INTRODUCTION

Sputum production is a common feature of chronic obstructive pulmonary disease (COPD), but for some patients, it is difficult to clear, leaving them potentially vulnerable to respiratory infections.

This resource will examine the rationale for mucolytic therapy in the management of patients with COPD. It will discuss the use of mucolytic therapies based on current evidence, and where the use of mucolytics is recommended in international and UK COPD guidelines.

LEARNING OBJECTIVES

After working through this resource, you will be more familiar with:

• Sputum production and clearance in patients with chronic obstructive pulmonary disease (COPD)
• The physiological process of mucus secretion
• Evidence for the use of mucolytics in patients with COPD
• Guideline recommendations
• Non-pharmacological interventions to improve symptoms of COPD

 

 

This resource is provided at an intermediate level. Read the article and answer the self-assessment questions, and reflect on what you have learned.

Complete the resource to obtain a certificate to include in your revalidation portfolio. You should record the time spent on this resource in your CPD log.

Management of COPD symptoms: the role of mucolytics

COPD affects up to 3 million people in the UK, although only a third of these – just over a million – have been currently diagnosed.^1,2 This means that there are a lot of ‘missing’ patients who remain symptomatic, living with symptoms and disability. Around a third of patients are only diagnosed following a first admission to hospital with an exacerbation.^3,4

Symptoms of COPD develop due to airway inflammation, causing narrowing and obstruction of the airways. This results in airflow limitation and air trapping which subsequently leads to poor gas transfer and ultimately respiratory failure.^1,3

Although breathlessness is the most common symptom in COPD,³ some patients have a productive cough, caused by hypersecretion of the mucus glands in the airways, and occasionally wheeze and or chest tightness, again caused by narrow airways.

The obstruction in the airways, unlike asthma, is irreversible and usually progressive over time.

CHRONIC BRONCHITIS

COPD is an umbrella term for emphysema and chronic bronchitis. The two phenotypes can also overlap, and some patients can have both emphysema and chronic bronchitis.⁵

To diagnose chronic bronchitis, patients will have a productive cough for at least 3 months of the year for 2 consecutive years,4 but the reality is that most patients cough every day throughout the year.

About a third of patients with COPD will have the chronic bronchitis phenotype and studies have shown that those patients with chronic bronchitis lose lung function, as defined by Forced Expiratory Volume in one second (FEV1), faster than those without, and that the death rate is higher in this patient group.⁴

MUCUS SECRETION

The respiratory tract contains specialised epithelial cells, known as goblet cells, that secrete mucins, which are a significant component of mucus. The normal physiological role of mucus in the airways is to act as a barrier against particles and micro-organisms that may have been inhaled.⁶ Goblet cells, and therefore mucus production, are significantly increased when the epithelium is irritated, for example, by inhaling cigarette smoke and other noxious fumes.

In normal circumstances, approximately 20-30ml of secretions are produced by the airways every day. A ‘mucociliary escalator’, made of beating cilia, brushes the mucus upwards from the bronchus, and away from the airways.⁷

These secretions are often swallowed. If the quantity of mucus exceeds 30ml, a cough is necessary to clear the airways of the mucus. Cough receptors around the trachea and pharynx induce a cough to expel the excessive mucus. Patients with chronic bronchitis have impaired mucociliary clearance and this is associated with increased vulnerability to respiratory tract infections.⁷

Other respiratory conditions are also associated with difficulty in expectorating mucus, for example, bronchiectasis, where there is damage to the epithelium and the cilia are destroyed,⁸ and cystic fibrosis, where the mucus can become dehydrated, making it thick and sticky so that the cilia are unable to propel the mucus upwards from the airways.^9,10 Accumulation of mucus can cause coughing, wheezing, shortness of breath and an increased risk of infection.

Mucolytic drugs act by altering and breaking the bonds that hold mucus together, reducing thickness and making it easier to expectorate. The mechanisms of action of mucolytics vary, with some acting only on goblet cells (carbocisteine),¹¹ while others also impact the viscosity of mucous secretion and improve mucocilliary clearance (N-acetylcysteine).¹²

EVIDENCE BASE

In 2019, an independent Cochrane review compared mucolytic agents versus placebo in patients with chronic bronchitis or COPD.¹³ The primary objective was to determine if there was a reduction in exacerbations and/or days of disability in patients prescribed a mucolytic. Secondary objectives included improvement in lung function or quality of life. The review also looked at the frequency of adverse events associated with the use of mucolytics.

The review looked at 38 different trials, involving over 10,000 participants. Most of the studies looked at the use of N-acetylcysteine (NAC) rather than carbocisteine. Some of the studies looked at mucolytics not available to prescribe in the UK. None of the studies were head-to-head between acetylcysteine and carbocisteine.

The review concluded found that patients prescribed a mucolytic were more likely to be exacerbation-free compared with those given placebo. The number needed to treat (NNT) was low, at only 8 to keep a patient exacerbation-free for an average of 9 months.

This compares favourably to the NNT of 14 patients on an ICS/LABA combination inhaler,¹⁴ and 12 on a LAMA/LABA combination inhaler¹⁵ to prevent an exacerbation over a 12-month period.

The review found that patients taking mucolytics had fewer days of disability, and were also less likely to be admitted to hospital. The review found an overall improvement in quality of life, but this did not reach the threshold for clinical importance. There was a small improvement in lung function and no increase in side effects in those patients taking a mucolytic compared with placebo.

GUIDELINE RECOMMENDATIONS

The main guidelines available to help clinicians diagnose and treat patients with COPD are the Global Initiative for Chronic Obstructive Lung Disease (GOLD) Report,¹ the clinical guideline from NICE (NG 115)³ and, in Scotland, the Best Practice guide.²

In both the GOLD report and NICE guidelines, non pharmacological therapies, such as smoking cessation, influenza, pneumococcal and COVID-19 vaccinations, and pulmonary rehabilitation are recommended.^1,3 Both guidelines also state that long-acting bronchodilators are the cornerstone of maintenance treatment. For some patients, if they are demonstrating features of asthma, or are having frequent exacerbations, inhaled corticosteroid treatment (ICS) is recommended.

NICE recommends considering mucolytic therapy for people with a chronic cough productive of sputum. Mucolytics should only be continued if there is improvement in symptoms (e.g. frequency of cough and sputum production). NICE does not currently recommend routine use of mucolytic drugs to prevent exacerbations in people with COPD.³

However, GOLD states that in patients not receiving ICS, regular treatment with mucolytics such as NAC and carbocisteine may reduce exacerbations and modestly improve health status.¹ GOLD also says that decreasing mucus viscosity and facilitating elimination of mucus by increasing ciliary transport should be among the goals of treatment for patients with chronic bronchitis.¹

CONSIDERATIONS WHEN PRESCRIBING A MUCOLYTIC

It is thought that 30–50% of medicines for long-term conditions are not taken as recommended. Non-adherence may limit the benefits of medication, resulting in lack of improvement or deterioration in the patient’s symptoms and health. Adherence is based on agreement between the patient and the prescriber about the prescriber’s recommendations, so it is important to explore the patient’s perspective and the reasons why they may not want – or are unable to – take the medication you recommend.¹⁶

In the UK there are currently two mucolytics licensed for long-term use in people with COPD. These are carbocisteine and NAC.^11,12 A third drug, erdosteine, is also available, but is only licensed for short-term use in acute exacerbations of chronic bronchitis.¹⁷

When prescribing a mucolytic, consider the dose form, pill burden, licensed indications, cost, and inclusion on local formularies.

• Dose forms: carbocisteine capsules are large (up to 2cm) and there are alternative forms (solutions/sachets) as well as effervescent forms (acetylcysteine) which some patients may find easier to take. The dose of carbocisteine should be down-titrated after 4 weeks.¹¹
• Pill burden: The number of capsules of carbocisteine is high (4-6 capsules per day in divided doses, usually three to four times a day) which can represent a significant burden to patients, who may be taking a number of other medications for COPD and/or comorbidities. Acetylcysteine is a once daily preparation.^11,12
• Licensed indication: be aware that erdosteine is only indicated for short-term use.
• Cost: Although generic mucolytic drugs are now available, the cost of carbocisteine (all forms) remains high (£8-£70/month) compared with acetylcysteine 600mg effervescent products (≤£5.50/month)*.¹⁸ Not all mucolytics will be included in local formularies – check local policies before prescribing.

The first two points above may have a significant impact on patient adherence. You should discuss the options before agreeing on which mucolytic to prescribe. In addition to the active ingredient, you should also consider the excipients in the mucolytic agent, as salt content, lactose, gelatine, sorbitol and aspartame are all relevant to some patient groups.

ANNUAL REVIEW

The annual review consultation, whether face-to-face or remote, provides an opportunity to discuss non-pharmacological interventions too. Patients should be asked about their fluid intake. In healthy individuals even mild dehydration can slow cognitive decision-making, increase fatigue, impair memory, alertness and concentration, and very importantly, physical performance.¹⁹ In people with chronic bronchitis this can further exacerbate problems with sputum clearance. The patient should be reminded to drink at least 1.2 litres of fluid a day to reduce the risk of dehydration.²⁰

Every patient should be asked if they are able to clear their chest effectively or if they are struggling with sputum clearance. They should be reminded of the importance of keeping physically active, to help with sputum clearance, and reminded about the active cycle of breathing techniques (ACBT), which has been found to improve sputum production and cough efficiency in patients with COPD.²¹ If the patient continues to struggle to expectorate their sputum, a referral to a respiratory physiotherapist may be of benefit. Some patients are suitable for positive expiratory pressure (PEP) devices. In PEP therapy the patient exhales against a fixed-orifice resistor. This generates a pressure during expiration ranging from 10-20 cm H2O. This can then help promote effective airway clearance by mobilising secretions.²²

For those patients who, despite being well hydrated and trying to keep physically active and coughing effectively, continue to struggle to expectorate sputum, a mucolytic drug may be trialled.

Whenever a change is made to a medication the patient should be offered a review to assess the effect of the drug and if any side effects have been noted. Only then should the drug be added to their repeat prescription list.

*Prices correct at the time of publication. Please visit the Dictionary of Medicines and Devices (dm+d), at https://www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/dictionary-medicines-and-devices-dmd

 

Job code: AL0313                                Date of preparation: September 2023

REFERENCES

1. NICE NG115. Chronic obstructive pulmonary disease in over 16s diagnosis and management guidance; https://www.nice.org.uk/guidance/ng115

2. Scottish Government. Chronic obstructive pulmonary disease (COPD): best practice guide; 2017 https://www.gov.scot/publications/copd-best-practice-guide

3. Global Initiative for Chronic Obstructive Lung Disease (GOLD). Global Strategy for the Diagnosis, Management and Prevention of COPD, 2021. https://goldcopd.org

4. Kim V, Criner G. The Chronic Bronchitis Phenotype in COPD: Features and Implications. Curr Opin Pulm Med 2015;21(2):133-141

5. Boka K, Emphysema. Medscape 2019. https://emedicine.medscape.com/article/298283-overview

6. Bustamante-Marin XM, Ostrowski LE. Cilia and Mucociliary Clearance. Cold Spring Harb Perspect Biol 2017;9(4):a028241.

7. Camner P, Mossberg B, Philipson K. Tracheobronchial clearance and chronic obstructive lung disease. Scand J Respir Dis 1973;54:272–81

8. Bronchiectasis Toolbox: Airway Clearance in the Normal Lung. https://bronchiectasis.com.au/physiotherapy/principles-of-airway-clearance/airway-clearance-in-the-normal-lung.

9. Cystic Fibrosis Foundation. Reasearch into mucus. https://www.cff.org/research-mucus

10. Tilley A, Walters M, Shaykhiev R, et al. Cilia dysfunction in lung disease. Annu Rev Physiol 2015: 77:379-406

11. Carbocisteine 375mg Capsules. Summary of product characteristics. Last updated 21 October 2021. https://www.medicines.org.uk/emc/product/3291/smpc

12. Nacsys 600mg Effervescent Tablets. Summary of product characteristics. Last updated 31 July 2023. https://www.medicines.org.uk/emc/product/8576/smpc#gref

13. Poole P, Sathananthan K, Fortescue R. Mucolytic agents versus placebo for chronic bronchitis or chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2019:5(5): CD001287

14. Suissa. S. Number needed to treat in COPD: exacerbations versus pneumonias. Thorax 2013;68(6):540-3

15. Treatment of Chronic Obstructive Pulmonary Disease: Guidelines from the American Thoracic Society. Am Fam Physician 2021;104(1):102-103.

16. NICE CG76. Medicines adherence: involving patients in decisions about prescribed medicines and supporting adherence; 2009. https://www.nice.org.uk/guidance/cg76

17. Erdotin 300mg capsules. Summary of product characteristics. Last updated 31 May 2019. https://www.medicines.org.uk/emc/product/287/smpc#gref

18. NHS Business Services Authority. Drug Tariff; June 2023. https://www.nhsbsa.nhs.uk/pharmacies-gp-practices-and-appliance-contractors/drug-tariff

19. Cheuvront SN, Kenefick RW. Dehydration: physiology, assessment, and performance effects. Compr Physiol 2014;4:257-85.

20. NHS Choices. Water, drinks and your health, 2018. https://www.nhs.uk/live-well/eat-well/water-drinks-nutrition/

21. Shen M, Li Y, Ding X, et al. Effect of active cycle of breathing techniques in patients with chronic obstructive pulmonary disease: a systematic review of intervention. Eur J Phys Rehabil Med 2020 Oct;56(5):625-632.

22. Fagevik Olsen F, Lannefors L, Westerdahl E. Positive expiratory pressure. Common clinical applications and physiological effects. Respir Med 2015;105(3):297-307.