Biomedical subjects
Publications and source records attributed to P Tfelt-Hansen.
Despite the recent advantages in abortive treatment of migraine, a significant group of patients still needs prophylactic treatment. A general checklist for prophylactic pharmacotherapy of migraine is provided. The use of the diagnostic headache diary is emphasized. Some practical guidelines of the prophylactic treatment of migraine are listed, taking the benefit-risk ratio into account.
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A combination of lysine acetylsalicylate (equivalent to 900 mg aspirin) and 10 mg metoclopramide (LAS + MTC) was compared with oral sumatriptan (100 mg) and placebo in 421 patients with migraine in a randomized, double-blind, clinical trial. LAS + MTC was as effective as sumatriptan with a decrease in headache from severe or moderate to mild or none in 57% and 53%, respectively, for the first migraine attack treated, the primary efficacy parameter. Both treatments were better than placebo (success rate 24%, p < 0.001). LAS + MTC was better tolerated than sumatriptan (adverse events in 18% and 28%, respectively, p < 0.05).
Most current randomised controlled trials concern the acute treatment of migraine. Sumatriptan, a serotonin receptor agonist, was evaluated in 8 randomised controlled trials. Using a novel cartridge self-injector system subcutaneous sumatriptan was found superior to placebo, and oral sumatriptan in doses from 25 mg to 100 mg was found superior to placebo with no difference among doses. An oral dose of 100 mg sumatriptan was not superior to a combination of lysine acetylsalicylate plus metoclopramide, and 100 mg sumatriptan given 4 hrs after subcutaneous sumatriptan could not prevent recurrence of headache. Nasal dihydroergotamine was found to have some efficacy in acute migraine treatment, whereas nasal butorphanol, although effective in repeated doses, was hampered by many side effects. The prophylactic effect of valproate was confirmed in one randomised controlled trial.
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Aspirin is commonly used to treat migraine attacks, although sumatriptan, a much more expensive treatment, is also effective. We compared a combination of lysine acetylsalicylate (equivalent to 900 mg aspirin) and 10 mg metoclopramide (LAS+MTC) with oral sumatriptan (100 mg) and placebo in 421 patients with migraine. LAS+MTC was as effective as sumatriptan with a decrease of headache from severe or moderate to mild or none of 57% and 53%, respectively, for the first migraine attack treated. Both treatments were better than placebo (success rate 24%, p < 0.0001). LAS+MTC was significantly more effective in the treatment of nausea than sumatriptan (p < 0.0001) and was better tolerated (adverse events in 18% and 28%, respectively, p < 0.05). LAS+MTC is as effective as sumatriptan in the treatment of migraine attacks. It is also much cheaper.
A novel self-injector for the administration of subcutaneous sumatriptan in the treatment of migraine attacks was tested in 138 patients recruited by family physicians in Denmark: 108 patients completed the initial double-blind, crossover part of the study. Sumatriptan 6 mg s.c. was significantly better than placebo at 30, 60, 90 and 120 min after injection in relieving moderate or severe headache to mild or none as well as relieving any headache to none. At 60 min after injection, the treatment response rate was 61% for sumatriptan and 6% for placebo. During the following open-phase trial of four attacks treated with sumatriptan, treatment response rates were 68-74%. During the total of 538 attacks treated, 12 attempts at using the self-injector failed. In the double-blind and open phases, 81% and 90% of patients respectively found the device easy or very easy to use. Adverse effects were benign and short-lasting, but led seven patients to discontinue the study. In conclusion, subcutaneous sumatriptan administered with a novel self-injector is an effective treatment for migraine compared to placebo in patients treated by their family physician.
A checklist is presented to assist with the evaluation of a controlled trial in migraine prophylaxis. The following points are discussed briefly: aim of the study, design of the study, efficacy parameters, and presentation of results and statistics. Choice among drugs for migraine prophylaxis is described taking into account: clinical efficacy, scientific proof for efficacy, and contraindications.
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The new classification of headaches will be briefly described. The main primary headaches are migraine with and without aura, tension-type headache and cluster headache. The operational diagnostic criteria for migraine with aura, migraine without aura and episodic tension-type headache will be presented. After this the clinical pictures of migraine with aura (previously classic migraine) and migraine without aura (previously common migraine) will be described. At last the current concepts concerning pathophysiology, regional cerebral blood flow changes, changes in extra- and intracranial arteries and mechanisms of action of ergotamine and sumatriptan will be presented.
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Nitroglycerin-(NTG)-induced headache and dilatation of the radial artery were followed in a double blind, randomized, placebo-controlled, cross-over study in 6 healthy volunteers. NTG 0.5 microgram.kg-1 x min-1 or saline were infused i.v. for 7 h, and subsequently the infusion rate was doubled for 10 min. The radial artery diameter was measured repeatedly with high frequency ultrasound and pain was scored using a 10 point verbal scale. After 5 min of NTG infusion both headache and the arterial diameter differed significantly from baseline, and no further significant change occurred. The intensity of the headache was mild to medium (median headache score 3, range 1-7). The mean dilatation of the radial artery was 36%. The dilatation in each individual, was stable over time, both during NTG and placebo, and it did not change with the double infusion rate. The headache score in each individual was more fluctuant. No tolerance either to the NTG-induced headache or arterial dilatation was observed.
We have validated measurements of diameters of the superficial temporal artery and other small arteries in man with a newly developed 20 MHz ultrasound scanner with A, B and M-mode imaging. The diameter of a reference object was 1.202 mm vs. 1.205 mm as measured by stereomicroscopy (nonsignificant). In vitro measurements of porcine carotid arteries could be reproduced with a mean interobserver difference of 0.008 mm, and the repeatability coefficient was 0.04 mm (1.4%). The frontal branch of the human superficial temporal artery (mean 1.24 mm) was measured with intraobserver repeatability coefficients of 0.18 mm (13.8%) to 0.31 mm (23.4%). The interobserver mean difference was 0.01 mm (0.69%) and the interobserver repeatability coefficient was 0.16 mm (11.1%). Pulsatile changes of the cross sectional area of the radial plus the ulnar artery averaged 0.93 mm2 compared to 0.63 mm2 by strain-gauge plethysmography (nonsignificant). Pulsations were 4.6% in the radial artery. We conclude that high frequency ultrasound provides an accurate and reproducible measure of the diameter of small and medium sized human arteries in vivo.
Sumatriptan, a 5HT1-like receptor agonist, is a completely new treatment principle for migraine. In an extensive international programme of controlled clinical trials, sumatriptan, 6 mg subcutaneously and 100 mg orally, was superior to placebo in reducing headache and associated symptoms. The response rate for subcutaneous sumatriptan (70-84% after 1 h and 81-87% after 2 h) was higher than for oral sumatriptan (50-67% after 2 h). Additional doses did not increase efficacy. Oral sumatriptan was superior to Cafergot (2 mg ergotamine plus 200 mg caffeine) and somewhat better than aspirin (900 mg) plus metoclopramide (10 mg). Recurrence of migraine occurred in approximately 40% of attacks. Side effects were generally mild and short-lived in the controlled clinical trials. However, in clinical practice sumatriptan has subsequently caused rare cases of heart ischemia and sumatriptan is contraindicated in patients with a history of ischemic heart disease.
Four patients with clinical signs of cerebellar stroke were studied twice by SPECT using 99mTc-HMPAO as a tracer for cerebral blood flow (CBF). When first scanned 6 to 22 days after onset, all had a region of very low CBF in the symptomatic cerebellar hemisphere, and a mild to moderate CBF reduction (average 10%) in contralateral hemispheric cortex. In all four cases clinical signs of unilateral cerebellar dysfunction were still present when rescanned 1 to 4 months later and the relative CBF decrease in the contralateral cortex of the forebrain also remained. The basal ganglia contralateral to the cerebellar lesion CBF showed variable alterations. A relative CBF decrease was seen in upper part of basal ganglia in all four cases, but it was not a constant phenomenon. A relative CBF increase in both early and late SPECT scans was seen at low levels of neostriatum in two cases. The remote CBF changes in cerebellar stroke seen in the forebrain are probably caused by reduced or abolished cerebellar output. The term "Crossed Cerebral Diaschisis" may be used to describe these CBF changes that would appear to reflect both decreased and increased neuronal activity.
The 5HT-antagonistic effect of drugs in man is difficult to study because of side effects to 5HT. Ergotamine, however contracts human arteries, probably by acting on 5HT receptors. This effect can be antagonized in vitro by the 5HT antagonist ICI 169,369. After an initial ergotamine challenge to select responders to ergotamine, 10 selected volunteers were given in a double blind study an oral dose of either placebo, 30 mg or 120 mg of ICI 169,369. After 2 hr an intravenous dose of 0.5 mg ergotamine tartrate was given. From 6 to 8 hr after the administration, ergotamine caused a mean decrease in the toe-arm systolic gradient, measured by strain-gauge plethysmography of 32 mmHg (P < 0.001), which was not influenced by either 30 mg or 120 mg ICI 169,369 (P < 0.4). The most likely explanation for our inability to detect any effect of ICI 169,369 on blood pressure changes, induced by ergotamine may be high binding (99%) of ICI 169,369 to plasma proteins. There was, however, indication of a per se vasodilatory effect of ICI 169,369 since the dose of 120 mg increased the toe-arm systolic gradient by 4.7 mmHg.
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The aim of the present study was to compare the ability of different doses of isosorbide-5-mononitrate (5-ISMN) to cause dilatation of medium sized and small arteries, and to examine the intensity and duration of any headache produced. Ten healthy volunteers each received 3 doses of 5-ISMN and placebo on separate days. The diameters of the radial and superficial temporal arteries were repeatedly measured with high frequency ultrasound and pain was scored using a 10 point verbal scale. A clear dose-relationship was found for plasma concentrations and headache, and for changes in the diameter of the temporal artery, but not for the radial artery. It is concluded that headache after 5-ISMN is caused by arterial dilatation or by mechanisms responsible for the arterial dilatation. Ultrasound monitoring of arterial diameters is an important and sensitive tool in the evaluation of nitrates and other vasodilators.