Rebound insomnia after abrupt discontinuation of hypnotic treatment: double-blind randomized comparison of zolpidem versus triazolam

Abstract

Rebound insomnia is a transient intense worsening of sleep usually appearing within 3 days from the abrupt discontinuation of benzodiazepines (mainly short-acting), following long term use and abuse of these hypnotics. Zolpidem is an imidazopyridine, that binds selectively at mi-receptor subtypes within the GABAA receptor supramolecular complex. It has a rapid onset of action and short-elimination half-life; it reduces the latency of sleep and prolongs the duration of sleep in patients with insomnia, without any major effects on sleep stages and rebound effects upon discontinuation.The present multicentre trial (three Italian centres) was aimed at assessing the symptoms/signs of rebound insomnia after discontinuation of either zolpidem or triazolam. A double-blind, randomized, parallel group trial of 20-day duration was carried out in 22 patients suffering from either transient insomnia, or short-term (situational stress) insomnia, or patients who were poor sleepers. The trial consisted of three periods: a 3-day run-in period with placebo, a 14-day active treatment period (zolpidem 10 mg od or triazolam 0.25 mg od), a 3day withdrawal period with placebo.There were statistically significant [ p = 0.0064 for Total Sleep Time (TST) and p = 0.0051 for Sleep Efficiency (SE%)] differences between triazolam-and zolpidem-treated patients during the first withdrawal night versus baseline: TST decreased to 34.5 rnin after trkolam but increased to 43.8 min after zolpidem, and a similar evolution was shown on SETo (a decrease of 6.3 per cent after triazolam and an increase of 9.9 per cent after zolpidem). Also the Wake-time After Sleep Onset (WASO) showed a statistically significantly (p = 0.0083) different pattern, during the first withdrawal night, remaining decreased after zolpidem (37.5 min) but suddenly increasing after triazolam (1 7-3 rnin).Also the subjective time to fall asleep changed with a statistically significant difference (p = 0.042), being increased after triazolam (8.6 min) and decreased after zolpidem (20-8 min).The results of the study demonstrate the presence of clear rebound insomnia after triazolam discontinuation, whereas such a drawback is absent with zolpidem. This allows the abrupt discontinuation of zolpidem without any need for a tapering procedure and without any risk of pharmacological dependence.

A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia

“…The three studies that specifically address this topic failed to demonstrate signs of rebound insomnia after 2 or 4 weeks of treatment with IR-zolpidem 10 mg [66,108,109]. Two other studies using objective and subjective measurement corroborated these results with subjective data for sleep latency, TST, WASO and NAW being in accordance with polysomnographic findings [110,111]. One study in nonelderly insomniacs shows that cessation of a 4-week treatment with IR-zolpidem 10 mg induces, during a 1 week observation period, at least 1 night with worsening of TST or of sleep latency (defined as more than a 40% worsening of baseline assessments); there were, however, no differences between baseline and withdrawal TST or sleep onset latency [112].…”

“…Peculiar cases of delirium, hallucinations, or drug-induced, sleep-related complex behavior have been described with zolpidem, but also with zaleplon and zopiclone [89]. It has to be stressed that these adverse effects (including abuse, dependence and withdrawal syndrome) were mostly observed in insomniac patients having a psychiatric comorbidity, such as major depression (especially if zolpidem is added to a serotonin reuptake inhibitor [88] such as fluoxetine [87] or fluvoxamine [87]) or substance abuse disorder [89,115,111]. More generally, patients with a history of alcoholism or drug abuse should not receive GABAergic hypnotics, including zolpidem.…”

Pharmacotherapy of Insomnia: Focus on Zolpidem Extended Release

“…Slow wave sleep was increased after zolpidem but reduced after triazolam. 160 Zolpidem 10 mg and triazolam 0.5 mg also increased TST in patients with chronic primary insomnia. This increase observed in the zolpidem group was associated with a greater number of sleep cycles.…”

Ramelteon: A Novel Approach in the Treatment of Insomnia

“…MEDLINE (1996( -July 2008 and PsycINFO (1985-July 2008 were searched using the term ramelteon. All English-language articles identified from the search were evaluated.…”