Elsevier

Sleep Medicine

Volume 10, Issue 1, January 2009, Pages 19-25
Sleep Medicine

Review Article
Hypnotic use for insomnia management in chronic obstructive pulmonary disease

https://doi.org/10.1016/j.sleep.2008.06.005Get rights and content

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of mortality and morbidity worldwide. Because of the chronic nature of the disease, optimal care for patients includes successful treatment of comorbidities that accompany COPD, including insomnia. Insomnia symptoms and associated disruption of sleep are prevalent in COPD patients but treatment with traditional benzodiazepines may compromise respiratory function. This review summarizes the efficacy and safety consideration of current drugs available for the treatment of insomnia in COPD patients including benzodiazepines, non-benzodiazepine receptor agonists such as eszopiclone, zolpidem, and zaleplon, sedating antidepressants such as trazodone, and the melatonin receptor agonist ramelteon.

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.

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