RESERPINE FOR MIGRAINE PROPHYLAXIS
G. Nattero, M.D., F. Lisino, M.D., G. Brandi, M.D. L. Gastaldi, M.D. I. Kemp Genefke, M.D.
From: Instituto di Clinica Medica Generale e Terapia Medica II, dell Universita di Torino, Direttore Prof. F. Ceresa, Centro Cefalee Submitted for Publication: 7/22/75 Accepted: 8/26/75 SYNOPSIS
Because of the role of monoamines in the genesis of migraine and the pharmacologic action of reserpine, we have used this substance in prophylactic treatment of migraine for 10 years on 300 patients. 1 Intravenously administered reserpine in a dose of 0.2 mg every second or third day for a period of 6-8 weeks was employed. Statistically significant improvement in severe migraine was obtained. A double blind clinical trail of this method of therapy carried out in Turin and Copenhagen confirmed the efficacy of reserpine in the treatment of severe migraine if given in appropriate doses. No side effects were observed. It is suggested that the intravenous administration at regular intervals of small doses of reserpine depletes norepinephrine and/or serotonin, these vasoactive substances are not released at the time of a migrainous attack. WE ACCEPT Lance's definition of migraine2 which considers it to be a hereditary "paroxysmal vascular instability each episode of which comprises a phase of arterial vasoconstriction and a phase of vasodilatation". He believes that the initial change in blood vessel caliber in migraine is not due to an abnormal neural discharge and it can be explained in his view by altered vasomotion due to biochemical changes. A number of vasoactive and pain threshold lowering substances seem to be involved in the first stage of the migranous attack and they include norepinephrine and serotonin. The injection of reserpine intramuscularly can induce typical migraine attacks in susceptible individuals.3 On the other hand, the administration of serotonin and of 5-hydroxytryptophane (a serotonin precursor) can abolish spontaneous attacks and those induced by reserpine.3 Previous reports4,5 showed an increase in urinary excretion of 5-hydroxyindolacetic and vanilmandelic acids during the first 12 hours of the migraine attack. These findings were confirmed6 and we found a clear correlation between the percentage increase in urinary excretion of 5-hydroxyindolacetic and vanilmandelic acids during migraine attacks induced by nitroglycerin. In reserpine induced attacks, significant increases in the ratios of urinary 5-hydroxyindolacetic acid to creatinine and vanilmandelic acid to creatinine were also found.7 The drop of plasma 5-hydroxyindolacetic acid levels and the increased excretion in the urine seems to be a specific feature of the migranous attack.8 Reserpine has a profound effect on monoamine storage and metabolism.9 Reserpine causes release of serotonin from its storage sites in the brain, gastrointestinal tract and blood platelets and it also releases catecholamine from central and peripheral sites. In addition, reserpine inhibits monoamine uptake into tissues. This substance readily crosses the blood-brain barrier and is rapidly metabolized in the body. Because of these pharmacologic actions, it was logical to try reserpine in migraine.11,12 PATIENTS AND METHODS
There were 147 patients with classic migraine. They had the onset of headache in early life, a positive family history and neurologic deficits during the aura of the attacks. All had negative x-rays of the skull and cervical spine and normal funduscopic examinations. The electroencephalogram was dysrhythmic. All patients had inducible attacks with reserpine or nitroglycerin and no attacks were produced by the injection of
TABLE I Effect on migraine of intravenous 0.2 mg reserpine every other day for 20 doses No # of patients Improvement: # of patients improvement # of patients Classic Migraine.......... 147 123 (83.6%) Attacks Reduced By: 24 (16.3%) P
G. Nattero, M.D., F. Lisino, M.D., G. Brandi, M.D. L. Gastaldi, M.D. I. Kemp Genefke, M.D.
From: Instituto di Clinica Medica Generale e Terapia Medica II, dell Universita di Torino, Direttore Prof. F. Ceresa, Centro Cefalee Submitted for Publication: 7/22/75 Accepted: 8/26/75 SYNOPSIS
Because of the role of monoamines in the genesis of migraine and the pharmacologic action of reserpine, we have used this substance in prophylactic treatment of migraine for 10 years on 300 patients. 1 Intravenously administered reserpine in a dose of 0.2 mg every second or third day for a period of 6-8 weeks was employed. Statistically significant improvement in severe migraine was obtained. A double blind clinical trail of this method of therapy carried out in Turin and Copenhagen confirmed the efficacy of reserpine in the treatment of severe migraine if given in appropriate doses. No side effects were observed. It is suggested that the intravenous administration at regular intervals of small doses of reserpine depletes norepinephrine and/or serotonin, these vasoactive substances are not released at the time of a migrainous attack. WE ACCEPT Lance's definition of migraine2 which considers it to be a hereditary "paroxysmal vascular instability each episode of which comprises a phase of arterial vasoconstriction and a phase of vasodilatation". He believes that the initial change in blood vessel caliber in migraine is not due to an abnormal neural discharge and it can be explained in his view by altered vasomotion due to biochemical changes. A number of vasoactive and pain threshold lowering substances seem to be involved in the first stage of the migranous attack and they include norepinephrine and serotonin. The injection of reserpine intramuscularly can induce typical migraine attacks in susceptible individuals.3 On the other hand, the administration of serotonin and of 5-hydroxytryptophane (a serotonin precursor) can abolish spontaneous attacks and those induced by reserpine.3 Previous reports4,5 showed an increase in urinary excretion of 5-hydroxyindolacetic and vanilmandelic acids during the first 12 hours of the migraine attack. These findings were confirmed6 and we found a clear correlation between the percentage increase in urinary excretion of 5-hydroxyindolacetic and vanilmandelic acids during migraine attacks induced by nitroglycerin. In reserpine induced attacks, significant increases in the ratios of urinary 5-hydroxyindolacetic acid to creatinine and vanilmandelic acid to creatinine were also found.7 The drop of plasma 5-hydroxyindolacetic acid levels and the increased excretion in the urine seems to be a specific feature of the migranous attack.8 Reserpine has a profound effect on monoamine storage and metabolism.9 Reserpine causes release of serotonin from its storage sites in the brain, gastrointestinal tract and blood platelets and it also releases catecholamine from central and peripheral sites. In addition, reserpine inhibits monoamine uptake into tissues. This substance readily crosses the blood-brain barrier and is rapidly metabolized in the body. Because of these pharmacologic actions, it was logical to try reserpine in migraine.11,12 PATIENTS AND METHODS
There were 147 patients with classic migraine. They had the onset of headache in early life, a positive family history and neurologic deficits during the aura of the attacks. All had negative x-rays of the skull and cervical spine and normal funduscopic examinations. The electroencephalogram was dysrhythmic. All patients had inducible attacks with reserpine or nitroglycerin and no attacks were produced by the injection of
TABLE I Effect on migraine of intravenous 0.2 mg reserpine every other day for 20 doses No # of patients Improvement: # of patients improvement # of patients Classic Migraine.......... 147 123 (83.6%) Attacks Reduced By: 24 (16.3%) P
