Posted by mattdds on October 3, 2003, at 15:55:55
In reply to Re: Ambien- dependency potential?, posted by Budgie on October 3, 2003, at 14:53:05
Chris,
Here are some abstracts of the evidence that I found. There is much more, believe me!
Lack of tolerance and physical dependence upon repeated treatment with the novel hypnotic zolpidem
G Perrault, E Morel, DJ Sanger and B ZivkovicSynthelabo Recherche (L.E.R.S.), Bagneux, France.
Zolpidem is a new, short-acting hypnotic of imidazopyridine structure which binds selectively to a subpopulation of receptors involved in the action of benzodiazepines [omega 1 (BZ1) sites of the gamma- aminobutyric acidA receptors]. The present study investigated whether tolerance and physical dependence develop after repeated treatment with zolpidem as is observed with benzodiazepines. Mice were given zolpidem or the benzodiazepine midazolam (2 x 30 mg/kg, p.o.) for 10 consecutive days. Tolerance to central depressant effects (evaluated by recording spontaneous locomotor activity) and to anticonvulsant effects (measured against pentylenetetrazole-, electroshock- and isoniazid-induced convulsions) was assessed 42 hr after the last administration. A decrease in the latency to isoniazid-induced convulsions was taken as an index of physical dependence and was evaluated 3, 6, 14, 24, 42 and 67 hr after the end of chronic drug treatment. Repeated treatment with midazolam produced tolerance to its sedative and anticonvulsant activities as indicated by shifts of the dose-response curves by a factor of 3 to 5. Fourteen hr after discontinuation of treatment, spontaneous withdrawal was observed and lasted 3 days. When flumazenil was given 3 or 6 hr after the final midazolam injection, precipitated withdrawal was observed. In contrast, after repeated treatment with zolpidem, there was no change in its ability to produce sedative and anticonvulsant effects. Moreover, neither spontaneous nor flumazenil- induced precipitated withdrawal was observed in zolpidem-treated mice.
**Ok, that was with mice, but...it looks promising. Here's a human one.**
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Non-benzodiazepines for the treatment of insomnia.
Wagner J, Wagner ML.
Department of Clinical Practices and Therapeutics, Merck-Medco-Managed Care, L.L.C. Franklin Lakes, NJ, USA
Benzodiazepine hypnotics, the mainstay of pharmacological treatment for insomnia, have been associated with altered sleep architecture, psychomotor and memory impairment, rebound insomnia, withdrawal effects, tolerance, dependence, abuse potential and respiratory depression. Non-benzodiazepines, such as zolpidem, zopiclone and zaleplon, demonstrate hypnotic efficacy similar to that of benzodiazepines along with excellent safety profiles. Non-benzodiazepines generally cause less disruption of normal sleep architecture than benzodiazepines. Psychomotor and memory impairment may be less problematic with non-benzodiazepines, especially when compared to longer-acting benzodiazepines. Rebound insomnia and withdrawal symptoms occur infrequently upon discontinuation of non-benzodiazepines and may be less common and milder than those seen upon discontinuation of some benzodiazepines. For the long-term treatment of insomnia, which is generally not recommended, zolpidem and zopiclone are particularly good options because they do not develop tolerance rapidly and have a low abuse potential. Limited data indicate that zaleplon has low tolerance and abuse potential, although further experience is needed to determine its long-term efficacy and safety profile. Since non-benzodiazepines produce minimal respiratory depression, they may be safer than benzodiazepines in patients with respiratory disorders. The choice of which hypnotic to use should be based on the patient's primary sleep complaint, health history, adverse effects and cost.
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A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects.
Voderholzer U, Riemann D, Hornyak M, Backhaus J, Feige B, Berger M, Hohagen F.
Department of Psychiatry and Psychotherapy, Klinikum of the Albert-Ludwigs-University Hauptstrasse 5 79104 Freiburg, Germany. Ulrich_Voderholzer@psyallg.ukl.uni-freiburg.de
Rebound effects after withdrawal from hypnotics are believed to trigger their chronic use and to enhance the risk of tolerance and dependence. It was the purpose of this study to investigate the acute polysomnographic withdrawal effects after a 4 week treatment with standard doses of the non-benzodiazepine hypnotics zopiclone and zolpidem compared with triazolam and placebo. Healthy male subjects between 22 and 35 years of age participated in a parallel study design. They received either zopiclone 7.5 mg (n=11), zolpidem 10 mg (n=11), triazolam 0.25 mg (n=10) or placebo (n=7) over 4 weeks in randomized and double-blind order. Sleep EEG was registered during 2 nights before treatment under placebo, on days 1, 27 and 28 of treatment and on days 29,30,41 and 42 under placebo. Total sleep time and sleep efficiency were lower in the 1st night after discontinuation of triazolam (p < 0.05, t-test). After withdrawal from zopiclone or zolpidem slight but not significant rebound effects concerning sleep continuity were observed. Self-rating scales showed minimal rebound insomnia after discontinuation of all three hypnotics. In the placebo group no changes of sleep parameters were observed. Assuming that rebound insomnia is part of a withdrawal reaction, this study indicates that the risks of tolerance and dependency are low when administering zopiclone or zolpidem at the recommended doses.
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Precipitated and spontaneous withdrawal following administration of lorazepam but *not* zolpidem.
Elliot EE, White JM.
Department of Clinical and Experimental Pharmacology, University of Adelaide, South 5005, Australia.
Radiotelemetry was utilized to compare zolpidem and lorazepam tolerance and withdrawal in rats. Locomotor activity, electromyographic activity (EMG), and body temperatures were used to assess the acute drug effects, and as measures of tolerance and withdrawal. Lorazepam, zolpidem, or vehicle was administered for 12 days, and data were recorded daily, immediately, after treatment. Data were also recorded immediately after flumazenil (25 mg/kg, IP) precipitated withdrawal and during 4 days of spontaneous withdrawal. Complete tolerance to the acute effects of lorazepam administration developed within 7 days of treatment and both flumazenil-precipitated and spontaneous withdrawal were observed. In contrast, there was no tolerance to the sedative actions of zolpidem administration after 12 days, but complete tolerance to the hypothermic and muscle relaxant effects was apparent after 8 days of treatment. Despite the presence of tolerance, no evidence of either spontaneous or flumazenil-induced withdrawal was recorded in these rats. In conclusion, this model suggests that as a sedative zolpidem has significant advantages over the classic benzodiazepines.
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Hope these help,
Matt
P.S. Sorry (Dr. Bob) for all the bandwidth hogging, but I was too lazy to look up how to drop a link!
poster:mattdds
thread:264925
URL: http://www.dr-bob.org/babble/20030928/msgs/265279.html