Rebound sleep

A rebound sleep disturbance has been found after only 7—10 days of treatment with therapeutic doses of triazolam (Greenblatt et al. 1987). Others have described a withdrawal syndrome after substitution of a short-acting benzodiazepine for a long-acting benzodiazepine (Conell and Berhn 1983). Rebound insomnia may occur with zolpidem. 

Greenblatt DJ, Harmatz JS, Zinny MA, et al Effect of gradual withdrawal on the rebound sleep disorder after discontinuation of triazolam. N Engl J Med 317 722-728, 1987... 

Porkka-Heiskanen, T., Smith, S. E., Taira, T. et al. (1995). Noradrenergic activity in rat brain during rapid eye movement sleep deprivation and rebound sleep. Am. J. Physiol 268, R1456-63. 

Sleep disorder Rebound sleep disorder, which is characterized by recurrence of insomnia to levels worse than before treatment began, may occur following abrupt withdrawal of triazolam, usually during the first 1 to 3 nights. Gradual rather than abrupt discontinuation of the drug may help avoid this syndrome. 

As with other aspects of sleep studies, polysomnography (PSG) can provide an exact quantification of rebound in terms of both sleep stages and more sophisticated analyses [7], However, it cannot measure the clinical implications of the rebound, for example, does the patient feel compelled to resume medication Nor does it assess withdrawal reactions, except in as much as they often subsume rebound sleep phenomena. 

Ritanserin, a selective 5-HT2 receptor antagonist, increases slow-wave sleep in healthy volunteers (1). It improved sleep in middle-aged poor sleepers (2), but on withdrawal after 20 days treatment there was rebound sleep impairment, which was at its worst 3 nights after withdrawal, consistent with its long half-life (40 hours). Ritanserin is thus not a useful hypnotic, but analogues with more appropriate kinetics will be of interest. 

IL-ip is a well documented sleep factor (reviewed by Obal Krueger, 2003). Its administration increases sleep, its blockade decreases sleep and sleep rebound, and its transcription increases during waking. IL-1 receptor knock-out mice sleep less. Local application of IL-1 p in POA also stimulates NREM sleep. We examined the effects of local administration of IL-1 p and an antagonist through microdialytic application adjacent to lateral POA neurons (Alam et at, 2004). Neuronal activity is recorded within 0.5-1.0 mm of a microdialysis membrane in unrestrained rats. IL-ip potently inhibited the activity of 79% of wake-active neurons. The inhibitory response to IL-ip of wake-active neurons could be blocked by pre-treatment with IL-lra, an IL-ip antagonist. IL-ip application also excited some sleep-active neurons, but this response was inconsistent. 

There is also support for a role of PGD2 in sleep control and homeostasis (Hayaishi, 2002). PGD2 is synthesized in the subarachnoid space ventral to the POA. Administration of PGD2 in the subarachnoid space induces normal sleep, and inhibition of synthesis or receptors suppresses sleep. Sleep rebound after deprivation is reduced in mice in which the synthetic enzyme is knocked out. Administration of PGD2 to the subarachnoid space also induces c-Fos in the VLPO as well as dorsal POA neurons (Scammel et a ., 1998). The hypnogenic actions of PGD2 seem to be mediated by an adenosine A2a pathway (Satoh et al, 1966). 

Jouvet, M. (1982). Hypnogenic indolamine-dependent factors and paradoxical sleep rebound. In Sleep, ed. W. P. Koella, pp. 2-18. Basel Karger. 

Several studies suggest that cortistatin expression correlates with the sleep homeostat. The concentration of cortistatin mRNA oscillates with the light-dark cycle in rats, with maximal levels at the end of the dark (i.e. active) period. Further, the steady-state concentration of cortistatin mRNA increases four-fold after sleep deprivation, and returns to normal levels after sleep rebound, indicating that the expression of the peptide is associated with sleep demand (Spier de Lecea, 2000). Preliminary studies in cortical slices suggest that cortistatin-14 increases cortical synchronization by enhancing the H-current. Thus, cortistatin and somatostatin may be part of the intrinsic mechanisms of the cerebral cortex that are involved in the maintenance of excitability. 

BZD effects on human sleep are well characterized (Mendelson 2001) (a) decreased sleep latency (b) decreased awakenings (c) increased stage II sleep (d) suppressed stage III and IV sleep (e) increased REM sleep latency (f) initial reduction and fragmentation of REM sleep. Discontinuation of BZD treatment after three to four weeks produces a rebound of REM sleep as well as slow-wave sleep (SWS). BZD and non-BZD compounds are pharmacological agents indicated in the management of anxiety, insomnia, and other conditions in which anxiety is the main symptom, and should be considered as symptomatic medications (Nishino et al. 2004). 

Radulovacki M., Walovitch R., Yanick G. (1980). Caffeine produces REM sleep rebound in rats. Brain Res. 201, 497-500. 

Zolpidem, chemically unrelated to benzodiazepines or barbiturates, acts selectively at the y-aminobutyric acidA (GABAA)-receptor and has minimal anxiolytic and no muscle relaxant or anticonvulsant effects. It is comparable in effectiveness to benzodiazepine hypnotics, and it has little effect on sleep stages. Its duration is approximately 6 to 8 hours, and it is metabolized to inactive metabolites. Common side effects are drowsiness, amnesia, dizziness, headache, and GI complaints. Rebound effects when discontinued and tolerance with prolonged use are minimal, but theoretical concerns about abuse exist. It appears to have minimal effects on next-day psychomotor performance. The usual dose is 10 mg (5 mg in the elderly or those with liver impairment), which can be increased up to 20 mg nightly. Cases of psychotic reactions and sleep-eating have been reported. 

Zaleplon also binds to the GABAa receptor. It has a rapid onset, a half-life of about 1 hour, and no active metabolites. It does not reduce nighttime awakenings or increase the total sleep time. It may be best used for middle-of-the-night awakenings. It does not appear to cause significant rebound insomnia or next-day psychomotor impairment. The most common side effects are dizziness, headache, and somnolence. The recommended dose is 10 mg (5 mg in the elderly). 

Insomnia can be a common problem for people when first changing a drug problem. Sleeping problems can be related to the rebound effects of the drugs, or may be related to rumination and regret. Since insomnia is common, therapists and counselors will likely want to teach their clients how they can reduce the duration of this potentially uncomfortable problem. To orient the client, the counselor or therapist will want to emphasize to the client that insomnia is not life threatening, and that eventually he or she will sleep. This orientation is meant to put the client at ease... 

A contact dermatitis occurs infrequently. Because feverfew also inhibits human blood platelet aggregation, interactions are possible with antithrombotic medications such as aspirin or warfarin (Groenewegen and Heptinstall 1990). Abrupt discontinuation of feverfew by people taking it chronically for treatment of migraine can produce rebound withdrawal symptoms. These consist of migraines, anxiety, poor sleep patterns, and stiffness of the muscles and joints. 

The most common side effect of clonidine is drowsiness. This can begin with the very hrst dose and usually goes away after a few weeks. Clonidine s sedating effects can actually be useful when it s taken at bedtime. Insomnia is a common problem for patients with ADHD either as a side effect of stimulants or as a consequence of rebound hyperactivity at night when the daytime dose of stimulant has worn off. Clonidine can help the ADHD patient with insomnia to go to sleep. Other side effects of clonidine include low blood pressure, dizziness, depression, dry mouth, nausea, and slowed heart rate. One important point to remember is that not only does clonidine not cause tics, it can, in fact, relieve tics when they appear in patients with ADHD. 

Like the barbiturates, the benzodiazepines make it easier to fall asleep and to stay asleep through the night. However, they also suppress REM sleep, which can lead to REM rebound when they are discontinued. Tolerance to their sleep-promoting effects often develops after chronic use. Some long-acting benzodiazepines, such as flurazepam (Dalmane), are associated with pronounced hangover effects in the morning and are therefore problematic as sedative-hypnotics. Others, with a short-to-intermediate dnration of action, are more desirable as hypnotics. 

Use of a hypnotic drug should not be extended beyond 4 wk, because tolerance may develop. The risk of a rebound decrease in sleep propensity after drug withdrawal may be avoided by tapering off the dose over 2 to 3 wk. 

Histamine Hi receptor antagonists which enter the brain (diphenhydramine, promethazine and others) have sedative actions and polysomnographic recordings have shown that they suppress REM sleep and modestly increase SWS. A rebound in REM sleep sometimes occurs on discontinuation. Stimulation of central Hi and H2 receptors markedly potentiates signals produced by excitatory amino acids and it has been suggested that histamine acts as a waking amine (Schwartz et al., 1986). The effects of centrally acting antihistamines on sleep may be due to inhibition of these effects. 

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