History of treatment of sleep disorders

Humans spend about a third of their life sleeping, and sleep disorders, which affect a large proportion of the general population and occur in all age groups, represent a major public health and global economic burden.¹ It is estimated that 50 million to 70 million adults in the United States have a chronic sleep disorder that interferes with their daily functioning and adversely affects their health and quality of life. Until the mid-1960s, the field of sleep medicine focused primarily on describing and treating insomnia, parasomnias (e.g., sleep walking, night terrors) and hypersomnias, such as narcolepsy. Patients experiencing these symptoms typically sought consultations from neurologists, psychiatrists, psychologists, or their family physician. Until more recently, treatments were generally based on empiric pharmaceutical intervention and behavioral modification protocols or psychotherapy or both.

The role of the respiratory therapist in sleep medicine is still emerging, and areas of necessary proficiency and expertise are yet to be fully defined. An authoritative knowledge about sleep, sleep disorders, pharmacology, and the therapeutic actions of drugs on sleep architecture is required, together with knowledge of associated side effects or adverse drug reactions and toxicities. In the future, respiratory therapists may be involved with the attending physician in determining appropriate pharmacotherapy for sleep-related disorders, such as narcolepsy or periodic limb movement disorder (PLMD). At a minimum, it is highly probable that during the course of performing sleep diagnostic procedures, the respiratory therapist will assess the patient’s current therapeutic regimen and, after consultation with the physician, determine whether medications should be temporarily suspended before diagnostic procedures. Chapter 23 provides basic knowledge about sleep medicine for both the respiratory therapist who is still developing clinical skills and the experienced therapist who is actively participating in patient care with physicians.

It is beyond the scope of this chapter to address the entire spectrum of sleep disorders classified in the International Classification of Sleep Disorders, Revised (ICSD-R) or to provide an exhaustive summary of all the pharmacologic, neutraceutical, or cognitive behavioral therapies employed in this field. This chapter describes the classes of drugs that are likely to be encountered when treating patients with sleep disorders. First, a broad but brief overview of the history and evolution of sleep research and sleep pharmacology is presented followed by a brief overview of the brain mechanisms underlying the processes of wakefulness and sleep, including circadian aspects. Some key sleep-related disorders are described, and typical compounds that may be used to treat those disorders are reviewed. Adult sleep apnea syndrome, which is primarily treated with mechanical devices such as oral appliances or application of continuous positive airway pressure (CPAP), are not discussed. Apnea and bradycardia of prematurity, which are treated primarily with respiratory stimulants, are discussed in Chapter 8.

The onset and duration of sleep are orchestrated through multiple brain structures and neurotransmitter substrates, and pathology within those structures or neurotransmitter systems become manifest as a sleep disorder. For example, loss of orexin/hypocretin-producing neurons in the lateral hypothalamus is associated with the inability to maintain prolonged periods of wakefulness or sleep and the intrusion of rapid eye movement (REM) sleep, or the signs of REM sleep, into wakefulness. Sleep pharmacotherapeutics evolved with the understanding that normalization of activity within perturbed brain regions or neurotransmitter systems, or both, leads to a reduction of the signs and symptoms of specific sleep disorders.

As a result of increased public awareness about sleep disorders and scientific advances, sales of sleep-related drugs have increased markedly. Sales of medications to treat insomnia in the United States increased from $1.3 billion in 2001 to approximately $4.6 billion in 2006. However, the interest in pharmaceutical sleep aids is not new; sleep-inducing compounds were discovered and used thousands of years ago. Perhaps the first compound to be used as a sleep-inducing aid was the juice from the opium poppy. Some of the earliest written descriptions of the opium poppy have been found on Sumerian clay tablets dating to approximately 3000 bc. At that time, the juice of the poppy was harvested and consumed because of its ability to induce a euphoric state; this led to the plant being considered a Gil Hul, or “joy plant.” Descriptions of the opium poppy have also appeared in writings of the Assyrians and Persians. The Greeks eventually were introduced to the opium poppy, which may represent the first time it was used expressly for sleep induction. Greek mythology depicts many sleep-related deities, including Hypnos (sleep), Morpheus (dreams), Nyx (night), and Thanatos (death, the twin brother of Hypnos) in association with opium extracted from the poppy. Homer described the properties of opium in both The Iliad and The Odyssey as an intoxicating, pain-relieving, and sleep-inducing substance.

More recent literature also expounds the sleep-inducing power of opium in the Wizard of Oz with Dorothy, her dog Toto, and the Cowardly Lion falling into a deep sleep as they passed through a field of poppies on their approach to the Emerald City. The sleep-inducing effects of the opium poppy can be attributed to numerous alkaloids contained within the plant, including morphine and codeine. Both are central nervous system (CNS) depressants and opioid pain relievers.

Development of sleep-inducing compounds was revolutionized in the early 19th century by the synthesis of opium. Shortly after this, chloral hydrate and the bromides were developed. Chloral hydrate, a CNS depressant, rapidly induces deep sleep. Bromides, invented in the mid-19th century, are also CNS depressants and induce sleep relatively quickly. Their popularity as sleep aids increased through the late 19th century and into the early 20th century. Also during the 19th century, nitrous oxide was rediscovered, and ether and nitrous oxide were inhaled as “party favorites” of upper-class Europeans and Americans. The initial discoveries of ether by the Spanish alchemist Lullius in 1275 and nitrous oxide by the English chemist Priestly in 1772 were lost to medical science until their reintroduction in 1842. At that time, Long, a surgeon in Georgia, employed the recreational drug ether in surgical procedures because of its incredibly rapid induction of “sleep, amnesia and pain relief.” In doing so, he unknowingly ushered in the modern era of anesthesia.

Barbiturates, first discovered in the mid-19th century, soon replaced bromides as the “sleeping pills” of choice in the early 20th century. This class of drugs comprises more than 25,000 compounds that were synthesized by combining various compounds with barbituric acid. Although multiple barbituric acid compounds were developed, only a select few (including a diethyl derivative) resulted in sleep-promoting properties. Barbiturates, such as phenobarbital, are very effective at inducing sleep. However, they also have multiple side effects, not the least of which is the potential risk for barbiturate addiction, and, if taken with alcohol, they can result in respiratory suppression and death. These hypnotic agents have now been replaced by newer, more effective, and safer compounds.

Benzodiazepines such as diazepam (Valium), temazepam (Restoril), and clonazepam (Klonopin) were first marketed in the 1970s. Early formulations of these CNS depressants shared similar side-effect profiles to the barbiturates, although their margin of safety was much greater. However, benzodiazepines possess the potential for addiction, and because of the long half-life and the duration needed to eliminate some benzodiazepines from the body (more than 12 to 24 hours), next-day “hangover” sleepiness effects and memory impairments are common. Since the introduction in the 1990s of nonbenzodiazepine and analogues of these compounds (e.g., zopiclone, zolpidem, zaleplon, and eszopiclone), the use of benzodiazepines for insomnia has declined.

The “ideal hypnotic” should possess the following principal characteristics. It should induce sleep rapidly (in about 10 to 15 minutes); maintain sleep over prolonged periods (about 7 to 8 hours); and be devoid of daytime residual side effects on memory, cognition, or alertness. It should also possess additional characteristics such as rapid absorption; optimal half-life; receptor-specific binding; no active metabolite; no potential for abuse, tolerance, or dependence; no respiratory depressive effect; and no interaction with alcohol or other CNS depressants.

In addition to “sleeping pills,” many nondepressant medications are used in sleep medicine. In disorders such as restless legs syndrome (RLS) and PLMD, sleep onset is often delayed and fragmented. First-line therapy for these disorders includes dopamine agonists and, in some cases, opiates. Respiratory stimulants are another class of medications sometimes employed in the treatment of sleep disorders. Medroxyprogesterone and acetazolamide have been used in an effort to enhance ventilation in patients with high altitude–induced central sleep apnea or obesity-hypoventilation syndrome. More recently, the antidepressant mirtazapine has been shown to reduce apnea severity in animal models emulating sleep apnea as well as in some patients.² An effective pharmaceutical treatment for obstructive sleep apnea does not yet exist.

Progression of sleep

Sleep was originally thought to be a passive rather than an active process. Canton, a physiologist at the Royal Infirmary in Liverpool, is credited with the discovery of electroencephalography (EEG), an important milestone in the understanding of sleep as an active process. His experimental observations on cortical currents in rabbits and monkeys were published in the British Journal of Medicine.³ Using a mirror galvanometer, Canton observed an increase in the amplitude of waves measured from the cortex during states of sleep as opposed to a decrement in cortical amplitudes during wakefulness. Canton was the first to perform sleep EEG in mammals.⁴ Subsequently, several observations including those of von Economo and the experiments by Morruzi and colleagues clearly showed that sleep is not a passive phenomenon but involves several brain regions, especially the diencephalon and the brainstem, which actively control sleep and states of arousal.^5–8 In 1957, Dement and Kleitman reported the cyclical alternating pattern of non–rapid eye movement (NREM) and REM sleep.⁹

When determining the most appropriate pharmaceutical intervention for a sleep disorder, it is important first to consider how sleep is defined and measured and the normative values of time spent in sleep and in each sleep stage (i.e., sleep architecture). Mammalian sleep can be defined as a cyclical, reversible behavioral state of perceptual disengagement from, and unresponsiveness to, the external environment. Within normal human monophasic sleep, sleep is polygraphically characterized into two distinct stages based on a constellation of behavioral and electrophysiologic parameters. These two stages are NREM and REM sleep. NREM sleep is categorized further into stages N1-N3 (formerly known as stages 1 to 4); N1 is the lightest and stage N3 is the deepest sleep stage. Figures 23-1 to 23-4 show examples of EEG-defined wakefulness followed by examples of stages N1 to N3.

The term for REM sleep is derived from the periodic bursts of REMs during sleep. REM sleep has both tonic (persistent) and phasic (episodic) components. During tonic REM sleep, the EEG tracing shows a similar pattern to that of N1, but it may also exhibit increased activity in the theta frequency range (3 to 7 Hz) and sawtooth-type waves. REM sleep is also accompanied by a generalized muscle atonia, with the exception of the extraocular muscles and the diaphragm. Figure 23-5 shows an example of EEG-defined REM sleep.

Aserinsky and Kleitman were the first to observe the electrophysiologic characteristics of REM sleep and, in particular, the rapid, jerky, and binocularly symmetric eye movements in this sleep stage.¹⁰ EEG patterns similar to wakefulness were noted, showing the characteristic fast desynchronized rhythms in the cortical EEG, and the term paradoxical sleep was introduced by Jouvet and Michel in 1960; the term active sleep was used by other researchers. These terms are used interchangeably in the literature, although subtle differences exist. Additionally, autonomic activation occurs during this state as respiratory and heart rates are increased. Dream recall is also common when subjects are awakened during this stage, whereas dream recall during NREM sleep is relatively rare (Table 23-1).

Sleep stages occur in cycles that repeat approximately every 90 to 120 minutes. A normal sleep cycle begins with N1 and proceeds through N3. Sleep rapidly passes through the same stages in reverse order before REM sleep is initiated, usually first occurring about 90 minutes after sleep onset. Although significant interindividual variation in sleep need is noted, adult humans typically sleep about 7 to 9 hours per night and spend almost one-third of their life sleeping. Figure 23-6 provides a graphic representation of the cyclical distribution of sleep states across a single night in a normal healthy adult.

In a series of postmortem examinations of the brains of patients who had died as a result of the outbreak of encephalitis lethargica after World War I, von Economo⁸ observed that lesions in the rostral midbrain and posterior hypothalamus had a profound effect on sleep and wakefulness. He derived two significant correlates from his observations. The first was that lesions in the preoptic and basal forebrain (BF) areas caused severe insomnia. The second was that lesions in the posterior and lateral hypothalamus (LH) caused severe hypersomnia. On the basis of these data, von Economo hypothesized the existence of a group of sleep-promoting neurons around the hypothalamic optic chiasm and, conversely, a group of wake-promoting neurons in the area of the posterior hypothalamus. Both observations have been proved to be essentially correct, but it was only toward the end of the 20th century that the hypothalamic influences on sleep and wakefulness were integrated into the mechanisms of vigilance state control. Before that, the emphasis had been on brainstem mechanisms and the ascending reticular activating system (ARAS).