Ambien illustrates mysteries of the brain

In 2006, when John Whyte first started studying the remarkable effect that the sleep medicine Ambien can have on people with severe brain damage, he hoped the drug might be a miracle treatment.

Six years later, Ambien's ability to rouse some people from oblivion remains tantalizingly mysterious. But Whyte, director of the Moss Rehabilitation Research Institute in Elkins Park, no longer sees the drug as a potentially dramatic improvement in care.

Now he sees something far more complex.

Ambien, he said, reveals how little we understand about consciousness.

"What this drug shows is that not everybody who appears to be permanently unconscious with no hope of regaining consciousness is," Whyte said.

That knowledge can make family decisions about when to let go even more agonizing. It provides an argument for giving more aggressive medical treatment to people in vegetative or minimally conscious states and for waiting longer before giving up.

In addition, a drug that helps doctors separate people whose brains are still capable of working from those with more devastating damage could help scientists identify the best candidates for clinical trials. If people can be awakened, however briefly, by a medicine, Whyte said, "it implies they have the machinery for consciousness." It is far more cost-effective, he said, to study new treatments among those most likely to benefit.

Ambien, or its generic form, zolpidem, is widely used to help people fall asleep, but it is also famed for its strange side effects. Not only do some users walk in their sleep, but they drive, prepare and eat food, make phone calls, and have sex. They usually don't remember it.

After anecdotal reports that Ambien could "wake" some people from unconsciousness, Whyte conducted a small trial of the drug in people in vegetative and minimally conscious states (one or two steps above coma) and is now completing a larger study with 75 patients.

Because these patients had severe brain tissue damage, no one who took the drug suddenly became normal. "I haven't had anyone who started a conversation after the drug," Whyte said. But about 7 percent of the patients improved noticeably after they took Ambien - someone was able to follow an object with his eyes, or follow a command.

"They weren't dramatic results, but they were dramatic for those patients," Whyte said.

Bonnie and Jim Trainor's son Jimmy is the only Philadelphia-area resident so far who responded to Ambien. Now 32, he has been in what she calls a "semi-vegetative state" since a car accident nine years ago.

He had just graduated from Temple University. He was coming home from work when a drunk driver hit him. "The surgeon said he might make it, and [then] he said, 'I don't know if that's a good thing.'" Bonnie Trainor said. Jimmy Trainor cannot follow a command or purposefully move anything.

In 2006, his parents, who live in Northeast Philadelphia, heard about Whyte's trial. They asked to join. When Jimmy was given the drug, "it was the most amazing thing I had ever seen," Bonnie Trainor said. "You could see that his whole face changed." He still could not talk, but he raised his hand when asked. He lifted his knee to kick a soccer ball. "We were shocked," his mother said.

The next time they tried, the dose was lower and the response was less. They tried the drug every week for a while, but the results were inconsistent and became barely visible.

Bonnie Trainor thinks it's because her son is on a high dose of an antiseizure drug that sedates him. She's trying to wean him to a lower dose so that she can try Ambien again. Her more immediate problem is the respiratory problems that have plagued him since the accident; he's in the hospital this week with pneumonia.

Jimmy Trainor's reaction to Ambien was evidence of what his parents had hoped, that he might be able to hear them and understand, his father said. "We always wanted to believe he wasn't just a vegetable."

He still hopes the drug will someday make his son alert enough to watch a baseball game or show emotion. "He hasn't smiled in nine years," Jim Trainor said.

In Whyte's most recent study, patients were given a placebo on one day and zolpidem on another through their feeding tubes. They were evaluated by experts who did not know whether they had taken zolpidem or a placebo. Patients who responded to the drug typically started doing so within an hour. The effect lasted from two to five hours.

Whyte's team has also been examining the patients, including Jimmy Trainor, with functional MRIs that illuminate brain activity to figure out why some respond and others do not. That analysis is not complete.

Patients do not seem to learn anything during their Ambien awakenings. While some have consistent reactions, the effect diminishes over time in others, Whyte said. Some have to wait a few days before taking a dose again to get results.

Families have told Whyte, "When Grandma comes for Sunday dinner, we wake him up to be with the family." Whyte said a couple of families have told him they saw improvements in unmedicated behavior after an injured relative took zolpidem.

"What we presume that it's doing is reenergizing circuits that are not destroyed but are for some reason dormant," Whyte said, "but it's only going to reenergize the circuits that are dormant, not dead."

What the drug does is reveal potential that may not be visible to family members or doctors.

A study in 2010 that used fMRI also showed surprising brain activity in patients thought to be unconscious.

David Long, medical director of the brain injury program at Bryn Mawr Rehabilitation Hospital, said doctors have learned that brains are capable of far more healing and repair than previously thought. Half of people who are discharged from an acute care hospital in a vegetative state eventually regain consciousness and many have "meaningful lives," he said. "You don't want to give up too soon."

Arthur Caplan, a University of Pennsylvania bioethicist, said doctors and patients have always had to adjust their thinking as medical science changed. Diseases that weren't curable a hundred years ago now are. Centuries from now, people will marvel at how little we could do today.

He added that the relatively unusual changes in consciousness that have been reported with Ambien probably are not large enough to change most medical decisions. One possibility worth considering, he said, is that whatever thoughts are hidden in people considered vegetative or minimally-conscious are not happy ones. What if they are frightened or claustrophobic? "Being responsive is a very good thing," Caplan said, "but it's not always the best thing."

Bonnie Trainor now sees her son's response as a mixed blessing.

"The scary part is, 'Are people like my son in there?" she asks. She'd like for him to be more awake so that she's not always guessing what he wants or needs.

But even though she takes pride in giving him the best care she can, she knows she wouldn't want to live as he does. "The sad part is, I don't want him to be in there, to be honest, because, if he's in there, his life is living hell."