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.     

Tolfenamic acid and caffeine: A useful combination in migraine

Tolfenamic acid is a potent inhibitor of prostaglandin biosynthesis, which has been proved effective in the treatment of acute migraine attacks. The usefulness of caffeine, metoclopramide and pyridoxine as adjuncts to tolfenamic acid was tested in acute migraine attacks in ten patients. A combination of tolfenamic acid (200 mg) with either caffeine (100 mg), metoclopramide (10 mg) or pyridoxine (300 mg) was given twice to each patient in random order. Thus 60 attacks were treated. The tolfenamic acid-caffeine combination proved the most effective as judged by duration and intensity of attacks, working ability, vigilance, and overall evaluation of the drugs by the patients. Metoclopramide was somewhat better than pyridoxine as an additive.     

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.     

A Comparative Trial of Ergotamine Tartrate, Acetyl Salicylic Acid and a Dextropropoxyphene Compound in Acute Migraine Attacks

SYNOPSIS
The effect of a dextropropoxyphene compound (Doleron(r)) was compared with that of ergotamine tartrate and acetyl salicylic acid on 525 acute migraine attacks in a double blind study of 25 adult female patients. Ergotamine and the dextropropoxyphene compound were approximately equally effective and significantly superior to acetyl salicylic acid in preventing the attacks entirely. In the cases in which the attack was only partially prevented, the dextropropoxyphene compound was more effective than ergotamine and acetyl salicylic acid in making the attacks milder and shorter. Side effects, especially gastrointestinal symptoms and fatigue, were less common with the dextropropoxyphene compound than from either of the two drugs. Probably for this reason, the patients' overall preference was clearly in favor of the dextropropoxyphene compound. The addition of dextropropoxyphene, a centrally active analgesic, to acetyl salicylic acid, gives an antimigraine compound which has an efficacy comparable with ergotamine but with less side effects.     

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.     

Ergotamine-induced anorectal strictures: report of five cases.

Dis Colon Rectum . 2002 Feb;45(2):271-2
Purpose: Ergotamine tartrate suppositories are used for treatment of migraine headache attacks. Chronic abuse may lead to severe anorectal complications such as ulceration, stricture, and rectovaginal fistula. These complications are rare, and only sporadic reports may be found. Nevertheless, awareness of this entity on the part of prescribing physicians and treating colorectal surgeons is essential for a successful outcome, because withdrawal of this medication is an inherent part of treatment.
Patients: Five female patients were referred for treatment of symptomatic strictures of the anal canal and lower rectum. All of these patients admitted prolonged, nearly daily use of three to seven ergotamine tartrate suppositories.
Results: Three patients with severe stenosis of the anal verge and anal canal were treated by Y-V anoplasty, and two patients with circular stricture of the lower third of the rectum had balloon dilatations. In all patients the use of ergotamine suppositories was stopped, and alternative medication was instituted. Long-term follow-up (3-12 years) showed complete resolution of symptoms.
Conclusion: In view of the availability of new effective drugs for treatment of migraine headache (serotonin agonists) and considering the potentially severe complications of chronic use of ergotamine, the use of this medication should be abandoned.
Comment: Ergotamine users beware of the sting in the tail! DSM.     

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.     

Migraine headache. Its diagnosis and treatment

Many theories exist on the pathogenesis of migraine. However, the clinical picture of migraine is agreed on universally as a familial disorder characterized by recurrent attacks of headache that are variable in intensity, frequency, and duration. The attacks are usually unilateral and often associated with anorexia, nausea, and vomiting. Migraine therapy is complex and difficult, focusing on abortive and prophylactic regimens. General therapeutic measures, including diet and establishing schedules for meals and sleeping, may benefit many migraineurs. A variety of medications, including ergotamine, propranolol, the calcium channel blockers, antidepressants, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been beneficial in the prophylactic treatment of migraine. Ergotamine is the drug of choice in the abortive treatment, although other agents, such as the NSAIDs, have been used successfully. Inpatient therapy in a specialized unit for headache patients may be indicated for the recidivist patient, the patient habituated to analgesics or ergotamine, or the patient with the mixed headache syndrome, i.e., migraine occurring with coexistent muscle contraction headaches.     

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.     

Treatment of the acute migraine attack current status

The main treatment of the acute migraine attack remains sleep, sedation, an anti-nauseant and analgesics, and in some patients 1 or 2 mg of ergotamine tartrate. Drugs containing large amounts of caffeine should not be used. Absorption of drugs may be impaired in a migraine attack. Metoclopramide is probably the anti-emetic of choice because it is an effective anti-nauseant and promotes normal gastrointestinal activity. Domperidone has a similar action but is said not to go through the blood-brain barrier, so is less likely to cause extrapyramidal reactions. All drugs, including analgesics such as aspirin and paracetamol, are best given in a soluble or effervescent form. Where vomiting occurs early in the attack, suppositories may be indicated. Ergotamine tartrate is necessary in about one third of attacks and is best given by suppository or by inhalation. Doses higher than 2 mg per attack or 6 mg in one week may cause toxic symptoms, the early signs of which are headache, nausea, vomiting and a feeling of not being very well. The non-drug treatments of an acute attack include pressing on the temporal artery, hot and cold compresses and relaxation.     

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.     

Application of Metoclopramide Specificity in Migraine Attacks Therapy

SYNOPSIS
The 5-HT₃ antagonism property of metoclopramide, acting on receptors presumably located in the trigeminovascular system, is the theoretical basis of its remarkable success, as a single intravenous agent, in the treatment of migraine attacks. The specific anti-migraine activity of oral metoclopramide is, most probably, applicable only when its plasma level is equivalent to 10 mg injected intravenously. The clinical effective dose of ergotamine, beginning from the minimal dose of 1 mg, correlates well with its affinity for 5-HT₁₈ and 5-HT_1D receptors, and the rank order of clinical potency of ergotamine is superior to sumatriptan. The presumed synergic power of drugs that interact with both 5-HT₁ and 5-HT₃ receptors is examined, in order to formulate a highly potent, low headache recurrence, oral combination.     

Sumatriptan for the treatment of migraine attacks-a review of controlled clinical trials

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.     

Rizatriptan vs. rizatriptan plus trimebutine for the acute treatment of migraine: a double-blind, randomized, cross-over, placebo-controlled study

Gastroparesis frequently happens during migraine attacks, postponing the onset of action of orally administered drugs. Furthermore, triptans seem to work better in the earlier phases of the migraine attacks. Therefore, associating a gastrokinetic drug with a triptan may translate into better efficacy and higher consistency of response. Trimebutine is an opioid derivative with exclusive action on receptors of the Meissner and Auerbach plexus throughout the digestive tube. It has no absorption or central penetration. Herein we contrast the combination of rizatriptan plus trimebutine with rizatriptan alone in the acute treatment of migraine. Forty patients with migraine consecutively seen in our clinic were randomized to treat two consecutive moderate or severe attacks with one tablet of 10 mg rizatriptan plus one capsule of 200 mg trimebutine and two attacks with the same triptan and placebo, in counterbalanced order. We collected information on the severity of the attack, as well as presence of nausea and photophobia at the time of drug intake, and after 1, 2 and 4 h. Recurrence and adverse events were also contrasted. Sixty-four attacks were treated with each drug regimen. At 1 h postdose, 30 (46.8%) of 64 attacks treated with the combination resolved completely, vs. eight (12.5%) of the rizatriptan-treated attacks, a difference of 34% (P < 0.01). At 2 h postdose, 47 (73.4%) attacks treated with the combination vs. 20 (31.2%) of those treated with rizatriptan alone resolved completely, a difference of 42% (95% confidence interval 26, 58, P < 0.001). Regarding nausea and photophobia, the combination was also associated with significantly better response. Recurrence was similar among the two drug regimens, as well as adverse events. The combination rizatriptan and trimebutine is more effective than rizatriptan alone. The combination does not increase adverse events or recurrence of pain.     

A randomized open-label study of sodium valproate vs sumatriptan and metoclopramide for prolonged migraine headache

ObjectiveThe objective of this study is to compare the efficacy and tolerability of intravenous valproic acid (iVPA) with intramuscular metoclopramide + subcutaneous (SQ) sumatriptan for prolonged acute migraine.BackgroundIntravenous valproic acid has been explored as a possible treatment of acute migraine. Sumatriptan and newer generation triptans are also effective for migraine. However, iVPA has not yet been compared with triptans in head-to-head studies.MethodsPatients presenting with moderate to severe intensity migraine without aura were randomized to receive either 400 mg of iVPA or 10 mg intramuscular metoclopramide + 6 mg SQ sumatriptan (30 patients in each study arm). The severity of headache and other associated symptoms such as photophobia and phonophobia were assessed at baseline and after 20 minutes and 1, 2, 4, and 24 hours. The primary end point was to compare the efficacy of the 2 study treatments in relieving headache from moderate-severe to none-mild and of other associated symptoms within a period of 24 hours.ResultsPain relief from severe or moderate to mild or none was obtained in 53.3% of subjects in the iVPA arm and 23.3% in the metoclopramide + sumatriptan arm at 1 hour following treatment (P = .033), whereas 60% and 30% reported pain relief at 2 hour (P = .037). There was no other significant difference in alleviation of associated migraine symptoms between the 2 arms. No serious adverse effects were noted.ConclusionTreatment with iVPA was more effective than metoclopramide + SQ sumatriptan during the first 2 hours in patients with a prolonged migraine.     

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.     

Atenolol for Migraine Prophylaxis

SYNOPSIS
The preventive effect of atenolol on migraine attacks was compared to placebo in a double-blind cross-over study. 24 patients with classic and/or common migraine entered the 36-week study; four subsequently dropped out. The effect of atenolol was significantly better than that of placebo. The number of headache attacks was reduced in 15 of 20 patients (r<0.05) and the values for integrated headache diminished in 19 of 20 patients (r<0.001).
Intake of ergotamine products was significantly lower in all patients using such drugs, while the consumption of common analgesics did not differ between the trial periods. No serious side effects were noted.     

Naproxen Sodium Versus Ergotamine Tartrate in the Treatment of Acute Migraine Attacks

A double-blind parallel study compared the efficacy and safety of naproxen sodium (NPX) and ergotamine tartrate (ERG) as abortive therapy for acute headache in 79 patients with classical or common migraine. The design study was of the double-blind design. Forty-two patients completed the study. Discontinuation of treatment was generally due to lack of efficacy or adverse reactions. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (p less than 004). NPX was comparable to ERG in reducing the severity and duration of the headache and its associated symptoms. In classical migraine, NPX was better than ERG in alleviating the severity of headache. Patients in the NPX group tended to use less rescue medication. There was no significant difference in the frequency of side-effects reported by the patients under NPX or ERG. This study demonstrates that NPX is as safe as ERG, and somewhat more effective in acute migraine attacks (although the difference is not statistically significant) and that migrainous patients tend to prefer NPX to ERG in treating their acute migraine headaches.     

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.     

A randomized prospective placebo-controlled study of intravenous magnesium sulphate vs. metoclopramide in the management of acute migraine attacks in the Emergency Department

The objective of this randomized, placebo-controlled, double-blind study was to determine the effectiveness of intravenous magnesium sulphate and intravenous metoclopramide in the treatment of acute migraine attacks in the Emergency Department when compared with placebo. Adult patients who presented to the Emergency Department with a headache that met International Headache Society (IHS) criteria for acute migraine were infused with either 10 mg of intravenous metoclopramide, 2 g of intravenous magnesium sulphate or normal saline over 10 min. At 0, 15, and 30 min, patients were asked to rate their pain on a standard visual analogue scale. At 30 min, patients were asked in a standard manner about the need for rescue medication. Adverse affects were also recorded. Patients were followed up by telephone within 24 h for any recurrence after discharge. The primary endpoint of the study was the difference in pain relief between the groups at 30 min. Of the 120 patients who met IHS criteria, seven were excluded from the study due to insufficient data. The number of patients, gender, age and initial visual analogue scale (VAS) scores were comparable between groups. Each group experienced more than a 25-mm improvement in VAS score at 30 min. However, there was no significant difference detected in the mean changes in VAS scores for pain. The rescue medication requirement was higher in the placebo group. The recurrence rate in 24 h was similar between the groups. Although patients receiving placebo required rescue medication more than the others, metoclopramide and magnesium have an analgesic effect similar to placebo in migraine attacks.