A double-blind placebo-controlled study of the effects of amphetamine and physiotherapy after stroke. No benefit from D-amphetamine when added to physiotherapy after stroke: a randomized, placebo-controlled study. Evidence that amphetamine with physical therapy promotes recovery of motor function in stroke patients. Amphetamine paired with physical therapy accelerates motor recovery after stroke. Further evidence. Physiotherapy coupled with dextroamphetamine for rehabilitation after hemiparetic stroke: a randomized, double-blind, placebo-controlled trial. Amphetamine fails to facilitate motor performance and to enhance motor recovery among stroke patients with mild arm paresis: interim analysis and termination of a double blind, randomised, placebo-controlled trial. A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia. Safety of dexamphetamine in acute ischemic stroke: a randomized, double-blind, controlled dose-escalation trial.
Major therapeutic advances in the rehabilitation of subacute stroke are lacking. One promising approach is treatment with amphetamine in combination with physiotherapy so as to promote motor function. In a randomized, double-blind, placebo-controlled clinical trial, the effect of 10 sessions with 10 mg of amphetamine combined with physiotherapy during a 5-week period was investigated in 39 geriatric patients who had been admitted to a stroke rehabilitation unit. Motor function (Fugl-Meyer motor performance score) and activities of daily living (ADL; Barthel's index) were assessed at baseline and at the end of treatment. All patients improved significantly over the intervention period. Amphetamine-treated patients did not show any increase in motor function or ADL as compared to the control group. Rehabilitation with amphetamine at this dosage and interval, combined with physiotherapy, did not promote motor recovery or functional capacity in patients suffering from stroke.
                Copyright 2001 S. Karger AG, Basel To assess the effect of D-amphetamine on the recovery of activities of daily living and motor functions after stroke,
                Randomized, placebo-controlled study,
                Inpatient rehabilitation centre,
                Twenty-four stroke survivors after a first ischaemic supratentorial stroke within six weeks before study onset, severely to moderately affected, with a Barthel Index (0-100) ranging from 25 to 50, no severe concomitant internal, neurological or psychiatric diseases, and participating in a comprehensive rehabilitation programme of 10-12 weeks,
                Ten sessions with 10 mg D-amphetamine (or placebo) every fourth day totalling 100 mg in a time period of 36 days combined with physical therapy according to the neurodevelopmental concept within 60 minutes after drug intake.
                Barthel Index (0-100) served as the primary outcome measure and the Rivermead Motor Assessment Score with its three sections (gross function, leg and trunk, and arm) as the secondary outcome measure, assessed at days 0, 20, 36, 90, 180 and 360.
                The two groups did not differ with respect to clinical data and outcome measures at study onset. All patients improved significantly except for arm function over the intervention period and up to day 90 after study onset. The comparison between groups did not reveal any difference at any time; amphetamine-treated patients did not show any increase in motor function or ADL compared with the control group.
                The placebo-controlled study failed to show any effect of D-amphetamine on stroke recovery compared with control. The small number of patients, the timing and content of physical therapy were limiting factors of the present study. Further trials are warranted. We conducted a double-blind pilot study of 8 patients with established cerebral infarction to evaluate the effect of a single dose of amphetamine on recovery of motor function using the Fugl-Meyer scale. Four patients received amphetamine; the rest were given placebo. All underwent a session of physical therapy. Patients treated with amphetamine obtained greater increments in motor scores than the controls. Along with animal studies, these findings may allow the development of a pharmacological approach to stroke rehabilitation. In animal models of brain injury, administration of numerous pharmaceuticals is reported to facilitate functional recovery. However, only drugs that increase the release of norepinephrine have been shown to promote recovery when administered late (days to weeks) after injury. To determine whether these findings were applicable to humans, we administered the norepinephrine stimulant dextroamphetamine, paired with physical therapy, to hemiplegic stroke patients.
                Ten hemiplegic patients who suffered an acute ischemic infarction were entered between days 16 and 30 after onset and randomly assigned to receive either 10 mg of dextroamphetamine or a placebo orally every fourth day for 10 sessions paired with physical therapy. The Fugl-Meyer Motor Scale was used at baseline, within each session, and for 12 months after onset as the dependent measure. Confounding medications such as alpha-adrenergic antagonists or agonists were excluded in all subjects.
                Although there were no differences between the groups at baseline (P = .599), there was a significant (P = .047) difference between the groups when the drug had been discontinued for 1 week and at the 12-month follow-up visit (P = .047).
                Administration of dextroamphetamine paired with physical therapy increased the rate and extent of motor recovery in a small group of hemiplegic stroke patients. These data support and extend previous findings of the facilitatory aspects of certain types of drugs on recovery from brain injury. The use of neuromodulation may allow the nervous system to adapt previously unused or alternative pathways to relevant external input. Hemiparesis is the commonest disabling deficit caused by stroke. In animals, dextroamphetamine (AMPH) paired with training enhances motor recovery, but its clinical efficacy is uncertain.
                In a randomized, double-blind, placebo-controlled trial, 71 stroke patients were stratified by hemiparesis severity and randomly assigned to 10 sessions of physiotherapy coupled with either 10 mg AMPH or placebo. Study treatments were administered by 1 physiotherapist, beginning 5 to 10 days after stroke and continuing twice per week for 5 weeks. Outcomes were assessed by 1 physiotherapist at baseline, after each treatment session, at 6 weeks, and at 3 months. The primary outcome was motor recovery (impairment level) on the Fugl-Meyer (FM) scale. Secondary outcomes assessed mobility, ambulation, arm/hand function, and independence in activities of daily living.
                Baseline hemiparesis was severe overall (mean FM score 27.7+/-20.0). Motor scores improved during treatment in both groups (mean change, baseline to 3 months 29.5+/-16.6). Repeated-measures ANOVA revealed no significant differences in recovery between the treatment groups for the entire cohort (n=67) or for subgroups with a severe hemiparesis (n=43), moderate hemiparesis (n=24), or cortically based stroke (n=26). In the moderate subgroup, there was a significant drug x time interaction for upper extremity motor recovery (F=5.14; P<0.001), although there was a significant baseline imbalance in motor scores in this subgroup.
                In stroke patients with a severe motor deficit, 10 mg AMPH coupled with physiotherapy twice per week for 5 weeks in the early poststroke period provided no additional benefit in motor or functional recovery compared with physiotherapy alone. Patients with moderate severity hemiparesis deserve further investigation. Increased intensity and longer duration drug/therapy dosing regimens should be explored, targeting the upper and lower limbs separately. To assess the effects of d-amphetamine on motor facilitation and recovery in stroke patients with mild arm paresis receiving the Arm Ability training.
                Thirty-one stroke patients with mild arm paresis were randomly assigned to either (a.) receiving placebo or (b.) d-amphetamine twice a week 2 hours before Arm Ability training sessions for three weeks. Main outcome measure: time needed to perform TEMPA tasks, a measure of upper extremity performance reflecting everyday life tasks. Secondary measures: aimed movements, tapping, and a 10 m walkway as well as motor performance during training sessions.
                The interim efficacy analysis of 26 stroke patients who completed the study intervention showed overall arm motor recovery both from pre to post test after 3 weeks of training and from pre test to follow-up 1 year later. No superior effect of d-amphetamine over placebo could be substantiated for either motor facilitation during training or motor recovery (post training or long-term). D-amphetamine exerted mild effects on blood pressure. Serious adverse events were not observed.
                d-Amphetamine failed to facilitate motor performance during training sessions, to promote skill acquisition with training tasks, and most importantly to enhance motor recovery among patients with mild arm paresis after stroke. A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late (days to weeks) after brain injury in animals. A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke. To determine whether these findings extend to communication deficits subsequent to stroke, we administered dextroamphetamine, paired with speech/language therapy, to patients with aphasia.
                In a prospective, double-blind study, 21 aphasic patients with an acute nonhemorrhagic infarction were randomly assigned to receive either 10 mg dextroamphetamine or a placebo. Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions. Thirty minutes after drug/placebo administration, subjects received a 1-hour session of speech/language therapy. The Porch Index of Communicative Ability was used at baseline, at 1 week off the drug, and at 6 months after onset as the dependent language measure.
                Although there were no differences between the drug and placebo groups before treatment (P=0.807), by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups (P=0.0153), with the greater gain in the dextroamphetamine group. The difference was still significant when corrected for initial aphasia severity and age. At the 6-month follow-up, the difference in gain scores between the groups had increased; however, the difference was not significant (P=0.0482) after correction for multiple comparisons.
                Administration of dextroamphetamine paired with 10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke. Neuromodulation with dextroamphetamine, and perhaps other drugs that increase central nervous system noradrenaline levels, may facilitate recovery when paired with focused behavioral treatment. Amphetamine is reported to enhance recovery after experimental stroke, but results from the first few trials in humans are inconclusive. Limited information is available on treatment safety. This study intended to investigate the safety and tolerability of dexamphetamine in patients with acute cerebral ischemia.
                Forty-five patients with cerebral ischemia were enrolled within 72 hours after onset of symptoms. Patients were randomized to 1 of 3 dose levels (2.5, 5, or 10 mg orally twice daily) or placebo for 5 consecutive days. Adverse events, blood pressure, heart rate, body temperature, consciousness level, and functional outcome measures were followed up daily during treatment. Follow-ups were made at day 7 and 1 and 3 months after stroke.
                Mean systolic and diastolic blood pressures and heart rate increased 14 mm Hg, 8 mm Hg, and 9 bpm, respectively, with dexamphetamine treatment compared with placebo (P< or =0.01). There was no difference between dexamphetamine and placebo regarding adverse events, body temperature, or consciousness level. During treatment, there was a benefit of dexamphetamine in neurological and functional outcome (P<0.05), but differences were not maintained at follow-up.
                Overall, dexamphetamine was safe and well tolerated by patients with acute cerebral ischemia, but blood pressure and heart rate increased during treatment in comparison to placebo. These observations may be important in the future planning of amphetamine trials because changes in these variables have been observed to interfere with clinical outcome. The suggestions of improvement in outcome must be confirmed in further studies.
At present, too few patients have been studied to draw any definite conclusions about the effects of amphetamine treatment on recovery from stroke. The suggested benefits on motor function and the non-significant trend towards increased risk of death could be related to imbalances in prognostic variables or other bias in the studies. Further research is therefore justified.