Safety of Dexamphetamine in Acute Ischemic Stroke
A Randomized, Double-Blind, Controlled Dose-Escalation Trial
Louise Martinsson, PT, MSc; Nils Gunnar Wahlgren, MD, PhD
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Background and Purpose—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.
Methods—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.
Results—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 (Pⱕ0.01). 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.
Conclusions—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. (Stroke. 2003;34:475-481.)
Key Words: blood pressure 䡲 cerebral infarction 䡲 dextroamphetamine 䡲 recovery of function 䡲 safety
T
he effect of amphetamine on promoting recovery after
focal cortical lesions has been extensively studied in
animal models. Most evidence shows an acceleration of
recovery with amphetamine treatment, leading to a final
higher functional level than without this therapy1 if the
treatment is combined with concomitant training.1,2 The
acceleration of recovery has been found to correspond to
enhanced neural sprouting and synaptogenesis after experimental infarction.3 In contrast, a detrimental effect of amphetamine on recovery has been reported after lesions in the
cerebellum4 or substantia nigra.5
An increase in central noradrenergic activity seems to
underlie the effect of amphetamine on recovery in experimental models6 (see References 1 and 2 for a review).
Boyeson and coworkers7,8 have shown that infusion of
norepinephrine but not dopamine into the brain facilitates
motor recovery in animals after brain injury. The noradrenergic theory is further supported by the observation that drugs
acting as antagonists to norepinephrine have reinstated motor
deficits in animal models.9
So far, few clinical studies have been published. Results
from the first relatively small studies (8 to 42 patients) are
inconclusive, with some studies reporting effects in line with
the animal models10 –12 and others reporting no such effects.13–15 From human studies, no adverse events or side
effects have been reported besides insomnia.16 To the best of
our knowledge, no published study has been designed specifically to evaluate adverse effects and tolerability of amphetamine in patients with stroke. We therefore intended to
investigate the safety and tolerability of dexamphetamine
(d-amph) at 3 different doses compared with placebo in
patients with acute cerebral ischemia. A secondary aim was to
study the effects of d-amph on neurological and functional
recovery compared with placebo.
Subject and Methods
Trial Organization
The study was performed at the Department of Neurology, Karolinska Hospital (Stockholm, Sweden). Patient recruitment and
follow-up were done by the authors. A safety committee was
responsible for unblinded examination of the adverse events reports.
The study was performed in accordance with the Declaration of
Helsinki, and the protocol was approved by the local ethics committee at Karolinska Hospital and by the Medical Products Agency in
Sweden. All patients or their relatives gave informed consent.
Received June 13, 2002; final revision received August 15, 2002; accepted August 27, 2002.
From the Institution of Clinical Neurosciences (L.M., N.G.W.), Karolinska Institute, and Department of Neurology, Karolinska Hospital (N.G.W.),
Stockholm, Sweden.
Reprint requests to Louise Martinsson, Stroke Research Unit, R2:03, Department of Neurology, Karolinska Hospital, S-171 76 Stockholm, Sweden.
E-mail [email protected]
© 2003 American Heart Association, Inc.
Stroke is available at http://www.strokeaha.org
DOI: 10.1161/01.STR.0000050161.38263.AE
475
476
Stroke
February 2003
Patient Selection
Patients with first or recurrent stroke admitted to the stroke unit at the
Department of Neurology, Karolinska Hospital, were screened for
inclusion in the study from October 1998 to January 2001. Patients
fulfilling the following criteria were included: (1) age, 18 to 85
years; (2) clinical diagnosis of acute hemispheric cerebral infarction
within the carotid-supplying area confirmed by excluding hemorrhagic stroke on a CT scan; (3) onset of symptoms ⱕ72 hours before
the start of treatment; (4) score of ⱕ15 on arm, hand, and leg motor
items of the Scandinavian Stroke Scale (SSS)17 or a presumed need
for hospital care at the stroke unit for at least 5 days because of other
focal neurological symptoms such as aphasia or neglect; (5) symptoms present for ⱖ1 hour and still present at the start of treatment;
and (6) informed consent. The diagnosis of stroke was based on the
medical history and clinical examination of the patient according to
World Health Organization criteria.18 Main exclusion criteria were
other serious diseases with short life expectancy or that could
interfere with the study protocol and known ongoing alcohol or drug
abuse. There were no limits set to blood pressure (BP).
Design and Randomization
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A prospective randomized, placebo-controlled, double-blind approach was used. The study was designed as a dose-escalation trial
with 3 groups of 15 patients (10 d-amph and 5 placebo) in each
group. If unacceptable side effects arose in ⬎4 patients in a group of
15, this level would be stopped for an analysis. If all patients with
unacceptable side effects had received d-amph, this dose level would
have been closed and a new one opened at a lower intermediate dose
level. The basis for the dimensioning of sample size was a judgment
on clinical relevance of the side effects.
The Karolinska Pharmacy prepared and numbered 45 matching
boxes with d-amph capsules of different doses (2.5, 5, and 10 mg)
and placebo randomly. Patients received boxes in consecutive order.
The pharmacy kept the codes until the end of the trial.
measures: (1) the SSS-5817 and SSS-68, which is an internal but
unvalidated modification of the scale in which neglect has been
added with a maximum of 10 points; (2) Lindmark motor assessment
chart (LMAC)20,21; (3) Activity Index (AI)22; (4) Barthel ADL Index
(BAI)23; and (5) 10-m self-paced walk24 and a walk at maximum
walking speed (patients were asked to walk at a maximum safe
speed). Patients were reassessed with LMAC and SSS at days 1, 2,
3, and 5 of treatment and with AI, BAI, and the 10-m walking test at
day 3. Follow-ups were made at day 7 and at 1 and 3 months.
All patients who were alive, including treatment withdrawals, had
follow-up visits at day 7 and after 1 and 3 months or until death.
Statistical Analysis
Descriptive statistics were used to estimate demographic parameters
and baseline scores. The number of adverse events was compared
between groups with the ␹2 test. Repeated-measures analysis was
used to analyze time-dependent data. Statistical significance for
intergroup differences in outcome was assessed by the MannWhitney U test, ␹2, Kruskal-Wallis, and Student’s t test, as appropriate. The analyses of LMAC, SSS, AI, and BAI were based on
linear transformation, which gives a relative change in score. The
transformed score was calculated according to a previously used
formula25 and ranged from ⫺100 (maximal worsening) to 100
(maximal improvement). The analyses of body temperature, BP,
heart rate, and 10-m walking were based on differences from each
assessment point compared with placebo. The study used multiple
testing in which each hypothesis (intergroup differences) was analyzed separately and the existence of patterns and the consistency of
the results were considered in the analysis. All analyses were carried
out by use of Statistica 6.0 (Statsoft, Inc).
Safety analysis was based on all patients randomized. Efficacy
analysis was based on surviving d-amph and placebo patients who
completed the 5-day treatment protocol.
Results
Treatment
Patients received either d-amph or placebo in capsules given orally
twice daily for 5 consecutive days (the treatment period). The first
capsule was given within 72 hours after stroke on the day after
baseline assessments (day 1) at approximately 8 AM; the second was
given 4 hours later. Treatment was carried out in a double-blind
manner, with d-amph or placebo in identical packages.
Assessments
Demographic details, medical and cerebrovascular history, general
characteristics of the present stroke, ECG, and laboratory tests were
collected at baseline. Adverse events were recorded daily during the
treatment period and 2 days after drug discontinuation. After day 7,
only serious adverse events (stroke, progressive stroke, transient
ischemic attack, myocardial infarction, psychic disturbances, and
epilepsy) and death were registered. Progressive stroke was defined
as a loss of ⱖ2 points on the SSS17 and fever as a temperature of
ⱖ37.5°C. Systolic and diastolic BPs and heart rate was recorded
hourly from 8 AM until 4 PM during the first, third, and fifth days of
treatment and at 8 AM, noon, and 4 PM the second and fourth days of
treatment. Registrations were made in the supine or seated position
after 5 minutes of rest with a Datascope Accutorr 3 (Datascope
Corporation). The same arm was used in the same patient at all
registrations. Body temperature was recorded in the ear with a
ThermoScan pro 1 (Thermoscan Inc) at 8 AM, noon, and 4 PM during
the treatment period. Level of consciousness was recorded with the
Reaction Level Scale (RLS 85)19 hourly between 8 AM and 4 PM
during the treatment period. Patients with slight disorientation but
who were fully awake were accepted in reaction grade 1, because our
assessment focused on the level of consciousness rather than on
cognitive functions. We used a category of 0 for normal sleep. The
quantity of physiotherapy, occupational therapy, and speech therapy
was recorded on a special form daily during the treatment period
until the first follow-up (day 7) 2 days after discontinuation of
treatment. At baseline, patients were assessed for the following
Baseline
Recruitment, Patient Baseline Characteristics, and
Amount of Rehabilitation
Forty-eight patients fulfilled the inclusion criteria and were
asked to participate in the trial; of these, 45 gave informed
consent for participation and were randomized to the trial. All
patients were followed up for 3 months or until death according
to the principles of intention to treat and formed the basis for the
safety analysis. Of the 45 patients included in the study, 41 were
valid for efficacy analysis at day 1, 40 at day 2, 39 at day 3, 38
at days 5 and 7, 33 at 1 month, and 32 at 3 months. Four patients
were excluded because they did not complete the treatment
program for the following reasons: epileptic seizure (placebo),
consent withdrawn (placebo), icterus (d-amph), and hallucination (d-amph). The other patients were excluded because of
death. Treatment initiation did not cause any identifiable effects
of d-amph, which could cause unblinding of the study.
Demographic and medical history are summarized in Table 1;
baseline characteristics are given in Table 2. There was a
statistically significant difference between the whole group of
d-amph–treated patients (all d-amph, n⫽30) and placebo-treated
patients (n⫽15) in number of smokers, with the number of
smokers being higher in the all d-amph group (P⫽0.042). The
number of patients not alert was statistically higher in the all
d-amph group compared with the placebo group (P⫽0.042).
There were no statistically significant differences between
treatment groups in the amount of rehabilitation during or after
the treatment period.
Martinsson and Wahlgren
TABLE 1.
Safety of Dexamphetamine in Acute Ischemic Stroke
477
Demographic and Medical History by Group
D-amph
Characteristic
Mean age, y
⫾95% CI for mean age
Sex, F, n (%)
Mean weight, kg
⫾95% CI for median weight
Mean height, cm
⫾95% CI for median height
Placebo
(n⫽15)
All
(n⫽30)
Low
(n⫽10)
Median
(n⫽10)
High
(n⫽10)
68
67
68
67
67
62–74
63–72
60–76
60–73
57–77
6 (40)
13 (43)
2 (20)
7 (70)
4 (40)
79
73.5
77.5
72
71
71–86.5
68.5–78.5
69.5–89.5
60–84
61–81
171
169
174
166
168
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166–176
166–173
167–181
160–172
162–173
Cigarette smoking, n (%)
2 (13.3)
11 (36.7)
5 (50)
5 (50)
2 (20)
Diabetes mellitus, n (%)
4 (26.7)
7 (23.3)
4 (40)
2 (20)
1 (10)
Hypertension, n (%)
3 (20)
9 (30)
2 (20)
5 (50)
2 (20)
Atrial fibrillation, n (%)
0 (0)
6 (20)
3 (30)
3 (30)
0 (0)
Myocardial infarction, n (%)
2 (13.3)
3 (10)
2 (20)
1 (10)
0 (0)
Cardiac failure, n (%)
0 (0)
3 (10)
3 (30)
0 (0)
0 (0)
Angina pectoris, n (%)
1 (6.7)
4 (13.3)
2 (20)
1 (10)
1 (10)
Previous stroke, n (%)
4 (26.7)
10 (33.3)
4 (40)
4 (40)
2 (20)
Previous TIA, n (%)
1 (6.7)
4 (13.3)
0 (0)
3 (30)
1 (10)
D-amph, dexamphetamine; Low, 2.5 mg; Median, 5 mg; High, 10 mg; TIA, transient ischemic attack.
Safety
pneumonia (n⫽3) and coronary heart disease (n⫽1); in the
median-dose d-amph group, pneumonia (n⫽1), coronary heart
disease (n⫽1), and pleurocarcinosis (n⫽1); and in the high-dose
d-amph group, coronary heart disease (n⫽1) and initial stroke
(n⫽1). In the placebo group, 1 patient died because of pneumonia and 1 because of coronary heart disease. Coronary deaths
Adverse Events and Mortality
All adverse events during the treatment and follow-up periods
are listed in Table 3. The mortality rate in the all d-amph group
was 20% compared with 13.3% in the placebo group (P⫽NS).
The primary causes of death in the low-dose d-amph group were
TABLE 2.
Baseline Characteristics of Present Stroke
D-amph
Characteristic
Alert, n (%)
Placebo
(n⫽15)
15 (100)
Left side affected, n (%)
3 (20)
Right side affected, n (%)
12 (80)
All
(n⫽30)
Low
(n⫽10)
Median
(n⫽10)
High
(n⫽10)
23 (76.7)
8 (80)
6 (60)
9 (90)
11 (36.6)
3 (30)
5 (50)
3 (30)
18 (60)
6 (60)
5 (50)
7 (70)
5 (33.3)
15 (50)
5 (50)
7 (70)
3 (30)
PACI
7 (46.7)
11 (36.7)
3 (30)
3 (30)
5 (50)
LACI
3 (20)
4 (13.3)
2 (20)
0 (0)
2 (20)
12 (80)
29 (96.7)
10 (100)
10 (100)
9 (90)
1 (6.7)
7 (23.3)
3 (30)
3 (30)
1 (10)
OCSP classification, n (%)*
TACI
CT abnormal on admission, n (%)
Cardioembolic infarction, n (%)
Mean time since onset until treatment start
(⫾95% CI, h)
55 (49–61)
52 (47–57)
48 (35–60)
54 (46–62)
56 (46–65)
Functional median score (IQR)
LMAC motor score (0–210)
140 (88–157)
112 (84–159)
112 (94–121)
SSS-58 (0–58)
38 (20–43)
30 (15–40)
34 (27–37)
SSS-68 (0–68)
46 (30–53)
36.5 (22–47)
Activity Index (16–92)
72 (48–80)
65 (49–77)
Barthel Index (0–100)
25 (0–75)
25 (5–50)
92 (47–159)
131 (91–172)
20.5 (12–37)
32.5 (20–43)
39.5 (32–46)
26.5 (20–42)
38.5 (25–53)
71 (58–77)
53.5 (35–71)
63 (54–79)
40 (10–50)
10 (0–65)
32.5 (10–60)
*OCSP indicates Oxfordshire Community Stroke Project.26
D-amph indicates dexamphetamine; Low, 2.5 mg; Median, 5 mg; High, 10 mg; TACI, total anterior circulation infarct; PACI, partial anterior
circulation infarct; LACI, lacunar infarct; IQR, interquartile range; LMAC, Lindmark motor assessment chart; SSS, Scandinavian Stroke Scale.
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Stroke
February 2003
TABLE 3. Adverse Events During the Treatment and
Follow-Up Period
D-amph
Placebo
All
Low
Median
High
Treatment period: days 1–5
No. of patients
15
30
10
10
10
Progression of stroke
6
13
6
5
2
Fever
6
10
5
4
1
Difficulty sleeping
1
3
0
1
2
Headache
0
4
1
2
1
Death
0
3
2
0
1
Disturbances of mental functions*
1
2
1
1
0
Fall
2
1
0
1
0
Urinary tract infection
0
3
1
2
0
Diarrhea
1
1
0
1
0
Dryness of mouth
0
2
0
1
1
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Epilepsy
1
1
1
0
0
Pain
0
2
1
0
1
Sickness
0
2
2
0
0
Dreams†
1
0
0
0
0
Hiccups
1
0
0
0
0
Icterus
0
1
0
1
0
Pleuritis
0
1
0
1
0
Psychic excitation
1
0
0
0
0
Shortness of breath
1
0
0
0
0
Vomiting
1
0
0
0
0
No. of patients
15
27
8
10
9
Headache
2
2
1
1
0
Difficulty sleeping
0
3
0
0
3
Sickness
1
2
0
2
0
Progression of stroke
0
2
0
0
2
Aspiration pneumonia
0
1
1
0
0
Dizziness
0
1
0
1
0
Tiredness
0
1
0
0
1
13
23
7
8
8
Death
2
4
1
2
1
Myocardial infarction
1
1
0
0
1
8
Follow-up period: days 6 and 7
Day 7–1 month
No. of patients
1–3 months
No. of patients
13
23
7
8
Death
0
2
1
1
0
TIA
0
1
0
1
0
D-amph indicates dexamphetamine; Low, 2.5 mg; Median, 5 mg; High, 10
mg; TIA, transient ischemic attack.
*Disturbances of mental functions; includes confusion, hallucination, and
psychosis.
†The patient has a kind of dream that patient has never experienced before.
Adverse events during the periods day 7 through 1 month and 1 to 3 months
are limited to severe events (myocardial infarction, stroke, TIA, and death).
occurred 12, 20, and 27 days after drug discontinuation. Deaths
were clinically classified as not being related to the study drug in
9 of the cases and as probably not related in 2 cases (1 d-amph
and 1 placebo) according to the safety committee. Severe
adverse events occurred in 66.7% of the patients in the all
d-amph group and in 66.7% of the placebo patients. The mean
number of total adverse events per patient was 2.0 in the all
d-amph group and 1.8 for placebo (P⫽NS).
Physiological Parameters
Body Temperature
Differences between the all d-amph and the placebo groups
were not statistically significant.
Systolic BP
The systolic BPs for the all d-amph groups and placebo at each
time point are shown in Figure 1A; the mean systolic BPs for the
whole treatment period compared with baseline are given in
Figure 2A. Differences between treatment arms were statistically significant (analysis of variance [ANOVA], P⫽0.023),
with the d-amph–treated groups having the highest systolic BP.
The mean systolic BP for the whole treatment period increased
14 mm Hg in the all d-amph group (P⫽0.004), 16 mm Hg in the
median-dose d-amph group (P⫽0.008), and 16 mm Hg in the
high-dose d-amph group (P⫽0.005) compared with placebo
(P⬍0.05, r⫽0.44).
Diastolic BP
The diastolic BPs for the all d-amph group and placebo for each
time point are shown in Figure 1B, and the mean diastolic BPs
for the whole treatment period compared with baseline are given
in Figure 2B. Differences between the 3 dose groups and
placebo were significant (ANOVA, P⫽0.024). The mean diastolic BP for the whole treatment period increased 8 mm Hg in
the all d-amph group (P⫽0.010), 9 mm Hg in the median-dose
d-amph group (P⫽0.009), and 10 mm Hg in the high-dose
d-amph group (P⫽0.005) compared with placebo (P⬍0.05,
r⫽0.43).
Heart Rate
The heart rates for the all d-amph and placebo groups at each
time point are shown in Figure 1C; the mean heart rates for the
whole treatment period compared with baseline are given in
Figure 2C. Differences between the 3 dose groups and placebo
were significant (P⫽0.0001), with the d-amph–treated patients
having the highest heart rate (P⬍0.05, r⫽0.61). The mean heart
rate during the whole period increased 9 bpm in the all d-amph
group (P⫽0.007), 8 bpm in the median-dose group (P⫽0.023),
and 17 bpm in the high-dose group (P⫽0.00008) compared with
placebo and 15 bpm in the high-dose d-amph group compared
with the low-dose group (P⫽0.001).
Level of Consciousness
During treatment, there were no statistically significant differences between treatment groups in level of consciousness.
Efficacy
The all d-amph–treated group had significantly better improvement (P⬍0.05) during the treatment period assessed
with the LMAC motor function score (days 1, 2, 3, and 5; see
Martinsson and Wahlgren
Safety of Dexamphetamine in Acute Ischemic Stroke
479
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Figure 1. Change from baseline in systolic
BP (A), diastolic BP (B), and heart rate (C)
during the treatment period. Assessments
were made hourly between 8 AM and 4 PM
during treatment days 1, 3, and 5 and at 8
AM, noon, and 4 PM during days 2 and 4.
1 indicates administration of study drug
at 8 AM; 2, administration of the study
drug at noon. Error bars represent SEM.
*Statistically significant difference (P⬍0.05)
between all d-amph(䢇; n⫽30) and placebo
(䡲; n⫽15).
Figure 3), SSS-58 (days 1 and 5), SSS-68 (day 5), AI motor
score (day 3), and BAI (day 3). At the day 7 follow-up, all
d-amph group had significantly better improvement with the
LMAC motor function score (P⫽0.025), SSS-68 (P⫽0.044),
and AI motor score (P⫽0.009). There were no statistically
significant differences at 1 or 3 months. No other outcome
measure, including the 10-m walking test, was statistically
significant at any time point.
Discussion
There were no statistically significant increases in total
number of severe adverse events, deaths, body temperature,
or level of consciousness. Systolic and diastolic BPs and heart
rate increased during treatment with d-amph compared with
placebo. The increase seemed to be dose dependent, most
obviously for heart rate. During treatment, there were statistically significant differences between the groups in functional and neurological outcome in favor of d-amph, but these
differences were not maintained at follow-up.
Differences in mortality between the all d-amph and placebo
groups were not statistically significant, but there were more
deaths in the all d-amph group. The all d-amph group had a
higher extent of cardiac failure, atrial fibrillation, and neglect at
baseline compared with the placebo group, as well as having a
higher number of smokers. Some of these factors may predict a
worse outcome. One patient in the all d-amph group who died
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February 2003
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Figure 2. Mean change from baseline in
systolic BP (A), diastolic BP (B), and heart
rate (C) during the treatment period.
during the follow-up period was diagnosed with pleurocarcinosis after inclusion in the study and would not have
been included if this condition had been known. In the
judgment of the safety committee, none of the deaths were
related to the study drug. There was no increase in the
number of deaths (or serious adverse events) with increasing dose.
The increases in BP and heart rate are in agreement with
the sympathomimetic properties of amphetamines, but they
have not previously been described in studies providing
information on treatment safety in stroke patients.10,11,15,27
Our study differs from earlier studies in a number of ways.
Walker-Batson et al11,12 started treatment 16 to 45 days after
stroke onset, administered 10 mg d-amph at an interval of 3
to 4 days, and excluded patients with uncontrolled hypertension (⬎160/110 mm Hg), whereas we started d-amph treatment within 72 hours, administered 5 to 20 mg d-amph twice
daily, and included patients with hypertension. It seems likely
that the effect on BP and heart rate might be more pronounced
with more frequent administration. In this study, BP and heart
rate were monitored hourly 3 of 5 days during the treatment
period; Walker-Batson et al reported a baseline measurement
followed by a measure 2 hours after drug administration.
From our own experience, the effect on BP and heart rate
differs substantially between patients and does not always
appear within the first hours after the first dose administra-
Martinsson and Wahlgren
Safety of Dexamphetamine in Acute Ischemic Stroke
Figure 3. Transformed LMAC score during the treatment and
follow-up periods. Number of patients included in the analysis
were as follows: at baseline, 30 and 15 on d-amph and placebo,
respectively; day 1, 28 and 13; day 2, 27 and 13; days 5 and 7,
25 and 13; and 1 and 3 months, 21 and 11.
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tion. Therefore, late effects might be missed if the patient is
not followed for a longer period (Figure 1A through C).
The importance of combining d-amph administration with
training has been emphasized in the context of improving
recovery.2 It has also been argued that a “continuous [daily]
administration of d-amph could have a diminishing effect on
therapeutic efficacy”11 because daily dosing theoretically could
lead to neurotransmitter depletion.1 In this study, we did not
systematically correlate d-amph treatment and rehabilitation in
time, but all patients except 1 had training (physiotherapy,
occupational therapy, speech therapy) during the treatment
period. It seems likely that the patients had their training sessions
within the time of potentially effective plasma concentration
because the drug was administered twice daily. The effect of a
more strict combination of d-amph and rehabilitation and a more
spaced d-amph administration remains to be investigated.
Overall, d-amph seemed to be safe and well tolerated by
patients with acute cerebral ischemia during the first week after
symptom onset. Because at least changes in BP28 and body
temperature29 are related in different ways to stroke outcome and
because BP and heart rate seem to be related to amphetamine
dose, monitoring these parameters should be relevant in future
amphetamine studies. Whether the effect of BP may contribute
to a better outcome with d-amph should be studied further.
Efficacy results should be interpreted with caution because of
the limited sample size and short treatment period in the
subacute phase when the neurological condition frequently is
unstable. However, a benefit of d-amph was suggested for
patients who followed the study protocol. This needs to be
confirmed in future trials.
Acknowledgments
This trial was supported by grants for the Federation of County
Councils (main sponsor), Family Janne Elgqvist foundation, Swedish Association of Neurologically Disabled, Åke Wiberg Foundation, Karolinska Institute, and Swedish Stroke Association. We
gratefully acknowledge Anita Hansson-Thyrén and Lena Lundqvist
for assistance with data collection and Dr Hans-Göran Hårdemark
(chairman), Professor Jesper Swedenborg, and Associate Professor
Jan Östergren for participating in the safety monitoring committee.
Per Näsman is acknowledged for statistical advice.
References
1. Gladstone DJ, Black SE. Enhancing recovery after stroke with noradrenergic pharmacotherapy: a new frontier? Can J Neurol Sci. 2000;27:
97–105.
481
2. Feeney DM, Gonzalez A, Law WA. Amphetamine, haloperidol, and experience interact to affect rate of recovery after motor cortex injury. Science.
1982;217:855–857.
3. Stroemer RP, Kent TA, Hulsebosch CE. Enhanced neocortical neural
sprouting, synaptogenesis, and behavioral recovery with d-amphetamine
therapy after neocortical infarction in rats. Stroke. 1998;29:2381–2395.
4. Boyeson M, Feeney D. Adverse effects of catecholaminergic drugs following
unilateral cerebellar ablations. Restor Neurol Neurosci. 1991;3:227–233.
5. Mintz M, Tomer R. Exposure to amphetamine after substantia nigra lesions
interferes with the process of behavioral recovery. Pharmacol Biochem
Behav. 1986;25:1307–1311.
6. Feeney D. Mechanisms of noradrenergic modulation of physical therapy:
effects on functional recovery after cortical injury. In: Goldstein LB, ed.
Restorative Neurology: Advances in Pharmacotherapy for Recovery After
Stroke. New York, NY: Futura Publishing Co Inc; 1998:35–78.
7. Boyeson M, Feeney D. Intraventricular norepinephrine facilitates motor
recovery following sensorimotor cortex injury. Pharmacol Biochem Behav.
1990;35:497–501.
8. Boyeson M, Harmon R, Jones J. Comparative effects of fluoxetine, amitriptyline and serotonin on functional motor recovery after sensorimotor cortex
injury. Am J Phys Med Rehabil. 1994;73:76–83.
9. Sutton R, Feeney D. ␣-Noradrenergic agonists and antagonists affect
recovery and maintenance of beam-walking ability after sensorimotor cortex
ablation in the rat. Restor Neurol Neurosci. 1992;4:1–11.
10. Crisostomo E, Duncan P, Propst M, Dawson D, Davis J. Evidence that
amphetamine with physical therapy promotes recovery of motor function in
stroke patients. Ann Neurol. 1988;23:94–97.
11. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R. Amphetamine
paired with physical therapy accelerates motor recovery after stroke: further
evidence. Stroke. 1995;26:2254–2259.
12. Walker-Batson D, Curtis S, Natarajan R, et al. A double-blind, placebocontrolled study of the use of amphetamine in the treatment of aphasia.
Stroke. 2001;32:2093–2098.
13. Mazagri R, Shuaib A, McPherson M, Deighton M. Amphetamine failed to
improve motor function in acute stroke. J Can Sci Neurol. 1995;22:S25.
Abstract.
14. Reding M, Solomon B, Borucki S. Effect of dextroamphetamine on motor
recovery after stroke. Neurology. 1995;45(suppl 4):S01. Abstract.
15. Sonde L, Nordström M, Nilsson C-G, Lökk J, Viitanen M. A double-blind
placebo-controlled study of the effects of amphetamine and physiotherapy
after stroke. Cerebrovasc Dis. 2001;12:253–257.
16. Walker-Batson D, Unwin H, Curtis S, et al. Use of amphetamine in the
treatment of aphasia. Restor Neurol Neurosci. 1992;4:47–50.
17. Scandinavian stroke study group. Multicenter trial of hemodilution in ischemic stroke: background and study protocol. Stroke. 1985;16:855–890.
18. Recommendations on stroke prevention, diagnosis, and therapy. Stroke.
1989;20:1407–1431.
19. Starmark J-E, Stålhammar D, Holmgren E. The Reaction Level Scale (RLS
85): manual and guidelines. Acta Neurochir (Wien). 1988;91:12–20.
20. Lindmark B, Hamrin E. Evaluation of functional capacity after stroke as a
basis for active intervention: validation of a modified chart for motor capacity
assessment. Scand J Rehab Med. 1988;20:111–115.
21. Lindmark B, Hamrin E. Evaluation of functional capacity after stroke as a
basis for active intervention. Presentation of a modified chart for motor
capacity assessment and its reliability. Scand J Rehab Med. 1988;20:
103–109.
22. Hamrin E, Wohlin AI. Evaluation of the functional capacity of stroke patients
through an activity index. Scand J Rehab Med. 1982;14:93–100.
23. Mahoney F, Barthel B. Functional evaluation: the Barthel Index. Md Med J.
1965;14:61–65.
24. Witte US, Carlsson JY. Self-selected walking speed in patients with hemiparesis after stroke. Scand J Rehab Med. 1997;29:161–165.
25. Gelmers H, Gorter K, Weerdt CD, Wiezer H. A controlled trial of nimodipine
in acute ischemic stroke. N Engl J Med. 1988;318:203–207.
26. Bamford J, Sandercock P, Dennis M, Burn J, Warlow C. Classification and
natural history of clinically identifiable subtypes of cerebral infarction.
Lancet. 1991;337:1521–1526.
27. Unwin H, Walker-Batson D. No side effects after low-dose amphetamine
administration in stroke rehabilitation. Stroke. 2000;31:1788–1789.
28. Ahmed N, Näsman P, Wahlgren N. Effect of intravenous nimodipine on
blood pressure and outcome after acute stroke. Stroke. 2000;31:1250 –1255.
29. Fukada H, Kitani M, Takahashi K. Body temperature correlates with functional outcome and the lesion size of cerebral infarction. Acta Neurol Scand.
1999;100:385–390.
Safety of Dexamphetamine in Acute Ischemic Stroke: A Randomized, Double-Blind,
Controlled Dose-Escalation Trial
Louise Martinsson and Nils Gunnar Wahlgren
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Stroke. 2003;34:475-481; originally published online December 26, 2002;
doi: 10.1161/01.STR.0000050161.38263.AE
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