HONOLULU – Amantadine hydrochloride effectively improved functional recovery in patients in a vegetative or minimally conscious state after traumatic brain injury, results from a 6-week, randomized, multicenter study showed.
"The improvements with amantadine were clinically significant in that they were associated with more frequent emergence of functionally meaningful behaviors [that are] associated with returning to full consciousness," Dr. Douglas I. Katz said at the annual meeting of the American Academy of Neurology. "We believe that amantadine is the first proven pharmacotherapy to promote recovery from severe traumatic brain injury, and should be considered for patients with disorders of consciousness lasting more than 4 weeks."
Patients with disorders of consciousness after traumatic brain injury (TBI) are commonly treated off-label with stimulant and dopaminergic medications to enhance recovery of consciousness and functional recovery. "But to date there has been no proven therapy to promote recovery of consciousness or improve functional outcome after TBI," noted Dr. Katz, medical director of the acquired brain injury program at Braintree (Mass.) Rehabilitation Hospital.
The Centers for Disease Control and Prevention estimates that 1.7 millions Americans sustain a TBI each year, and that there are 3.2 million Americans living with a TBI-related disability. TBI is the leading cause of death and disability of Americans under the age of 44.
Amantadine was first approved to treat influenza A in 1966. By accident it was found to benefit Parkinson’s disease patients 3 years later. "The mechanism of action of amantadine is not fully understood, but it’s known to be a noncompetitive NMDA receptor antagonist and a dopamine agonist," said Dr. Katz, who also in the department of neurology at Boston University Medical Center. "It may have some anticholinergic effects, and it’s been shown to promote glial cell line–derived neurotropic factor."
As for amantadine’s use in TBI, "there has been no class I evidence to support its benefit," he added. "There have been some case series and one randomized, controlled trial – which had some flaws in its methodology – which have suggested benefit of amantadine in TBI."
A seven-center pilot study of 124 patients with TBI and severe disorders of consciousness found that amantadine was the only drug associated with a favorable recovery ( Arch. Phys. Med. Rehabil. 2005; 86:453-62 ). This led to the design of the current trial , which was a randomized, double-blind, parallel-group, placebo-controlled trial carried out at 11 centers. It set out to determine if amantadine given in a dose of 200-400 mg/day would improve functional recovery from post-traumatic vegetative state or minimally conscious state and if the gains in function persisted after the drug was discontinued.
Secondary aims were to evaluate the safety of amantadine and to determine whether response to amantadine differs by time post-injury (21-71 days vs. 72-112 days) or diagnosis (vegetative state or minimally conscious state) at the time of treatment initiation.
To be eligible for enrollment patients had to be aged 16-65 years, have a traumatic etiology, have a Disability Rating Scale (DRS) score of 12 or greater, be unable to follow commands or communicate reliably, and be at least 4 weeks but less than 16 weeks post-injury.
Pregnant subjects were excluded from the trial, as were those with missile-type penetrating brain injury, those with premorbid CNS/developmental abnormality, those with prior exposure to amantadine post-TBI, those with significant impairment of renal function, and those who had more than one seizure in the month prior to enrollment.
After screening and consent, patients were randomized and received a baseline assessment. They went on to receive 4 weeks of either amantadine or placebo, followed by a 2-week washout period. The starting treatment dose was 100 mg twice daily. This was increased by 100 mg daily in weeks 3 and 4 if patients failed to make at least 2 points of improvement on the DRS. Amantadine was tapered at 4 weeks and the patients were monitored across the two-week washout.
The main study outcome was rate of change in the DRS, which was administered at baseline and weekly, and the<cf number="\"2\""></cf> Coma Recovery Scale Revised (CRS-R), which was administered at baseline and week 4 and week 6. The DRS includes assessments from the Glasgow Coma Scale and items to rate a patient’s cognitive ability to perform activities of daily living, such as grooming, toileting, and feeding; it also includes ratings of the patient’s level of dependency and employability. The CRS-R has six subscales, including arousal, auditory, visual, motor, oromotor/verbal, and communication, and was administered to examine specific functionally-relevant markers of consciousness.
Of the 184 patients randomized for analysis, 181 completed the 6-week study . One patient in the amantadine group died from unrelated causes, and two patients in the placebo group were transferred to acute care hospitals and lost to follow-up.
The mean age of patients was 36 years and 72% were male. The mean baseline DRS scores in the amantadine group and placebo group were 21.8 and 22.2, respectively, while the mean baseline CRS-R scores were 9.6 and 9.2. Scores on the DRS can range from 0 to 29, and scores on the CRS-R can range from 0 to 23.
Dr. Katz reported that patients who received amantadine had significantly faster functional recovery over 4 weeks of treatment, compared with patients in the placebo group ( P = .007). In addition, patients in the amantadine group maintained functional gains during the 2-week washout period, but their recovery slowed, compared with that of patients in the placebo group after the medication was discontinued ( P = .02).
Patients treated with amantadine tended to have more rapid recovery, compared with those treated with placebo, regardless of whether they were diagnosed in a vegetative state or a minimally conscious state at enrollment. Treatment with amantadine also was more effective in improving recovery regardless of whether it was administered within 4-10 weeks or 10-16 weeks postinjury.
After 4 weeks of treatment, a lower percentage of patients in the amantadine group remained in a vegetative state or an extreme vegetative state, compared with their counterparts in the placebo group (18% vs. 31%, respectively).
Dr. Katz went on to report that patients in the amantadine group achieved a higher percentage of cognitive behaviors associated with full consciousness based on the CRS-R at week 4, compared with the placebo group, including more consistent following of commands (40% vs. 32%, respectively), object recognition (44% vs. 34%), functional object use (42% vs. 26%), intelligible verbalization (39% vs. 34%), reliable yes/no communication (31% vs. 27%), and sustained attention (35% vs. 29%).
Vomiting and gastrointestinal side effects were the most common adverse events observed, but there were no differences between the two groups in the incidence of adverse events.
"This study demonstrates that amantadine is safe and effective in promoting more rapid functional recovery in patients with disorders of consciousness after severe TBI," Dr. Katz concluded. "Although the rate of improvement slowed, the benefits of amantadine were maintained after the drug was discontinued."
He acknowledged certain limitations of the study, including the limited interval of treatment and assessment, and that it was not controlled for the effects of standard rehabilitation interventions.
The study was funded by the National Institute on Disability and Rehabilitation Research. The project director was Joseph Giacino, Ph.D., of the Spaulding Rehabilitation Hospital in Boston (formerly of the JFK Johnson Rehabilitation Institute, Edison, N.J.). The project codirector was Dr. John Whyte of the Moss Rehabilitation Research Institute, Elkins Park, Pa.
Dr. Katz said that he had no relevant financial disclosures.