Evidence exists to support that:
Chronic insomnia is associated with older age.
Benzodiazepines and nonbenzodiazepines are effective in the management of chronic insomnia. However, benzodiazepines, nonbenzodiazepines, and antidepressants pose a risk of harm.
Benzodiazepines have a greater risk of harm than nonbenzodiazepines.
Melatonin is effective in the management of chronic insomnia in subsets of the chronic insomnia population, and there is no evidence that melatonin poses a risk of harm.
Relaxation therapy and cognitive behavioral therapy are effective in the management of chronic insomnia in subsets of the chronic insomnia population.
Common drug classes used to treat insomnia, but not FDA approved for that use, include antihistamines (e.g., diphenhydramine), antidepressants (e.g., amitriptyline, doxepin, trazodone), atypical antipsychotics (quetiapine), and sedatives (e.g., chloral hydrate). These drug classes are used due to their sedative properties.
FDA-Approved Pharmacologic Therapies for Management of Insomnia
The FDA-approved therapies for the management of insomnia are classified as sedative-hypnotic agents. These sedative hypnotics can be categorized into three groups: benzodiazepines, nonbenzodiazepine selective GABA agonists, and melatonin receptor agonists (see Table 9.2).
Table 9.2
Food and Drug Administration–approved drugs for insomnia
Drugs | Adult dose (mg) | Half-life (h) | Onset (min) | Peak effect (h) |
|---|---|---|---|---|
BzRAs | ||||
Estazolam | (1, 2) | 10–24 | 15–60 | 0.5–1.6 |
(ProSom TM ) | 0.5–2 | |||
Flurazepam | (15, 30) | 47–100 | 15–20 | 3–6 |
(Dalmane TM ) | 15–30 | |||
Quazepam | (15) | P: 25–41 | 15–60 | 15–3 |
(Doral TM ) | 7.5–15 (max. 30) | AM: 40–114 (2-oxoquazepam-[2 h] N-desalkyl-2-oxoquazepam [40–114 h]) | ||
Temazepam | (17.5, 15, 22.5, 30) | 6–16 | 15–60 | 1.5–3 |
(Restoril TM ) | 7.5–30 | |||
Triazolam | (0.125, 0.25) | 1.5–5.5 | 15–30 | 1.7–5 |
(Halcion TM ) | 0.125–0.25 (max. 0.5) | |||
Non–BzRAs | ||||
Eszopiclone | (1, 2, 3) | 6 | 30 | 1 |
(Lunesta TM ) | 1–2 (max. 3) | (9 in elderly) | ||
Zaleplon | (5, 10) | 1 | Rapid | 1 |
(Sonata TM , Starnoc TM ) | 5–10 (max. 20) | |||
Zopiclone | (5, 7.5) | ∼5–6 | 30 | 1–2 |
(Imovane TM ) | 5–15 | (5–10 in elderly) | ||
Zolpidem tartrate IR | (5, 10) | ∼2.5 | 15–30 | 1–3 |
(Ambien TM ) | 5–20 | |||
Zolpidem tartarate ER | (6.25, 12.5) | ∼3 | 30 | 1.5–4 |
(Ambien CR TM ) | 6.25–12.5 | |||
Melatonin receptor agonist | ||||
Ramelton | (8) | P: 0.5–2.6 | 30 | 0.5–1.5 |
(Rozerem TM ) | 8½ h before bedtime | AM: 2–5 (M-II) | ||
Benzodiazepines
The first benzodiazepine, chlordiazepoxide (discovered serendipitously by Leo Sternbach in 1955), is a fusion of a benzene ring and a diazepine ring. Benzodiazepines such as chlordiazepoxide (Librium) and diazepam (Valium) were first developed as sedatives in the 1960s and rapidly gained popularity essentially replacing barbiturates as the sedatives of choice for “sleeping pills” [25]. Benzodiazepines could be acting on receptors directly within the VLPO to promote sleep, or they could be acting more globally to facilitate inhibitory GABA transmission [26]. The α1 subunit of the GABAA receptor is especially important for benzodiazepine-induced sedation. Mice with mutations in the α1 subunit are insensitive to the sedative effects of the traditional benzodiazepine diazepam but maintain sensitivity to its anxiolytic, myorelaxant, and motor-impairing functions, indicating that the sedating effects of benzodiazepines are primarily mediated by actions on the α1 subunit [27].
Nonbenzodiazepine Selective GABA Agonists
The GABAA receptor is a pentameric molecule composed of a combination of one or more specific subunit types. Although 19 different subunits are known to exist, the majority of GABAA receptors in the central nervous system consist of α(1–6), β(1–3), and γ(1–3) subunits [28]. The interaction of benzodiazepines with multiple GABAA receptor subunits containing α(1–3,5) is thought to elicit the variety of effects seen with these agents such as anxiolysis, amnesia, muscle relaxation, sedation, and anticonvulsant activity [28]. The theoretical advantage of having a selective α1 subunit agonist of the GABA receptor is that sedating effects are achieved while avoiding other effects thought to be mediated by the other α subunits to which benzodiazepines bind.
In contrast to benzodiazepines, the nonbenzodiazepine sedative hypnotics (i.e., zolpidem, eszopiclone, zopiclone, zaleplon) are more selective for the GABAA receptors with the α1-receptor subunit [29]. Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine γ-aminobutyric acid (GABA) agonist with a high affinity and selectivity for the α1 subunit associated with sedation for the treatment of insomnia [29]. Petroski and colleagues [30] showed indiplon to be at least nine times more selective for α1 as compared to α2, α3, and α5 subunits [30]; a greater degree of selectivity for α1, over the α2 and α3 subunits, was greater for indiplon as compared to zolpidem, zopiclone, and zaleplon.
“Z-DRUGS”
Initial nonbenzodiazepine selective GABA agonists are often referred to as the “Z-drugs” because they include zolpidem (Ambien), zaleplon (Sonata), zopiclone (Imovane), and eszopiclone (Lunesta). Zaleplon and zolpidem have much higher efficacy at benzodiazepine receptors containing the α1 subunit compared with other types of α subunits, whereas traditional benzodiazepines (e.g., triazolam) lack this specificity [31].
Zaleplon
It appears that zaleplon binds preferentially to alpha 1-containing GABAA receptors [32] and may be considered alpha 1-selective, and so zaleplon’s effects are likely mediated via the alpha 1 receptor and are predominantly sedative in nature [30]. Zaleplon has a short T max and the shortest t ½ of the current Z-drugs (see Table 9.2), explaining its fast onset and the fastest offset of action. Zolpidem IR has a longer t ½ than zaleplon, resulting in a longer duration of action. Zolpidem CR consists of a two-layer tablet: The outer layer dissolves quickly, while the second layer dissolves slowly to maintain plasma zolpidem concentrations above those seen for the IR formulation, particularly at 3–6 h post-dose [33].
Zolpidem
Zolpidem was the first subtype-selective GABAA receptor agonist and has the highest affinity at the alpha 1 subtype of all the nonbenzodiazepine GABAA receptor modulators. Zolpidem will activate alpha 2 and alpha 3 receptors, though at considerably higher concentrations than those that activate the alpha 1 subtype.
Zopiclone
Zopiclone shows relatively high binding affinity for the alpha 1 over the alpha 3 receptor subtype [34], and zopiclone also binds to the alpha 5 receptor with high affinity [35]. Sivertsen et al. examined polysomnographic parameters and sleep apnea and periodic limb movement disorder (PLMD) in chronic users of zopiclone compared with aged-matched drug-free patients with insomnia versus “good sleepers” [36]. Forty-one percent of the patients treated pharmacologically for insomnia also had sleep apnea. There were no differences between the zopiclone and insomnia group on any of the polysomnography parameters, and a similar pattern was found for data based on sleep diaries [36]. This study suggests that the sleep of chronic users of zopiclone is no better than that of drug-free patients with insomnia [36].
Zopiclone is a racemic mixture of (S)- and (R)-isomers, with stereoselective PK profiles [37, 38] and clinical outcomes [39]. Racemic zopiclone has the longest T max of the Z-drugs, and plasma concentrations of the more active enantiomer, (S)-zopiclone, remain below the sleep-inducing threshold (of 10 ng/ml) for more than half an hour after administration [40]. Racemic zopiclone has a longer t ½ than either zaleplon or zolpidem, suggesting a longer duration of action. However, this means that (S)-zopiclone plasma concentrations may not fall below the sleep-inducing threshold until more than 9 h after racemic zopiclone dosing. An additional consideration is the duration of effects of zopiclone’s active metabolite, (S)-desmethylzopiclone (SDMZ), and the less active enantiomer, (R)-zopiclone. Measurable plasma concentrations of both SDMZ and (R)-zopiclone are present 8 h after zopiclone dosing and could contribute to unwanted next-day residual effects [41].
Eszopiclone
Eszopiclone is the pure (S)-enantiomer of racemic zopiclone [42] and was licensed in the USA in December 2004. Although eszopiclone is the isolated (S)-enantiomer of zopiclone, this study revealed notable differences in the pharmacodynamic effects of eszopiclone compared with racemic (R, S)-zopiclone. The pattern of eszopiclone binding at alpha 1, alpha 2, alpha 3, and alpha 5 subtypes is similar (although not identical) to that of zopiclone, but the binding affinities of eszopiclone are all higher than those seen with zopiclone. Eszopiclone’s potency is greatest at alpha 5 receptors, followed by alpha 2 and alpha 3 receptors, but it is still a very potent drug at the alpha 1 receptor subtype with an EC50 of the same order of magnitude as zaleplon and zopiclone. Eszopiclone is particularly efficacious at alpha 2 and 3 receptors, with the highest efficacy of the nonbenzodiazepine GABAA modulators when examined in the same study [35].
Melatonin Receptor Agonists (MRAs)
Melatonin is an endogenous neuromodulator synthesized by the pineal gland, and its secretion is regulated by the suprachiasmatic nucleus (SCN), the circadian pacemaker of the brain [43]. The SCN receives light signals from the retina, which are transmitted to the dorsal medial hypothalamus (DMH), which acts as a relay center for signals to regions involved in sleep and wake maintenance [e.g., VLPO, locus coeruleus (LC)]. Melatonin acts largely through MT1 receptors in the SCN to suppress firing of SCN neurons, thereby disinhibiting the sleep-promoting neurons in the VLPO [43]. Secretion of melatonin is low during the day and high at night, and the onset of melatonin secretion coincides with the onset of nightly sleepiness. Exogenous melatonin crosses the blood–brain barrier, and various over-the-counter melatonin preparations are used to treat insomnia, jet lag, shift-work-related sleepiness, and delayed phase syndrome, with various degrees of effectiveness [44]. Melatonin, ramelteon (Rozerem), and agomelatine (Valdoxan) are all agonists for melatonin 1 (MT1) and melatonin 2 (MT2) receptors [43]. Ramelteon has an affinity for both receptors that is 3–16 times greater than melatonin, and it has a longer half-life. Agomelatine also has a high affinity for melatonin receptors, in addition to acting as an antagonist at serotonin 5-HT2C receptors to decrease anxiety as well as promote sleep. Both MT1 and MT2 play a role in sleep induction; MT1 activation suppresses firing of SCN neurons, and MT2 receptors are involved in entraining circadian rhythms.
The administration of melatonin (MEL) during the daytime, i.e., out of the phase of its endogenous secretion, can facilitate sleep [45]; however, if the treatment goal is to maintain daytime sleep for ∼8 h, then fast-release oral MEL with its short elimination half-life (∼40 min) may be more appropriate [46]. Aeschbach et al. show in healthy subjects that transdermal delivery of MEL during the daytime can elevate plasma MEL and reduce waking after sleep onset, by promoting sleep in the latter part of an 8-h sleep opportunity [46].
Antihistamines
Antihistaminergics exert their sedative effects by antagonizing the H1 receptors in the brain. The H1 antagonist cyproheptadine (Periactin) is effective at increasing slow-wave sleep and REM sleep in rats [47], whereas the H1 antagonists diphenhydramine (Benadryl) and chlorpheniramine (Chlor-Trimeton) decrease sleep latency but have no effect on amount of sleep. In humans, diphenhydramine initially increases subjective sleepiness and reduces latency to sleep compared with placebo, but after 4 days of administration, this effect is abolished, indicating tolerance to its effects [48].
Antidepressants/Atypical Antipsychotics
The effects of antidepressants on sleep are diverse, even within a class of medications. Sedation and drowsiness are common side effects of the TCAs (e.g., desipramine (Norpramin), imipramine (Tofranil), and amitriptyline (Elavil)). Amitriptyline increases drowsiness and shortens sleep latency compared with placebo, whereas imipramine actually increases sleep latency and decreases total sleep time. MAOIs and SSRIs (e.g., fluoxetine (Prozac), sertraline (Zoloft), and citalopram (Celexa)) can cause insomnia and decreased sleep efficiency. The TCAs which seem to be utilized most commonly to help combat insomnia include amitriptyline and doxepin. Notably, all these classes of antidepressants suppress REM sleep to some degree and have significant anticholinergic effects while doxepin has significant antihistaminergic effects. Cyclobenzaprine (an agent traditionally viewed as a muscle relaxant but structurally very similar to amitriptyline) has been used to help combat insomnia by some clinicians.
Trazodone (Desyrel) is an antidepressant that is also commonly prescribed for insomnia [49]. Trazodone acts as both a weak serotonin (5-HT) reuptake inhibitor and as an antagonist at 5-HT2A and 5-HT2C, α1-adrenergic, and histamine H1 receptors [50]. Trazodone has been shown to suppress REM sleep; however, its effects on sleep latency, sleep duration, and number of wakenings are controversial.
Schwartz et al. attempted to compare the effectiveness and tolerability of two hypnotic agents, trazodone (Desyrel) (50–100 mg) and zaleplon (Sonata) (10–20 mg), on psychiatric inpatients with insomnia. Schwartz and colleagues suggested that in their pilot study, it appeared that trazodone may be a better agent to promote longer, deeper subjective quality sleep for psychiatric inpatients with insomnia in terms of effectiveness. However, tolerability was much better with zaleplon as daytime residual side effects were less [51]. Meta-chlorophenylpiperazine (mCPP) is a synthetic drug that was identified for the first time in 2004 in Sweden as an illicit recreational drug and is also a metabolite of trazodone [52]. mCPP has stimulant and hallucinogenic effects similar to those of 3,4-methylenedioxymethamphetamine (MDMA) and has the potential to lead to the development of serotonergic syndrome when interacting with certain agents [53].
Cankurtaran and colleagues compared the effectiveness of mirtazapine and imipramine on multiple distressing symptoms (e.g., pain, nausea) and other symptoms, e.g., sleep disturbances and also depressive and anxiety symptoms [54]. For initial, middle, and late insomnia, only the mirtazapine group showed improvements, suggesting that mirtazapine is effective for helping to resolve insomnia [54].
If antidepressants are used to address insomnia, sedating ones should be preferred over activating agents such as serotonin reuptake inhibitors. In general, drugs lacking strong cholinergic activity should be preferred over agents with strong cholinergic activity (e.g., amitriptyline). Drugs blocking serotonin 5-HT2A or 5-HT2C receptors should be preferred over those whose sedative property is caused largely by histamine receptor blockade (e.g., doxepin). However, sometimes these “nonpreferred” agents (which tend to be very sedating) appear to address insomnia the best. The dose should be as low as possible (e.g., as an initial dose: doxepin 25 mg, mirtazapine 15 mg, trazodone 50 mg, trimipramine 25 mg) [55]. Regarding the lack of substantial data allowing for evidence-based recommendations, we are facing a clear need for well-designed, long-term, comparative studies to further define the role of antidepressants versus other agents in the management of insomnia. Atypical antipsychotic agents which have been utilized (largely because of their sedative effects) in patients that also have chronic insomnia with relatively little data include olanzapine, quetiapine, and clozapine [56].
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