ItaL J. NeuroL ScL 12:557-563, 1991
A double blind randomized pilot trial of naloxone in the treatment of acute ischemic stroke Federieo F., Lucivero V., Lamberti P., Fiore A, Conte C.
I ClinicaNeurologica,Universitlldi Bari
Attention has focused on naloxone, an opiate receptor antagonist, because of its potential benefit in reversing neurological damage after acute cerebral ischemia. To evaluate the safety and possible efficacy of high-dose naloxone in ischemic stroke patients we planned a double blind pilot study. Between January 1989 and May 1990 24 patients were randomly assigned to the naloxone or placebo group according to age and neurological deficit. Naloxone was given in a loading dose o f 5 mg/kg over 10 minutes followed by a 24-hour infusion at the rate o f 3.5 m g / kg/h. 10 patients experienced minor side effects but none of them had to discontinue the treatment. 9patients improved: 6 in the naloxone group and 3 in the placebo group, but no significant difference was found using the non parametric Mann- Whitney test. Our study suggests that naloxone is safe at the dose used, but the results do not support the planning o f similar trials on a larger scale.
Key Words: Naloxone -- stroke -- pilot trial
Introduction The therapeutic potential of Naloxone (N) [2, 15, 16] was suggested by experimental and clinical studies showing that endogenous opioids delivered after an acute cerebral infarction may have a negative effect on neurological functions, though the mechanism is still unclear [CBF (Cerebral Blood Flow) and CMR02 (Consumption Metabolic Rate of Oxygen) reduction? electric neuronal function impairment?]. [19, 26, 29]. The administration of Naloxone was found to improve functional neurological deficit [3, 7, 22, 40], cerebral blood flow [I 4, 34], and electrophysiological responses [14, 12] in experimental models of focal ischemia. Some of the pharmacological properties of Naloxone, which are not dependent on the opioid system, seem to have a favorable effect on cereReceived 20 January - accepted 30 April 1991
bral ischemia. High concentrations of Naloxone have antioxidant actions [39], the drug modulates transmembrane calcium flux [35, 21], stabilizes lysosomal membranes and inhibits proteolysis [10], may have an antiaggregating effect [20], blocks vasoconstriction [25, 36, 37], may attenuate cerebral edema [38] and N-methyl-D-aspartate-receptor mediated neurotoxicity [24]. For these reasons and thanks to its greater availability and manageability compared to other opiate antagonists, Naloxone was tested on a small number of patients. To date, only a few isolated clinical cases [2, 5, 6, 27, 31] or small planned trials [11, 13, 17, 23, 32, 1, 30, 8, 18] have been reported. The results they supplied were conflicting: ranging from prompt reversal [2, 5, 6, 27, 13, 23], to modest improvement [13, 30], to no effect on neurological deficits [11, 17, 32]. 557
The Italian Journal of Neurological Sciences
This might have been due to the fact that the patients were few, therapy was delayed and doses were much lower (only a few milligrams) than those used in experimental studies. Further, only single doses of the drug were administered while the short plasma half-life of Naloxone necessitates prolonged infusion. The scant side effects recorded in healthy volunteers [8], in subjects with acute spinal cord injury [18] and in patients with acute ischemia [1] warranted a clinical trial in which large doses of Naloxone were to be used. Our pilot trial was therefore undertaken to test the safety and potential efficacy of large doses of Naloxone in treating patients with ischemic stroke. Method A double blind, randomized pilot trial was conducted between the beginning of 1989 and May 1990. 24 patients were assigned to two groups: one treated with N and the other with placebo (P). We included men and women with acute neurological deficits of cerebrovascular origin involving the supratentorial region. Patients who fulfilled the inclusion criteria were under 80, could be randomized within 12 hours of onset ofsymptoms, had a motor deficit in at least one limb - either associated or not to aphasia --, were not in coma and had CT scans negative for previous ischemic injury, hemorrhages and tumours. Patients with a previous history of strokes, severe neurological and/or systemic diseases, and severe hypertension (AP > 200/120 mmHg) were excluded. Also excluded were pregnant or lactating women. None of the patients had a history of opiate use. Informed consent was obtained from each patient. The study protocol was approved by the F.D.A. (Federal Drug Administration - Ind. N. 1088) and by the local committee on medical ethics. Paraben-free Narcan * (Naloxone hydrochloride) provided by Dupont de Nemours and Co., Wilmington, Delaware, U.S.A., was used at a concentration of 50 mg/ml (2 ml ampules). In the treated group, a loading dose of Natoxone (5 ml/kg) diluted in 100 ml of normal saline was injected intravenously over 10 minutes. A 24hour continuous infusion followed at a rate of 3.5 mg/kg/hour with Naloxone diluted in 1000 ml of normal saline. The control group received only saline following the same procedures. Other treatment was similar in both groups. No drug was administered before, during and 2 hours after treatment. Two hours after infusion and for the first 15 days, antiaggregating, vase558
active and potentially neuroactive drugs, cortisone, and exogenous opioids were avoided. Osmotic diuretics were used only in cases with an altered level of consciousness. In both groups, the aim of general therapy was to keep water balance, and arterial pressure within the ranges prior to stroke. It also aimed at preventing infections and deep venous thrombosis in patients at risk. Neurological assessment and measurements of vital parameters (e.g. arterial blood pressure, heart and respiration rates) were performed before treatment, every 30 minutes after bolus injection for the first 4 hours, at 12 hours, every day for the first week and after 15 days. Follow-up was carded out after 4 months. Neurological deficits were graded on the Canadian Neurologic Scale (CNS) [9] and the degree of impairment was assessed by means of the Barthel Index (BI) [28]. The patients neurological status was defined as normal (CNS score 10), mild deficit (9.5-7), or severe deficit (6.5). According to their disabilities the patients were categorized as having no handicap (BI 100), moderate handicap (BI 50-95), or severe handicap (45). Laboratory evaluations before treatment and on each subsequent day for seven days included: blood glucose, serum electrolytes, bilirubin concentrations, serum chemistry panel, GOT, GPT, complete blood count, CPK, LDH, and urinalysis. Serial electrocardiography (ECG) was performed during bolus administration at 24 hours and on day 7. Each patient had a CT scan of the brain before entry and after two weeks. Results
12 patients were assigned to the N-treated group and 12 to the P-treated group. The mean age of the treated group was 66.9 + 8.4 (range 49-76), and of the control group 61-2 _ 7.6 (range 50-75). The N group included 6 men and 6 women, while the P group comprised 9 men and 3 women. Average interval from the onset of symptoms until treatment was 8.5 hours. In the N group 4 patients started treatment before 6 hours and 8 from 6 to 12 hours. The risk factors involved were arterial hypertension [ 14], diabetes [ 13], alteration of lipid metabolism [18], smoking [5], heart disease [10], alcohol abuse [1]. lschemic lesions were detected in the supratentorial region in 17 patients (1 in the territory of the ACA and 16 in the territory of the MCA). They were medium-sized or large in 9 cases and small in 8. The lesions were detected early ( > 8 hr) in 10
Federico F.: Naloxone in the treatment of acute ischemie stroke
TABLE L Response to naloxone therapy in 12 patients with acute ischaemic stroke. N
1 2 3 4 5 6 7 8 9 10 11 12
age
66 59 75 75 75 62 63 62 76 49 67 74
sex
F F M F F M M M M M F F
basal
basal
24h
7 days 15 days120 days
Initial
final
deficit
CNS*
CNS*
CNS*
CNS*
deficit
B.I.+
B.I. +
severe severe mild mild severe mild severe mild severe severe sever mild
6 3 7.5 7 5.5 7 6.5 8.5 4.5 1.5 4 7
7 3 8.5 8.5 5.5 7.5 6,5 9 4 1.5 4 7
7.5 3 10 8.5 5.5 8.5 7.5 10 4 3 3 8.5
7,5 4 7.5 9.5 5.5 9 7 10 4.5 3 3 8.5
mild severe normal mild mild normal mild normal severe severe exitus mild
moderate severe moderate moderate severe moderate severe moderate severe severe severe moderate
moderate moderate independent independent independent independent moderate independent moderate severe exitus independent
Canadian Neurological Scale; 10 = normal; 7-9.5 = mild deficit;
A double blind randomized pilot trial of naloxone in the treatment of acute ischemic stroke Federieo F., Lucivero V., Lamberti P., Fiore A, Conte C.
I ClinicaNeurologica,Universitlldi Bari
Attention has focused on naloxone, an opiate receptor antagonist, because of its potential benefit in reversing neurological damage after acute cerebral ischemia. To evaluate the safety and possible efficacy of high-dose naloxone in ischemic stroke patients we planned a double blind pilot study. Between January 1989 and May 1990 24 patients were randomly assigned to the naloxone or placebo group according to age and neurological deficit. Naloxone was given in a loading dose o f 5 mg/kg over 10 minutes followed by a 24-hour infusion at the rate o f 3.5 m g / kg/h. 10 patients experienced minor side effects but none of them had to discontinue the treatment. 9patients improved: 6 in the naloxone group and 3 in the placebo group, but no significant difference was found using the non parametric Mann- Whitney test. Our study suggests that naloxone is safe at the dose used, but the results do not support the planning o f similar trials on a larger scale.
Key Words: Naloxone -- stroke -- pilot trial
Introduction The therapeutic potential of Naloxone (N) [2, 15, 16] was suggested by experimental and clinical studies showing that endogenous opioids delivered after an acute cerebral infarction may have a negative effect on neurological functions, though the mechanism is still unclear [CBF (Cerebral Blood Flow) and CMR02 (Consumption Metabolic Rate of Oxygen) reduction? electric neuronal function impairment?]. [19, 26, 29]. The administration of Naloxone was found to improve functional neurological deficit [3, 7, 22, 40], cerebral blood flow [I 4, 34], and electrophysiological responses [14, 12] in experimental models of focal ischemia. Some of the pharmacological properties of Naloxone, which are not dependent on the opioid system, seem to have a favorable effect on cereReceived 20 January - accepted 30 April 1991
bral ischemia. High concentrations of Naloxone have antioxidant actions [39], the drug modulates transmembrane calcium flux [35, 21], stabilizes lysosomal membranes and inhibits proteolysis [10], may have an antiaggregating effect [20], blocks vasoconstriction [25, 36, 37], may attenuate cerebral edema [38] and N-methyl-D-aspartate-receptor mediated neurotoxicity [24]. For these reasons and thanks to its greater availability and manageability compared to other opiate antagonists, Naloxone was tested on a small number of patients. To date, only a few isolated clinical cases [2, 5, 6, 27, 31] or small planned trials [11, 13, 17, 23, 32, 1, 30, 8, 18] have been reported. The results they supplied were conflicting: ranging from prompt reversal [2, 5, 6, 27, 13, 23], to modest improvement [13, 30], to no effect on neurological deficits [11, 17, 32]. 557
The Italian Journal of Neurological Sciences
This might have been due to the fact that the patients were few, therapy was delayed and doses were much lower (only a few milligrams) than those used in experimental studies. Further, only single doses of the drug were administered while the short plasma half-life of Naloxone necessitates prolonged infusion. The scant side effects recorded in healthy volunteers [8], in subjects with acute spinal cord injury [18] and in patients with acute ischemia [1] warranted a clinical trial in which large doses of Naloxone were to be used. Our pilot trial was therefore undertaken to test the safety and potential efficacy of large doses of Naloxone in treating patients with ischemic stroke. Method A double blind, randomized pilot trial was conducted between the beginning of 1989 and May 1990. 24 patients were assigned to two groups: one treated with N and the other with placebo (P). We included men and women with acute neurological deficits of cerebrovascular origin involving the supratentorial region. Patients who fulfilled the inclusion criteria were under 80, could be randomized within 12 hours of onset ofsymptoms, had a motor deficit in at least one limb - either associated or not to aphasia --, were not in coma and had CT scans negative for previous ischemic injury, hemorrhages and tumours. Patients with a previous history of strokes, severe neurological and/or systemic diseases, and severe hypertension (AP > 200/120 mmHg) were excluded. Also excluded were pregnant or lactating women. None of the patients had a history of opiate use. Informed consent was obtained from each patient. The study protocol was approved by the F.D.A. (Federal Drug Administration - Ind. N. 1088) and by the local committee on medical ethics. Paraben-free Narcan * (Naloxone hydrochloride) provided by Dupont de Nemours and Co., Wilmington, Delaware, U.S.A., was used at a concentration of 50 mg/ml (2 ml ampules). In the treated group, a loading dose of Natoxone (5 ml/kg) diluted in 100 ml of normal saline was injected intravenously over 10 minutes. A 24hour continuous infusion followed at a rate of 3.5 mg/kg/hour with Naloxone diluted in 1000 ml of normal saline. The control group received only saline following the same procedures. Other treatment was similar in both groups. No drug was administered before, during and 2 hours after treatment. Two hours after infusion and for the first 15 days, antiaggregating, vase558
active and potentially neuroactive drugs, cortisone, and exogenous opioids were avoided. Osmotic diuretics were used only in cases with an altered level of consciousness. In both groups, the aim of general therapy was to keep water balance, and arterial pressure within the ranges prior to stroke. It also aimed at preventing infections and deep venous thrombosis in patients at risk. Neurological assessment and measurements of vital parameters (e.g. arterial blood pressure, heart and respiration rates) were performed before treatment, every 30 minutes after bolus injection for the first 4 hours, at 12 hours, every day for the first week and after 15 days. Follow-up was carded out after 4 months. Neurological deficits were graded on the Canadian Neurologic Scale (CNS) [9] and the degree of impairment was assessed by means of the Barthel Index (BI) [28]. The patients neurological status was defined as normal (CNS score 10), mild deficit (9.5-7), or severe deficit (6.5). According to their disabilities the patients were categorized as having no handicap (BI 100), moderate handicap (BI 50-95), or severe handicap (45). Laboratory evaluations before treatment and on each subsequent day for seven days included: blood glucose, serum electrolytes, bilirubin concentrations, serum chemistry panel, GOT, GPT, complete blood count, CPK, LDH, and urinalysis. Serial electrocardiography (ECG) was performed during bolus administration at 24 hours and on day 7. Each patient had a CT scan of the brain before entry and after two weeks. Results
12 patients were assigned to the N-treated group and 12 to the P-treated group. The mean age of the treated group was 66.9 + 8.4 (range 49-76), and of the control group 61-2 _ 7.6 (range 50-75). The N group included 6 men and 6 women, while the P group comprised 9 men and 3 women. Average interval from the onset of symptoms until treatment was 8.5 hours. In the N group 4 patients started treatment before 6 hours and 8 from 6 to 12 hours. The risk factors involved were arterial hypertension [ 14], diabetes [ 13], alteration of lipid metabolism [18], smoking [5], heart disease [10], alcohol abuse [1]. lschemic lesions were detected in the supratentorial region in 17 patients (1 in the territory of the ACA and 16 in the territory of the MCA). They were medium-sized or large in 9 cases and small in 8. The lesions were detected early ( > 8 hr) in 10
Federico F.: Naloxone in the treatment of acute ischemie stroke
TABLE L Response to naloxone therapy in 12 patients with acute ischaemic stroke. N
1 2 3 4 5 6 7 8 9 10 11 12
age
66 59 75 75 75 62 63 62 76 49 67 74
sex
F F M F F M M M M M F F
basal
basal
24h
7 days 15 days120 days
Initial
final
deficit
CNS*
CNS*
CNS*
CNS*
deficit
B.I.+
B.I. +
severe severe mild mild severe mild severe mild severe severe sever mild
6 3 7.5 7 5.5 7 6.5 8.5 4.5 1.5 4 7
7 3 8.5 8.5 5.5 7.5 6,5 9 4 1.5 4 7
7.5 3 10 8.5 5.5 8.5 7.5 10 4 3 3 8.5
7,5 4 7.5 9.5 5.5 9 7 10 4.5 3 3 8.5
mild severe normal mild mild normal mild normal severe severe exitus mild
moderate severe moderate moderate severe moderate severe moderate severe severe severe moderate
moderate moderate independent independent independent independent moderate independent moderate severe exitus independent
Canadian Neurological Scale; 10 = normal; 7-9.5 = mild deficit;
