Upper airway cough syndrome' above.)
First-generation antihistamines (eg, brompheniramine, chlorpheniramine, clemastine,
doxylamine), although more sedating, have stronger anticholinergic effects than secondgeneration agents (eg, cetirizine, loratadine, fexofenadine) and therefore may be superior
for treating cough secondary to the common cold [36,52-55].
Some patients with postviral cough without UACS have transient airway hyperreactivity
that is associated with a positive methacholine challenge test in research studies [20].
Albuterol may be of benefit in such patients, although data are limited. Alternatively, in
patients with postviral cough who have no evidence of airway hyperreactivity, inhaled
ipratropium has been reported to produce improvement in the cough [56]. Among 14 such
patients in one report, 12 had clinical improvement with administration of 320 mcg of
inhaled ipratropium, and of these, five had complete resolution of cough [57].
Infection due to Bordetella pertussis (whooping cough) may be responsible for
approximately 20 percent of cases of prolonged cough in adolescents and adults. It is
therefore important to consider this diagnosis in the patient with an apparent
postinfectious cough, especially if cough is associated with an inspiratory whooping sound
or posttussive vomiting [6,56,58]. A systematic review did not find evidence that
antihistamines (diphenhydramine) or beta adrenergic agonists alleviated cough due to
pertussis [59]. For the majority of patients, antibiotic therapy does not reduce the duration
of symptoms but may be appropriate in certain patients to reduce disease transmission, as
discussed separately. (See "Pertussis infection in adolescents and adults: Treatment and
prevention".)
Angiotensin-converting enzyme inhibitors — For patients who develop a chronic cough
during treatment with an angiotensin-converting enzyme (ACE) inhibitor, the treatment of
choice is withdrawal of the ACE inhibitor [1]. The cough will typically resolve within one to
four weeks after stopping the ACE inhibitor but occasionally will last up to three months
[60]. Reinitiation of the same or another ACE inhibitor usually leads to recurrent cough.
(See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II
receptor blockers", section on 'Cough'.)
Angiotensin II receptor antagonists are alternative antihypertensive agents that act via a
related mechanism but do not affect kinin metabolism. They are not associated with an
increased incidence of cough, even in patients who had previously had an ACE inhibitorinduced cough [1,60,61]. Angiotensin II receptor antagonists also do not increase cough or
bronchial hyperresponsiveness in symptomatic asthmatics [62].
UNEXPLAINED CHRONIC COUGH
General approach — A portion of patients experience a cough that persists for more than
eight weeks and is not adequately treated despite systematic assessment and empiric
therapies (
algorithm 1) [63]. (See 'Empiric therapy for common causes' above.)
For patients whose cough remains unexplained despite thorough evaluation and empiric
trials of specific therapies, the next step includes nonpharmacologic therapy such as
speech therapy and treatment with nonspecific antitussive agents.
Several studies have noted a substantial minority of patients who do not respond or
respond inadequately to specific interventions and treatments [16,64,65]. Rarely, these
patients have another underlying airway, parenchymal disease, or extrapulmonary vagal
irritation as the cause of their cough; a careful history, physical examination, and chest
imaging should be performed to ensure these causes are not overlooked. (See 'Exclude
serious underlying processes' above and "Causes and epidemiology of subacute and
chronic cough in adults", section on 'Causes of acute cough'.)
More often, however, they have what may be called "unexplained chronic cough," "chronic
idiopathic cough," "neurogenic cough," or "cough hypersensitivity syndrome" [66]. This
disorder may in part be due to an abnormally sensitive cough reflex, perhaps in the form of
heightened sensory nerve receptor sensitivity due to alterations in receptor ion channels,
such as transient receptor potential vanilloid 1 or transient receptor potential ankyrin 1 [6670]. (See "Neuronal control of the airways".)
Research is underway to develop cough receptor antagonists, but until such specific
receptor antagonists are available, the nonspecific cough remedies are reasonable choices
for the management of disabling chronic cough that has not responded to specific therapy
[71-74]. (See 'Investigational agents' below.)
Ipratropium — The muscarinic antagonist (anticholinergic agent) ipratropium has been
proposed to have at least two potential mechanisms by which it may alleviate cough when
orally inhaled [73]:
● Blocking the efferent limb of the cough reflex
● Decreasing stimulation of cough receptors by alteration of mucociliary factors
As mentioned above, a beneficial effect of ipratropium has been noted in a small group of
patients with persistent cough following upper respiratory tract infection [57], although
this observation has not been replicated [63]. The usual dose of ipratropium is two
inhalations by metered dose inhaler four times a day. (See 'Persistent cough after upper
respiratory tract infection' above.)
Nonpharmacologic interventions — Modalities such as speech therapy, breathing
exercises, cough suppression techniques, and patient counseling have been tried in the
management of chronic cough [75-78]. A systematic review reported that studies of such
interventions showed improved cough severity and frequency, but few of them used
validated cough measurement tools [77]. While the robustness of these findings is limited,
in accordance with guidelines, we suggest a therapeutic trial of multimodality speech
therapy in motivated patients with unexplained chronic cough who have not responded to
an algorithmic approach, such as the one described above (
algorithm 1).
Nonspecific antitussive agents — The role of nonspecific antitussive agents in the
management of chronic cough remains unclear. Many patients have already tried home
remedies such as throat lozenges, hot tea, and honey without success and are eager for
symptomatic relief while the evaluation proceeds. We typically try dextromethorphan or
benzonatate as nonspecific agents that are helpful for some patients with unexplained
chronic cough before using more sedating agents. Definitive evidence of benefit is lacking
for these nonspecific agents.
Dextromethorphan — Dextromethorphan is probably the most common nonopioid
agent used for cough. It decreases the sensitivity of cough receptors and is an N-methyl-Daspartate receptor antagonist. We suggest a therapeutic trial of this agent in patients with
chronic refractory cough whether due to an unknown mechanism or a cause such as lung
cancer that is not otherwise remediable [1]. The usual dose is extended release 60 mg
orally twice a day. Dextromethorphan is also available as a component of over-the-counter
cough syrups.
In a systematic review that analyzed studies of dextromethorphan versus placebo, the
quality of the studies was generally felt to be fair to poor [79]. Nonetheless,
dextromethorphan was found to modestly decrease cough severity (five studies) and
frequency (two studies).
Studies that have compared codeine and dextromethorphan have shown variable results,
but the number of subjects in each study is small [79]. (See 'Codeine' below.)
● In a crossover study of 16 patients with chronic, stable cough, codeine (20 mg) and
dextromethorphan (20 mg) were equally effective in reducing cough frequency [80].
However, because cough intensity was lowered more by dextromethorphan than by
codeine, the majority of patients preferred the use of dextromethorphan.
● An observational study of eight patients demonstrated equal antitussive effects from
codeine 30 mg and dextromethorphan 60 mg, each of which was superior to
dextromethorphan 30 mg and to placebo [81].
Benzonatate — Benzonatate is a peripherally acting antitussive agent that presumably
acts by anesthetizing stretch receptors in the lungs and pleura. For patients with mild
chronic cough, a trial of benzonatate, usually in addition to or after a failed trial of
dextromethorphan, is reasonable, although often of limited benefit. The usual dose is 100
to 200 mg orally three times a day. One report showed that a combination of 200 mg of
benzonatate and 600 mg of guaifenesin significantly suppressed capsaicin-induced cough
compared with guaifenesin alone [82].
There are case reports of effective use of benzonatate in the palliative treatment of cough
in advanced cancer [83]. It may be tried as an adjunctive treatment to narcotics in such
cases.
Accidental ingestion of benzonatate and fatal overdoses have been reported in children
<10 years of age [84]. Signs and symptoms of overdose (restlessness, tremors, convulsion,
coma, cardiac arrest) may occur within 15 to 20 minutes after ingestion.
Guaifenesin — Proposed mechanisms by which guaifenesin might reduce cough include
decreasing the viscosity of airway mucus and inhibiting cough reflex sensitivity in patients
with transiently hypersensitive cough receptors. While individual patients report benefit,
formal study is lacking. The dose of extended-release guaifenesin is 600 to 1200 mg every
12 hours as needed. Possible adverse side effects include nausea, abdominal pain, and
dizziness.
Nebulized lidocaine — Nebulized lidocaine may reduce the frequency of cough, but its
use is generally limited by adverse effects, particularly unpleasant taste and symptomatic
aspiration.
In an observational study, nebulized lidocaine (3 mL of 4 percent lidocaine [120 mg]) was
prescribed two or three times daily to patients with chronic cough, with the option to
increase the dose (to 5 mL [200 mg]) if numbness of the throat lasted less than 20 minutes
[85]. Among 99 patients who responded to a follow-up questionnaire, cough severity
scores decreased, generally by two weeks. Only 34 percent of patients reported being
satisfied with the treatment and less than 30 percent chose to continue it beyond three
months. Adverse events, such as unpleasant taste, throat irritation, and choking on water
or food, were reported by 43 percent.
Gabapentin and pregabalin — Gabapentin and pregabalin, gamma aminobutyric acid
analogs that bind to the voltage-gated calcium channels and inhibit neurotransmitter
release, are thought to ameliorate chronic neuropathic pain via a central mechanism [5,86].
It is hypothesized that these agents may also act to reduce chronic cough via a central
mechanism. Neither medication is approved for use in chronic cough, although gabapentin
is recommended for unexplained chronic cough in the American College of Chest
Physicians (ACCP) guidelines [63]. The supportive data for the use of pregabalin were
published after the ACCP guidelines were prepared. These agents may be helpful in
patients with cough refractory to nonspecific antitussive therapy, particularly those who
wish to avoid or do not tolerate opioid agents.
● Gabapentin – To reduce adverse effects of sedation and dizziness, gabapentin is
initiated at a low dose (300 mg once a day) with gradual increases until cough relief,
dose-limiting adverse effects, or a dose of 1800 mg a day in two divided doses is
achieved [63]. For patients who have significant somnolence with 300 mg capsules,
the 100 mg capsule may provide benefit without somnolence. There is a liquid
formulation, as well, for the occasional patient who would benefit from even lower
doses. Other than somnolence, adverse effects may include diarrhea, nausea,
emotional lability, nystagmus, tremor, weakness, and peripheral edema. After six
months, therapy should be reassessed to determine whether gabapentin is still
needed to control cough [63].
The evidence in favor of using gabapentin for chronic cough includes a randomized
trial in which 62 patients with refractory chronic cough were assigned to receive
either gabapentin (in doses up to 1800 mg daily) or placebo for 10 weeks [87]. Coughspecific quality-of-life measures were significantly improved in the gabapentin group
(between group difference in Leicester Cough Questionnaire during treatment period
1.80, 95% CI 0.56-3.04; number needed to treat 4). Additionally, cough appeared to
worsen upon cessation of the gabapentin. Side effects, chiefly nausea and fatigue,
occurred in over 30 percent of those receiving gabapentin and were often managed
by dose reduction.
● Pregabalin – As with gabapentin, pregabalin is initiated at a low dose and gradually
increased over a week to 300 mg/day to minimize sedation and dizziness.
The evidence for using pregabalin in chronic cough comes from a randomized trial in
which 40 adults with chronic refractory cough (>8 weeks duration) were assigned to
take pregabalin 300 mg daily with speech pathology treatment (SPT) or placebo with
SPT for 14 weeks [75]. Baseline cough frequency was 24 coughs/hour in both groups;
spirometry was normal. Both groups experienced a reduction in cough severity by
visual analog scale (VAS), cough frequency, and Leicester Cough Questionnaire quality
of life (QOL). The pregabalin group experienced greater improvement in VAS (mean
difference 25.1, 95% CI 10.6-39.6) and in QOL (mean difference 3.5, 95% CI 1.1-5.8).
Adverse effects in the pregabalin group included dizziness in 45 percent and cognitive
changes in 30 percent, although these did not lead to discontinuation of the study
drug. Four weeks after withdrawal of study medication, there was no deterioration in
symptom control.
Opiates — Opiates are thought to suppress cough via an action on the central cough
center and may have efficacy in patients with chronic refractory cough whether due to an
unknown mechanism or a cause such as lung cancer that does not respond to a trial of
typical nonspecific antitussive agents (eg, dextromethorphan and benzonatate) [1]. Our
authors typically prefer other methods, reserving opiate therapies for occasional timelimited use or as palliative therapy for advanced interstitial lung disease or pulmonary
malignancy.
For patients in whom nonopiate options are ineffective, and they are willing to accept the
risk of opiate-related adverse effects, a limited trial (typically four to six weeks) of longacting morphine or codeine may be helpful by allowing mucosal healing from repetitive
cough injury. We discontinue therapy promptly in those who do not have symptomatic
improvement over the first two weeks. Because of concern about opiate dependence,
longer-term use should be limited to patients for whom palliation of symptoms due to
serious disease (eg, intrathoracic malignancy) outweighs the risk of opiate dependence.
(See "Palliative care: Overview of cough, stridor, and hemoptysis in adults", section on
'Symptom-directed treatment'.)
Morphine — Sustained-release morphine reduced cough within a week in approximately
half of patients with chronic cough in one clinical trial of patients with refractory chronic
cough [1]. Low doses of long-acting formulations are preferred to allow a steady
antitussive effect. We begin with the lowest extended-release or sustained-release dose
available (typically 10 to 15 mg once or twice daily, depending on preparation and
availability), with cautious escalation to no more than 15 mg twice daily for those who
tolerate the lower dose and have minimal relief after the first week. Patients should be
warned about potential somnolence and constipation. (See "Prevention and management
of side effects in patients receiving opioids for chronic pain".)
In a double-blind crossover trial, 27 patients who had a persistent cough of greater than
three months duration and had failed specific treatment were randomly assigned to
receive slow-release morphine (5 mg twice daily) or placebo for four weeks [88]. Morphine
reduced daily cough severity scores (Leicester Cough Questionnaire) by 40 percent,
although the cough reflex was unaltered. Among those patients who did not respond to 5
mg twice daily, improvement was detected when the dose was increased to 10 mg twice
daily.
Codeine — Codeine, a pro-drug metabolized to morphine in the liver, is the traditional
opiate used for cough, but morphine likely has a less variable response and is now
preferred by some guidelines [1]. Despite widespread use, evidence regarding codeine’s
efficacy for chronic cough is limited, with variable patient responses observed [79-81,8991]. When prescribing codeine, the usual initial dose is 30 mg every four to six hours as
needed and increased to 60 mg if the lower dose is insufficient. We caution patients about
potential adverse effects such as somnolence and constipation. (See "Prevention and
management of side effects in patients receiving opioids for chronic pain".)
In a systematic review, codeine was more effective than placebo in reducing the severity
and frequency of cough, although the quality of the available studies was judged to be fair
or poor [79]. In a randomized trial, 64 subjects with subacute cough were randomly
assigned to receive codeine (30 mg twice daily), an investigational antitussive, or placebo
[90]. Codeine reduced cough counts relative to placebo, but the effect was not statistically
significant. However, the dose of codeine was low, as the usual dosing in adults is 30 to 60
mg every four hours. In a brief intervention study, 21 patients with cough due to chronic
bronchitis were randomly assigned to codeine 60 mg twice a day or placebo for a one-day
study [89]. No significant difference was noted in cough counts or subjective cough scores
between the study groups, although the study size was small and the dose of codeine low.
Investigational agents
Work is underway to identify treatments for patients who have a chronic cough without a
remediable cause despite careful investigation (
algorithm 1) and empiric trials of
therapy.
P2X3 antagonists — Based on laboratory studies, increased sensitivity of P2X3 receptors
on the airway sensory nerve fibers (eg, vagal afferent C fibers) is a potential cause of
refractory cough [92]. Early studies of some of these agents showed efficacy but high rates
of taste disturbance [93,94]. Multiple P2X3 antagonists are undergoing development as
potential therapies for chronic cough [95,96].
● Gefapixant – Gefapixant is the most well-studied P2X3 antagonist. In a meta-analysis
of six trials including 2472 patients, gefapixant 45 mg twice daily reduced 24-hour
cough frequency to a greater extent than placebo (66 versus 50 percent reduction
[mean difference 16 percent, 95% CI 9.4-22] [97], accompanied by a modest
improvement in cough-specific quality of life. Nearly one-third of patients experienced
taste-related adverse events, 30 percent of which were serious enough to lead to
discontinuation. These data reflect moderate certainty that gefapixant yields
improvement in cough outcomes despite the robust placebo effect seen in these
trials. Unfortunately, such improvements come with a significant risk of serious taste
disturbance.
● Sivopixant – Sivopixant is a P2X3 antagonist designed to be more selective for P2X3
receptors to avoid taste disturbance side effects. In a cross-over trial of 30 subjects
with refractory cough, cough counts decreased by 53 percent with sivopixant
compared with 31 percent with placebo (a 31 percent relative difference) [98]. Mild
taste disturbance occurred in only two patients (6.5 percent).
Therapies without benefit
Macrolide antibiotics — Patients with chronic cough tend to have increased levels of
neutrophils in their induced sputum. This led to the hypothesis that macrolide antibiotics,
which have antineutrophil effects independent of antimicrobial effects, might be
efficacious in treating chronic cough. However, trials with azithromycin and erythromycin
have not demonstrated benefit in cough frequency or severity [99,100].
COMPLICATIONS
During vigorous coughing, intrathoracic pressures may reach 300 mmHg and expiratory
velocities approach 500 miles per hour [101]. While these pressures and velocities are
responsible for the beneficial effects of cough on mucus clearance, they are also
responsible for many of the complications of cough, including exhaustion, selfconsciousness, insomnia, headache, dizziness, musculoskeletal pain, hoarseness, excessive
perspiration, urinary incontinence, and concern that "something is wrong" (
table 4)
[102,103]. Cough-induced rib fractures are another painful and potentially serious
complication of chronic cough. Fractures often involve multiple ribs, particularly ribs five
through seven. Females with decreased bone density are at the greatest risk of this
complication; however, fractures can occur in patients with normal bone density as well
[104]. Paroxysmal or violent coughing, such as that in patients with pertussis or
tracheomalacia, may even induce syncope.
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions
around the world are provided separately. (See "Society guideline links: Subacute and
chronic cough in adults".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have
about a given condition. These articles are best for patients who want a general overview
and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces
are longer, more sophisticated, and more detailed. These articles are written at the 10th to
12th grade reading level and are best for patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to
print or e-mail these topics to your patients. (You can also locate patient education articles
on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
● Basics topic (see "Patient education: Cough in adults (The Basics)")
● Beyond the Basics topic (see "Patient education: Chronic cough in adults (Beyond the
Basics)")
SUMMARY AND RECOMMENDATIONS
● Excluding serious underlying processes – The initial evaluation (detailed history and
physical examination) should identify any danger signs (eg, fever, night sweats,
purulent sputum, dyspnea, hemoptysis) that may indicate a diagnosis that needs
urgent attention. (See 'Exclude serious underlying processes' above.)
● Initial evaluation – The characteristics of cough should be determined: duration,
productive or nonproductive, associated symptoms, and prior episodes. Particular
attention should be paid to a postinfectious etiology and cough related to tobacco
use. In adult patients whose cough has lasted more than eight weeks, a chest
radiograph is typically performed as part of the initial evaluation to rule out a
potential etiology that would require additional evaluation or focused treatment. (See
"Causes and epidemiology of subacute and chronic cough in adults", section on 'Lung
cancer'.)
● Diagnostic trial of therapy for common causes – The best approach to the
evaluation of chronic cough (present for more than eight weeks) is to use a systematic
combination of empiric therapy and objective testing (
algorithm 1). Therapy aimed
at a particular etiology should be selected based on clues from the initial evaluation.
(See 'Empiric therapy for common causes' above.)
• Asthma – When asthma is the suspected cause, spirometry pre- and
postbronchodilator should be performed. In patients with subacute or chronic
cough due to suspected asthma, we recommend regular use of an inhaled
glucocorticoid (GC) and as-needed use of an inhaled bronchodilator or combined
inhaled GC-formoterol, rather than use of an inhaled bronchodilator alone (Grade
1B). Combination therapy with a leukotriene receptor antagonist and an asneeded, short-acting inhaled bronchodilator is a reasonable alternative. (See
'Asthma' above.)
• Nonasthmatic eosinophilic bronchitis (NAEB) – NAEB accounts for
approximately 10 to 30 percent of patients with chronic cough referred for
specialist evaluation. NAEB should be suspected in patients with atopy,
eosinophilic airway inflammation, and potential exposure to occupational
allergens but is often diagnosed empirically based on improvement with the use of
inhaled glucocorticoids in the absence of airway obstruction or bronchodilator
responsiveness. For patients undergoing a treatment trial for suspected NAEB, we
suggest the use of low- to medium-dose inhaled glucocorticoids rather than highdose inhaled glucocorticoids or systemic therapy (Grade 2C). A partial response
suggests potential benefit from a trial of dose escalation or add-on leukotriene
modifiers. We continue inhaled glucocorticoids for at least two months following
improvement in symptoms to reduce the risk of relapse.
• Upper airway cough syndrome (UACS) – In patients with UACS who have a
personal or family history suggestive of atopy, we recommend treatment with an
intranasal GC, rather than an oral antihistamine (Grade 1B). Combination therapy
with an intranasal GC and an oral antihistamine is an acceptable alternative,
particularly in a patient with severe symptoms. (See 'Upper airway cough
syndrome' above and "Pharmacotherapy of allergic rhinitis".)
For patients with suspected nonallergic UACS, we suggest a trial of therapy with
intranasal administration of one or more of the following: azelastine, GC, or
ipratropium. (See 'Upper airway cough syndrome' above.)
• Gastroesophageal reflux – For patients with suspected cough due to
gastroesophageal reflux, we suggest a trial of lifestyle modifications in
combination with acid suppression medication (Grade 2C). Proton pump inhibitors
appear to be more effective than H2 antagonists in this setting. (See
'Gastroesophageal reflux' above.)
• Postinfectious cough – For patients with prolonged cough following an upper
respiratory infection and clinical features suggestive of UACS, the treatment
follows that for nonallergic UACS, as described above. (See 'Persistent cough after
upper respiratory tract infection' above and 'Upper airway cough syndrome'
above.)
For patients with cough following an upper respiratory infection but few or no
features of UACS, we treat bronchial hyperreactivity, as described above for cough
variant asthma. (See 'Persistent cough after upper respiratory tract infection'
above.)
• Angiotensin-converting enzyme (ACE) inhibitor cough – For patients who
develop a chronic cough while taking an ACE inhibitor, the ACE inhibitor should be
discontinued as the first therapeutic approach. ACE-induced cough will usually
resolve within a couple of weeks, although it will occasionally last up to four
months. (See 'Angiotensin-converting enzyme inhibitors' above.)
● Unexplained chronic cough – In some patients, the cause of chronic cough cannot
be identified and empiric therapy for suspected causes has failed. For such patients,
we suggest initial treatment with the nonopiate agent, dextromethorphan, rather
than using an opiate (Grade 2C). Benzonatate can be added if the cough persists
despite dextromethorphan. Additionally, we suggest a therapeutic trial of
multimodality speech therapy (Grade 2C). (See 'Unexplained chronic cough' above.)
For patients whose cough does not respond to the above measures, we suggest a
trial of the neuromodulators gabapentin or pregabalin rather than opiates or other
agents (Grade 2C). Gabapentin and pregabalin are inhibitors of gamma aminobutyric
acid release that are thought to reduce chronic cough via a central mechanism.
Opiates also suppress cough centrally, with codeine and morphine most commonly
used for antitussive properties. Any of these centrally acting agents may have
sedating adverse effects.
When occasionally using opiates in patients whose cough is refractory to other
measures, we typically prescribe a time-limited (eg, four- to six-week) course to
facilitate mucosal healing while avoiding the risks associated with chronic therapy.
Palliative opiates may also be useful in those with advanced interstitial lung diseases
or malignancy. (See 'Opiates' above and "Palliative care: Overview of cough, stridor,
and hemoptysis in adults", section on 'Cough'.)
ACKNOWLEDGMENT
The UpToDate editorial staff acknowledges Ronald C Silvestri, MD, who contributed to
earlier versions of this topic review.
Use of UpToDate is subject to the Terms of Use.
Topic 1428 Version 31.0
GRAPHICS
Evaluation of subacute or chronic cough in adults
GERD: gastroesophageal reflux disease; ACE: angiotensin-converting enzyme; CT: computed
tomography; PFT: pulmonary function test; HRCT: high resolution computed tomography.
* Also consider postinfectious etiology for subacute cough (3 to 8 weeks duration).
Graphic 67147 Version 7.0
Estimated comparative daily doses for inhaled glucocorticoids in
adolescents ≥12 years and adults
Medium dose
(total daily
dose)
High dose
(total daily
dose) *
80 to 160 mcg
>160 to 320 mcg
>320 to 640 mcg
40 mcg per actuation
2 or 4 inhalations
¶
¶
80 mcg per actuation
2 inhalations
4 inhalations
6 or 8 inhalations
100 to 200 mcg
>200 to 400 mcg
>400 to 800 mcg
50 mcg per actuation
2 to 4 inhalations
¶
¶
100 mcg per actuation
2 inhalations
4 inhalations
6 or 8 inhalations
180 to 360 mcg
>360 to 720 mcg
>720 to 1440 mcg
90 mcg per actuation
2 or 4 inhalations
¶
¶
180 mcg per actuation
2 inhalations
4 inhalations
6 or 8 inhalations
200 to 400 mcg
>400 to 800 mcg
>800 to 2400 mcg
100 mcg per actuation
2 to 4 inhalations
¶
¶
200 mcg per actuation
1 to 2 inhalations
3 to 4 inhalations
¶
Drug
Beclomethasone HFA
(Qvar RediHaler product available in
United States)
Low dose
(total daily
dose)
Administer as 2 divided doses
Beclomethasone HFA Δ
(Qvar product available in Canada,
Europe, and elsewhere)
Administer as 2 divided doses
Budesonide DPI
(Pulmicort Flexhaler product available
in United States)
Administer as 2 divided doses
Budesonide DPI Δ
(Pulmicort Turbuhaler or Turbohaler
product available in Canada, Europe,
and elsewhere)
Administer low doses (ie, ≤400
mcg/day) once daily; administer higher
doses (ie, >400 mcg/day) as 2 to 4
divided doses
400 mcg per actuation
1 inhalation
2 inhalations
3 to 6 inhalations
160 mcg
320 mcg
640 mcg
80 mcg per actuation
2 inhalations
4 inhalations
¶
160 mcg per actuation
◊
2 inhalations
4 inhalations
100 to 200 mcg
>200 to 400 mcg
>400 to 800 mcg
100 mcg per actuation
1 to 2 inhalations
3 to 4 inhalations
¶
200 mcg per actuation
1 inhalation
2 inhalations
3 to 4 inhalations
176 to 220 mcg
>220 to 440 mcg
>440 to 1760 mcg
44 mcg per actuation
4 inhalations
¶
¶
110 mcg per actuation
2 inhalations
4 inhalations
¶
220 mcg per actuation
◊
2 inhalations
4 to 8 inhalations
100 to 250 mcg
>250 to 500 mcg
>500 to 2000 mcg
50 mcg per actuation
2 to 4 inhalations
¶
¶
125 mcg per actuation
2 inhalations
4 inhalations
¶
250 mcg per actuation
◊
2 inhalations
4 to 8 inhalations
Ciclesonide HFA
(Alvesco product available in United
States, Europe, and elsewhere)
United States: Administer as 2 divided
doses
Australia, Europe, and elsewhere:
Administer lower doses (ie, 160 to 320
mcg/day) once daily; administer 640
mcg dose as 2 divided doses
Ciclesonide HFA Δ
(Alvesco product available in Canada)
Administer lower doses (eg, 100 to 400
mcg) once daily; administer 800 mcg
dose as 2 divided doses
Fluticasone propionate HFA
(Flovent HFA product available in
United States)
Administer as 2 divided doses
Fluticasone propionate HFA Δ
(Flovent HFA product available in
Canada; Flixotide Evohaler product
available in Europe and elsewhere)
Administer as 2 divided doses
Fluticasone propionate DPI
(Flovent Diskus product available in
United States and Canada; Flixotide
Accuhaler product available in Europe
and elsewhere)
100 to 250 mcg
>250 to 500 mcg
>500 to 2000 mcg
50 mcg per actuation
2 to 4 inhalations
¶
¶
100 mcg per actuation
2 inhalations
4 inhalations
¶
250 mcg per actuation
◊
2 inhalations
4 to 8 inhalations
500 mcg per actuation (strength
not available in United States)
◊
◊
2 or 4 inhalations
110 mcg
226 mcg
464 mcg
55 mcg per actuation
2 inhalations
¶
¶
113 mcg per actuation
◊
2 inhalations
¶
232 mcg per actuation
◊
◊
2 inhalations
50 mcg (by use of
pediatric DPI,
which is off-label
in adolescents
and adults)
100 mcg
200 mcg
50 mcg per actuation
1 inhalation
¶
¶
100 mcg per actuation
◊
1 inhalation
2 inhalations
200 mcg per actuation
◊
◊
1 inhalation
Administer as 2 divided doses
Fluticasone propionate DPI
(Armonair Digihaler product available
in United States; Aermony Respiclick
product available in Canada)
Administer as 2 divided doses
Fluticasone furoate DPI
(Arnuity Ellipta product available in
United States, Canada, Australia, and
elsewhere, but not available in Europe
or UK)
Administer once daily
NOTE: Inhaled fluticasone furoate has
a greater anti-inflammatory potency
per microgram than fluticasone
propionate inhalers. Thus, fluticasone
furoate is administered at a lower daily
dose and used only once daily.
Mometasone DPI
(Asmanex Twisthaler product available
in United States)
220 mcg
>220 to 440 mcg
>440 to 880 mcg
110 mcg per actuation
2 inhalations
¶
¶
220 mcg per actuation
1 inhalation
2 inhalations
4 inhalations
200 mcg
>200 to 400 mcg
>400 to 800 mcg
100 mcg per actuation
2 inhalations
4 inhalations
¶
200 mcg per actuation
◊
2 inhalations
4 inhalations
200 mcg
>200 to 400 mcg
>400 to 800 mcg
200 mcg per actuation
1 inhalation
2 inhalations
¶
400 mcg per actuation
◊
1 inhalation
2 inhalations
May administer lower doses (ie, 220 to
440 mcg/day) once daily; administer
880 mcg dose as 2 divided doses
Mometasone HFA
(Asmanex HFA product available in
United States)
Administer as 2 divided doses
Mometasone DPI Δ
(Asmanex Twisthaler product available
in Canada, Europe, and elsewhere)
May administer lower doses (ie, 200 to
400 mcg/day) once daily; administer
800 mcg dose as 2 divided doses
The most important determinant of appropriate dosing is the clinician's judgment of the
patient's response to therapy. The clinician must monitor the patient's response on several
clinical parameters and adjust the dose accordingly. The stepwise approach to therapy
emphasizes that once control of asthma is achieved, the dose of medication should be carefully
titrated to the minimum dose required to maintain control, thus reducing the potential for
adverse effects.
Suggested total daily doses for low, medium, and high dose inhaled glucocorticoid regimens are
based on daily doses recommended by Global Initiative for Asthma (GINA), National Asthma
Education and Prevention Program (NAEPP), and/or product labeling [1-5] . This is not a table of
equivalence.
Depending on the specific product, total daily doses are administered once or divided and given
twice daily. Refer to local product information or a clinical drug reference (eg, UpToDate
Lexidrug).
Some doses are outside the approved product information recommendations.
DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant metered dose inhaler.
* Evidence for additional improvement with dose increases >1000 mcg/day is limited.
¶ Select alternate preparation with higher mcg/actuation to improve convenience.
Δ Products shaded in light gray color are not available in the United States but are available widely
elsewhere.
◊ Select preparation with fewer mcg/actuation.
Data from:
1. Global Initiative for Asthma (GINA); Global Strategy for Asthma Management and Prevention; 2021. Available at
www.ginasthma.org.
2. National Heart, Blood, and Lung Institute Expert Panel Report 3 (EPR 3): Guidelines for the Diagnosis and
Management of Asthma; 2007. NIH Publication 08-4051 available at http://www.nhlbi.nih.gov/healthpro/guidelines/current/asthma-guidelines/full-report and pro.
3. US Food & Drug Administration (FDA) approved product information. US National Library of Medicine. (Available
online at www.dailymed.nlm.nih.gov/dailymed/index.cfm.)
4. Health Canada-approved product monograph. Health Canada. (Available online at https://healthproducts.canada.ca/dpd-bdpp/index-eng.jsp.)
5. European Medicines Agency (EMA) summary of product characteristics. European Medicines Agency. (Available online
at www.ema.europa.eu/en/medicines.)
Graphic 78011 Version 18.0
Usual doses of combined inhaled glucocorticoids and bronchodilators
Medication
Low-dose
Medium-dose
High-dose
ICS-SABA combination
Budesonide-albuterol HFA (Brand name: Airsupra) *
NOTE: Not used for maintenance therapy.
Acute symptom relief: Budesonide-albuterol (80 mcg/90 mcg) 2 inhalations as needed (usual
maximum: 12 inhalations/day).
ICS-LABA combinations
Beclomethasone [beclometasone]-formoterol DPI or HFA (Not available in United States or
Canada, but available elsewhere [sample brand names: Formodual, Fostair, Foster]) ¶Δ
100 mcg/6 mcg
1 inhalation twice daily
2 inhalations twice
daily
200 mcg/6 mcg
2 inhalations twice
daily
Budesonide-formoterol HFA (Brand names: Symbicort, Breyna) ¶
80 mcg/4.5 mcg
2 inhalations twice
daily
160 mcg/4.5 mcg
2 inhalations twice
daily
Fluticasone furoate-vilanterol DPI (Brand name: Breo Ellipta) Δ
NOTE: Inhaled fluticasone furoate has a greater anti-inflammatory potency per microgram than
fluticasone propionate inhalers. Thus, fluticasone furoate is administered at a lower daily dose and
used only once daily.
50 mcg/25 mcg ◊
1 inhalation once daily
100 mcg/25 mcg
1 inhalation once daily
200 mcg/25 mcg
1 inhalation once daily
Fluticasone propionate-formoterol MDI (Not available in United States or Canada, but
available elsewhere [sample brand name: Flutiform])
50 mcg/5 mcg
125 mcg/5 mcg
2 inhalations twice
daily
2 inhalations twice
daily
250 mcg/10 mcg
2 inhalations twice
daily
Fluticasone propionate-salmeterol DPI (Brand names: Advair Diskus, Wixela Inhub) Δ
100 mcg/50 mcg
1 inhalation twice daily
250 mcg/50 mcg
1 inhalation twice daily
500 mcg/50 mcg
1 inhalation twice daily
Fluticasone propionate-salmeterol HFA (Brand name: Advair HFA)
45 mcg/21 mcg
2 inhalations twice
daily
115 mcg/21 mcg
2 inhalations twice
daily
230 mcg/21 mcg
2 inhalations twice
daily
Fluticasone propionate-salmeterol DPI (Brand names: AirDuo RespiClick, AirDuo Digihaler) Δ§
55 mcg/14 mcg
1 inhalation twice daily
113 mcg/14 mcg
1 inhalation twice daily
1 inhalation twice daily
232 mcg/14 mcg
1 inhalation twice daily
Mometasone-formoterol HFA (Brand name: Dulera)
100 mcg/5 mcg
1 inhalation twice daily
2 inhalations twice
daily
200 mcg/5 mcg
2 inhalations twice
daily
Mometasone-indacaterol DPI (Brand name: Atectura Breezhaler; available in Canada) Δ
80 mcg/150 mcg
1 inhalation (capsule)
once daily
160 mcg/150
mcg
1 inhalation (capsule)
once daily
320 mcg/150
mcg
1 inhalation (capsule)
once daily
ICS-LAMA-LABA combinations ¥
Fluticasone furoate-umeclidinium-vilanterol DPI (Brand name: Trelegy Ellipta) Δ
100 mcg/62.5
mcg/25 mcg
1 inhalation once daily
200 mcg/62.5
mcg/25 mcg
1 inhalation once daily
Mometasone-glycopyrrolate (glycopyrronium)-indacaterol DPI (Brand name: Enerzair
Breezhaler; available in Canada) *Δ
160 mcg/50
mcg/150 mcg
1 inhalation (capsule)
once daily
Do not exceed the maximum number of inhalations/puffs per day listed in the table due to the risk
of toxicity from an excess dose of long-acting beta-agonist (ie, salmeterol, formoterol, or vilanterol).
Brand names and dose per puff or per inhalation of commercially available fixed dose combinations
are according to United States prescribing information, unless otherwise noted. Consult local
product information before use.
DPI: dry powder inhaler; HFA: metered-dose inhaler with hydrofluoroalkane propellant; ICS: inhaled
glucocorticoid (inhaled corticosteroid); LABA: long-acting beta-agonist; LAMA: long-acting
muscarinic antagonist; SABA: short-acting beta-agonist; SMI: soft mist inhaler.
* Not approved for use in patients <18 years old.
¶ When using ICS-formoterol as reliever, use one to two inhalations as needed. Maximum daily dose
of maintenance and rescue is 12 inhalations.
Δ DPI contains lactose which may have small amounts of milk protein.
◊ Fluticasone furoate-vilanterol 50 mcg/25 mcg DPI is approved for use in patients 5 to 11 years old;
use in adolescents and adults is off-label.
§ In AirDuo inhalers, the daily dose of salmeterol is approximately one-fourth of the dose in Advair,
and the daily dose of fluticasone is approximately one-half that of the comparable low-, medium-,
and high-dose strengths of Advair.
¥ Alternatively, tiotropium SMI (Brand name: Spiriva Respimat) can be used with an ICS or ICS-LABA
inhaler. The dose in asthma is two inhalations (1.25 mcg/inhalation) once daily.
Reference: Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention.
https://ginasthma.org/wp-content/uploads/2023/05/GINA-2023-Full-Report-2023-WMS.pdf. Updated 2023 (Accessed on
June 13, 2023).
Graphic 68143 Version 27.0
Glucocorticoid nasal sprays for treatment of rhinitis
Name
Common
brand
name(s) and
strength
Generic
available
Available
without a
prescription
(OTC)
Usual
adult
dose per
nostril
Lower
age
limit
when
used in
children
(years) *
Second-generation (systemic bioavailability <1% or undetectable)
Ciclesonide
Omnaris (50
mcg/spray)
No
No
Two
sprays
once daily
2 years
Zetonna (37
mcg/spray)
No
No
One spray
once daily
12 years
Fluticasone
furoate
Flonase
Sensimist (OTC)
(27.5 mcg/spray)
No
Yes
Two
sprays
once daily
2 years
Fluticasone
propionate
Flonase Allergy
Relief (OTC) (50
mcg/spray)
Yes
Yes
Two
sprays
once daily
or one
spray
twice daily
4 years
Mometasone
Nasonex 24HR
Allergy (OTC) (50
mcg/spray)
Yes
Yes
Two
sprays
once daily
2 years
First-generation (systemic bioavailability 10 to 50%)
Beclomethasone
Beconase AQ (42
mcg/spray)
No
No
One or
two sprays
twice daily
6 years
Pediatric: Qnasl
Children's (40
mcg/spray)
No
No
Two
sprays
once daily
using 80
mcg/spray
product
4 years
Yes
Yes
One to
two sprays
once daily
6 years
Adolescent/adult:
Qnasl (80
mcg/spray)
Budesonide
Generic (formerly
Rhinocort
Allergy) (OTC) (32
mcg/spray)
Flunisolide
Generic (formerly
Nasalide) (25
mcg/spray)
Yes
No
Two
sprays two
or three
times daily
(maximum
two sprays
6 years
four times
daily)
Triamcinolone
GoodSense Nasal
Allergy (OTC),
Nasacort Allergy
24HR (OTC) (55
mcg/spray)
Yes
Yes
Two
sprays
once daily
2 years
Nasal sprays work best when they are administered properly and the medication remains in the
nose rather than draining down the back of the throat. Note that the recommended techniques for
the aqueous and aerosol sprays are different. If the nose is crusted or contains mucus, it should first
be cleaned with a saline nasal spray prior to use of intranasal sprays. Some people find that holding
the other nostril closed with a finger improves their ability to draw the spray into the upper nose.
Once symptoms are controlled, the daily dose can be reduced to the lowest dose that maintains
control.
Dosing and product descriptions are based upon products available in the United States and some
other countries. Product descriptions in other countries may differ in some detail. Consult the drug
monographs included within UpToDate and local product information for additional detail.
OTC: over-the-counter (available without a prescription in the United States and some other
countries).
* Lowest age use may differ from approved product labeling.
¶ Alcohol may contribute to dryness or irritation.
Data from: UpToDate Lexidrug. More information available at https://online.lexi.com/.
Graphic 55833 Version 41.0
Complications of cough
Cardiovascular
Arterial hypotension
Loss of consciousness
Rupture of subconjunctival, nasal, and anal veins
Dislodgement/malfunctioning of intravascular catheters
Bradyarrhythmias, tachyarrhythmias
Neurologic
Cough syncope
Headache
Cerebral air embolism
CSF rhinorrhea
Acute cervical radiculopathy
Malfunctioning ventriculoatrial shunts
Seizures
Stroke due to vertebral artery dissection
Gastrointestinal
Gastroesophageal reflux events
Hydrothorax in peritoneal dialysis
Malfunction of gastrostomy button
Splenic rupture
Inguinal hernia
Genitourinary
Urinary incontinence
Inversion of bladder through urethra
Musculoskeletal
From asymptomatic elevations of serum creatine phosphokinase to rupture of rectus abdominis
muscles
Rib fractures
Respiratory
Pulmonary interstitial emphysema, with potential risk of pneumatosis intestinalis,
pneumomediastinum, pneumoperitoneum, pneumoretroperitoneum, pneumothorax,
subcutaneous emphysema
Laryngeal trauma
Tracheobronchial trauma (eg, bronchitis, bronchial rupture)
Exacerbation of asthma
Intercostal lung herniation
Miscellaneous
Petechiae and purpura
Disruption of surgical wounds
Constitutional symptoms
Lifestyle changes
Self-consciousness, hoarseness, dizziness
Fear of serious disease
Decrease in quality of life
CSF: cerebrospinal fluid
Reproduced with permission from Irwin, RS, Boulet, LP, Cloutier, MM, et al. Managing a cough as a defense mechanism and
as a symptom. A consensus panel report of the American College of Chest Physicians. Chest 1998; 114(suppl 2):133S.
Graphic 63151 Version 2.0
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