Preparing for a New Era in Chronic Cough Management

Abstract

Chronic cough, defined as cough lasting 8 weeks or more in adults, accounts for approximately 16 million outpatient visits per year. Chronic cough exerts a significant burden on the quality of life of patients, which is often why they initially seek treatment. Various factors have contributed to the high cost associated with the burden of chronic cough, from multiple referrals and unnecessary repeat testing to polypharmacy and development of comorbidities due to lack of proper treatment. Although treatment guidelines for chronic cough are available, they vary in their recommendations. There are no FDA-approved agents indicated specifically for chronic cough at this time, but medications such as inhaled corticosteroids and narcotic antitussives are frequently used for treatment, while speech and behavioral therapy have also been potential options. New targeted therapies in the clinical pipeline are expected to expand the treatment landscape and meet the unaddressed gaps for safe and efficacious agents that can provide relief and better management for patients. Access to appropriate care based on clinical guidelines is associated with favorable outcomes. Managed care organizations should consider treatment guidelines, patient factors, and emerging pharmacologic as well as nonpharmacologic treatment options to create a streamlined approach to managing chronic cough treatment in an evidence-based and cost-effective manner.

Am J Manag Care. 2020;26:S246-S250. ​https://doi.org/10.37765/ajmc.2020.88516

Introduction

Chronic cough, defined as cough lasting 8 weeks or more in adults or 4 weeks or more in children, accounts for about 16 million outpatient visits each year.^1,2 The condition affects 8% to 10% of the population.³ Several underlying conditions are often responsible, including asthma, gastroesophageal reflux disease (GERD), and postnasal drip syndrome (PNDS). Despite comorbidities associated with chronic cough, up to 10% of patients experience unexplained chronic cough (UCC) in which no clear cause can be identified.⁴ The American College of Chest Physicians (CHEST) suggests using the term “unexplained” over “idiopathic” for these patients, as it is likely that there is more than 1 source of underlying disease. While it is a commonly used term, the European Respiratory Society (ERS) identifies this condition as refractory chronic cough (RCC), and this is the term that will be used throughout.⁵

Economic Burden of Chronic Cough

Chronic cough exerts a substantial economic burden due to multiple primary care and specialty office visits. The use of medications to manage symptoms and comorbid conditions, such as depression, anxiety, and insomnia, is also another factor that contributes to the significant burden of RCC. Some patients with a history of smoking may have a concomitant chronic cough diagnosis code.³ However, for many patients who have RCC, it is due to vagal hypersensitivity/enhanced cough reflex sensitivity. In a questionnaire survey, patients were a mean age of 65 years, although another survey revealed the condition was most common in patients aged 50 years and older.⁶ The most common age for presentation is shown to be between 50 and 69 years.⁷ Based on these age demographics, it is reasonable to infer that patients eligible for Medicare coverage may be more affected than those with other benefits.⁸

Chronic cough accounts for up to 38% of a pulmonologist’s outpatient practice.^9,10 RCC is a diagnosis of exclusion. Diagnosis of chronic cough can involve numerous tests for common causes and comorbidities. Most patients visit their physicians at least 3 times, and 53% are diagnosed with an underlying condition.¹¹ Patients may consult up to 6 medical providers while their symptoms persist for a median of almost 7 years.¹²

Cough is the most common reason for primary care visits, with up to 85% receiving prescriptions for treatment.^3,12 Despite these high prescribing rates, the majority of patients report no symptom improvement.^11-13 For example, it is reported that almost 60% of patients receive codeine-containing antitussives; 45%, proton pump inhibitors; 26%, antidepressants; 15.5%, antianxiety medications; and 13.9%, neuromodulators, such as gabapentin.¹⁴ An average of $3266 is attributed to annual medical costs per patient (including prescription medications, office visits, and hospitalizations).¹⁵ Emergency department visits and hospital utilization due to negative sequelae of continued coughing also contribute to the increased cost of managing chronic cough. Even annual costs for over-the-counter (OTC) antitussives, which only temporarily suppress symptoms, are estimated at as high as $1 billion to $3.5 billion.^10,16

Treatment of Chronic Cough With Underlying Conditions

Successful treatment of chronic cough is dependent on identifying the underlying cause. Given the known association between chronic cough diagnosis and history of smoking in patients, smoking-cessation treatment options should be offered first line for patients.¹⁷ Smoking was associated with $168 billion in healthcare spending across all payers in the United States in 2010.¹⁸ In addition, another $107.6 billion is attributed to loss of productivity in the United States each year due to smoking.¹⁹ Results of a study estimated that the return on investment (ROI) for providing up to 2 quit attempts per year with no patient cost sharing would increase to a positive value in the fourth year for commercial and Medicaid plans, and in the third year for Medicare plans. The ROI over 10 years would be $1.18, $2.50, and $3.22 savings for every dollar spent on smoking cessation prescriptions for commercial, Medicaid, and Medicare plans, respectively.²⁰

Patients with asthma, especially cough-variant asthma (in which cough is the sole or predominant symptom),usually benefit from treatment with an oral or inhaled corticosteroid (ICS).^21-24 An analysis of managed care claims found that 38% of patients with chronic cough had been prescribed an ICS; 24%, an ICS/long-acting β-agonist combination; and 15.2%, ICS monotherapy.¹⁴ Results of a large international survey found that while 23% of patients with chronic cough had been diagnosed with asthma, 37% had been prescribed corticosteroids.¹¹ Another survey found similar results, with 24% of respondents reporting a preexisting diagnosis of asthma, and 32% prescribed an oral or ICS at some point.¹² Although more robust studies are lacking, antileukotrienes, such as montelukast and zafirlukast, have also shown beneficial effect in treating cough-variant asthma.²⁵ Medication costs for asthma treatment may also vary based on individual payer contracts and formulary status.

COPD can often cause a chronic cough, and symptoms can be similar between COPD and asthma. Patients with mild COPD frequently experience cough lasting an average of 1 year before they seek medical help and confirm a diagnosis.^26,27 They also report nightly symptoms that affect sleep quality, which affects energy levels and the ability to perform daily tasks.⁶

Impact of Chronic Cough on Quality of Life (QOL)

Patients with chronic cough most often seek medical attention when it impacts their QOL. Patients with persistent symptoms can cough up to thousands of times a day, and their condition may persist for several years without diagnosis or effectivetreatment.¹⁴ These patients report that symptoms affect their daily activities, such as going up and down stairs and getting out of bed.²⁷ Depression and frustration are common among patients with chronic cough, and 94% reported that their cough disturbed or worried their friends and family.¹¹ A study conducted in a specialty center identified significant symptoms of depression in 53% of the 100 patients evaluated, noting a substantial improvement in depression as the patients’ cough improved.²⁸

One of the first investigations of the impact of chronic cough on QOL enrolled 39 patients. Most sought medical care because they were afraid something was wrong, but about half sought care because of retching and exhaustion due to the cough, embarrassment, and because others thought something was wrong with them. They reported difficulty being heard during phone calls and giving up pleasurable activities, such as singing in church. Several reported that consistent coughing contributed to feelings of exhaustion as well as absenteeism from work and school.¹⁰ Another study demonstrated how many patients who sought medical care at specialty cough clinics took early retirement because of their cough but did not qualify for disability insurance coverage.²⁹

Other ways chronic cough has severely impacted the QOL of patients is through development of other comorbidities. Chronic cough is also linked to high rates of anxiety, as almost half of the patients evaluated in a specialty clinic reported in a study.³⁰ In another survey, participants reported that their cough interfered with their social life, causing anger, anxiety, and depression. They also experienced numerous physical effects, including breathlessness (55%), wheeze (37%), fatigue (72%), and disturbed sleep (70%). More than half of the women in the survey also reported incontinence.¹²

Managed Care Considerations for Chronic Cough

Guideline Recommendations

Guideline development is complicated given limited evidence and access to standardized assessments and diagnostic tools.^4,9,31,32 Finding effective treatment for chronic cough, especially RCC, poses a challenge. Although there are some differences, the CHEST and ERS guidelines offer treatment algorithms to help appropriately diagnose and treat patients with chronic cough.^3,4,31 These algorithms can be used to inform considerations for utilization management, prior authorization, and benefits coverage.

Diagnosis and Pharmacologic Treatment

Because RCC diagnosis is one of exclusion, testing for other common causes, such as asthma/COPD and GERD, should be reviewed in consideration for treatment coverage. For example, ICS should not be required in prior authorization criteria for patients who do not have signs or symptoms of chronic respiratory disease (eg, bronchial hyperresponsiveness, eosinophilia).⁴ Treatment response should also be reviewed on at least an annual basis, as many patients still report limited efficacy when medications are prescribed.^33,34

Some studies have explored various algorithms for their effectiveness and economic value. Lin et al conducted a cost-effectiveness analysis comparing 6 common treatment options for RCC involving a stepwise approach to testing for underlying conditions, then testing for PNDS, asthma, and GERD, and then treating each condition sequentially. The model assumed no overlap among the 3 diseases and a maximum treatment period of 12 weeks, with 1 week to receive the outcomes and no more than 2 weeks to judge the effectiveness of the treatment drug, which was considered 100% effective.³⁵ The authors found that a “test all, then treat” approach had the shortest treatment duration but the highest cost per treated patient ($556), whereas empirical treatment (treat sequentially starting with PNDS) was the least costly approach ($149).³⁵

The CHEST and ERS guidelines suggest a therapeutic trial of gabapentin for treating UCC, which has been associated with significant improvement in patient QOL with reduced cough frequency and severity.^34,36,37 Common adverse effects associated with gabapentin use include confusion, dizziness, and dry mouth.^34,36 For this reason, CHEST guidelines suggest assessing the risk−benefit profile of continued treatment with gabapentin every 6 months.⁴ In addition, managed care organizations may recommend adherence monitoring at least every 6 months to ensure appropriate use of the medication to continue coverage.

CHEST and ERS differ in their recommendations for morphine use in the treatment of UCC. Although a low dose is recommended by ERS for treatment, this recommendation should be weighed against policies regarding opioid utilization within the organization. Morphine is also commonly associated with constipation and drowsiness.^35,36,38 These adverse reactions are even more concerning as the majority of patients who experience chronic cough are in the older adult population, making the medication potentially inappropriate for use.³⁹ Prescription drug monitoring programs should be reviewed to limit abuse and diversion. Patient education on opioid-reversal agents and techniques should also be performed on a regular basis.⁴⁰

Emerging Therapies

As highlighted in the second part of this supplement, several novel therapies that address chronic cough at the molecular level are in late-stage clinical trials. The phase 3 results of the P2X3 antagonist gefapixant, released in September 2020, suggest that it may be the first to reach the market.^41,42 Phase 2 studies were also completed in spring 2020 for a second P2X3 antagonist, BLU-5937.⁴³ The emerging P2X3 antagonists are highly selective and may cause less dysgeusia.^41,43-45 Additional agents include BAY1817080 and S-600918, which are in the pipeline. ^46,47 Clinical considerations, benefits coverage decisions, and monitoring requirements should be made based on available evidence, treatment guidelines, and consideration of cost-effectiveness of existing alternatives.

Nonpharmacologic Approaches

In addition to pharmacologic treatment, the CHEST guidelines suggest a trial of speech and language therapy for UCC.⁴ Behavioral treatment involves education, cough-suppression strategies, reducing laryngeal irritation, and psychoeducational counseling. This all occurs within 3 to 4 sessions.⁴⁴

The first randomized, placebo-controlled study of speech pathology therapy in patients (N = 87) with RCC compared a 4-session intervention involving education about the nature of chronic cough, strategies to control the cough, psychoeducational counseling, and vocal hygiene education to reduce laryngeal irritation with a 4-session placebo group that received healthy lifestyle education. Overall, 88% of participants in the interventional group demonstrated clinically significant improvements in cough frequency, dyspnea, voice, and upper airway symptoms compared with 14% in the placebo group (P <.001).⁴⁴

Results of a study in which behavioral therapy was instituted earlier in the treatment algorithm found it improved patients’ QOL and condition faster than empirical treatment and reduced costs.⁵ In another study of behavioral therapy, results found it effectively resolved or showed marked improvement in cough symptoms in 84% of patients who were refractory to medical treatment.⁴⁸ While there is not yet a standardized tool to assess which patients are most likely to benefit from speech pathology interventions, results of a study found that patients with paradoxical vocal fold movement or muscle tension dysphonia may be most likely to experience symptom improvement (see Table).⁵

Although there is limited high-quality evidence, studies show that speech pathology-based treatment provides a positive benefit with no adverse effects.³ Despite positive evidence found in studies, speech therapy is significantly underused in clinical practice.⁵ Zeiger et al analyzed more than 11,000 managed care claims and found that 1.9% of patients had seen a speech therapist.¹⁴ Speech therapy may be recommended at any time during a patient’s treatment, and should certainly be considered for patients who are refractory to multiple medications.

Conclusions

Diagnosis and treatment of UCC/RCC can lead to considerable patient frustration and increased costs due to extensive testing and numerous primary care and specialty visits. Emergency department and hospital utilization are additional cost drivers, as patients may experience additional complications from frequent coughing. Narcotic antitussives (eg, morphine) and gabapentin have been shown to be efficacious for chronic cough, particularly RCC. Opioid utilization management policies should be considered and the risk−benefit profile of using these medications should be frequently assessed to ensure patient safety during treatment. Educating patients about their disease and its management has been shown to enhance patient efficacy and engagement, leading to lower healthcare costs and greater adherence.⁴⁹ Speech and behavioral modification therapy are currently underutilized and may produce more favorable outcomes for patients, especially those who have tried several medications in the past.

Existing guidelines (eg, CHEST and ERS) may be used to inform organizational policies on diagnosis and continued treatment of UCC/RCC. Although some differences exist between guidelines, they serve as valuable resources to streamline patient care based on clinical evidence in a cost-effective manner.

The introduction of new, targeted therapies may dramatically change the treatment landscape. Consideration for their use should be evidence based and in examination of patient factors and existing alternatives. Managed care organizations have the potential to ensure a more systematic approach to the treatment of chronic cough through utilization management and prior authorization policies. Patient follow-up for therapy efficacy is also important to ensure adherence and continuity of treatment.

Author affiliation: Desola Davis, PharmD, BCPS, BCACP, is a drug use management clinical pharmacy specialist, Kaiser Permanente Georgia, Atlanta, GA.

Funding source: This activity is supported by an educational grant from Merck Sharp & Dohme Corp.

Author disclosure: Dr Davis has no relevant financial relationships with commercial interests to disclose.

Authorship information: Substantial contributions to concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.

Address correspondence to: desola.davis@kp.org

Medical writing and editorial support: Debra Gordon, MS

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