Acute migraine attack therapy: comparison of naproxen sodium and an ergotamine tartrate compound

The efficacy of safety of naproxen sodium and ergotamine tartrate were compared for the treatment of acute migraine attack in a randomized, parallel trial with 114 participating patients. At the start of symptoms, patients took either three tablets of naproxen sodium (275 mg each) or one of an ergotamine combination (containing 2 mg ergotamine tartrate, 91.5 mg caffeine, and 50 mg cyclizine chlorhydrate). Patients were followed for three months or until six attacks were monitored, whichever came first. Both medications substantially shortened the duration of migraine attacks and reduced the severity of symptoms. When the test medications were taken within 2 h of onset of attack, naproxen sodium was statistically significantly more effective than the ergotamine combination in reducing the severity of headache pain, nausea, and lightheadedness. The ergotamine combination was associated with significantly more vomiting, need for rescue medication, and side effects than was naproxen sodium. Four patients required discontinuation of the ergotamine combination and one of naproxen sodium. Both patients and investigators rated tolerance for naproxen sodium as superior to tolerance for the ergotamine combination. Naproxen sodium seems to be an effective and safe treatment for migraine attacks.     

Comparison of pharmacodynamic effects and plasma levels of oral and rectal ergotamine

Plasma levels and the vasoconstrictive effect of 1 mg ergotamine tartrate given as tablets or suppositories were compared. In a crossover study, eight male volunteers received tablets or suppositories containing ergotamine in a drug combination (Anervan) and, as a control, suppositories without ergotamine. Blood sampling and measurement of toe-arm systolic gradients with a strain-gauge technique were done for up to 6 h and again after 24 h and 48 h. Only 29 of 160 blood samples contained detectable (greater than 0.1 ng/ml) amounts of ergotamine, and kinetic comparison could not be performed. Only ergotamine-containing suppositories caused a significant (p less than 0.008) decrease in toe-arm systolic gradient which was significantly different (p less than 0.003) from the effects of ergotamine tablets and control suppositories. Rectal ergotamine is thus more biologically active, for the factor used, than oral ergotamine. We suggest that a rectal dose of 1 mg ergotamine tartrate should be tried as the initial dose in the treatment of migraine attacks.     

Sublingual Flunarizine: a New Effective Management of the Migraine Attack. A Comparison versus Ergotamine

SYNOPSIS
Flunarizine was found to be effective in the acute treatment of isosorbide dinitrate induced migraine attacks, when given in a dosage of 10 mg sublingually.
The present study consists of two parts: in the first preliminary investigation, 7 out of 8 migraine patients who developed a typical migraine attack after isosorbide dinitrate were relieved of pain within about 10 minutes. On the basis of this result a second, randomized controlled open trial was performed, in which the acute efficacy of flunarizine was compared with ergotamine tartrate, 0.25 mg i.m., on 40 migraine patients. Flunarizine was found as effective as ergotamine (75% positive responses in the flunarizine group, 70% in the ergotamine group). The mean latency of the flunarizine effect was significantly lower than that of the ergotamine ( r < 0.001, Student's t test). Moreover sublingual flunarizine was found to be virtually devoid of side effects.     

Placebo-controlled double-blind trial of pirprofen and an ergotamine tartrate compound in migraine attacks

Sixty-one patients, 16 with classic and 45 with common migraine, were treated during three subsequent attacks with pirprofen, a new inhibitor of prostaglandin synthesis; an ergotamine tartrate compound; or placebo, in a randomized, double-blind multicentre study. Pain relief after a single dose and reduction of the attack intensity occurred most often with pirprofen in patients who needed more than one dose. Among them, however, the duration of attack was shortest with ergotamine. Working ability was well preserved with pirprofen, especially among patients with common migraine, and this treatment was ranked highest by the patients. However, no statistically significant differences were found between pirprofen and ergotamine. No serious side effects were observed with pirprofen. This study establishes the usefulness of pirprofen in the treatment of acute migraine.     

Tolfenamic acid, metoclopramide, caffeine and their combinations in the treatment of migraine attacks

Tolfenamic acid is a fenamate which inhibits prostaglandin (PG) biosynthesis and may act as a PG antagonist as well. Caffeine and metoclopramide are used in combination with analgesics and ergotamine in the treatment of migraine attacks, but controlled clinical studies on fixed combinations with analgesics are rare. The effects of orally given tolfenamic acid (200 mg), caffeine (100 mg), metoclopramide (10 mg), tolfenamic acid + caffeine (200 mg + 100 mg), tolfenamic acid + metoclopramide (200 mg + 10 mg) and placebo were studied in 49 migraine patients (3 men, 46 women) in a double-blind randomized cross-over study comprising 482 migraine attacks. The patients were allowed to take either one or two capsules of each preparation for an attack. Additional drugs were allowed after 3 h. Parameters characterizing the effects and side-effects of the drugs were registered. Tolfenamic acid and its combinations were found to be effective in the treatment of acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Combination with metoclopramide was better than tolfenamic acid alone as judged by the smaller dose needed and the intensity of attack. Between tolfenamic acid alone and its caffeine combination there were no statistically significant differences.     

Ergotamine and dihydroergotamine: a review

The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.     

Tolfenamic Acid and Ergotamine Abuse

SYNOPSIS
Thirteen migraine patients using ergotamine tartrate on a daily basis for their headaches were found to have developed the so called "ergotamine headache," a dull constant headache always reappearing if the patient did not take their daily doses. They were treated with tolfenamic acid, an inhibitor of prostaglandin synthesis and action, combined with chlordiazepoxide during the acute withdrawal phase after discontinuing their daily habit of taking ergotamine. As a whole, the results of the discontinuation of the use of ergotamine were encouraging in the group of these patients showing a serious medical problem. None of the patients relapsed into ergotamine abuse, and during the subsequent 3–6 months nine of the patients also treated their migraine attacks solely with tolfenamic acid.     

Optimal routes of administration of ergotamine tartrate in cluster headache patients. A pharmacokinetic study

Bioavailability and rate of absorption of ergotamine were studied in eight cluster headache patients outside attacks. In a cross-over design, approximately 2 mg ergotamine tartrate was administered as effervescent tablets, suppositories, and from an inhalation device, with 0.25 mg intravenously as the reference. Ergotamine in plasma was measured by high performance liquid chromatography with fluorescence detection from 5 to 420 min. For all three routes of administration, a similar low (0.5-4.2%) bioavailability of ergotamine was estimated. Only inhalation of ergotamine resulted in early (at 5 min) peak concentrations of ergotamine in plasma and is therefore most likely to relieve the short-lived attacks of cluster headache. The inhalation route for ergotamine poses problems, however, and we suggest ways of improving the inhalation device.     

Response of Cluster Headache Attacks to Oxygen Inhalation

SYNOPSIS
Fifty-two randomly selected patients diagnosed as having either active episodic or chronic cluster headaches were evaluated for symptomatic response to oxygen inhalation. At the onset of attacks, 100% oxygen was administered through a facial mask at a rate of 7 liters per minute, for 15 minutes. Each patient self-treated ten attacks, and timed the rated reduction of pain. A successful treatment result required complete or almost complete reduction of pain in seven of ten attacks, within 15 minutes.In a second (crossover) trial involving an additional 50 patients, sublingual ergotamine tartrate (ErgomarÒ) was compared to oxygen inhalation for symptomatic relief of cluster attacks. Each patient treated ten attacks with either preparation in accordance with the crossover design. Oxygen was administered as described above. Sublingual ergotamine was used every five minutes, to a maximum of three tablets, if necessary.In the first trial 3952 (75%) of patients obtained significant relief from cluster pain. The greatest benefit (92.9%) was found among episodic patients under 50 years of age. The least benefit (57%), was found among chronic patients over 49 years of age. In the second trial, results among oxygen users were better (82%) than those of ergotamine users (70%), but not significantly. Rapidity of relief was similar in both groups.The results of both series indicate that oxygen inhalation is an efficacious symptomatic treatment for cluster attacks. It is superior to ergotamine since there are neither complications nor contraindications to its use. Ergotamine, however, has the advantage of convenience.     

Ergotamine vs. metoclopramide vs. their combination in acute migraine attacks

The effect of ergotamine tartrate was compared with that of the antiemetic agent metoclopramide and with those of two combinations in a double-blind trial of 24 adult female patients with migraine. The following combinations of the drugs were used in oral administration in a total of 176 acute migraine attacks: (a) Ergotamine 1 mg, (b) Metoclopramide 20 mg, (c) Ergotamine 1 mg + metoclopramide 20 mg, (d) Ergotamine 2 mg + metoclopramide 20 mg. The duration of attacks was significantly shorter on both of the combinations compared with the single drugs. The intensity of the pain was somewhat weaker and the appearance of nausea and vomiting somewhat but not significantly less during the combination treatments. In their overall opinion the patients favored the 2 mg + 20 mg combination significantly more than the others. Both ergotamine and metoclopramide are efficient in acute migraine attacks. Their combination seems to enhance the therapeutic response in some respects.     

Cluster headache: aetiology, diagnosis and management.

Drugs . 2002;62(1):61-69
Cluster headache is characterised by repeated attacks of strictly unilateral pain in the orbital region associated with local autonomic symptoms or signs. The attacks are brief but of a very severe, almost excruciating intensity. For unknown reasons males are affected more often than females. Recent studies suggest that an autosomal dominant gene has a role in some families with cluster headache. Hormonal studies indicate a dysfunction in the central nervous system. Neuroimaging has revealed primary defects in the hypothalamic grey matter. Local homolateral dilatation in the intracranial segment of the internal carotid and ophthalmic arteries during attacks is the result of a generic neurovascular activation, probably mediated by trigeminal parasympathetic reflexes. Sumatriptan 6mg subcutaneously is the drug of choice in the treatment of acute attacks. Inhalation of 100% oxygen can also be recommended. In the prophylactic treatment, verapamil is the first option. Other drugs that can be considered are corticosteroids, which may induce a remission of frequent, severe attacks, and lithium. Oral ergotamine tartrate may be sufficient for patients with night attacks and/or short, rather mild to moderately severe cluster headache periods. Third line drugs are serotonin inhibitors (methysergide and pizotifen) and valproic acid. Patients should be encouraged to keep headache diaries and be carefully instructed about the nature and treatment of the headaches. Alcohol can bring on extra attacks and should not be consumed during active periods of cluster headache.
Comment: A useful review of clinical options. Given the effectiveness of injectable sumatriptan and the prophylactic use of ergotamine mentioned, one might speculate that the new intranasal formulations of triptans (eg, zolmitriptan) and triptans with a longer half-life (eg, frovatriptan) may prove to be effective in the treatment of cluster headache. DSM     

Aborting a Migraine Attack: Naproxen Sodium v Ergotamine plus Caffeine

SYNOPSIS
The tolerability and efficacy of naproxen sodium and of ergotamine tartrate plus caffeine (ergotamine) were compared in the treatment of acute migraine attacks and associated symptoms. In this multicenter, double-blind, parallel study of up to six headaches over a 3-month period, patients took naproxen sodium 825 mg, ergotamine 2 mg, or placebo at the time of the first symptom of an attack; 30 minutes later, if necessary, patients repeated naproxen sodium 275 mg, ergotamine 1 mg or placebo, as appropriate. Rescue medication was allowed 30 minutes following the second dose if needed. Active drugs provided notably better relief of head pain than did placebo; 1 hour following the first dose the difference between naproxen sodium and placebo was statistically significant. Naproxen sodium was as efficacious as ergotamine in the relief of migraine attacks and associated symptoms. Relief of vomiting, nausea, photophobia, and motor symptoms favored naproxen sodium over ergotamine; these differences were statistically significant for nausea and motor symptoms. Ergotamine-treated patients reported more complaints and had more severe and longer-lasting complaints than patients on the other two regimens. Overall tolerance ratings by both investigators and patients indicated that naproxen sodium and placebo were tolerated significantly better than ergotamine.     

Whole-bowel irrigation versus activated charcoal in sorbitol for the ingestion of modified-release pharmaceuticals

Overdose with modified-release pharmaceuticals is an increasing phenomenon. This study examines whole-bowel irrigation as a potential decontamination strategy after overdose with enteric-coated acetylsalicylic acid and compares it with administration of activated charcoal in sorbitol, which is currently the recommended intervention. A three-phase randomized crossover protocol was used in 10 adult volunteers. Each volunteer ingested nine 325 mg doses of enteric-coated acetylsalicylic acid on three occasions, with at least 1 week between each administration period. Serum samples were analyzed for salicylic acid concentration by HPLC. Both interventions decreased peak salicylic acid concentration, time-to-zero salicylic acid concentration, and AUC when compared with control (p less than 0.01). Whole-bowel irrigation was superior to activated charcoal in sorbitol by all three criteria (p less than 0.05). Adverse effects were qualitatively and quantitatively greater during activated charcoal in sorbitol, and the volunteers preferred whole-bowel irrigation over charcoal in sorbitol. Our data suggest that whole-bowel irrigation should be considered for overdose of other modified-release pharmaceuticals.     

The impact of different antimigraine compounds on platelet and erythrocyte aggregation

Clinical and experimental data suggest that ergotamine compounds and triptans may contribute to vascular events such as myocardial infarction and stroke. The role of blood cell aggregation in this context is, however, not clarified. We aimed to evaluate the impact of different acute antimigraine compounds on platelet and erythrocyte aggregation in a human ex vivo experimental design. In 20 healthy subjects without migraine and in 20 healthy subjects with migraine without aura, platelet and erythrocyte aggregation were measured before and after intake of placebo, acetylsalicylic acid, ergotamine tartrate, zolmitriptan and sumatriptan. Platelet aggregation was measured by the so-called platelet reactivity index. Erythrocyte aggregation was measured by photometric assessment in an aggregometer. Ergotamine tartrate induced a significant increase of platelet aggregation, whereas acetylsalicylic acid induced a significant decrease in both subject groups. After placebo, after sumatriptan and after zolmitriptan, no significant changes of platelet aggregation were noted. Erythrocyte aggregation was affected by neither compound. We can conclude that platelet aggregation, but not erythrocyte aggregation, is increased after intake of ergotamine tartrate. This may in part contribute to vascular side-effects of this compound. Acetylsalicylic acid and the triptans appeared to be safe with respect to platelet and erythrocyte aggregation.     

Bioavailability and antimigraine efficacy of effervescent ergotamine

SYNOPSIS
In about 20% of migraine patients treatment with enterally administrated ergotamine tartrate proves unsuccessful. One of the causes for this might be a poor systemic availability of the drug from the ordinary solid tablets. The present study aimed to investigate the bioavailability and the therapeutic value of ergotamine tartrate in effervescent form.
In twenty volunteers the plasma ergotamine levels were measured by using a radioimmunoassay after oral administration of 2.0 mg ergotamine tartrate combined with 50.0 mg caffeine in effervescent form. Measurable plasma drug levels were found in 14 (70%) of the subjects and the mean maximum plasma ergotamine level of 0.45 ng/ml was achieved at 30 minutes.
In the clinical part of the study 25 migraine patients treated their migraine attacks with effervescent ergotamine. The therapeutic value of it was considered as good by 9, moderate by 11 and poor by 5 of the patients. Among 18 of them the therapeutic effect seemed to be equal to their earlier ergotamine medications. The results indicate that the plasma pharmacokinetics of ergotamine tartrate in effervescent form is similar to and possibly faster on the absorptive phase than that reported earlier after enteral administration. In patients who do not gain benefit from the usual ergotamine tablets or suppositories, effervescent ergotamine would appear to be an alternative worth consideration.     

Medical therapy for menstrual migraine

A menstrual migraine occurs in approximately 7-10 % of women suffering from migraine. The migraine occurs from 2 days before until 3 days after the end of the menstrual period. The choice of treatment depends on the duration of the attack, which ranges from 3 to 7 days. An attack of up to 3 days duration should be treated with acetylsalicylic acid, ergotamine tartrate or naproxen, each in combination with an antiemetic (domperidone, metoclopramide). If there is no response, sumatriptan can be administered orally (25-100 mg) or subcutaneously (6 mg). In the attacks continue for more than 3 days, short-term prophylaxis with naproxen or the application of an estrogen-containing patch is indicated. Neither ovulation inhibitors nor traditional migraine prophylaxis has an influence on menstrual migraine. Patients should keep a headache diary. Short-term prophylaxis with ergotamine tartrate or tamoxifen is obsolete.     

Tolfenamic acid decreases migraine recurrence when used with sumatriptan

Although sumatriptan is an effective drug for the treatment of acute migraine attacks, recurrence has been cited as an important limitation for its use. Tolfenamic acid is also effective in the acute treatment of migraine attacks. We studied the recurrence rate of migraine attacks with the use of sumatriptan plus tolfenamic acid among patients who presented frequent recurrence with sumatriptan. Fifty migraineurs were retrospectively studied, all having treated at least 10 attacks with 100 mg P.O.; sumatriptan was effective in at least eight of them. The patients also presented recurrence in less than 24 h in at least five of the treated attacks. We then used sumatriptan 100 mg plus tolfenamic acid 200 mg P.O. during the first 60 min of the attack; 240 attacks were treated and there was recurrence in 57 (23.8%). With sumatriptan alone, 5 out of 8 attacks (62.5%) presented recurrence. We therefore conclude that the combination sumatritpan plus tolfenamic acid is effective in reducing the recurrence rate from 5 of 8 (62.5%) to 1.19 of 5 (23.8%). Further prospective studies with a double-blind design and a higher number of treated attacks are necessary to confirm these initial observations.     

Pain relief by somatostatin in attacks of cluster headache

The pain relieving effect of somatostatin treatment during 72 attacks of cluster headache in 8 male patients was compared to treatment with ergotamine or placebo in a double-blind study. Infusion of somatostatin (25 micrograms/min for 20 min i.v.) reduced the maximal pain intensity and the duration of pain significantly compared to placebo treatment, and to a degree comparable to ergotamine tartrate treatment (250 micrograms i.m.). The results obtained provide new information concerning the possible mechanism of cluster headache attacks and suggest a new therapeutic approach.     

Reduced serotonin vascular sensitivity in ergotamine abusers

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.