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, evaluation, and complications of subacute and chronic cough are discussed separately. (See "Causes and epidemiology of subacute and chronic cough in adults".)
OVERVIEW — There is broad agreement that the initial approach to a patient with subacute or chronic cough should follow a systematic algorithmic or tiered approach to treatment (algorithm 1) [1-3]. If initial investigations fail to reveal the underlying cause of chronic cough, a multidisciplinary care team (including internist or geriatrician, otorhinolaryngologist, pulmonologist, allergist, and gastroenterologist) should work together 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), rheumatic disease, 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); the most common causes of chronic cough are asthma, gastroesophageal reflux, UACS due to rhinosinus conditions, 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, 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 adventitial sounds.
●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].
●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 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'.)
DIAGNOSTIC TRIAL OF 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-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 improvement in cough with inhaled GC, but absence of variable airway obstruction or airway hyperresponsiveness [9]. Exposure to potential occupational allergens (eg, isocyanate, 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".)
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.
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 [32]. 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 [33]. 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 [34]. 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 [35]. 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: Management".)
For patients with suspected nonallergic UACS, we suggest a trial of therapy with intranasal administration of one or more of the following: azelastine, glucocorticoid, and ipratropium [33]. 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 [36]. (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 should 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: Management".)
Gastroesophageal reflux — Cough due to gastroesophageal reflux disease (GERD) generally responds to a regimen that includes lifestyle modifications and acid suppression medication [12,37-39]:
Lifestyle modifications — The evidence in favor of lifestyle modifications to reduce or prevent GERD and thereby treat cough is limited [12,37]. 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 meta-analysis 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 [40]. 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 [41]. 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 [12,37].
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. (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 [42-44]. 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 portion of patients (15 to 95 percent) experienced improvement in extraesophageal symptoms (including but not limited to cough) after surgical fundoplication [44]. 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 [43]. A meta-analysis of the results of antireflux surgery in GERD with respiratory symptoms found that different surgical techniques or a combination of them lead to cough relief in 83.4 percent of patients [45]. Nissen fundoplication has been reported to result in complete resolution of chronic cough in approximately three-fourths of patients [46,47]. (See "Medical management of gastroesophageal reflux disease in adults" and "Surgical management 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 [48]. (See 'Upper airway cough syndrome' above.)
First-generation antihistamines (eg, brompheniramine, chlorpheniramine, clemastine, doxylamine), although more sedating, have stronger anticholinergic effects than second-generation agents (eg, cetirizine, loratadine, fexofenadine) and therefore may be superior for treating cough secondary to the common cold [32,48-51].
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 [52]. Among 14 such patients in one report, 12 had clinical improvement with administration of 320 mcg of inhaled ipratropium, and of these, 5 had complete resolution of cough [53].
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 [6,52,54]. A systematic review did not find evidence that antihistamines (diphenhydramine) or beta adrenergic agonists alleviated cough due to pertussis [55]. 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 [56]. 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 inhibitor-induced cough [1,56,57]. Angiotensin II receptor antagonists also do not increase cough or bronchial hyperresponsiveness in symptomatic asthmatics [58].
UNEXPLAINED CHRONIC COUGH — A portion of patients experience a cough that persists for more than eight weeks and is unexplained despite a systematic assessment, as described above (algorithm 1) [59]. (See 'Diagnostic trial of therapy for common causes' above.)
Several studies have noted a substantial minority of patients who do not respond or respond inadequately to specific interventions and treatments [16,60,61]. Rarely, these patients have another underlying airway or parenchymal disease as the cause of their cough. More often, however, they have what may be called "unexplained chronic cough," "chronic idiopathic cough," or "cough hypersensitivity syndrome" [62]. 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 [62-65]. (See "Neuronal control of the airways".)
For patients whose cough remains unexplained despite the above evaluation and empiric trials of specific therapies, the next step includes one or more of the following: nonpharmacologic therapy such as speech therapy or therapy with gabapentin or pregabalin, low-dose amitriptyline, or opiates.
Research is underway to develop cough receptor antagonists, but until they are available, the nonspecific cough remedies are reasonable choices for the management of disabling chronic cough that has not responded to specific therapy [66-69]. (See 'Investigational agents' below.)
Nonpharmacologic interventions — Modalities such as speech therapy, breathing exercises, cough suppression techniques, and patient counseling have been tried in the management of chronic cough [70-72]. A systematic review reported that studies of such interventions showed improved cough severity and frequency, but few of them used validated cough measurement tools [72]. While the robustness of these findings is limited, in accordance with guidelines, we suggest a therapeutic trial of multimodality speech therapy in patients with unexplained chronic cough who have not responded to an algorithmic approach, such as the one described above (algorithm 1).
Empiric agents — Occasional patients have chronic cough without clearly demonstrable reversible airway obstruction or chronic obstructive pulmonary disease (COPD) but nonetheless respond to inhaled glucocorticoids (GCs) or ipratropium.
Inhaled glucocorticoids — The observation that chronic cough is associated with airway inflammation even in nonasthmatic patients has prompted use of inhaled GCs for nonspecific management of chronic cough [73-77]. One theory is that some patients with chronic unexplained cough have nonasthmatic eosinophilic bronchitis. (See "Causes and epidemiology of subacute and chronic cough in adults".)
The evidence in favor of using inhaled GCs in patients with chronic unexplained cough 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 [76].
●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 [75]. 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 [73].
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) [74]. Another potential reason for variable results may reflect variable numbers of patients with nonasthmatic eosinophilic bronchitis in the study population. (See 'Nonasthmatic eosinophilic bronchitis' above.)
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 [68]:
●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 [53], although this observation has not been replicated [59]. 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.)
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 [5,78]. 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 [59]. The supportive data for the use of pregabalin were published after the ACCP guidelines were prepared.
●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 [59]. Adverse effects may include diarrhea, nausea, emotional lability, somnolence, nystagmus, tremor, weakness, and peripheral edema. After six months, therapy should be reassessed to determine whether gabapentin is still needed to control cough [59].
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 [79]. Cough-specific 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 [70]. 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 can be useful 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]. If nonopiate options are ineffective, then long-acting morphine or codeine can be tried, recognizing the risk of addiction and other narcotic-related adverse effects.
Morphine — Morphine reduces cough within a week in approximately half of patients with chronic cough [1]. A reasonable starting dose is 5 mg (slow release preparation) twice a day; if unimproved after a week, the dose can be doubled [1]. 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 [80]. 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 is the traditional opiate used for cough, although morphine is now preferred due to more predictable results [1]. Despite widespread use, evidence regarding its efficacy for chronic cough is limited and the response varies among patients [81-86]. 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 [86]. In a randomized trial, 64 subjects with subacute cough were randomly assigned to receive codeine (30 mg twice daily), an investigational antitussive, or placebo [84]. 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 [83]. 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.
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. For patients who desire a medication to take while awaiting definitive therapy, dextromethorphan, benzonatate, or guaifenesin may be tried, although high-quality trials demonstrating benefit are lacking.
Dextromethorphan — Dextromethorphan is probably the most common nonopioid agent used for cough. It decreases the sensitivity of cough receptors and is an N-methyl-D-aspartate receptor antagonist. It can be useful 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.
In a systematic review that analyzed studies of dextromethorphan versus placebo, the quality of the studies was generally felt to be fair to poor [86]. 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 [86]. (See 'Codeine' above.)
●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 [81]. 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 [82].
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 is reasonable, although we have found it to be 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 [87].
There are case reports of effective use of benzonatate in the palliative treatment of cough in advanced cancer [88]. 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 [89]. 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.
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 antagonist – 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. In a randomized, crossover trial of 24 subjects with refractory cough, an investigational P2X3 antagonist (gefapixant) decreased cough counts during the two-week study blocks by 75 percent compared with placebo [90]. However, taste disturbance was noted in all patients taking gefapixant and caused six subjects to withdraw from the study; nausea was also common (38 percent). Two large phase 3 studies of gefapixant (45 mg oral twice daily) showed a 15 to 20 percent reduction in cough in patients with refractory unexplained cough, although taste disturbance occurred in more than 20 percent of patients [91]. Other P2X3 antagonists with less potential for taste disturbance are in clinical development [92].
●Thalidomide – Thalidomide has been evaluated as an antitussive agent for patients with cough due to idiopathic pulmonary fibrosis (IPF). The mechanism by which thalidomide might suppress cough in IPF is not known, but it is speculated to be due to its anti-inflammatory or antifibrotic properties or to its inhibition of pulmonary sensory nerve fibers. In a randomized crossover trial, participants were randomly assigned to receive either thalidomide (in doses up to 100 mg daily) or placebo for 12 weeks [93]. Cough was significantly decreased in the thalidomide group compared with placebo, although patients in the thalidomide group had more adverse events, chiefly constipation, dizziness, and viral upper respiratory infections. Additional study of thalidomide is needed before widespread implementation for chronic cough because of its serious adverse effect profile, including teratogenicity. (See "Treatment of idiopathic pulmonary fibrosis", section on 'Future directions'.)
●Nebulized lidocaine – Nebulized lidocaine can reduce the frequency of cough, but its use is limited by adverse effects. 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 to 5 mL (200 mg) if numbness of the throat lasted less than 20 minutes [94]. Among 99 patients who responded to a follow-up questionnaire, cough severity scores significantly 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.
●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 [95,96].
COMPLICATIONS — During vigorous coughing, intrathoracic pressures may reach 300 mmHg and expiratory velocities approach 500 miles per hour [97]. 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, self-consciousness, insomnia, headache, dizziness, musculoskeletal pain, hoarseness, excessive perspiration, urinary incontinence, and concern that "something is wrong" (table 4) [98,99]. 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 [100]. 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".)
●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 'Diagnostic trial of 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 as-needed, short-acting inhaled bronchodilator is a reasonable alternative. (See 'Asthma' above.)
•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, we recommend stopping the ACE inhibitor rather than trying to suppress the cough with other agents (Grade 1C). The 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 nonopioid agent, dextromethorphan, rather than using an opioid (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 dextromethorphan with or without benzonatate, we suggest a trial of an opioid antitussive (Grade 2B). Codeine and morphine are commonly used opioid antitussives. (See 'Unexplained chronic cough' above.)
Gabapentin and pregabalin are alternative, symptomatic treatments for patients whose cough is refractory to the above measures. (See 'Gabapentin and pregabalin' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Ronald C Silvestri, MD, who contributed to earlier versions of this topic review.
