Zolpidem, first described for brain damage in the South African Medical Journal of 2000 (1) is a prescription medication registered for the short-term treatment of insomnia, invented and marketed by Sanofi Aventis (see also Wikipedia). In a normal brain it works as a short-acting nonbenzodiazepine hypnotic that potentiates the function of gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, by binding to gamma-aminobutyric acid (GABAA) receptors at a location similar to the benzodiazepines. Its onset is quick (usually within 15- 30 minutes), reaching maximum effect at 1 hour after application. It has a short half-life (2–3 hours clinical effect). Chemically it belongs to the imidazopiridine class, distinct from sedatives such as barbiturates, antihistamines, benzodiazepines and cyclopyrrolones. It has no active metabolite and it does not accumulate with repeated administrations. The drug is oxidised and hydroxilated by the liver to inactive metabolites that are eliminated primarily through renal excretion (2).
In general zolpidem has a good safety record even in overdose and reports of adverse events are rare. Krystal et al reported that there were no serious adverse events in a thousand patients who took 12.5mg zolpidem for sleep at night for 6 months (3). In longer term use as a sedative there are reports of effects that disturb patients without having life threatening implications, ie: recurrent cases of antegrade amnesia, hallucinations and sleepwalking.
In terms of acute overdose, zolpidem safety far exceeds that of other GABA agonist sedatives such as the benzodiazepines midazolam and triazolam. Wyss et al, 1996, have published a survey of such overdose patients and reported that with forty fold the normal 10mg dose no severe symptoms occurred in patients with zolpidem single-drug poisonings (4).
Abrupt withdrawal of high long-term doses have produced letters citing epileptic seizures. They include a 50 year old woman who started on normal doses daily for 5 years then due to tolerance increased the dose to 450mg per day in divided doses (5). She abstained for 12 hours and suffered an epileptic fit which she survived without permanent sequelae. Reports from Greece and India each cite an individual patient who had an epileptic seizure after long term high doses of zolpidem and another report from France describes a dependence syndrome in two patients who were dependent on other drugs and were diagnosed with severe personality disorders. However these are rare cases (6, 7, 8).
Although zolpidem is not part of the benzodiazepine group of pharmaceuticals, some potential benzodiazepine like side effects have been reviewed in the medical literature. One analysis suggests that zolpidem should be used with caution in patients with a previous history of substance abuse (9). Lemoine et al have described withdrawel symptoms after discontinuation of chronic zolpidem treatment (10). Such effects seem to be linked to the applied dose (11). However, most studies on zolpidem have failed to show any significant withdrawel symptoms. In 2012 there was a study by Kripke et al, showing that in the short or long term, many hypnotics, including zolpidem carry an increased mortality risk, similar to smoking (12). To be on the safe side, any dosing and dosing changes should be subject to clinical consideration and should occur under medical monitoring.
The original non generic version of zolpidem that is commonly used in patients after brain damage is manufactured by Sanofi Aventis, sold under the trade names Stilnoct in the UK, Stilnox in South Africa and Ambien in the USA. Other trade names for zolpidem include Adormix, Ambien CR, Edluar, Damixan, Hypnogen, Ivedal, Lioran, Myslee, Nytamel, Sanval, Somidem, Stilnox CR, Sucedal, Zoldem, Zolnod and Zolpihexal. Please see 'clinical dosing' for information on application in patients after brain damage.
References 1. Clauss R P, Güldenpfennig W M, Nel HW, Sathekge M M, Venkannagari RR (2000). Extraordinary arousal from semi-comatose state on zolpidem. S Afr Med J, 2 90 68.
2. Salva P, Costa J. Clinical pharmacokinetics and pharmacodynamics of zolpidem.Therapeutic implications. Clin Pharmacokinet. 1995, 29:142-153. 3 Krystal AD, Erman M, Zammit GK, Soubrane C, Roth T; ZOLONG Study Group (2007). Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep, 31(1) 79-90. 5 Barrero-Hernández FJ, Ruiz-Vequilla M, Lopéz-Lopéz MI, Casado-Torres A (2002). Epileptic seizures as a sign of abstinence from chronic consumption of zolpidem. Rev Neurol, 34(3) 253-6. 6 Tripodianakis J, Potagas C, Papageorgiou P, Lazaridou M, Matikas N (2003). Zolpidem-related epileptic seizures: a case report. Eur Psychiatry, 18(3) 140-1. 7 Sethi PK, Khandelwal DC (2005). Zolpidem at supra-therapeutic doses can cause drug abuse, dependence & withdrawal seizure. J Ass Physicians India, 53 139-40.
8 Boulanger-Rostowsky L, Fayet H, Benmoussa N, Ferrandi J (2004). Dependence on zolpidem: a report of two cases. Encephale, 30(2) 153-5. 9 Victorri-Vigneau C, Dailly E, Veyrac G, Jolliet P. Evidence of zolpidem abuse and dependence: results of the French Centre for Evaluation and Information on Pharmacodependence (CEIP) network survey. Br J Clin Pharmacol. 2007 August; 64(2): 198- 209.
10 Lemoine P, Allain H, Janus C. Gradual withdrawel of zopiclone (7.5mg) and zolpidem (10mg) in insomniacs treated for at least 3 months. Eur Psychiatry. 1995; 10 (Suppl. 3): 161s- 165s.
11 Bourin M, Nic Dhonnchadha BA. Psychopharmacology of hypnotics. Bull Clin Psychopharmacol. 2001; 11: 124-31.
12 Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort study. BMJ Open. 2012 27;2(1): e000850.
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