Zolpidem tartrate (Ambien), which is commonly used to treat insomnia, may also benefit patients with a diverse range of noninsomnia neurologic disorders, including patients with movement disorders and those in a vegetative state, new research suggests.
A systematic review of 67 studies and a total of 551 patients showed a drug response rate of 18% or higher for the patients with movement disorders, such as Parkinson’s disease or dystonia. The response rate was 5% to 7% in those with disorders of consciousness (DOC).
These effects included improvements in minimally conscious state and, in some cases, patients trying to speak for the first time in years. Although the effects lasted an average of 1 to 4 hours before the patients returned to their baseline condition, they could be replicated with additional dosing.
The most commonly reported adverse event was sedation, but long-term use of the drug needs to be examined, note the investigators.
“We saw a dramatic effect in a small number of patients with a variety of conditions,” lead author Martin “Nick” Bomalaski, MD, from the University of Michigan, Ann Arbor, said in a press release.
“I think it’s largely to do with where in the brain the lesion or injury is. If certain areas get damaged, zolpidem can help to restore equilibrium to the circuits in the brain,” Dr Bomalaski, who is now at the University of Washington on a brain injury fellowship, told Medscape Medical News.
The findings were published online June 26 in JAMA Neurology.
Commenting on the findings for Medscape Medical News, Douglas I. Katz, MD, professor of neurology at Boston University School of Medicine in Massachusetts, noted that “it’s worthwhile” for clinicians to try zolpidem, at least in DOC.
“It’s not a cure, but it may improve family interactions and quality of life in the 1 in 20 patients who see an effect,” said Dr Katz, who is also the medical director of the Acquired Brain Injury Program at HealthSouth Braintree Rehabilitation Hospital.
In January of this year, Dr Bomalaski published a case report of a 24-year-old man in a minimally conscious state who had increased arousal and motor function after receiving zolpidem.
In addition, he found other, similar case reports that prompted him to pursue this line of research.
“To see that something as simple as an average dose of a sleeping medicine had, in 15 minutes, woken someone from a vegetative state seemed extraordinary, and I wanted to pursue it further,” he said.
The investigators found 2314 articles mentioning the use of zolpidem published up to March 2015. After exclusions, they assessed a total of 67 of the studies, which included 31 that looked at movement disorders, 22 at DOC, and 14 at other neurologic conditions, including stroke, traumatic brain injury, dementia, and encephalopathy.
Of these, 28 were case reports, 13 were single-patient interventional studies, 9 were randomized controlled trials, and 8 were case series reports. Only 11 of the studies had more than 10 participants.
“Wide-ranging” effects of the drug were shown on a variety of measures, including the JFK Coma Recovery Scale-Revised, Burke-Fahn-Marsden Dystonia Rating Scale, and Unified Parkinson Disease Rating Scale.
The most common dose was 10 mg across all the DOC studies. One report noted response to this rate was maintained for more than 2 years “without diminishing effects.” Another reported that a patient in a vegetative state had improvements after being treated with 20- and 30-mg doses of the study drug.
Across the movement disorders studies:
- a 2012 study showed improvements in 24% (8 of 34) of patients with dystonia, 27.8% of those with generalized dystonia, 31.0% with hand dystonia, and 17.8% with Meige syndrome or blepharospasm;
- a 2010 study showed improvements in 41% of 29 patients with dystonia; and
- a 1997 study showed improvements in 60% of 10 patients with Parkinson disease, especially in facial expression, rigidity, and gait.
As with the DOC studies, 10-mg doses were most commonly used.
Among the studies that assessed zolpidem in other neurologic disorders, case reports or case series showed verbal communication improvements in cerebellar mutism, encephalopathy, and catatonia; improved cognitive function in dementia from corticobasal atrophy; and improved gait balance in spinocerebellar ataxia.
“Several studies using functional neuroimaging [also] reported improvements in cerebral perfusion and metabolic activity” on single-positron emission computed tomography and positron emission tomography, respectively, write the investigators.
Sedation was the most commonly reported adverse event, but occurred in only 13 of the 551 total patients and was usually considered to be mild. At 30- to 40-mg doses, a 2012 case report found increased agitation and distractibility in patients who were in a minimally conscious state.
“This is one of those strange paradoxes where the effects of an insomnia drug seem to have the opposite effect for [some] patients who have paralysis or neurologic conditions,” co-investigator Mark Peterson, PhD, also from the University of Michigan, said in the release.
“This kind of report brings up more questions than answers, although something like this is really foundational to guide a larger clinical trial,” he added.
Dr Bomalaski noted that, along with long-term safety and efficacy, he would like to see future trials assess the mechanism for these effects. The investigators write that patients with injury to information processing and arousal areas of the brain may see better outcomes.
“The restorative effects on the basal ganglia may surpass the hypnotic effects on the frontal cortex,” said Dr Bomalaski. However, “we still need to learn much more in order to answer the question about whether we should be using this in our clinical practice.”
Improved Quality of Life
In a previously published study, Dr Katz and colleagues also assessed zolpidem’s effects on the restoration of consciousness. They found that 4.8% of their 84 patients responded to the drug. However, the investigators could not determine beforehand who would and would not respond.
“We were looking at a specific population, with very severe traumatic brain injury and disorders of consciousness. But we only found that 1 in 20 seemed to have any kind of response to it,” said Dr Katz.
Still, “when people do respond, it’s very interesting, especially if it brings them to a level of improvement that is meaningful so that they can interact or communicate,” he said.
He noted that a patient he had who was minimally conscious off the drug, became “significantly more communicative,” at least temporarily, while receiving zolpidem. This included being able to play board games with family members.
“This really improved quality of life for the patient and family, which is important,” said Dr Katz. But he added that the outcomes lasted only as long as the drug lasted.
“This interesting effect should promote more research to understand how it works because that may lead to other ways of treating such patients, and to find out what the long-term effects might be,” he said.
“I thought this was an interesting review of zolpidem for off-label purposes,” Anna Hohler, MD, associate professor of neurology and assistant dean at Boston University School of Medicine, told Medscape Medical News.
“As a movement disorder specialist, it was revealing that there were several studies that did show some objective improvement in functioning, particularly in Parkinson’s disease and dystonia,” said Dr Hohler, who was not involved with this research.
Echoing Dr Katz and the investigators, she noted that more safety research is now needed, “as well as a rigorous, double-blind design to replicate these results.”
The investigators, Dr Katz, and Dr Hohler have reported no relevant financial disclosures.
JAMA Neurol. Published online June 26, 2017. Abstract