Amantadine Speeds Recovery After Severe TBI

Susan Jeffrey

March 02, 2012

March 2, 2012 — Results of a randomized trial confirm that treatment with amantadine can accelerate functional recovery among patients in vegetative or minimally conscious states after a traumatic brain injury (TBI).

Compared with placebo, amantadine effectively accelerated the pace of recovery of cognitively mediated behaviors, such as recognition of objects or verbalization, activities that form the foundation for functional independence, the researchers report. At week 4, more patients in the amantadine than the placebo group had recovery of all 6 behaviors.

"I do think this is going to influence practice," lead author Joseph T. Giacino, PhD, from the Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Harvard Medical School, Boston, Massachusetts, told Medscape Medical News. "This is first time we have convincing evidence in a Class I study, for any treatment — at all — for brain injury."

Dr. Joseph T. Giacino

The study will have to be replicated before amantadine could be viewed as a standard of care, he added, "but it's certainly a big step toward having a standard of care for treatment of this population."

The trial results were published in the March 1 issue of the New England Journal of Medicine.

Disorders of Consciousness

Between 10% and 15% of patients with severe TBI are discharged from acute care in a vegetative state, the authors write. The prevalence of minimally conscious states is estimated to be 8 times that of vegetative states. Vegetative state is defined as wakefulness without behavioral evidence of conscious awareness, whereas in a minimally conscious state, there is at least 1 clearly discernible sign of consciousness, they note.

Although outcomes for patients in minimally conscious states are generally more favorable than those in vegetative states, about half of these patients remain severely disabled at 1 year after the injury, the authors note. To date, no treatment has been shown to change the pace of recovery or improve functional outcome in these patients, although several therapies are used off label, they note, with amantadine being one of the most commonly prescribed.

Amantadine has been used since the 1980s to address parkinsonian symptoms in patients with brain injury, a natural follow-on to its use in Parkinson's disease, Dr. Giacino said. The mechanism is unclear, but amantadine appears to act as an N-methyl-D-aspartate antagonist and indirect dopamine agonist, the researchers note.

Two small previous trials in patients with disorders of consciousness after a TBI suggested it can be effective, but small, unbalanced sample sizes prevented definitive conclusions, they note. "Our intent was to do a definitive trial," Dr. Giacino noted.

The current trial, a prospective, double-blind, randomized, placebo-controlled study of patients in post-traumatic vegetative or minimally conscious states, involved 9 centers in the United States and 3 in Europe.

"We needed that many centers because it's very difficult to enroll these patients, because many of them never make into rehabilitation settings," he said. "Often insurance companies will not authorize rehabilitation because they view these individuals as beyond repair. In fact all of the centers, over the 6 and a half years that it took to complete the trial, we saw slowing in our enrollment because it was getting more and more difficult just to get access to these patients in inpatient rehab settings."

They also limited treatment in the trial to 4 weeks because the average length of stay in an inpatient brain injury program for someone with a severe brain injury is about 4.5 weeks in the United States, he added.

The researchers' hypothesis for this trial, then, was that 4 weeks of treatment with amantadine, given 4 to 16 weeks after injury in patients in vegetative and minimally conscious states after TBI, would improve functional recovery and that the improvement would be maintained 2 weeks after drug washout.

During the 4-week treatment period, recovery was significantly faster in the amantadine group, measured by using the Disability Rating Scale (DRS), a global functional outcome measure. The difference in the slope for this measure was 0.24 point per week (P = .007) indicating a benefit, the researchers note.

Subgroup analysis showed that the treatment effect was similar whether patients were in vegetative or minimally conscious states.

However, Dr. Giacino said, "we were surprised to find, when we stopped the drug, an almost immediate leveling off of the pace of recovery in the amantadine group, so much so that the placebo group caught up to the amantadine group in 2 weeks. So at week 6, they were no longer significantly different."

The difference in the slope on the DRS was 0.30 point per week at this point (P = .02).

To see such a sharp change in that trajectory when the drug was stopped makes a compelling case that it was influencing neural function when it was on board.

Dr. Giacino points out, though, that this provides compelling evidence that the drug worked. "To see such a sharp change in that trajectory when the drug was stopped makes a compelling case that it was influencing neural function when it was on board."

There were no significant differences in the incidence of serious adverse events between groups, the researchers note.

"Whether treatment with amantadine, as compared with placebo, improves the long-term outcome or simply accelerates recovery en route to an equivalent level of function remains unknown," the researchers conclude. "In view of health care cost restraints and declining lengths of stay for inpatient rehabilitation, amantadine-induced acceleration of recovery may represent an important advance."

Future research should look at trying to identify characteristics of the patients who have a response to amantadine, the most effective dosage, the optimal duration of treatment, and timing of initiation of treatment. The efficacy of amantadine in patients with nontraumatic brain injuries will also be of interest.

"After having completed this trial, I think for the first time there is cause for optimism in patient population that has been viewed as largely beyond repair and hopeless," Dr. Giacino concluded.

"Elegant" Design

Asked for comment on these findings, Jose A. Cardenas, MD, a neurologist in North Platte, Nebraska, and a member of the American Academy of Neurology, said the study is "elegantly designed, and although it contains some variables that could not be controlled due to the clinical settings of the patient population, it does provide good evidence to favor the use of amantadine in the treatment of patients with post-traumatic disorders of consciousness."

He agreed with the researchers that one of the greatest challenges for clinical studies in these conditions is enrollment and sample size. "This study certainly excels in this area with a very significant sample size," he told Medscape Medical News. "The observed clinical effect of amantadine has long been hypothesized, and is widely used in clinical practice."

Despite a number of limitations that were pointed out in the discussion section of the publication, Dr. Cardenas concludes, "I believe its greatest strength is that we now have clinical evidence via a randomized, placebo-controlled trial that amantadine is safe and effective to be used in patients with post-traumatic disorders of consciousness and we can expect to see a faster recovery in some of these patients."

The study was supported by a grant from the National Institute on Disability and Rehabilitation Research. Disclosures for the researchers are available at www.nejm.org.

N Engl J Med. 2012;366:819-826. Abstract

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