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Normal Sleep

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J. A. Rowley and M. S. Badr

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Chapter 2

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Pharmacology ofSleep

JanetH.Dailey andSusmitaChowdhuri

Keywords GABA γ(gamma)-aminobutyric acid · Histamine-3 inverse agonist ·

Benzodiazepines · Nonbenzodiazepine receptor agonists · Melatonin andmelatonin receptor agonist: ramelteon ·Orexin antagonists: suvorexant andlemborexant · Antidepressants, low-dose doxepin · Antipsychotics · Antihistamines · Amphetamines · Methylphenidate · Modanil · Armodanil · Sodium oxybate · Solriamfetol · Pitolisant

Introduction

Drugs that modulate sleep and wakefulness operate by modifying a complex network of sleep–wake neurotransmitters and neuromodulators in multiple locations in the brain. The pharmacologic agents used to treat two common sleep disorders, chronic insomnia and disorders of central hypersomnia, i.e., narcolepsy and idiopathic hypersomnia, are reviewed with emphasis on current updates. Several drugs target one or more of the sleep or wake–sleep-promoting neurotransmitters and neuromodulators [1], to treat insomnia and excessive daytime sleepiness, respectively.

J. H. Dailey Pharmacy Benets Management Services, Veterans Health Administration, Washington, D.C, USA e-mail: Janet.Dailey@va.gov

S. Chowdhuri ( Sleep Medicine Section, Medical Service John D. Dingell VA Medical Center, Detroit, MI, USA

Department of Medicine, Wayne State University, Detroit, MI, USA e-mail: schowdh@med.wayne.edu

M. S. Badr, J. L. Martin (eds.), Essentials of Sleep Medicine, Respiratory Medicine, https://doi.org/10.1007/978-3-030-93739-3_2

21© Springer Nature Switzerland AG 2022

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J. H. Dailey and S. Chowdhuri

Nonpharmacologic therapies of these disorders and drugs indicated for other sleep disorders and recreational drugs that affect sleep will not be reviewed.

Sleep-promoting Drugs

Overall, drugs that are agonistic to the sleep-promoting GABA (γ(gamma)- aminobutyric acid) receptor or antagonistic to the wake-promoting neurotransmitters, norepinephrine, serotonin, histamine, acetylcholine, dopamine, and orexin are potentially sleep promoting. The major sleep-promoting region is located in the GABAergic ventrolateral preoptic (VLPO) nucleus of the hypothalamus. Conversely, inhibition of the wake-promoting regions of the brain, including the orexinergic lateral hypothalamus, histaminergic tuberomammillary nucleus, cholinergic pedunculopontine, lateral dorsal tegmental nuclei, noradrenergic locus coeruleus, serotonergic raphe nuclei, and the dopaminergic ventral tegmental area, could potentially promote sleep onset and maintenance [1].

Most hypnotics potentiate sleep via GABA by binding to the GABAA receptor [2] while others antagonize monoaminergic and/or orexin neurons or are agnostic to melatonin receptors (Fig.2.1). An ideal drug for insomnia aims to enhance sleep onset and/or sleep maintenance without signicant residual hangover, tolerance, dependence, or rebound insomnia upon discontinuation.

Fig. 2.1 Demonstrates the potential sites of action of sleep-promoting drugs. *Off label use; urazepam, quazepam, estazolam, temazepam and triazolamare FDA approved for insomnia

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Pharmacology ofSleep

Benzodiazepines

Benzodiazepines (BDZs) had been the pharmacotherapy mainstay for insomnia for decades, and despite current recommendations for short-term use, persistent inappropriately prolonged use of BDZscontinues. Perhaps due to the established dependence level of patients chronically taking BDZsand/or the lack of knowledge or resources to implement non-pharmacological insomnia management, continuing BDZsversus discontinuing them for treating insomnia is deemed the path of least resistance. Benzodiazepines bind non-selectively to the GABA addition to sedation, also mediate antianxiety, anticonvulsant, anterograde amnesia, and myorelaxant effects. They increase sleep duration and modify the sleep architecture by increasing slow-wave sleep (SWS) and decreasing rapid-eye movement (REM) sleep [3–5]. Table2.1 includes the FDA-approved hypnotic agents for the treatment of insomnia; however, other BDZs are routinely used off-label despite inadequate efcacy and safety data.

Efcacy A meta-analysis [6] of 52 randomized controlled trials (RCTs) in adults

treated with BDZsfor chronic insomnia (4 weeks or more) decreased sleep onset latency (SOL) and wake after sleep onset (WASO), with increased total sleep time (TST) and sleep efciency (SE) versus placebo. Compared with placebo, BDZs(≤4weeks of therapy in most studies) signicantly decreased SOL by polysomnography (PSG) weighted mean difference (WMD): −10.0minutes or by sleep diary, WMD: −19.6 minutes, respectively. Additionally, objective WASO was decreased −16.7minutes, or subjectively using a sleep diary −39.9minutes; SE was

receptor, and in

Table 2.1 Pharmacokinetics and dosing of oral benzodiazepinesa in adults [71, 72]

Generic name

Long acting (>24) h

Flurazepam Quazepam Diazepam Valium 2–10 20–80 40–120 1–2

Intermediate acting (6–24h)

Estazolam

Temazepam Lorazepam Ativan 0.5–2 10–20 None 1–6 Oxazepam Serax 10–15 5–15 None 1–4

Short acting (<6h)

Triazolam

hhours

Pregnancy: All BDZs cross the placenta. Symptoms of withdrawal occurring in newborns if

exposed in utero have been reported

FDA-approved agents for treatment of insomnia

Trade name

Dalmane 15-30mg 2.3 47–100 1.5–4.5

Doral 7.5–15 39 73 2

ProSom 1–2 10–24 2 major metabolites;

Restoril 7.5–30 8-15 None 1–2

Halcion 0.125–0.5 2–6 None 1–5

Daily dose (mg)

Half-life range (h)

Longest active metabolites half-life (h)

minimal hypnotic effect

Peak effect (h)

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Table 2.2 Effects on sleep parameters of FDA-approved sleep-promoting agents [2, 72–75]

Sleep continuity parameters NREM sleep parameters

Drugs

BDZs ↓ ↑ ↑ ↓ ↑ ↓ ↑ ↓ Z-drugs ↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔ Ramelteon ↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔ Suvorexant ↓ ↑ ↑ ↓ ↓ ↔↓ ↓ ↑ Low-dose

doxepin

BDZs benzodiazepines, Z-drugs zolpidem, zaleplon, eszopiclone; ↓ decreased, ↑ increased, ↔ minimal change, arrows do not represent the same degree of weight for each category. SL sleep latency, SE sleep efciency, TST total sleep time, SWS slow-wave sleep, NREM non-rapid eye movement, REM rapid eye movement

SL SE TST

↓ ↑ ↑ ↔ ↑ ↔ ↔ ↔

Stage N1Stage N2Stage N3

REM sleep parameters

(SWS)

REM onset latency REM

increased 7.4% by PSG and 7.9% by sleep diary, and TST (by PSG)and sTST (by sleep diary) increased 32.7 and 52.6 minutes, respectively. In a separate metaanalysis [7] of 24 RTCs in the elderly with insomnia for at least 5 consecutive nights, signicant improvement in sleep quality (SQ) and TST along with decreased nighttime awakening were experienced by those taking BDZs compared to placebo, although the authors reported the benets may not outweigh the increased risk of adverse events (AEs). In one systematic review (SR) [8], BDZswere favored over placebo in many outcomes including SE, SOL, SQ, TST, and WASO (Table2.2).

Safety The pharmacokinetics and pharmacodynamics differences of BDZscan often predict the potential incidence of AEs. Benzodiazepines are categorized into short-, intermediate-, and long-acting agents based on the duration of action (Table2.1). Agents with longer duration of action are often associated with more dose-dependent AEs, including daytime drowsiness due to hangover effect, dizziness, anterograde amnesia, tolerance, drug dependence, withdrawal, rebound insomnia, and REM rebound [3–5]. Gradual dose reduction of BDZs, if taken chronically for the treatment of insomnia, is recommended versus abrupt discontinuation to avoid physical and psychological withdrawal effects [9].

Ingesting BDZs with opioid medicines, alcohol, or other CNS depressants can cause severe drowsiness, breathing problems, coma, and death. Many BDZs are identied as potentially inappropriate medications in patients 65years and older due to an increased risk of impaired cognition, delirium, falls, fractures, and motor vehicle accidents.

Summary Treating insomnia with FDA-approved BDZs has demonstrated favorable short-term sleep outcomes. However, the increased risk of potential AEs precludes BDZsfrom being the ideal rst-line therapy for treating insomnia especially in the elderly and a limited role in treating individuals with chronic insomnia.

2 Pharmacology ofSleep

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Nonbenzodiazepine Receptor Agonists (Non-BzRAs)

The non-BzRAs have no anxiolytic, myorelaxant, and anticonvulsant properties but have strong hypnotic properties due to their selective binding to the GABAA receptor [2]. The three non-BzRA agents available in the United States, zolpidem, zaleplon, and eszopiclone are FDA-approved for treating insomnia. Zolpidem is currently available as immediate-release (IR) tablets, oral spray, sublingual (SL) tablets, and controlled/extended-release (ER) tablets. Zolpidem IR is indicated for short-term treatment of insomnia characterized by difculties with sleep onset. Two zolpidem tartrate SL formulations are available. One SL product (Intermezzo IR®) is used for middle-of-the-night awakening followed by difculty returning to sleep and only if >4hours of bedtime remain. Edluar™ is a second sublingual zolpidem product approved for sleep initiation and should only be taken if 7–8hours remain before arising. Agents with shorter-acting half-life such as zolpidem mist and zaleplon should be administered immediately before bedtime.

The non-BzRAs used mostly for sleep maintenance insomnia, zolpidem ER, and eszopiclone have been studied in clinical trials >6months in duration. With many of these agents, the recommended initial doses in women compared to men are different because the non-BzRA clearance is lower in women. For faster sleep onset, all zolpidem products including eszopiclone should not be administered with or immediately after a meal.

Efcacy

There are few head-to-head trials comparing the three U.S. available non-

BzRAs. A SR [8] reviewed 31 RCTs in adults with insomnia disorder. Because the trials evaluated included various formulations, doses, and different frequency of administration including short duration (i.e., <6weeks), comparisons were difcult. Four non-BzRAs (zolpidem, zaleplon, eszopiclone, and zopiclone) were objectively evaluated to placebo and efcacy data were compiled. About one-half of studies deemed of moderate quality, non-BzRAs were favored over placebo for objective SE.In addition, SOL, SQ, TST, and WASO were improved with non-BzRAs compared to placebo (Table2.3).

Safety Despite non-BzRAs being effective in treating many sleep outcomes, all these agents especially those with longer half-lives have the potential to cause nextday impairment including residual sedation, somnolence, memory impairment, confusion, lethargy, and dizziness. Several FDA warnings exist about rebound insomnia, complex sleep behaviors including sleepwalking, and in some cases, sleep-driving resulting in death. Falls and withdrawals have also been reported. Adverse events (AEs) may occur even at the lowest dose and after one dose, and if so, the drug should be discontinued immediately [10]. The risk of AEs can compound when co-administered with other CNS depressants, alcohol, or with other drugs that increase the blood levels. Eszopiclone can cause unpleasant taste and dry mouth. Rare cases of anaphylactic and anaphylactoid reactions have been reported. These agents should only be used during pregnancy if the potential benet outweighs the risk to the fetus as no adequate and well-controlled studies in pregnant

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C-IV

Controlled

substance

placenta; reports of

Use in pregnancy

Dose in

elderly

Usual adult daily

dose (mg)

severe neonatal

6.25

5 Zolpidem crosses the

Women: 5

respiratory

depression and

sedation with other

CNS depressants

Women: 6.25

Women: 5

concurrently.

1.75

well-controlled

Women: 1.75

studies in pregnant

women.

Duration of

Onset of

Table 2.3 Characteristics of non-BzRAs [10, 76, 77]

action

action (min)

Sleep onset/ maintenance <30 Intermediate Men: 12.5

Sleep onset < 30 Short Men: 5–10

Generic/trade name FDA indication(s)

Zolpidem ER

Zolpidem IR

Ambien®

Zolpidem sublingual

Ambien CR®

Intermezzo® MOTN 20 Ultra-short Men: 3.5

Edular® Sleep initiation <30 Short Men: 5–10

Sleep onset < 30 Ultra-short 10 5 Not recommended

Sleep onset/ maintenance <30 Intermediate 2–3 1–2

Sleep initiation 20 Short 10 (2 sprays) 5 No adequate and

Zaleplon

Eszopiclone

Zolpidem oral spray

Zolpimist™

Sonata®

Lunesta®

Or in mild-moderate hepatic impairment

IR intermediate release, ER extended release, CR controlled release, MOTN middle-of-the-night

2 Pharmacology ofSleep

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women exists. Drugs that increase levels of all these non-BZRA agents include the CYP3A4 inhibitors.

Summary Despite the strong evidence base that non-BzRAs have favorable sleep outcomes, treating insomnia chronically with non-BZRAs may have a limited role due to potential AEs. If prescribed, the lowest dose for the shortest period of time possible should be exercised.

Melatonin

Melatonin is a neurohormone of the pineal gland that is modulated by thesuprachiasmatic nucleus (SCN) of the hypothalamus. Regulation of melatonin synthesis by the SCN determines the circadian rhythm of sleep and wakefulness.

Efcacy Clinical guidelines do not support the use of melatonin for insomnia [11]. In a meta-analysis [12] including 19 studies (n=1683) in adults and children, the study durations (average 50days, range 7–182), dosing strategies (0.1mg– 5mg), and formulations varied, making comparison of the results impossible. Although a ~7-minute SOL reduction, an 8-minute TST increase, and a very small improvement in SQ favoring melatonin over placebo were seen, the clinical signicance of these ndings was unclear. However, strategically timed melatonin is effective for treating intrinsic circadian rhythm sleep-wake disorders such as delayed sleep phase disorders, non-24-hour sleep-wake disorder, and also REM sleep behavior disorders (RBD) [13]. In treating circadian rhythm sleep disorders with melatonin, optimal administration at the proper circadian time, based on an individual’s circadian timing, is essential. If not administered correctly, melatonin may fail to produce the desired results or even produce opposite effects and perpetuate sleep disorders and important to remember when treating elderly due to a decreased production of endogenous melatonin during aging.

Melatonin is often used to treat insomnia because of its availability over-thecounter (OTC). While marketed as a “nutritional supplement”, no proof of safety and effectiveness is required for OTCs, thus composition of melatonin varies and may have impurities [14]. To minimize potential differences in compositions, consumers and healthcare systems should always purchase melatonin that bears a Good Manufacturing Practices (GMP) seal as proof that the product is prepared, manufactured, and properly stored to the highest standards.

Overall, when reported, most studies report minimal side effects to melato-

Safety

nin. However, in a recent review, 50% of the melatonin trials reported AEs including psychomotor and neurocognitive dysfunction, fatigue, or excessive sedation [15]. A few AEs impacting the phase-shifting circadian rhythms of other physiological functions besides sleep including endocrine/reproductive and cardiovascular param-

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