Pharmacotherapy considerations for morning symptoms in chronic obstructive pulmonary disease

KEYWORDS:

• Chronic obstructive pulmonary disease
• circadian rhythm
• long-acting bronchodilators

1. Introduction

Morning symptoms are often underrecognized in clinical practice but constitute a significant concern for patients with chronic obstructive pulmonary disease (COPD). In fact, many patients report that morning is the worst time of day in terms of dyspnea, quality of life, and functional capacity. This may reflect underlying circadian variability in airway physiology. A personalized and rational pharmacotherapy regimen is thus important to reduce symptom variability. While prescribing bronchodilators to a patient with COPD, the health-care provider should first ascertain the impact of morning dyspnea using a validated questionnaire, and consider the medication’s pharmacokinetics including therapeutic duration and onset of action, which will also inform dosing schedule. More research is required to inform our understanding on how pharmacotherapy can optimize morning symptoms and quality of life.

2. Morning symptoms in COPD

Morning symptoms significantly impact quality of life and ability to perform daily activities. In a quantitative internet interview with 803 COPD patients from Europe and the United States (US), 37% of the cohort and 46% of those with severe COPD reported that morning was the worst time of the day for symptoms [1]. A majority of those with severe disease were awoken by their symptoms at least 3 days a week [1]. In a cross-sectional study involving 1239 COPD participants in the US, the most commonly reported symptoms were cough (74.5%), shortness of breath (73.9%), and mucus production (69.6%) [2]. Approximately 60% of respondents reported a limitation in their morning activities due to these symptoms [2]. This was also reflected in frequent rescue medication use during this time of the day, with 43% of those with morning symptoms requiring medications on average 5.1 ± 2.4 mornings during the prior week [2]. It should be noted that morning symptoms such as dyspnea are not specific and may reflect pathology and/or disease activity in other organs such as the cardiovascular system (e.g. congestive heart failure, CHF). For example, one study suggested a prevalence of previously undiagnosed CHF of 21% in patients with COPD or asthma [3]. The distinction in diagnosis has important therapeutic implications as short-acting beta-2 agonists can potentially exacerbate cardiac function [3]. Moreover, patients with CHF should be treated with cardiac medications such as diuretics for symptom relief.

In one study, patients who experienced morning symptoms were older, had been diagnosed with COPD for a longer duration, demonstrated worse lung function, and showed lower treatment adherence [4]. After controlling for potential confounders, the authors found that morning symptoms were significantly associated with a higher exacerbation frequency [4], which may indicate increasing underlying disease severity or instability in disease control. Notably, studies which have evaluated circadian variability of patient-reported symptoms in COPD often did not collect concurrent pulmonary function measurements. Thus, the relationship between morning symptoms and lung function within individuals is not entirely clear. Moreover, it remains uncertain whether therapies that improve morning flow rates will necessarily ameliorate morning symptoms or vice versa.

2.1. Circadian variability in COPD

One reason why respiratory symptoms may be more pronounced in the mornings is related to circadian variations in lung function, which have been frequently described in asthma but less so in COPD. Airway caliber exhibits variation during the 24-h day cycle with its maximum at noon and minimum in the early morning, and this variation in lung function fluctuates around 16 L/min/day in subjects with COPD [5]. Similarly, FEV₁ in stable COPD tends to peak at 1600 h and reaches a nadir at 0400 h, with similar trends in inspiratory capacity, forced vital capacity, and peak inspiratory flow [6–8]. In a study of COPD participants, a drop in FEV₁ in the early morning coincided with a decrease in partial pressure of oxygen (PaO₂) and oxygen saturation (SaO₂) in arterial blood [9]. The correlation between FEV₁ and PaO₂ at all hours of observation was strong (r = 0.79, p < 0.01) [9]. Compared to healthy participants, the circadian rhythm of FEV₁, PaO₂, and SaO₂ fluctuated with a higher amplitude in those with COPD. The circadian variability was 20% for FEV₁ and 17% for PaO₂ in patients with COPD [9]. The physiologic mechanism underlying FEV₁ variability is attributed to higher sympathetic activity during the day and increased parasympathetic activity at night. The latter results in a higher cholinergic tone in the airway smooth muscle, which can lead to airflow limitation [7,8]. However, data from COPD patients already taking tiotropium, a long-acting anticholinergic medication, suggest that this is not the only factor involved [5].

3. Patient perspectives on pharmacologic treatment

Some studies report patient perspectives on the role of pharmacologic treatment for their morning respiratory symptoms. In a cross-sectional study involving 17 European countries, over half (51.3%) of the patients who reported significant morning symptoms did not adjust treatment when symptoms worsened [10]. Among those who modified their treatment, 28% reported increased rescue inhaler use and 29% followed instructions from their physicians [10]. Medication adherence also plays a crucial role. Approximately 37% of patients declared that their symptoms worsened because they forgot to take their daily medications [10]. This emphasizes the importance of patient education on the use of COPD medications to reduce symptom variability.

3.1. Pharmacologic treatment considerations

Long-acting beta-2 agonists (LABA) and long-acting muscarinic antagonists (LAMA) are the cornerstone of COPD pharmacotherapy. To address morning respiratory symptoms in this patient population, there are several relevant considerations including therapeutic duration, onset of action, and medication timing.

3.1.1. Therapeutic duration

There was a historical paradigm shift from using short-acting bronchodilators with multiple daily doses to longer acting bronchodilators that can be used once or twice daily. This has resulted in better clinical outcomes including improved symptom control, quality of life, FEV₁, and reduced exacerbations [11]. For example, salmeterol and formoterol (both twice-daily LABAs) are superior to short-acting bronchodilators (given every 4–8 h) in improving FEV₁ [11]. Tiotropium (a once-daily LAMA) consistently improved morning trough FEV₁, dyspnea, and exacerbations compared to ipratropium (a short-acting muscarinic antagonist taken every 6 h) [11]. Indacaterol (a once-daily LABA) was superior with regard to trough FEV₁, dyspnea, and rescue medication use compared to formoterol or salmeterol [11]. A possible mechanism to explain the superiority of prolonged bronchodilation is more effective lung emptying during tidal breathing which reduces lung hyperinflation and increases expiratory flow rates and improves compliance over the entire 24-h period [11]. Overall, these findings point to a number of benefits with long-acting bronchodilators, such as improved clinical outcomes and reduced dosing frequency [11]. Longer duration of bronchodilation leads to improved airflow over 24 h leading to a net increase in the 24-h area-under-the-curve for FEV₁ and also an improvement in morning FEV₁ after the last inhalational dose (Figure 1).

Figure 1. Schematic of the theoretical variation in airway caliber due to circadian rhythm and the bronchodilation effect of long-acting (1× or 2× daily) and short-acting (4× daily) therapies. Long-acting bronchodilators lead to an increased net area under curve and higher morning FEV₁ following the last inhalation (trough FEV₁). Administration of bronchodilator at 0800 h (trough) coincides with a lower airway caliber which is hypothesized to worsen morning symptoms. Shifting the time of medication administration may mitigate this effect. Figure 1 adapted with permission from Springer Nature: Kai M. Beeh et al, Advances in Therapy, 2010 [11].

There is a paucity of data on the effects of dual long-acting bronchodilator therapy (LAMA/LABA fixed combinations) on morning symptoms in COPD. However, they improve health status and reduce dyspnea compared to monotherapy with LABA or LAMA. Thus, they may be considered for patients who have persistent morning symptoms on LABA or LAMA monotherapy. There are no data directly comparing twice-daily LAMA/LABA versus once-daily LAMA/LABA [12]. Similarly, there is a scarcity of studies that have compared once-daily triple- versus twice-daily triple therapy. A recent pool analysis of two phase IV trials showed that once-daily triple therapy (with fluticasone furoate/umeclidinium/vilanterol) was non-inferior to twice-daily budesonide/formoterol plus tiotropium bromide with regard to symptom burden, health status, or lung function measurements including morning flow rates [13]. However, these data should be interpreted cautiously as it did not directly evaluate morning symptoms. Theoretically, once-daily triple therapy (ICS/LABA/LAMA) may provide the steadiest and longest duration of action to address morning symptoms. However, some patients may still report differences in therapeutic effects depending on the time of administration, and therefore, this is an interesting and worthwhile area of further research.

3.1.2. Onset of action

Bronchodilators are often prescribed to be taken in the morning, but this poses a challenge for patients who are not taking their medications in time to specifically address morning dyspnea [1]. As a result, patients with COPD often take their medications too late after waking up to optimally control their morning symptoms [4]. Pharmacokinetic differences among the bronchodilator regimens may also matter. In a randomized, double-blind, crossover study comparing the maintenance combination of budesonide/formoterol and fluticasone/salmeterol in 442 patients with COPD, the authors found that the former regimen (despite a lower corticosteroid dose) enabled patients to perform early morning activities more effectively because formoterol had a more rapid onset of action than salmeterol [14].

3.1.3. Medication timing

Only several studies have specifically addressed the question of whether bronchodilator timing affects clinical efficacy (Table 1). In one randomized, placebo-controlled trial, the timing of tiotropium (given once daily either at 9 am or 9 pm) did not lead to significant differences in mean change in FEV₁ [5]. Another randomized, crossover study involving 80 subjects with stable moderate-to-severe COPD compared five different combinations of tiotropium (Tio) with or without formoterol (Form): Tio 8 am; Tio 8 am and Form 8 pm; Form 8 am and 8 pm; Tio + Form 8 am, and Form 8 pm; Form 8 am, and Tio + Form 8 pm [15]. While regimen 4 (Tio + Form 8 am, and Form 8 pm) was the most effective, regimen 5 (Form 8 am, and Tio + Form 8 pm) showed the least variability in FEV₁ during the 24 h. In addition, regimen 5 also provided the greatest patient symptom control and the lowest use of salbutamol in patients with predominant nighttime symptoms [15]. This suggests that individual tailoring of pharmacotherapy timing is required to optimally control patient symptoms.

Table 1. Clinical studies that address the impact of medication timing on clinical efficacy in COPD.

Treatment	Study design	Patient population	Outcomes	Reference
Tiotropium bromide 18 mg once daily: (1) 0900 h (Tio-AM) vs. (2) 2100 h (Tio-PM) vs. placebo	6-week, multicenter, double-blind, randomized, placebo-controlled trial	Stable COPD aged ≥40 years and a smoking history of at least 10 pack-years (n = 121; mean FEV1 = 41% predicted)	No significant difference in mean nocturnal or steady state FEV1 or forced vital capacity (FVC) between Tio-AM and Tio-PM groups after 6 weeks.	[5]
Tiotropium (Tio) with or without formoterol (Form): (1) Tio 0800 h vs. (2) Tio 0800 h and Form 2000 h vs. (3) Form 0800 h and 2000 h vs. (4) Tio + Form 0800 h, and Form 2000 h vs. (5) Form 0800 h, and Tio + Form 2000 h	Randomized, blind, crossover study	Stable moderate-to-severe COPD with a smoking history (n = 80; mean post-bronchodilator FEV1 = 54% predicted)	At day 30, Treatment (5) showed the largest mean ∆ FEV1 increase compared to day 1. Treatment (5) showed the least FEV1 variability during the 24 h.	[15]
Sustained-release oral Theophylline: (1) 8 mg/kg at 0700 h and 4 mg/kg at 1900 h vs. (2) 6 mg/kg at 0700 h and 6 mg/kg at 1900 h vs. (3) 4 mg/kg at 0700 h and 8 mg/kg at 1900 h	Randomized, crossover study	Males with COPD and a history of asthma (> 15% response to inhaled β2 stimulants) (n = 12; mean FEV1 84% predicted)	24-h average peak expiratory flow was significantly higher in Treatment (3).	[16]

4. Expert opinion: strategies to improve pharmacologic management

Two ways to better understand morning dyspnea in COPD are to improve clinical assessment and to increase clinical research on pharmacotherapy with a focus on symptom variability and morning symptoms as outcomes.

A survey by Partridge et al. reported that only 22–44% of COPD patients are asked about their morning symptoms, and 9–22% are asked about their morning routines [1]. There is little emphasis on morning symptoms in the Global Initiative for Chronic Obstructive Lung Disease (GOLD) reports [17]. Furthermore, traditional patient-reported questionnaires used in COPD, such as the St George’s Respiratory Questionnaire (SGRQ) and the Baseline and Transition Dyspnea Index (TDI) do not specifically address the impact of symptoms on morning activities [8]. Alternatively, the Capacity of Daily Living during the Morning (CDLM) and the Global Chest Symptoms Questionnaire (GCSQ) are validated, reliable, self-administered questionnaires that report on morning symptoms and activities [18]. Better awareness of morning symptoms in the COPD population can lead to a more rational prescription practices. For example, use of long-acting bronchodilators in the evening may be a simple way to address bothersome morning symptoms.

More research in this area is needed. Most pharmacologic studies in COPD answer the question of what bronchodilators to use, but do not address other important aspects of when and how to use these medications. New clinical trial designs are needed to elucidate the most optimal dosing schedule of therapeutics in controlling morning symptoms and quality of life of COPD patients.

From a drug development perspective, an interesting area of research is to investigate inhaled therapies that are convenient and simple to use, and can provide a more rapid onset of action, greater stability, and longer lasting therapeutic effects. For instance, the delivery and release of drug may be modulated to maximize therapeutic levels at the most suitable time of the day that aligns with the circadian airway physiology. Drugs with delayed release properties may ensure a more stable therapeutic plasma level between doses. Another research area of interest is investigating how specific timing of bronchodilators affects medication adherence. A particular challenge stems from the fact that the experience of morning respiratory symptoms is unique to each patient according to their disease and lifestyle. Therefore, bronchodilator therapy in COPD also requires a more personalized approach.

Morning respiratory symptoms are a major concern for patients with COPD, but there has been little attention on this particular issue in the field. Pharmacotherapy has the potential to further optimize quality of life, symptoms, and functional capacity for patients. This requires collaboration among patients, clinical researchers, pharmaceutical industries, and health-care providers. More clinical research is urgently to help inform our management of COPD patients.

Declaration of interest

DD Sin has received honorarium for talks on chronic obstructive pulmonary disease from AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Funding

This paper was not funded.