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1.         INTRODUCTION

Zolpidem is a chemically distinct imidazopiridine molecule, used routinely for insomnia. It induces sleep by attaching to GABA(A)receptors in the brain.  It has a highly selective effect binding specifically to the alpha sub-unit of GABA(A) receptors, referred to as the benzodiazepine (omega) receptor. There are at least three omega receptor subtypes to which benzodiazepines bind non-selectively while zolpidem binds preferentially to omega-1 receptors.  In this way it produces sedative, anticonvulsant, anxiolytic and myo-relaxant effects.

2.        ZOLPIDEM EFFICACY AFTER BRAIN DAMAGE

2.1       Literature

In 2001 the first report appeared in the medical journals of unexpected improvement after zolpidem in a patient with impaired consciousness caused by a traumatic brain injury that had occurred three years earlier (Clauss & Nel, 2001).  Other written reports continue to appear and are listed below in table 1. Individual anecdotal personal and internet communications are legion.  The original centre in South Africa has now treated over 500 patients.

TABLE 1      JOURNAL PUBLICATIONS

PS: For further peer reviewed literature, please see updated references.

 
2.2           Neurodormancy, the mechanism of effect

Remarkably, SPECT and PET brain imaging studies have shown that parts of damaged brain that are inactive before dosing start to function again after zolpidem (Clauss et al 2000, 2004, Cohen et al 2004, Brefel Courbon et al 2007, Clauss 2010).  The inactive areas have no typical location or distribution pattern and vary from patient to patient which may explain the wide variation in the nature of the clinical response.  Such areas had previously been considered as dead but evidently they are dormant rather than dead so the new term ‘neurodormancy’ has been coined to refer to the areas that zolpidem affects (Clauss et al, 2004).  The reversal of neurodormancy has been reproduced in animal experiments (Clauss et al, 2001) and it could be demonstrated that flumazenil, a benzodiazepine antagonist blocked this effect of zolpidem, thereby proving that the mechanism is mediated via GABA receptors (Clauss et al, 2002).

The exact mechanism of Neurodormancy is not known but a recent magnetoenchalographic (MEG) investigation of a post-stroke subject at Aston University, Birmingham, UK has suggested that zolpidem (as opposed to placebo or another sedative called zopiclone) seems to achieve its clinical effect by reducing the pathological slow waves associated with neurodormant brain tissue and known to be associated with other neurological conditions (Hall et al, 2010).

Crucially the positive changes observed in scans cannot be due to the placebo effect. Moreover the timing of the clinical responses conforms to the known pharmacokinetics of zolpidem and they appear only after a dose and each time a dose is taken with relapses in between doses.  Accordingly, the evidence fulfils the accepted criteria for proof of efficacy without a formal placebo-controlled clinical trial according to the working party report of the Evidence Based Medicines Group 2000 (Guyatt et al, 2000, Glasziou et al, 2007) Recent controlled multi patient trials have now confirmed these earlier findings (Du et al, 2008, Whyte et al, 2009, Nyakale et al 2010).

2.3           Proportion of Responders

The proportion of responders is not known but appears to be between 10 and possibly 30%.  A recent study at the University of Pretoria in unselected brain damage patients has found a 40% response rate in patients who had a degree of dependency on carers as shown by Barthel Index scores of less than 100 (Nyakale et al, 2010). The evidence of efficacy was based on SPECT scan results and Tinetti Falls Efficacy Scale evaluations.   Further studies on response rate are required, especially in view of a stroke patient who took 8 consecutive days of treatment to respond.

3.             SAFETY AND ADVERSE EFFECTS


3.1           Use in patients after brain damage

In general zolpidem has an exceptional safety record till now, 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. An increased mortality risk, similar to smoking, has been reported in patients using hypnotics, including zolpidem (Kripke et al 2012) but it is not known if this applies to patients after brain damage.

Clearly at higher doses zolpidem will sedate a patient, but there has been no evidence that it presents a greater risk than normal sleep in patients with brain damage.  However, sedation will mask any beneficial effect and one report from Edinburgh to this effect has appeared by Singh et al, in 2008.


3.2        Long term use

In longer term use as a sedative there are occasional reports of effects that disturb patients without having life threatening implications, ie: recurrent cases of antegrade amnesia, hallucinations and sleepwalking. They have not been reported in patients with brain damage. One VS patient has been treated every day for nearly ten years and he has steadily improved without any adverse effect apart from the expected sedation. Recently his SPECT scan was repeated prior to a dose of zolpidem and it was much improved compared with his first scan, indicating that reversal of neurodormancy has progressed pari passu with his clinical improvement. Although fully conscious now, he still shows benefit from an individual dose, in particular his IQ test result improves from 70 to 90 on a 5mg dose.


3.3        Overdose safety

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 the only known 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, while coma was encountered in 4 cases (11%) with triazolam and 4 cases (10%) with midazolam.

3.4        Withdrawal effects