The sleeping pill that wakes up damaged brains

A conservative estimate, based on hospital records from the 1990s, estimates that 170 000 people sustain brain damage every year. Sadly there is little than can be done to treat an injured brain, with the majority of post-accident interventions focussing on preventing further damage. Many of these patients end up in rehabilitative or palliative care for the rest of their lives. This is where our research on Zolpidem comes in.

As a researcher, I remember the first time that I was introduced to a group of Zolpidem responder patients. It’s not quite the elegant tale of the confident young neuroscientist swooping in with a charming smile and excellent bedside manner to have rousing conversations with enthusiastic patients who had been completely restored by a wonder drug. 

Instead, I stood frozen in the doorway of a small preparation ward, caught completely off guard by the three families in front of me as a nurse armed with syringes encased in lead shields moved between vulnerable patients with militant precision. She was administering a radioactive tracer in preparation for a SPECT scan, a unique way of imaging brain function by measuring blood flow.

The three patients, each with varying forms of brain damage, were lying on hospital beds. One was asleep. The other two were suffering incapacitating muscle spasms as their significant others sat next to their beds gingerly trying to do whatever they could to comfort their loved ones. 

I was acutely aware of the immense importance of this research and any associated discoveries, as even the smallest improvements can have a large impact on these bed-ridden patients’ quality of life.


Selling at just over R7 per 10mg tablet, Zolpidem, originally marketed as Stilnox in South Africa, was developed by the French pharmaceutical corporation Sanofi-Aventis as a sleeping pill. In healthy individuals, it decreases the amount of time required to fall asleep (known as sleep latency). But if you give this pill to someone with brain damage, in 5% to 6% of cases something miraculous happens. Often it’s a small change, an improvement in speech, reduced muscle spasms, improved gait. In drastic cases, patients are roused from vegetative states, returning to consciousness after many months, even years, of being completely unresponsive. It is these unbelievable events that have led to Zolpidem being dubbed by some as a “Lazarus Drug”.

The problem is, no one knows exactly how it is able to restore function to damaged brains. Bizarrely, once the drug wears off, so do the beneficial effects and vegetative patients are once again subconscious. If the dose is too high, the beneficial effects give way to the drug’s action as a sleeping pill.

So far researchers have been unable to pinpoint which patients will respond positively to the drug. There does not seem to be a particular type of brain damage or damage to a particular region of the brain that dictates, with certainty, whether there will be a rehabilitative response to Zolpidem. But that has not stopped researchers from hypothesising. 

One of the first theories was put forward by a research team from the Medical University of Southern Africa working in conjunction with the Royal Surrey County Hospital (UK): the pioneering concept of “neurodormancy”.

Established physiology states that after a traumatic brain injury, lightly damaged brain cells (neurons) will fully recover, whereas profoundly compromised cells will die off, often taking their neighbours with them. The neurodormancy hypothesis proposes a third option: select populations of neurons are caught in a grey zone between death and recovery. These cells are able to hibernate, buying themselves the necessary time to repair. However, occasionally, something goes wrong: instead of completing their repairs and waking up, they remain dormant.

Zolpidem works by binding to a specific cellular target, known as GABA receptors, and enhances the effect of gamma-aminobutyric acid (GABA), a signalling molecule. When it binds to these receptors, Zolpidem turns off individual brain cells. When you’re falling asleep, it is the release of GABA that steadily reduces the activity of brain cells. The neurodormancy hypothesis assumes that these hibernating cells have become supersensitive to GABA, and this is why they remain turned off. These scientists argue that Zolpidem transiently restores normal levels of GABA sensitivity, rousing the dormant cells.

A research team at Cornell University (USA) has offered an alternate hypothesis linking Zolpidem and the interaction between brain regions. In the centre of your brain, sitting on top of the brainstem is a structure known as the thalamus. It acts as a vital switchboard for information moving in, out and around your brain. Autopsies conducted on patients who died while they were in vegetative states found that a large percentage of them had damage to the thalamus or interconnected structures.

When operating as expected, there is a region of the brain (the globus pallidus interna), which is constantly trying to turn the thalamus off. Crucially, this region is itself shut down by a separate centre, the striatum. If the striatum detects enough background activity, it turns the globus pallidus off, leaving the thalamus to perform its duties unimpeded, and we perceive this as being conscious.

The problem arises in patients in comas and vegetative states where, either through damage to the network or to itself, the striatum no longer detects enough background activity to facilitate the shutdown of the globus pallidus interna. This allows the globus pallidus interna to run the show and turn the thalamus off — and this is also where Zolpidem comes in. Through silencing the globus pallidus interna, it eliminates the “off” impulse being sent to the thalamus, effectively flipping the thalamic’s “on” switch, reactivating the central switchboard and restoring consciousness.

Sadly neither of these hypotheses is perfect, or able to explain the complex spectrum of Zolpidem-related phenomena. However, researchers are still trying to take full advantage of Zolpidem’s unique action as well as developing new drugs which work in a similar manner. Despite the theoretical uncertainties, Zolpidem offers a glimmer of hope for many families coping with the aftermath of a loved one’s brain injury.

Petrie Jansen van Vuuren is a MSc candidate at the University of Pretoria

Subscribe to the M&G

These are unprecedented times, and the role of media to tell and record the story of South Africa as it develops is more important than ever.

The Mail & Guardian is a proud news publisher with roots stretching back 35 years, and we’ve survived right from day one thanks to the support of readers who value fiercely independent journalism that is beholden to no-one. To help us continue for another 35 future years with the same proud values, please consider taking out a subscription.

Supplement
Guest Author

Related stories

‘Plebs’ finally get to understand a bit of ‘lab-coat lingo’

Writing about their research in last year's Science Voices supplement has been beneficial to the 28 young scientists involved. Participate this year!

Making plant fibres flame-retardant might make them fly.

There is renewed interest in natural materials, as recyclability and environmental safety become more important in manufacturing and consumables.

Satellites can help save the environment

In 10 years, Thohoyandou in Limpopo has become unrecognisable.

The fundamental ties that bind also confuse the world’s chemists

It seems chemists are always out to make life harder for matric students and science undergraduates.

The climate behind human evolution

Investigating past climate change and its human impact.

Unique local genetic problem needs a unique local solution

Spinal muscular atrophy (SMA), a muscle-wasting disease that causes paralysis, is one of the most common genetic causes of infant death in the world.
Advertising

Subscribers only

Toxic power struggle hits public works

With infighting and allegations of corruption and poor planning, the department’s top management looks like a scene from ‘Survivor’

Free State branches gun for Ace

Parts of the provincial ANC will target their former premier, Magashule, and the Free State PEC in a rolling mass action campaign

More top stories

Why anti-corruption campaigns are bad for democracy

Such campaigns can draw attention to the widespread presence of the very behaviour they are trying to stamp out — and subconsciously encourage people to view it as appropriate

Tax, wage bill, debt, pandemic: Mboweni’s tightrope budget policy statement

The finance minister has to close the jaws of the hippo and he’s likely to do this by tightening the country’s belt, again.

SA justice delays extradition of paedophile to UK

Efforts to bring Lee Nigel Tucker to justice have spanned 16 years and his alleged victims have waited for 30 years

Former state security minister Bongo back in court

Bongo and his co-accused will appear in the Nelspruit magistrate’s court in Mpumalanga over charges of fraud, corruption and theft
Advertising

press releases

Loading latest Press Releases…

The best local and international journalism

handpicked and in your inbox every weekday