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

2. 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

3. 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

4. Blood levels

5. 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.

6. 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

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

8. ADRAC REPORTS
Between and 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

9. “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

10. “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

11. 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

12. 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

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

14. 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

15. 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

16. “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

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