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Zolpidem Paradox: Why Sleep Med Wakes Brain-Injured Patients

Researchers are gaining insights into why some minimally conscious patients with a severe brain injury appear to “awaken” after taking the sleep medication zolpidem (Ambien, Sanofi-Aventis).

The answer may lie in a pool of recruitable and functional brain cells that are activated in response to zolpidem treatment, Nicholas Schiff, Jerold B. Katz Professor of Neurology and Neuroscience, and professor, public health, Weill Cornell Medical College, New York, New York, told Medscape Medical News.

“What’s new here is that we have insights as to the mechanisms,” explaining the well-documented paradoxical awakening in brain-injured patients given zolpidem, said Dr. Schiff.

The new research was published online November 19 in the open-access journal eLife.

Additional Insights

The observation that zolpidem can have a paradoxical arousal effect on patients with a severe brain injury dates back about 6 years and has been reported by many different groups. For example, Dr. Schiff and his colleagues previously described the case of a 48-year-old woman who had been in a minimally conscious state for 2 years following a suicide attempt. She couldn’t move, feed herself, or speak. When given zolpidem to treat insomnia, she could communicate, eat, and move unassisted within 20 minutes.

At the time, researchers noted from imaging studies that regions of the woman’s brain, including the frontal cortex and the thalamus, were highly active when she was receiving zolpidem and very inactive when she wasn’t.

Brain damage can result in loss of a pathway consisting of excitatory projections from the cortex to the striatum, which in turn sends inhibitory projections to the globus pallidus, Dr. Schiff said. The net effect can be inhibition of the thalamus, which, along with the striatum, supports alertness and sleep as well as short-term memory, reward, motivation, and attention.

In this report, Dr. Schiff and colleagues present additional insights from observations of 3 patients with severe brain injury patient

s: One had sustained head trauma from a fall, another was oxygen deprived after nearly drowning, and the third had had multiple strokes from vasospasm after a subarachnoid hemorrhage. All 3 patients had shown strong arousal responses to zolpidem.

Using electroencephalography (EEG) while the patients were both on and off the drug, the researchers observed that despite having very different types of brain trauma, the patients had similar patterns of brain activity. The researchers found this “very surprising and very compelling,” said Dr. Schiff.

“They were so similar that they almost looked like different measurements of the same person.”

Off the drug, that pattern was a low-frequency rhythm or oscillation — about 7.5 cycles per second — in all parts of the brain, but more so in the front than in the back and on both sides, said Dr. Schiff. “This rhythm was about the same rate and was highly synchronized within each half of the brain and across the 2 halves of the brain.”

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When patients were receiving the drug, there was an increase in the average frequencies of brain waves, which correlated with improvement in alertness of the patients.

Dr. Schiff compared the initial arousal effect from zolpidem to the paradoxical excitation that sometimes occurs when low doses of an anesthetic induce excitation rather than sedation, or the initial “buzz” after consuming alcohol.

Zolpidem, which is selective for a subtype of gamma-aminobutyric acid (GABA) receptors, could block the inhibitory inputs from the globus pallidus to the thalamus, “thus allowing the thalamus to excite the cortex and help restore cognitive and motor functions,” Dr. Schiff and his colleagues write.

Predictive Model

The researchers believe that the initial excitation produced by zolpidem allows the brain to ride on this “buzz.” “It’s like catching a wave and as those cells get recruited, they turn on and as they start to actually function and do things, then they wake the brain up even more,” said Dr. Schiff. “That whole process can hold on until the drug wears off.”

The new findings should help identify residual capacity or untapped capacity in other people with severe structural brain injury, he said. “We discovered there is this marker for this potentially vast pool of usable cells.”

This model could also help explain past success with treatments for severe brain injury, including central thalamic brain stimulation and amantadine, said Dr. Schiff.

Whether zolpidem, another drug or device, or some combination, is the optimal method of targeting these cells for the reawakening effect is still to be determined, he said.

This effect doesn’t occur in every patient. One study that looked at this prospectively showed that less than 10% of brain-injured patients had a response, said Dr. Schiff. “The drug itself is a very specific agent; it acts at a very specific receptor subtype that can vary from person to person.”

This new work raises the prospect that it might be possible to eventually determine which patients may respond to the drug through genome analysis, he said.

The next step for the researchers is to look across larger numbers of brain-injured patients both longitudinally and cross-sectionally, said Dr. Schiff.

“We now have a predictive scientific model to go and see whether in a large population of structurally brain injured patients we can actually start to make estimates about recruitable reserve. Then, in patients who get better on their own or with medications, we might start to see if their improvements correlate with changes in the measures that are consistent with our model.”

The hope, said Dr. Schiff, is to eventually have a set of tools to track recovery and to assess the efficacy of different therapeutic strategies.

Zolpidem Paradox

In an accompanying commentary, Oluwaseun Akeju and Emery N. Brown, both from Massachusetts General Hospital, Boston, point out that while functional improvement following zolpidem is well documented, it is also rare. In this report, the researchers “offer significant insights into the zolpidem paradox based on a study of three severe brain injury patients with strong arousal responses to the drug,” they write.

In these patients, the researchers observed that off zolpidem, all 3 patients showed strong brain waves “with an unusually low frequency (between 6 and 10 Hertz), which were most prominent over fronto-central regions of the scalp, and which were highly coherent within and between hemispheres,” they write. “Zolpidem sharply reduced the strength and coherence of the 6-10 Hz activity, and led to an increase in the average frequencies of brain waves (15-30 Hz). These changes correlated with the improvements in alertness seen in the patients.”

The researchers reasoned that these 6- to 10-Hz oscillations probably arise from “the intrinsic membrane properties of the damaged neurons in the cortex,” the editorialists write. The researchers reason that the brain waves become coherent because any brain areas with residual electrical activity that remain connected will tend to begin firing together at a common frequency, they point out. The researchers “therefore interpret the 6-10 Hz brain waves as a marker of reserve capacity that could be recruited to restore function, for example, through the use of drugs such as amantadine and zolpidem, or devices such as deep brain stimulation and transcranial magnetic stimulation.”

Zolpidem probably breaks up the coherence in the network by these mechanisms, they add. “Williams et al. thus offer new insights into the therapeutic use of zolpidem and suggest a potential diagnostic and prognostic brain wave signature that is easy to measure.”

The findings support the need for further trials, they conclude, that should include genetic profiling of GABA receptor subtypes.

Medscape Medical News asked W. Christopher Winter, MD, a neurologist and the medical director, Martha Jefferson Hospital Sleep Medicine Center, Charlottesville, Virginia, to comment on research that might explain why a drug that is supposed to induce sleep actually does the opposite in some patients.

The new work on paradoxical excitation could represent a “huge key” to helping these patients restore a more normal level of functioning, said Dr. Winter.

“The consequences of brain injuries are incredibly difficult to manage,” said Dr. Winter.”While one would think that sleeping pills would be the last thing you would want to give a patient struggling with a persistently low level of consciousness, this is exactly what researchers are finding.”

The paradoxical effect may occur because the sleep aid enhances frontal cortex and thalamic activity, commented Dr. Winter.

Dr. Schiff and the editorialists have disclosed no relevant financial relationships.
[November 27, 2013, Pauline Anderson, Medscape Medical News > Neurology, ; eLife. Published online November 19, 2013]