ZOLPIDEM Dr Anne-Louise Swain Clinical Forensic Medical Officer Southport, Queensland, Australia

Purported advantages: Imidazopyridine hypnotic agent which binds selectively to α1 receptor of the GABAA complex Sole purpose is to induce sleep and is indicated for the short term treatment of insomnia Purported advantages: Decreased risk of abuse and tolerance seen with benzodiazepine use Decreased disruption of “sleep architecture” ► a better quality of sleep and less next day sedation

Rapid & almost complete initial absorption with ~70% bioavailability CR preparation shows biphasic absorption characteristics with extended plasma concentrations beyond 3h Terminal half-life of ~2.2 to 2.8h (extended release) ► completely eliminated after ~14h (5 to 6 half lives as with all drugs) No evidence of accumulation with daily dosing over 15 days

Blood levels

No significant decrease in performance (using neurocognitive tests assessing vigilance, memory or motor function) was observed with zolpidem CR 8h after administration in 5 studies & no evidence of next day residual effects were detected with zolpidem 12.5 & 6.25 mg using self ratings of sedation.

Cytochrome p450 enzyme metabolism – mainly CYP3A4 with minimal contribution from CYP1A2, CYP2C9, CYP2C19 and CYP2D6 Not a significant inducer or inhibitor of cytochrome p450 All metabolites are inactive Age → increased Cmax & AUC Liver disease → decreased clearance & increased half-life (~10h with cirrhosis) Renal insufficiency → moderate increase (~30%) in volume of distribution

Has been associated with post marketing reports of somnambulism including “sleep driving” & other complex behaviours whilst apparently asleep Reports are most common in Australia

ADRAC REPORTS Between 15.02.01 and 11.02.10 there were 368 reports of “sleep abnormalities” where zolpidem was been suspected as the cause Not on PBS therefore no record of the number of boxes dispensed Unable to determine how many tablets have actually been consumed Limited case details

“TYPICAL” PRESENTATIONS Behaviours commence when the blood level is high & exerting an effect Usually quite “bizarre” behaviour Limited goal direction Driven short distance and crashed car In pajamas or minimal clothing in cold weather Limited ability to interact with environment appropriately Total amnesia for event

“RISK FACTORS” Not going to bed after consumption Consumption at times other than the usual bedtime Taking more than the recommended dose Concomitant use of alcohol and other CNS depressants Concomitant use of SSRIs and other agents which act on the serotonergic system Past history of sleep related disorders

POSSIBLE MECHANISM OF ACTION Zolpidem attaches to the GABAA receptor and “excessively” stimulates it (as do benzodiazepines) ► inhibits activity of neuron This desensitises the receptor to further stimulation producing acute tolerance ► decreased inhibition of serotonergic neurons ► increased levels of serotonin The increased levels of serotonin (after some delay) ►compensatory decrease in serotonin

This results in a “window of opportunity” where The GABA receptor is “tired out” and not inhibiting the neuron The neurons that release serotonin are not being inhibited so they become “overexcited” AND Before the neuron has time to autoregulate the zolpidem level drops because it is metabolised quickly

The delay between the desensitisation of the GABA receptors and a compensatory decrease in serotonin release constitutes the time window for parasomnias

The extended release formula should decrease the risk Anything which slows down / speeds up metabolism is likely to decrease / increase the risk Liver disease will decrease the rate of metabolism

Need to consider behaviour before, during and after time When consumed ?intentional intoxication / misuse / abuse Concomitant use of other drugs and/or alcohol Previous experience Attempts to evade detection

“EVIDENCE” AVAILABLE Anecdotal evidence Observations are usually made by lay persons whose interpretation of behaviour as being “bizarre” is highly likely to very different to a doctor’s interpretation ADRAC and AME No EEG evidence

CONCLUSION Intoxication v somnambulism? An excuse for anything? Given the availability of reasonable substitutes should it be taken off the market?