Review ArticleHypnotic use for insomnia management in chronic obstructive pulmonary disease
Introduction
Chronic Obstructive Pulmonary Disease (COPD) encompasses a range of respiratory diseases including chronic bronchitis, emphysema, and others. The disease is defined as a progressive limitation of functional airflow that is not fully reversible with inhaled bronchodilators [1]. The disease is progressive and chronic, requiring long-term treatment to improve quality of life in affected patients.
Several comorbidities accompany COPD including unexplained weight loss, cardiovascular disease, peripheral muscle weakness, cognitive impairment, depression, anxiety, and sleep disorders [2], [3]. COPD patients are more likely to have difficulty falling and staying asleep and have increased sleepiness during the day. In some cases, they take hypnotics to combat their sleep disturbance. Arousals from sleep are more likely in these patients due to chronic coughing and nocturnal wheezing and also nocturnal oxygen desaturation [4]. In addition, an increased number of COPD patients also have obstructive sleep apnea syndrome (OSAS), a condition that is referred to as overlap syndrome [5]. The coincidence of OSAS has detrimental effects on respiratory physiology and exacerbates hypoxia and hypercapnia in COPD patients during sleep [6]. This is particularly important to recognize because hypoxia correlates strongly with nocturnal mortality [7].
The most common pharmacologic treatment prescribed for insomnia including those comorbid with COPD are the benzodiazepine receptor agonists (BZRAs), a group of drugs that function by binding to the benzodiazepine receptor at the GABAA complex. These receptors are expressed in the plasma membrane of neurons throughout the CNS and PNS [8]. BZRAs include both the traditional benzodiazepines, which bind a broad range of BZ receptors and a newer group of more selective BZRAs called the non-benzodiazepine BZRAs. These drugs are more selective to a BZ receptor subtype that is expressed in the CNS and people have hypothesized that they produce fewer adverse side effects on pulmonary function than do the traditional BZRAs [8]. The selective MT1/MT2 melatonin receptor agonist ramelteon is another option for the treatment of insomnia. Melatonin receptors, expressed in the hypothalamus, regulate neural and endocrine mediated processes that control mammalian circadian rhythms [9]. By engaging signaling pathways downstream of these G-protein coupled receptors, ramelteon is believed to decrease sleep latency and increase sleep efficiency. Finally, the antidepressant trazodone is sometimes used off-label for treatment of insomnia and may be considered for use in COPD patients, although there is a lack of data on its effectiveness and safety in this patient population (NIH consensus statement).
It has become clear that the COPD patient population comorbid for insomnia is underserved by current practices in sedative pharmacotherapy. The current treatment paradigm relies heavily on CNS depressants, namely benzodiazepines, that can lead to hypoxia [4]. While there are no pharmacological treatments specifically indicated for the treatment of sleep disturbances in the COPD population, evidence suggests a reevaluation of the current treatment paradigm for this cohort of patients. As our understanding of sleep mechanisms has increased, so too has our appreciation for the clinical potential associated with newer sleep therapies. This review will discuss the clinical impact of insomnia on the COPD population and will highlight special considerations to be taken for this population and the risks related to current pharmacological treatment options of insomnia in COPD.
Section snippets
Effects of sleep on respiratory function in the COPD population
During sleep, a number of respiratory functions are affected in normal healthy individuals, including alterations in central respiratory control, airway resistance and airway muscle tone. Overall, these effects result in hypoventilation, moderate hypercapnia, and hypoxia [10]. During sleep the response of the respiratory center in the brain to both hypoxia and hypercapnia is attenuated, particularly during phasic REM sleep [11], [12], [13]. The changes in arterial blood gases that occur in
Insomnia in the COPD population
Nocturnal hypoxia and hypercapnia cause increased arousals and sleep disruption in COPD patients to improve respiration. This leads to sleep disruption and, in vulnerable individuals, chronic insomnia [3]. Over 50% of COPD patients report a long sleep latency, frequent arousals during the night and/or general insomnia [8]. Insomnia tends to be more prevalent and severe with advanced disease, roughly correlating with the extent of underlying lung disease [24]. Analysis of a large COPD database
The effects of COPD treatment on the development of insomnia
Although few studies have been done to determine the role that drugs used to treat COPD have on sleep, it is clear that insomnia can be a side effect of some of these medications. For example, bronchodilators used to treat some COPD patients have been noted to cause insomnia in a small population of treated patients [26], [27], [28]. In addition, other medications commonly prescribed to COPD patients including corticosteroids and β-adrenoreceptor agonists contribute to insomnia [29]. In
Pharmacologic treatment of insomnia
There are currently a limited number of classes of medication that are used to treat insomnia (Table 1). Benzodiazepine receptor agonists (BZRAs) are the most commonly prescribed sleep agents used in the management of insomnia in the COPD population [8], [31], [32]. This class of drugs includes both the traditional benzodiazepines that share the formal benzodiazepine chemical structure and have affinities for multiple subtypes of BZ receptors as well as the newer non-benzodiazepines (zolpidem,
Traditional benzodiazepines
The benzodiazepines traditionally prescribed for insomnia include those indicated specifically for insomnia, namely, temazepam, triazolam, flurazepam, estazolam, and quazepam among others (Table 1) [33]. These drugs have varied half-lives and some result in the production of active metabolites which cause daytime impairment. Those with shorter half-lives that do not result in the production of active metabolites are most useful in elderly patients and significantly decrease sleep latency but
Conclusion
COPD is a leading cause of worldwide mortality. Managing quality of life in COPD patients is critical as they are likely to live with the disease as it progresses over significant periods of time. Among other comorbidities, insomnia is prevalent in the COPD population and affected individuals seek treatment to improve their quality of sleep. Additionally, a significant percentage of COPD patients also have OSAS, which further complicates treatment of sleep disorders in the COPD population [4],
Acknowledgements
I wish to thank Amy S. McKee, Fred W. Peyerl and Fabian D’Souza of Boston Strategic Partners Inc., for research assistance and manuscript preparation.
References (63)
- et al.
Survival in COPD patients with a daytime PaO2 greater than 60 mm Hg with and without nocturnal oxyhemoglobin desaturation
Chest
(1992) - et al.
Ramelteon for the treatment of insomnia
Clin Ther
(2006) Neurobiology of REM and NREM sleep
Sleep Med
(2007)Sleep in patients with chronic obstructive pulmonary disease
Clin Chest Med
(1998)- et al.
Ventilation and gas exchange during sleep and exercise in severe COPD
Chest
(1996) - et al.
A comparative study of patients with chronic obstructive pulmonary disease with and without obstructive sleep apnea syndrome
Arch Bronconeumol
(1999) - et al.
Prevalence of insomnia in patients with chronic obstructive pulmonary disease in a large database
Value Health
(2005) - et al.
Efficacy and safety of formoterol fumarate delivered by nebulization to COPD patients
Respir Med
(2008) - et al.
Aging, drugs and sleep
Neurobiol Aging
(1982) - et al.
Cardiopulmonary hemodynamics during sleep in subjects with chronic obstructive pulmonary disease. The effect of short- and long-term oxygen
Chest
(1984)
Management of chronic insomnia in elderly persons
Am J Geriatr Pharmacother
Treating insomnia: Current and investigational pharmacological approaches
Pharmacol Ther
Effects of repeated administration of zolpidem on sleep, diurnal and nocturnal respiratory function, vigilance, and physical performance in patients with COPD
Chest
Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist
Neuropharmacology
An efficacy, safety, and dose–response study of ramelteon in patients with chronic primary insomnia
Sleep Med
A cortical GABA-5HT interaction in the mechanism of action of the antidepressant trazodone
Prog Neuropsychopharmacol Biol Psychiatry
Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep
Chest
Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease
Am J Respir Crit Care Med
[Comorbidities of COPD]
Internist (Berl)
Chronic obstructive pulmonary disease and sleep: the interaction
Panminerva Med
Chronic obstructive pulmonary disease and sleep
Respir Care
Health-related quality of life in patients with obstructive sleep apnea and chronic obstructive pulmonary disease (overlap syndrome)
Int J Clin Pract
Sleep disordered breathing in patients with chronic obstructive pulmonary disease
Minerva Med
Perspectives on the management of insomnia in patients with chronic respiratory disorders
Sleep
Ventilatory and arousal responses to hypoxia in sleeping humans
Am Rev Respir Dis
Hypercapnic ventilatory response in sleeping adults
Am Rev Respir Dis
Respiration during sleep in normal man
Thorax
Breathing during sleep in patients with nocturnal desaturation
Am J Respir Crit Care Med
Influence of sleep on respiratory function in emphysema
Am J Respir Crit Care Med
Sleep-related disorders and chronic obstructive pulmonary disease
Respir Care Clin N Am
Mechanics of the respiratory system and breathing pattern during sleep in normal humans
J Appl Physiol
Cited by (69)
Assessing and treating insomnia with specific comorbidities
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionPerioperative anaesthetic management of patients with COPD
2022, Anesthesie et ReanimationInsomnia: Pharmacologic Treatment
2021, Clinics in Geriatric MedicineCitation Excerpt :The dosage of ramelteon for insomnia is 8 mg at bedtime. Although it has not been studied in elderly patients specifically, ramelteon has little effect on respiratory function and thus serves as a safe option for patients with chronic lung disease such as chronic obstructive pulmonary disease.45 Ramelteon is generally well-tolerated and has little effects on balance, memory, and stability.
Meeting the challenge of COPD care delivery in the USA: A multiprovider perspective
2016, The Lancet Respiratory MedicineCitation Excerpt :An often overlooked issue in COPD is insomnia and sleep disturbances, which substantially affect quality of life.315 Benzodiazepine receptor agonists such as zolpidem are effective.316 Antidepressants such as low-dose trazodone are effective, but only in patients with insomnia in the context of depression.
Comorbidities of COPD
2015, Revue de Pneumologie CliniqueSleep Disturbances in the Elderly
2015, Psychiatric Clinics of North AmericaCitation Excerpt :Sleep quality is decreased in patients with COPD, characterized by impaired sleep initiation and maintenance, daytime sleepiness, and consequently increased use of sedating medications.105 Use of hypnotic medications among patients with COPD is potentially dangerous and may result in hypoventilation, worsened hypercapnia and hypoxemia, diminished arousal response, and increased frequency of apnea.106 Melatonin receptor agonists,107 cognitive behavioral therapy,108 and noninvasive mechanical ventilation109 may be helpful and safer alternatives to hypnotic medications among patients with COPD and sleep-disordered breathing.