Sleep-onset

Insomnia complaints are common in the general population and can be dichotomized into problems of delayed sleep onset and those related to sleep maintenance. Increasing attention is being focused on the adverse daytime effects of insomnia. Sleep disturbances become more common with increased age and are more prevalent in women. Sleep complaints arise from very diverse etiologies which prominently include concomitant primary... 

It must be noted that the prerequisite to see distinct peaks in a TSC experiment is a sleep onset of the density of stales at the band edges. This is fully fulfilled... 

A measure used to assess sleep quality, usually determined by means of polysomnography. A parameter such as wake after sleep onset (WASO) is often used to describe sleep continuity. 

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

POA WSNs also initiates thermolytic autonomic processes with resulting heat loss. It is reasonable to speculate that the activation of these neurons underlies the peripheral vasodilation and evoked lowering of body temperature at sleep onset (reviewed by Heller, 2005) and the association of high sleep propensity with the low-body-temperature phase of the circadian temperature cycle... 

Some arousal-related neurotransmitters, including noradrenaline, serotonin, and acetylcholine, feed back to inhibit POA sleep-active neurons. This aspect of the system has been reviewed previously (McGinty Szymusiak, 2000 Saper et al., 2001). Therefore, once sleep-active neurons are activated, arousal-related neurons are inhibited, and inhibitory control of sleep-active neurons by arousal systems is reduced. In this way, sleep onset is facilitated. That is, the mutually inhibitory systems can switch more quickly from wake to sleep, and back. These mutually inhibitory interactions also promote stability of both waking and sleep. 

Boissard, R., Gervasoni, D., Schmidt, M. H. et al (2002). The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance a combined microinjection and functional neuroanatomical study. Eur. J. Neurosci 16, 1959-73. 

Figure 4.2 Model of the network responsible for paradoxical sleep onset and maintenance Abbreviations DRN, dorsal raphe nucleus 5-HT, serotonin LC, locus coeruleus NA, noradrenaline LDT, laterodorsal tegmental nucleus Ach, acetylcholine Me, magnocellular reticular nucleus Gly glycine DPMe, deep mesencephalic reticular nucleus PAG, periaqueductal gray DPGi, dorsal paragigantocellular reticular nucleus PPT, pedunculopontine nucleus PRN, pontine reticular nucleus SLD, sublaterodorsal nucleus Glu, glutamate Pef/HLA perifornical/lateral hypothalamic area Hcrt, hypocretin (i.e. orexin).

Boissard, R., Fort, P., Gervasoni, D., Barbagli, B. Luppi, P. H. (2003). Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset. Eur. J. Neurosci. 18, 1627-39. 

Sleep-wake state alterations in PD can be broadly classified into disturbances of (1) thalamocortical arousal state and (2) excessive nocturnal movement (Rye and Bliwise 2004 Rye and Iranzo 2005). The former includes the loss of sleep spindles and SWS, daytime sleepiness, and intrusion of REM sleep into daytime naps (i.e. sleep onset REM periods, or SOREMs), and the latter encompass periodic leg movements of sleep (PLMs) and REM sleep behavior disorder (RBD). The pathophysiological basis of sleepiness and SOREMs appears to be dopaminergic cell loss in PD, though excessive nocturnal movements are not as clearly related to dopaminergic deficits. 

Ferreira J. J., Galitzky M Thalamas C. et al. (2002). Effect of ropinirole on sleep onset a randomized placebo controlled study in healthy volunteers. Neurology 58(3), 460-2. 

Strogatz S. H., Kronauer R. E., Czeisler C. A. (1987). Circadian pacemaker interferes with sleep onset at specific times each day role in insomnia. Am. J. Physiol 253(1), R172-8. 

In contrast, another meta-analysis undertaken by Brzezinski et al., using 17 different studies involving 284 subjects, most of whom were older, concluded that melatonin is effective in increasing sleep efficiency and reducing sleep onset time (Brzezinski et al. 2005). Based on this meta-analysis the use of melatonin in the treatment of insomnia, particularly in aged individuals with nocturnal melatonin deficiency, was proposed. 

A number of clinical studies have now made use of the phase advancing property of melatonin for treating delayed sleep phase syndrome (DSPS). Melatonin, at a 5 mg dose, has been found beneficial in advancing the sleep onset time and wake time in DSPS subjects (Dahlitz et al. 1991 Nagtegaal et al. 1998 Kayumov et al. 2001). Melatonin was found to be effective when given five hours before its endogenous onset or seven hours before sleep onset. 

LY 156735 is a [1-substituted analog of melatonin that has greater bioavailability than melatonin (Nickelsen et al. 2002). It is in an earlier stage of clinical trials in initial trials, it reduced the sleep onset time in patients with moderate sleep-onset insomnia. Several other specific melatonin receptor agonists and antagonists are in development (Rivara et al. 2005 Zlotos 2005) and presumably will be clinically tested over the next few years. 

Marketed compounds display well-known efficacy in inducing sleep onset, but many fail in the maintenance of sleep throughout the night due to short half-lives. On the other hand, longer acting compounds, such as the benzodiazepines, elicited significant next-day adverse effects. Therefore, the balance between sustained efficacy and adequate pharmacokinetic profile remains to be solved. 

NG2-73 is a GABAa receptor partial agonist that, according to the information given by the company, modulates preferentially the a3 subunit - a subunit that is hypothesized to be associated with sleep induction - and is undergoing phase II trials for chronic insomnia with primary endpoints measuring sleep onset as well as maintenance (no structure disclosed) [25]. 

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