INTRODUCTION — Although an acute and self-limited cough often does not require therapy, prolonged cough can be a bothersome symptom that precipitates many outpatient visits to the clinician for treatment. Differing definitions for a chronic cough have been proposed that require symptoms for varying times from two weeks to three months [1,2]. Guidelines from the American College of Chest Physicians distinguish three categories of cough based upon duration [1]:

●Acute cough, lasting less than three weeks

●Subacute cough, lasting between three and eight weeks

●Chronic cough, lasting more than eight weeks

The initial priorities for patients with cough lasting more than three weeks (subacute or chronic cough) are to identify a precipitant or etiology, and then to eliminate the precipitant or treat the underlying cause [3-6].

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 "Evaluation of subacute and chronic cough in adults".)

OVERVIEW — Several older studies that used a systematic approach to the evaluation and treatment of persistent cough reported that treatment aimed at the underlying disorder was successful in more than 90 percent of patients [7-9]. More recent studies and reviews of chronic cough, however, have found the number of patients responding fully to specific therapy to be substantially fewer [10-12]. There remains widespread agreement, nonetheless, that the initial approach to a patient with chronic cough should follow a systematic algorithmic approach to treatment aimed at the most common causes or triggers (algorithm 1).

The initial step in the algorithm identifies patients who are immunosuppressed, smoke cigarettes, or have purulent sputum. Immunosuppressed patients should have a diligent and rapid evaluation for infection. Smokers need counseling to quit smoking and often a chest radiograph to exclude bronchogenic carcinoma. Patients with significant production of purulent sputum need evaluation for pulmonary and possibly sinus infection, and treatment of identified infections, prior to proceeding with the algorithm.

The algorithm uses a sequential approach to using specific empiric therapies for the most common causes of cough. These therapies are described in the following sections. Using an algorithm with a sequential, empiric approach to therapy is of diagnostic as well as therapeutic usefulness. Therefore, 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.

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 [5]. 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.

SPECIFIC TREATMENT

Upper airway cough syndrome — Upper airway cough syndrome (UACS; previously known as postnasal drip syndrome but revised to include all upper airway abnormalities causing cough) has a number of different etiologies, including allergic, nonallergic, and vasomotor rhinitis, acute nasopharyngitis, and sinusitis [13]. When an environmental precipitant for allergic rhinitis can be identified, exposure to this precipitant should be eliminated if at all possible. (See "Allergic rhinitis: Clinical manifestations, epidemiology, and diagnosis".)

Practice parameters for the diagnosis and management of rhinitis have been published [14]. These guidelines describe high-quality evidence that intranasal glucocorticoids are the most effective therapy for symptoms of allergic rhinitis (table 1). In addition, intranasal glucocorticoids are effective for several types of nonallergic rhinitis, including nonallergic rhinitis with eosinophilia (NARES) and vasomotor rhinitis. For patients with cough due to allergic rhinitis, intranasal glucocorticoids 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 for approximately three months [4].

Additional therapies for allergic rhinitis include oral and nasal antihistamines, oral decongestants, oral leukotriene receptor antagonists, and other agents. The use of these agents for allergic and nonallergic rhinitis is reviewed in detail separately. (See "Pharmacotherapy of allergic rhinitis" and "Chronic nonallergic rhinitis".)

Among patients without evidence for allergic rhinitis in whom nonallergic rhinitis may be more likely, our approach is to perform a diagnostic trial with an oral first generation antihistamine (eg, chlorpheniramine, clemastine) or a combined antihistamine-decongestant (eg, brompheniramine-pseudoephedrine) [1,4,15]. First generation antihistamines are preferred over second generation ones (eg, cetirizine, fexofenadine, loratadine) due to the stronger anticholinergic effect, but concern over the sedating effects may limit their use [13]. Improvement in the cough should lead to further evaluation for the cause of the rhinitis (eg, allergic, nonallergic, or rhinosinusitis) and optimization of the long-term treatment. (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 who are not candidates for use of an oral first generation antihistamine (eg, due to excess somnolence), other options include intranasal administration of one of the following: azelastine, glucocorticoid, and ipratropium bromide [14]. However, azelastine may cause somnolence even with intranasal use. Intranasal ipratropium bromide significantly reduces the rhinorrhea associated with perennial nonallergic rhinitis and has few side effects [16]. (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 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.

When sinusitis is documented by plain radiograph or sinus CT scan, treatment is guided by whether the patient has acute or chronic sinusitis. The treatment of these entities is discussed separately. (See "Acute sinusitis and rhinosinusitis in adults: Clinical manifestations and diagnosis" and "Chronic rhinosinusitis: Management".)

Cough variant asthma — Cough variant asthma may be suspected based on the presence of reversible airflow obstruction or a positive test for bronchial hyperresponsiveness (eg, methacholine or histamine challenge test). However, confirmation that cough is due to asthma requires a beneficial response to therapy for asthma [17]. Therapy for cough variant asthma follows the same general principles as standard therapy for asthma. (See "An overview of asthma management".)

Similar to therapy for moderate or severe asthma, the mainstays of therapy for cough variant asthma are regular use of inhaled glucocorticoids (GC) and as-needed use of inhaled bronchodilators [17]. In a case series, for example, 10 patients with cough variant asthma were treated with inhaled GCs; all were free of disabling cough at a mean follow up of 28 months [18].

The leukotriene receptor antagonists (LTRA) have also been shown to improve cough in patients with cough variant asthma [19]. In a small, randomized trial of 13 patients with cough variant asthma who were refractory to treatment with inhaled bronchodilators and inhaled glucocorticoids, therapy with an LTRA resulted in decreased cough scores compared with placebo [20]. LTRAs are an alternative among patients who wish to avoid or who have not responded to glucocorticoids. (See "Antileukotriene agents in the management of asthma".)

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 [17,18]. Once the patient has improved, prednisone is discontinued and maintenance therapy with inhaled GCs is continued.

Sputum eosinophil cell count and exhaled nitric oxide measurement have been used in patients with asthma as measures of airway inflammation [21-23]. 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 [10]. Further study of this approach is needed before widespread implementation.

Nonasthmatic eosinophilic bronchitis — The usual treatment for nonasthmatic eosinophilic bronchitis (NAEB) is an inhaled glucocorticoid. This choice is based on observational studies [24,25]. As an example, 11 patients with NAEB received open-label treatment with inhaled budesonide 400 mcg per day for four weeks [25]. Severity of cough and sensitivity to capsaicin-induced cough both improved. The optimal dose and duration of therapy have not been determined.

When an inciting agent (eg, occupational allergen) is identified, further exposure should be avoided. Rarely, oral glucocorticoids are needed for refractory symptoms.

Gastroesophageal reflux — Cough due to gastroesophageal reflux disease (GERD) generally responds to a regimen that includes lifestyle modifications and acid suppression medication [8,26-28]:

Lifestyle modifications — The evidence in favor of lifestyle modifications to reduce or prevent GERD and thereby treat cough is limited [8,28]. 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 three to four inches

●Cessation of smoking

●Avoidance of reflux-inducing foods (eg, fatty foods, chocolate, excess alcohol)

●Avoidance of very acidic beverages (eg, colas, 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 — Acid suppression medications are a key component to the treatment of cough due to GERD in combination with lifestyle modifications [28]. However, regimens proven effective in the management of GERD may not necessarily be the optimum regimen 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 effect is less universal than often suggested in consensus guidelines [29]. A possible explanation for failure to improve despite acid suppression is that of nonacidic reflux [28].

We suggest using an empiric trial of a proton pump inhibitor 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 [30]. 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 [8,28].

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 suggestive of 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 — 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).

The role of anti-reflux surgery to relieve extra-esophageal symptoms related to GERD is unclear [31-33]. 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 extra-esophageal symptoms (including but not limited to cough) after surgical fundoplication [33]. 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 [32]. (See "Medical management of gastroesophageal reflux disease in adults" and "Surgical management of gastroesophageal reflux in adults".)

Following an 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. Patients in whom postnasal drip (ie, upper airway cough syndrome or UACS) seems to be contributing to the prolonged cough following a viral upper respiratory tract infection should be treated the same as patients with nonallergic UACS, as described above [34]. First generation antihistamines (eg, chlorpheniramine, clemastine), 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 [13,15,34-36].

In patients with postviral cough without upper airway cough syndrome, the agents described above for cough variant asthma are used. These patients often have transient bronchial hyperreactivity and a positive methacholine challenge test [17]. Alternatively, in patients with postviral cough who have no evidence of airway hyperreactivity, inhaled ipratropium bromide has been reported to produce improvement in the cough [37]. Among 14 such patients in one report, the administration of 320 mcg of inhaled ipratropium bromide resulted in clinical improvement in 12 and complete resolution of cough in five [38].

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 post-tussive vomiting is present [37,39]. Patients are treated with a macrolide antibiotic, or trimethoprim-sulfamethoxazole, if a macrolide cannot be given. However, there is limited evidence for efficacy when these medications are administered beyond the first two weeks of the illness [37]. (See "Pertussis infection in adolescents and adults: Treatment and prevention".)

Angiotensin converting enzyme inhibitors and receptor blockers — Angiotensin converting enzyme (ACE) inhibitors produce a cough in 3 to 20 percent of patients, an effect that may be mediated by increased availability of kinins. The cough usually begins within one to two weeks of starting therapy, but may be delayed for as long as six months. Although theophylline [40], inhaled sodium cromoglycate [41], and a thromboxane antagonist (picotamide) [42] may partially alleviate this cough, the treatment of choice is withdrawal of the ACE inhibitor. The cough will typically resolve within one to four weeks after stopping the ACE inhibitor, but occasionally will last up to three months [43]. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Cough'.)

Angiotensin II receptor antagonists are alternatives to ACE inhibitors (acting via a related mechanism) that do not affect kinin metabolism. These agents do not appear to be associated with an increased incidence of cough, even in patients who had previously had an ACE inhibitor-induced cough [43,44]. Angiotensin II receptor antagonists also do not increase cough or bronchial hyperresponsiveness in symptomatic asthmatics [45].

NONSPECIFIC TREATMENT — Nonspecific therapy should be reserved for those patients who do not respond to the algorithm described above (algorithm 1). As noted, several studies have noted a substantial minority of patients who do not respond or respond inadequately to specific interventions and treatments [10-12]. Rarely, these patients may have another underlying airway or parenchymal disease as the cause of their cough. More often, however, they have what many now term “unexplained chronic cough”, “chronic idiopathic cough”, or “cough hypersensitivity syndrome” [46]. 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 (TRPV1) or transient receptor potential ankyrin 1 (TRPA1) [46-49].

Until cough receptor antagonists are developed and tested, the currently available nonspecific cough remedies described below are reasonable for the management of disabling chronic cough that has not responded to specific therapy [3,50-52].

Centrally acting antitussive agents — A number of agents, both opioid and non-opioid, are thought to suppress cough via an action on the central cough center. The data are limited regarding efficacy despite widespread use. We usually start with dextromethorphan, due to its better side effect profile. If that is ineffective, then codeine or long-acting morphine are tried, recognizing the risk of addiction and other narcotic-related adverse effects. Use of gabapentin for cough is “off-label”, but may be tried for cough refractory to other measures, as described below.

Dextromethorphan — Dextromethorphan is probably the most common non-opioid agent used for cough. In a systematic review that analyzed studies of dextromethorphan versus placebo, the quality of the studies was generally felt to be fair to poor [53]. 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 [53].

●In a cross-over study of 16 patients with chronic, stable cough, codeine (20 mg) and dextromethorphan (20 mg) were equally effective in reducing cough frequency [54]. 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 [55].

Codeine — Codeine is the traditional opiate used for cough, although evidence regarding its efficacy for chronic cough is limited [53-58]. 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 [53]. In a randomized trial, 64 subjects with subacute cough were randomly assigned to receive codeine (30 mg twice daily), an investigational antitussive, or placebo [57]. 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 4 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 [56]. 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.

In our practice, when prescribing codeine, we start at 30 mg every 4 to 6 hours as needed and increase to 60 mg, if the lower dose is insufficient. We caution patients about potential adverse effects such as somnolence and constipation.

Morphine — Morphine and other agents in the phenanthrene alkaloid group are effective in some but not all patients [51]. In a double-blind crossover trial, 27 patients who had a persistent cough of greater than three months duration and failed specific treatment were randomly assigned to receive slow-release morphine (5 mg twice daily) or placebo for four weeks [59]. Morphine improved daily cough severity scores, 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. Patients should be warned about potential somnolence and constipation.

Gabapentin and pregabalin — Gabapentin and pregabalin, gamma aminobutyric acid (GABA) analogs that bind to the voltage-gated calcium channels and inhibit neurotransmitter release, are thought to ameliorate chronic neuropathic pain via a central mechanism [60,61]. 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 [62]. 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 low dosage (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 [62]. 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 [62].

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 [63]. 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 [64]. 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.  

Peripherally acting antitussive agents — Benzonatate is a peripherally acting antitussive agent that presumably acts by anesthetizing stretch receptors in the lungs and pleura. It has been used as a nonspecific treatment for cough since 1958. While there are few good controlled studies of its use, one report showed that a combination of 200 mg of benzonatate and 600 mg of guaifenesin significantly suppressed capsaicin-induced cough compared to guaifenesin alone [65]. There are case reports of effective use of benzonatate in the palliative treatment of cough in advanced cancer [66]. 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 [67]. Signs and symptoms of overdose (restlessness, tremors, convulsion, coma, cardiac arrest) may occur within 15 to 20 minutes after ingestion.

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 cross over trial, participants were randomly assigned to receive either thalidomide (in doses up to 100 mg daily) or placebo for 12 weeks [68]. Cough was significantly decreased in the thalidomide group compared to 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 may be helpful in a minority of patients with refractory chronic cough. 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 [69]. 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.

Inhaled glucocorticoids — The observation that chronic cough is associated with airway inflammation even in nonasthmatic patients, has prompted use of inhaled glucocorticoids (GCs) for nonspecific management of chronic cough [70]. However, studies of inhaled glucocorticoids for the treatment of cough in the absence of asthma have yielded conflicting results.

●In one study, for example, there was a suggestion that more patients with chronic cough responded to inhaled GCs than to placebo, although overall mean daily cough scores were not significantly different in the two groups [70].

●Another study showed no benefit of inhaled GCs in patients with chronic nonasthmatic cough [71].

These differences in observed efficacy may be due to the presence of patients with eosinophilic bronchitis in some studies. These patients would not have physiologic evidence of asthma, but would likely respond to inhaled GCs. (See "Evaluation of subacute and chronic cough in adults", section on 'Nonasthmatic eosinophilic bronchitis'.)

Ipratropium bromide — The anticholinergic agent, inhaled ipratropium bromide, has been proposed to have at least two potential mechanisms by which it may alleviate cough [51]:

●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 [38], although this observation has not been replicated [62]. The usual dose of ipratropium is 2 inhalations by metered dose inhaler, four times a day.

Macrolide antibiotics — Patients with chronic cough tend to have increased levels of neutrophils in their induced sputum, which 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.

●The effect of azithromycin was examined in a trial that randomly assigned 44 patients with refractory cough to take low dose azithromycin (250 mg) or placebo three times a week for eight weeks [72]. Azithromycin did not significantly improve the Leicester Cough Questionnaire score compared with placebo.

●Similarly, a randomized trial in 30 patients with chronic cough found no reduction in cough frequency or severity with erythromycin 250 mg once daily for 12 weeks compared with placebo [73].

Non-pharmacologic interventions — Modalities such as speech therapy, breathing exercises, cough suppression techniques, and patient counseling have been tried in the management of chronic cough [64,74]. A systematic review reported that studies of such interventions showed improved cough severity and frequency, but few of them used validated cough measurement tools [75]. Thus, the robustness of these studies’ findings is limited.

FUTURE DIRECTIONS — Work is underway to identify treatments for patients who have a chronic cough without apparent cause despite careful investigation (algorithm 1) and empiric trials of therapy. 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, cross-over trial of 24 subjects with refractory cough, an investigational P2X3 antagonist (AF-219) decreased cough counts during the two-week study blocks by 75 percent compared with placebo [76]. However, taste disturbance was noted in all patients taking AF-219 and caused six subjects to withdraw from the study; nausea was also common (38 percent). These results support a role for P2X3 receptor hypersensitivity in refractory cough, but further study is needed to determine safety and efficacy in a larger number of patients, potentially using a lower dose.

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 5^th to 6^th 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 10^th to 12^th 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 topics (see "Patient education: Cough in adults (The Basics)")

●Beyond the Basics topics (see "Patient education: Chronic cough in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Specific therapy

●The first priority for management of a patient with persistent cough is establishing an etiology, so that therapy can be directed at the underlying cause (algorithm 1). The best approach is to use a systematic combination of empiric therapy and objective testing. (See "Evaluation of subacute and chronic cough in adults" and 'Specific treatment' above.)

●In patients with upper airway cough syndrome (UACS) who have a personal or family history suggestive of atopy, we recommend treatment with an intranasal glucocorticoid, rather than an oral antihistamine (Grade 1B). Combination therapy with an intranasal glucocorticoid 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".)

●In patients with suspected upper airway cough syndrome, but no features to suggest atopy, we suggest empiric treatment with a first generation oral antihistamine, rather than a second generation antihistamine (Grade 2B). A first generation intranasal antihistamine is an acceptable alternative. Addition of an oral decongestant medication may provide additional benefit. (See 'Upper airway cough syndrome' above.)

●In patients with subacute or chronic cough due to suspected cough variant asthma, we recommend regular use of an inhaled glucocorticoid and as-needed use of an inhaled bronchodilator, 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 'Cough variant asthma' above.)

●All patients suspected of having a cough due to gastroesophageal reflux should be advised regarding lifestyle modifications. In addition, we recommend using an empiric trial of acid suppression medication therapy, rather than direct testing for gastroesophageal reflux (Grade 1B). Proton pump inhibitors appear to be more effective than H₂ antagonists in this setting. (See 'Gastroesophageal reflux' above.)

●A small number of patients have cough due to nonacid gastroesophageal or laryngopharyngeal reflux and may be helped by antireflux surgery, although further studies are needed. (See 'Other therapies' above.)

●For patients with cough following an upper respiratory infection and clinical features suggestive of UACS, we suggest treatment with an oral first generation antihistamine, rather than a second generation antihistamine (Grade 2B). The addition of on oral or intranasal decongestant may be beneficial to some patients. (See 'Following an upper respiratory tract infection' 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 'Following an upper respiratory tract infection' above.)

●For patients who develop a chronic cough while taking angiotensin converting enzyme inhibitors (ACEI), we recommend stopping the ACEI 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 'Specific treatment' above.)

Nonspecific therapy

●There are patients for whom the etiology of the cough cannot be identified, no specific therapy exists, or specific therapy has failed. For such patients, we suggest treatment with the non-opioid agent, dextromethorphan, rather than using an opioid (Grade 2C). Benzonatate can be added if the cough persists despite dextromethorphan. (See 'Nonspecific treatment' above.)

●For patients who have a cough due to an unrelenting cause or a persistent cough despite both specific therapy and nonspecific therapy with non-opioid agents, we suggest a trial of an opioid antitussive (Grade 2B). Codeine and morphine are commonly used opioid antitussives. (See 'Nonspecific treatment' above.)

●Gabapentin and pregabalin are alternative, symptomatic treatments for patients whose cough is refractory to the above measures. (See 'Gabapentin and pregabalin' above.)