Latency to sleep onset

Roth T, Krystal A, Steinberg FJ, Singh NN, Moline M. Novel sublingual low-dose zolpidem tablet reduces latency to sleep onset following spontaneous middle-of-the-night awakening in insomnia in a randomized, double-blind, placebo-controUed, outpatient study. Sleep February 1,2013 36(2) 189-96. 

In rats, cocaine (6 mg/kg, i.p. or p.o.) has been shown to induce a significant increase in sleep latency and a reduction in total sleep time, including a decrease in both non-REM sleep and REM sleep (Schwartz 2004). In humans, cocaine, amphetamines, and methylphenidate also produce decreases in sleepiness, an increased latency to sleep, and a marked decrease in REM sleep associated with an increased latency to the onset of this state. Amphetamine, methylphenidate, and cocaine are known to act by enhancing the amount of the monoamines available within the synaptic cleft of synapses in the CNS. 

REM sleep time is preserved in depression (Benca et al. 1992 Mendlewicz and Kerkhofs 1991). Yet, REM sleep percentage is slightly increased, and the density of rapid eye movements is enhanced (Benca et al. 1992 Gillin et al. 1981 Mendlewicz and Kerkhofs 1991). Most notable of all REM sleep characteristics in depression is a short latency to the onset of REM sleep (C. E. Reynolds and Kupfer 1987). These REM sleep patterns were considered to be unique to depression in particular, the short REM latency was originally claimed to be a marker for primary depression (Kupfer 1976, 1984). Unfor-... 

In an earlier experiment, cumulative increases in PVT lapses across 7 days of sleep restricted to approximately 5 hr per night (29) were shown to be strongly related (r = -0.95) to sleep onset latency as assessed by the Multiple Sleep Latency Test (MSLT) in a nearly identical protocol (72). It appears that PVT performance lapse frequency and the well-validated physiological measure of sleep propensity may reflect the same basic process of escalating sleep pressure with sleep loss. 

Fig. 1. Schematized hypnogram demonstrating most of the sleep disorders described in the literature using laboratory recordings of untreated persons with schizophrenia. One category of sleep disorders in schizophrenia is the insomnia type , with long sleep latency, numerous and/or long awakenings, and short sleep duration. Another type of sleep disorders is more concerned with sleep organization, e.g.., short duration of SWS and/or short latency to the onset of REM sleep. Not all disorders are found in every study since variables such as symptoms or diagnosis subtype, severity and chronicity may influence the results (see text). REMS, REM sleep. A REM sleep period is defined as a succession of REM sleep epochs not interrupted for more than 15 min.

Reference C. Discloses the dissolution of essentially pure compound C in an aqueous vehicle, and the administration to laboratory rats to determine its effect on the sleep latency time in rats. The compound decreased sleep latency (time to sleep onset) by 22 minutes. A separate reference is cited that shows that compounds like compound C can be readily prepared by synthetic methods common to one of ordinary skill in the art. This reference is cited to show that compound C is enabled. 

Brotizolam is a triazolothienodiazepine used in the treatment of insomnia and also has anticonvulsant, antianxiety and muscle relaxant properties. It reduces latency to sleep, reduces the number of awakenings and waking time during sleep, and increases total sleep time (1). It may delay the onset of REM sleep but has no effect on slow-wave sleep (2). It has an intermediate half-life of about 5 hours, and is said to cause no early-morning rebound insomnia and minimal morning drowsiness (3). Its most common adverse effects are drowsiness, headache, and dizziness mild rebound insomnia can occur after withdrawal. 

A French group has tested the effects of ropinirole 3 mg on sleep latency in 20 healthy men (mean age 24 years) compared with placebo (35). The time to sleep onset was significantly quicker in the ropinirole-treated subjects (2.6 versus 4.8 minutes), but sleep attacks did not occur. Clearly this is a very different group of individuals from the usually much older group with Parkinson s disease, so again definite conclusions are elusive. 

In addition to showing statistically significant improvement on various parameters (for example, latency of sleep, onset of sleep, or total sleep time in transient insomnia or maintaining sleep and reducing wakefulness in chronic insomnia) the adverse effects caused by hypnotics are also measured. These include effects on residual sedation, rebound insomnia (referring to increase in wakefulness or anxiety), amnesia, and adverse cardiopulmonary effects. 

A decision analysis for dyssomnias is shown in Figure 71-1. Patients with short-term or chronic insomnia should be evaluated after 1 week of therapy to assess for drug efficacy, adverse effects, and adherence to nonpharmacologic recommendations. Patients should be instructed to keep a sleep diary. The diary requires daily recording of bedtime, wake time, latency of sleep onset, number and duration of awakenings, medication ingestion, naps, and an index of sleep quality. 

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. 

Noting that chronic insomniacs often underestimate their actual sleep time, Spielman et al. (183) conducted a study in which subjects initially were allowed to stay in bed only as long as their own estimate of time spent asleep. Results indicated that the mild sleep deprivation produced tended to improve sleep onset latency and efficiency. 

The technique most commonly used for objective evaluation of daytime sleepiness is the Multiple Sleep Latency Test (MSLT). It is composed of a series of naps during which subjects are asked not to resist sleep. The speed of falling asleep on tests across time is the chief outcome of the MSLT, which has achieved widespread acceptance because of its simple, intuitive approach to sleepiness. Hence, the greater levels of sleepiness are indicated by more rapid sleep onsets. Furthermore, the MSLT provides several opportunities to test for sleep-onset rapid-eye-movement (REM) episodes, the primary diagnostic sign of narcolepsy. 

The effect of sleep deprivation on different age groups has also been tested using the MSLT. Sleep loss in young adolescents was assessed by examining the effects of one night s sleep loss in 12 subjects whose ages ranged from 11.7 to 14.6 years. MSLTs showed a marked reduction of sleep-onset latency from 0530... 

Sleepiness is a primary symptom of narcolepsy, often preceding the onset of the other well-known symptoms of the disease, namely cataplexy, sleep paralysis, and hypnagogic hallucinations (44). Evaluation of the MSLT of narcoleptic patients has demonstrated a short sleep latency (<5 min) and multiple sleep-onset REM periods (SOREMPs). The more specific finding in the MSLT of narcoleptic patients is more than 2 SOREMPs, shown to reach a specificity of 99% by Amira et al. (45), which further increased to 99.2% if 3 SOREMPs were recorded (46). On the other hand, more than one SOREMP can occur in nonnarcoleptic patients, such as those with sleep apnea, sleep deprivation, depression, periodic limb movements, circadian rhythm disruption, or withdrawal from REM-suppressing medications (5,47). Thus, the findings of the MSLT, which is always performed for suspected narcoleptic patients, must be interpreted in view of the clinical history and nocturnal PSG. 

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