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.     

Enhancing the Effectiveness of Abortive Therapy: A Controlled Evaluation of Self-Management Training

Research suggests that approximately one half of recurrent headache sufferers fail to adhere properly to drug treatment regimens with as many as two thirds of patients failing to make optimal use of abortive medications such as ergotamine. In spite of these findings there are no controlled studies that have attempted to evaluate methods for improving adherence to drug regimens for the treatment of chronic headache disorders. In an initial effort to address this adherence problem thirty-four recurrent migraine sufferers were randomized to abortive therapy with ergotamine tartrate plus caffeine (standard abortive therapy) or to standard abortive therapy accompanied by a brief educational intervention designed to facilitate the migraine sufferer's effective use of ergotamine. Patients who received the adjunctive educational intervention attempted to abort a greater percentage of their migraine attacks (70% vs 40%) and showed larger reduction in headache activity (e.g., 40% vs 26% reduction in month two of treatment). However, patients in both treatment groups used similar amounts of abortive medication when attempting to abort a migraine attack and showed similar reductions in analgesic medication use with abortive therapy. There results suggest that brief educational interventions designed to address the problem of patient adherence may yield significant improvements in standard therapies. We argue that such educational interventions deserve more attention in the headache treatment literature than they have received to date.     

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.     

Migraine Treatment: The British Perspective

Migraine occurs in about 10% of the population in the United States and the United Kingdom. In the United States there seem to be more complicated patients and the expectations of the patient are higher. In the United Kingdom there is a tendency to use single rather than compound formulations, and drugs such as barbiturates cannot be prescribed for migraine. In treating migraine the first and most important thing is to get the correct diagnosis which depends on the history and the absence of abnormal physical signs. Investigations do not confirm the diagnosis of migraine, they are only necessary to exclude other causes of headaches. Most sufferers from migraine have less than four attacks a month. Attack therapy is usually all that is required, and over the past 20 years efficient attack therapy has been developed. This depends mainly on sleep, an antinauseant, analgesics, ergotamine and more recently sumatriptan.     

Practice and Economics Cost Considerations in Headache Treatment Part 2: Acute Migraine Treatment

Today's physician has many useful medication options available for acute migraine treatment. There is a wide cost range among these drugs and today's health care environment demands that cost be factored into the decision process. Effective migraine abortive treatment decreases the costs of repeat dosing and disability. Early use of migraine abortive medication can increase its rapidity of action and effectiveness. Adjunctive medication such as metoclopramide ($0.10) is inexpensive and may improve the effectiveness of the primary abortive medication.
Over-the-counter medications such as aspirin ($0.02/325 mg), Excadrin· ($0.09/tablet), ibuprofen ($0.04/200 mg), or naproxen sodium ($0.09/220 mg) are inexpensive and effective. "Triple therapy" combining metoclopramide, a nonsteroidal ant-inflammatory agent, and an ergotamine preparation may improve tolerance and effectiveness of the ergot. Locally compounded dihydroergotamine nasal spray is inexpensive ($0.78/1 mg spray). The cost of using oral sumatriptan can be almost halved by prescribing half of a 50-mg tablet.
Emergency department services are expensive. Huge cost savings occur through self-controlled administration of oral, rectal, or even intramuscular narcotic medications. Oral narcotic agents such as hydromorphone ($0.42/4 mg) and meperidine ($0.92/200 mg) are generally used in inadequate doses to be effective for severe migraine. Guidelines are given for more effective use of these agents.
Sophisticated comparative studies are needed to evaluate, not only the direct costs of medications, but all costs of treatment of an acute migraine attack, as well as Indirect costs to the patient, family, and society.     

Sumatriptan: a selective 5-hydroxytryptamine receptor agonist for the acute treatment of migraine.

OBJECTIVE: The clinical pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and associated drug interactions of the novel antimigraine drug sumatriptan are reviewed. DATA SOURCES: English-language publications pertaining to sumatriptan were identified via a search of the MEDLINE computerized database. STUDY SELECTION: Open and controlled clinical studies were reviewed in assessing clinical efficacy, although only the results of controlled, randomized trials from the basis for the conclusions pertaining to the effectiveness of sumatriptan. DATA EXTRACTION: The primary measure of drug effectiveness in all clinical studies was significant improvement in headache severity scores. Secondary measures included functional ability, time to relief, rescue medication use, associated symptoms of nausea/vomiting and photo/phonophobia, and, in some studies, headache recurrence rate. These data were obtained from each published clinical trial and used in the overall analysis of sumatriptan efficacy. DATA SYNTHESIS: Sumatriptan is a serotonin agonist that has been studied for the acute treatment of migraine and cluster headache. The drug appears to work via specific serotonin receptors to mediate selective vasoconstriction within the cranial vasculature and to prevent the release of inflammatory mediators from trigeminal nerve terminals. The recommended dose of sumatriptan is 6 mg given subcutaneously at the onset of headache; an oral formulation is under investigation. In the published clinical trials of the oral and subcutaneous dosage forms to date, sumatriptan was effective in reducing headache severity from moderate/severe to mild/absent in approximately 70-80 percent of patients treated with active drug, compared with only 20-30 percent in the placebo groups, and 48 percent in the oral ergotamine tartrate/caffeine (Cafergot)-treated group. Secondary measures of effectiveness also favored sumatriptan. There may be a higher rate of headache recurrence with sumatriptan compared with placebo or Cafergot, although further study is necessary to confirm this observation. Adverse effects associated with sumatriptan administration generally were mild and transient and included tingling, warm/hot sensations, and pressure and tightness in the chest and neck. No significant drug interactions have yet been identified. CONCLUSIONS: Sumatriptan appears to represent a safe and effective alternative to the ergot alkaloids for the abortive treatment of acute migraine. However, further clinical trials, especially those yielding comparative data with current antimigraine agents, are needed to determine the full therapeutic contribution of sumatriptan.     

Drug abuse in migraine patients

Records of all patients discharged with a diagnosis of migraine from 2 Danish neurological departments were examined to determine the incidence of drug abuse. These departments had fixed uptake areas with a population of approximately 500,000 during the 5 year study period (1-1-1976--31-12-1980). Patients were selected for detailed analysis if (1) they used morphinomimetic drugs once a month or more, (2) took 7 or more tablets of weak analgesics a day or (3) consumed more than 60 mg ergotamine a month. A total of 92 patients fulfilled these criteria, 27 only because of ergotamine overuse. Injections of morphinomimetic drugs were given once a week or more frequently to 32 patients. These patients also usually had an escalating consumption and were usually regarded as abusers by their doctors. During admission morphinomimetics were discontinued. None deteriorated, 1/3 remained unchanged whereas 2/3 improved. Thus 32 patients can be regarded as abusers of morphinomimetics which represents an annual incidence of 13 per million inhabitants. We caution against the use of morphinomimetics in migraine.     

Pharmacological synergy: the next frontier on therapeutic advancement for migraine

The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population. Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours. A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs. More recently, the Food and Drug Adminstration has approved a combination product containing 85mg of sumatriptan plus 500mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism. Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT(1B) and 5-HT(1D) receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect. The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.     

Sumatriptan in Acute Migraine: Pharmacology and Review of World Experience

SYNOPSIS
The introduction of sumatriptan, a novel abortive anti-migraine agent, has generated a significant amount of preclinical and clinical interest during the past few years. At the scientific level, sumatriptan is unique in terms of its selective pharmacological properties. The effects of sumatriptan in various experimental paradigms have led to new insights into the pathophysiology of migraine. At the clinical level, sumatriptan appears to be an effective abortive anti-migraine agent with minimal side effects. Its ability to decrease, rather than exacerbate, the nausea and vomiting of migraine appears to be an important advance in the treatment of migraine.     

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.     

History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.     

Treatment satisfaction, functional status, and health-related quality of life of migraine patients treated with almotriptan or sumatriptan

BACKGROUND: Patient-reported outcomes, such as treatment satisfaction, functional status, and health-related quality of life (HRQOL) are essential components of migraine research. Almotriptan is a new selective serotonin 1B/1D agonist triptan migraine treatment. OBJECTIVE: The purpose of this double-blind, multicenter, randomized, parallel-group study was to compare treatment satisfaction, functional status, and HRQOL of patients treated with oral almotriptan versus sumatriptan, the leading triptan on the market. METHODS: Migraine patients, aged 18 to 71 years, took equivalent oral doses of 12.5 mg almotriptan or 50 mg sumatriptan for the abortive treatment of a migraine headache. Treatment satisfaction differences between study groups were assessed using a 6-item measure to determine patients' satisfaction with pain relief and satisfaction with side effects 48 hours after drug administration. Functional status was assessed by analyzing the change in patients' ability to perform normal activities during the course of the migraine. HRQOL was compared between treatment groups at 24 hours using the Migraine Quality of Life Questionnaire. End points were assessed using entries from patients' 48-hour diaries. RESULTS: A total of 1173 patients were treated with almotriptan or sumatriptan. There were no significant differences between the 2 treatment groups in terms of satisfaction with pain relief; however, patients in the almotriptan group were significantly more satisfied (less bothered) with side effects than those receiving sumatriptan (P = 0.016). Functional status and HRQOL outcomes were not significantly different between groups. CONCLUSIONS: In this study, migraine patients treated with almotriptan were significantly more satisfied with the side-effect profile of the drug than patients treated with sumatriptan. The results of this study may help inform practicing physicians and neurologists about the potential treatment satisfaction advantages of almotriptan.     

Ergotamine Dependency- a Review

SYNOPSIS
Ergotamine tartrate has been recognized as the drug of first choice for the treatment of acute attacks of migraine. This paper draws attention to a common but poorly delineated state of addiction that can develop when ergotamine tartrate usage exceeds two or three days per week. This syndrome is characterized by a self-sustaining, rhythmic headache/medication cycle, with daily or almost daily migraine headaches and the irresistible and predictable use of ergotamine tartrate as the only means of alleviating the headache attacks. This report further delineates the clinical features, criteria for recognition, and treatment alternatives for this syndrome. In order to avoid this condition, usage should be restricted to 2 days per week.     

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.     

Efficacy of a fixed combination of indomethacin,prochlorperazine, and caffeine versus sumatriptan in acute treatment of multiple migraine attacks: a multicenter,randomized, crossover trial

OBJECTIVE: To compare the efficacy of a fixed combination of indomethacin, prochlorperazine, and caffeine suppositories with sumatriptan suppositories in the treatment of 2 consecutive migraine attacks of moderate or severe intensity in a multicenter, randomized, crossover study. BACKGROUND: A fixed combination of indomethacin, prochlorperazine, and caffeine is the most commonly used drug for the acute treatment of migraine in Italy. No studies have been published comparing the efficacy of this combination with sumatriptan, the most widely prescribed of the triptans. METHODS: One hundred twelve patients with migraine with or without aura according to the diagnostic criteria of the International Headache Society were randomized to treat 2 migraine attacks with a fixed combination of indomethacin, prochlorperazine, and caffeine and 2 migraine attacks with sumatriptan. Both drugs were rectally administered in a single dose for each attack. Patients were asked to take study medication as soon as possible at the onset of a headache. RESULTS: Of the 112 patients, 88 were compliant to the protocol. More attacks became pain-free at 2 hours postdose (primary end point) on the combination than on sumatriptan (49% versus 34%; P<.01), while there was no difference in the relief of headache at 2 hours postdose (71% versus 65%). The combination was statistically superior to sumatriptan in the time to a pain-free response (a higher percentage of attacks became pain-free from 0.5 hours postdose to 5 hours postdose), in alleviation of nausea, and in a sustained pain-free response (pain-free at 2 hours postdose with no use of rescue medication or relapses within 48 hours). Moreover, a significant consistent response was achieved for the combination compared with sumatriptan across (higher percentage of patients pain-free at 2 hours postdose in the first, second, third, and fourth treated attack) and within patients (pain-free in 2 of 2 treated attacks in 35% of patients taking the combination and 20% of patients on sumatriptan). Both drugs were well-tolerated. CONCLUSIONS: This study, analyzed according to the more recent guidelines for controlled trials in migraine, showed that a fixed combination of indomethacin, prochlorperazine, and caffeine is significantly more effective than sumatriptan in the acute treatment of migraine attacks. It is notable that the combination is less expensive than sumatriptan per unit dose.     

Sumatriptan nasal spray for migraine: a review of studies in patients aged 17 years and younger

This review considers the epidemiology, clinical manifestations and functional consequences of migraine in children and adolescents and surveys the studies establishing the efficacy and tolerability of sumatriptan nasal spray in this patient population. Although therapeutic advances in paediatric and adolescent migraine have lagged behind those in adult migraine, the first systematic studies of migraine medications in young patients have brought about progress in the past five years. These studies show that therapeutic approaches suitable for adult patients are not always applicable to paediatric and adolescent patients. Because of the unique characteristics of paediatric and adolescent migraine, it has been difficult to demonstrate in young patients the efficacy of oral sumatriptan and other triptan tablets, which are the medications of choice for adult migraine. With sumatriptan, this finding has proven to be a consequence of the form in which the drug was administered rather than the inherent properties of the drug. The availability of sumatriptan nasal spray allows the benefits of migraine-specific therapy to be extended to children and adolescents. In both well-controlled, single-episode studies and long-term, multiple-episode studies, sumatriptan nasal spray has been effective and well tolerated for the acute treatment of migraine in children and adolescents. Except for unpleasant taste, which is not significantly distressing to patients, sumatriptan nasal spray has a tolerability profile similar to thatof placebo in young patients.