Antimigraine drugs

Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, phonophobia, and malaise. This review summarizes new treatment options for therapy of the acute attack. Mild or moderate migraine attacks are treated with antiemetics followed by analgesics such as aspirin, paracetamol, nonsteroidal anti-inflammatory drugs, or antiemetics combined with ergotamine or dihydroergotamine. Sumatriptan, a specific serotonin (5-HT)_1B/D agonist is used when attacks do not respond to ergotamine, or when intolerable side effects occur. The new migraine drugs zolmitriptan, naratriptan, rizatriptan, and eletriptan differ slightly in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence, and side effects. New drugs in migraine prophylaxis include cyclandelate, valproic acid and magnesium. Received: 30 August 1998 Accepted: 10 October 1998     

Treatment guidelines for acute migraine attacks

The Treatment Guideline Subcommittee of the Taiwan Headache Society evaluated the medications currently used for acute migraine attacks in Taiwan according to the principles of evidence-based medicine. We have assessed the quality of clinical trials, levels of evidence, and referred to other treatment guidelines proposed by Western countries and Japan. After several panel discussions, we merged opinions from the subcommittee members in order to propose a Taiwan consensus regarding the major roles, recommended levels, clinical efficacy, adverse events and cautions of clinical practice for these medications in treatment of acute migraine attacks. Acute medications currently available in Taiwan can be categorized into "migraine-specific" and "migraine-nonspecific" groups. Migraine-specific triptans and ergotamine, and migraine-nonspecific nonsteroidal anti-inflammatory drugs (NSAIDs) have the best levels of evidence, and are recommended as the first-line medications for acute migraine attacks. The administration should follow the concept of "stratified care". For mild to moderate migraine attacks, oral NSAIDs are the first choice; with oral aspirin, combination analgesics, intravenous/intramuscular NSAIDs or ergotamine as alternatives. For moderate to severe attacks, oral or nasal spray triptans and ergotamine are recommended and the suggestion is to administer them in the early stage of migraine attacks. NSAIDs can be used as alternatives. Notably, a combination of a triptan and a NSAID yielded a better efficacy compared with either monotherapy. Parenteral steroid and fluid supply are the first choice in treatment of status migrainosus. Acetaminophen showed poor efficacy for moderate to severe migraine attacks but remains the first choice for children and pregnant women. Opiates are not recommended for acute migraine treatment at the present time because of serious adverse events. To prevent medication-overuse headache, the use of acute treatment should be limited to a maximum often days a month.     

Ergotamine,flunarizine and sumatriptan do not change cerebral blood flow velocity in normal subjects and migraneurs

Summary Changes in the diameter of extracranial and intracranial arteries resulting in changes in cerebral blood flow have previously been assumed to be the most important pathophysiological factor in migraine. To test this hypothesis 20 normal subjects, and three groups of patients (n=29) with migraine were investigated by means of transcranial Doppler sonography. Blood flow velocities in the middle cerebral (MCA) and in basilar (BA) arteries were measured. Data from patients were obtained in the interval between migraine attacks, during migraine attacks and following treatment with either ergotamine (0.5 mg i.m.; n=10); flunarizine, a calcium overload blocker (20 mg i.v.; n=13); or a 5-HT₁-like agonist (sumatriptan, 4 mg s.c.; n=6). Ergotamine and sumatriptan are constrictors of cerebral arteries in animal experiments. The arithemtic mean of flow velocity in the BA was reduced in normal subjects (45 cm/s) as compared with patients with migraine measured in between attacks (53 cm/s). Mean flow velocity in MCA was not different in normals (72.5 cm/s) as compared with migraineurs (75 cm/s). Neither ergotamine nor the 5-HT₁ agonist and flunarizine resulted in a significant change in blood flow velocity in MCA and BA. This was true irrespective of whether the drugs were given in the headache-free period, during a migraine attack or during the withdrawal phase of drug-induced headache. Ergotamine was effective in improving headache during migraine attacks and sumatriptan attenuated headache during drug withdrawal from chronic analgesic intake. These results indicate that the action of ergotamine and the 5-HT₁-receptor agonist is probably not mediated by their vasoconstrictor action on cerebral arteries.     

A retrospective long-term analysis of the epidemiology and features of drug-induced headache

Drug-induced headache is well known to resul from the abuse of compounds taken for the treatment of primary headache. The features of drug-induced headache depend on various features including the availability of drugs, the regional health system, and psychogenic factors of the patients. We performed a retrospective study on a series of 257 consecutive German patients presenting with drug-induced headache during the period 1983–1996. Our aim study was to evaluate the demographic features, the frequency of various drugs used, in particular of ergotamine derivates, and changes in these features during the study period. The frequency of drug-induced headache among all headache patients was 8%, with a female preponderance of 81%. Drug-induced headache occurred in all age groups, predominantly in migraine patients (35%). The mean number of substances used was 2.7, mainly, acetaminophen (47.9%), ergotamine tartrate (45%), and combined analgesics (56%). We did not find a significant difference between the associations with ergotamine tartrate and dihydroergotamine, although the latter was taken less frequently. Comparing the early and late years of our study period, there were no changes in the frequency of drug-induced headache (8% versus 7%), although changes in the frequency of some drugs changed (barbiturates, ergotamine tartrate, and codeine intake decreased whereas nonsteroidal anti-inflationary drugs, combined analgesics, and sumatriptan intake increased). Our data suggest that changes in drug availability and the introduction of classification criteria and treatment recommendations did not have a major impact on the frequency of drug-induced headache. Received: 17 July 1998 Received in revised form: 5 February 1999 Accepted: 18 February 1999     

Diagnosis and treatment of cluster headache

Cluster headache is an uncommon yet distinctive neurovascular syndrome occurring in either episodic or chronic patterns. The most unique feature of cluster headache is the unmistakable circadian and circannual periodicity. The attacks are stereotypical, that is, of extreme intensity, of short duration, occurring unilaterally, and associated with robust signs and symptoms of autonomic dysfunction. Unlike migraine, during an attack the patient with cluster headache often paces about. Attacks frequently occur at night, awakening the patient from sleep. Although the pathophysiology of cluster headache remains to be fully elucidated, several seminal observations have recently been made. The medical treatment of cluster headache includes acute, transitional, and maintenance prophylaxis. Agents used for acute therapy include inhalation of oxygen and triptans, such as sumatriptan, and dihydroergotamine. Transitional prophylaxis refers to the short-term use of fast-acting agents. This typically involves either corticosteroids or ergotamine derivatives. The mainstay of prophylactic therapy is verapamil. Lithium, divalproex sodium, or topiramate may also be useful. As the sophistication of functional neuroimaging increases, so too will our ability to better understand the anatomic and metabolic perturbations that underlie cluster headache.     

Estrogens, progestins, and headache

Migraine headaches appear to be linked to the menstrual cycle and the use of oral contraceptives (OCs). Migraine attacks occur during menses in 60% of women and appear to be related to the withdrawal of estrogen. The fluctuations in estrogen levels associated with migraine headaches produce biochemical changes in prostaglandin production, prolactin release, and opoid regulation. Treatment seeks to interrupt the pathophysiological sequence of menstrual-related migraine through the administration of nonsteroidal anti-inflammatory drugs, ergotamine, or, in refractory cases, hormonal agents. The frequency of migraine decreases with age, but tends either to regress or worsen during menopause. In some cases, estrogen replacement therapy for menopausal symptoms produces headache and it may be necessary to reduce the estrogen dose or change from conjugated estrogen to pure estradiol or estrone. The incidence and severity of migraines are also affected by OC use. OCs may trigger migraine episodes and exacerbate or alleviate pre-existing headache. This variable response seems to be a result of individual differences in intrinsic estrogen neuronal response. Although migraine itself may be a risk factor in stroke, there is no evidence that this risk is increased in migrainers who use OCs.     

A COMPARISON BETWEEN PLACEBO, PIZOTIFEN AND 1-ISOPROPYL-3-HYDROXY-5-SEMICARBAZONO-6-OXO-2.3.5.6.-TETRAHYDROINDOL (DIVASCAN®) IN MIGRAINE PROPHYLAXIS

The effects and side-effects in migraine prophylaxis of placebo, Divascan (1-isopropylnoradrenochrome--5--monosemicarbazone) and pizotifen were compared in a double-blind cross-over study. The dosage was for Divascan 15 mg a day and for pizotifen 3 mg a day. Data from the last 6 weeks of each test period of 8 weeks were used to assess the effect of the treatment. Thirty patients entered the trial. Data from 28 patients treated with placebo and Divascan and 27 patients treated with pizotifen were used for final evaluation. Pizotifen significantly reduced the number of migraine attacks, headache index and the consumption of ergotamine. Divascan also seemed to have effect. The consumption of ergotamine was reduced compared with placebo and there was a reduction, although not significant, of headache frequency and headache index. Pizotifen gave significantly larger reduction in headache frequency and headache index than Divascan and signficantly more patients stated a preference for pizotifen compared with Divascan. A good or very good effect was reported by 11 per cent of the patients on placebo, 39 per cent on Divascan and 70 per cent on pizotifen. Pizotifen had frequent side-effects, mainly drowsiness and weight gain, whereas Divascan in this respect did not differ from placebo. Physical examinations and laboratory investigations did not show any significant changes, apart from weight gain.     

Pharmacological approaches to migraine

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. This review summarises new treatment options both for the therapy of the acute attack as well as for migraine prophylaxis. Analgesics like aspirin or nonsteroidal antiinflammatory drugs (NSAIDs) are effective in treating migraine attacks. Few controlled trials were performed for the use of ergotamine or dihydroergotamine. These trials indicate inferior efficacy compared to serotonin (5-HT)1B/D-agonists (further on called "triptans"). The triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan) are highly effective. They improve headache as well as nausea, photo- and phonophobia. The different triptans have minor differences in efficacy, headache recurrence and adverse effects. The knowledge of their different pharmacological profile allows a more specific treatment of the individual migraine characteristics. Migraine prophylaxis is recommended, when more than 3 attacks occur per month, if attacks do not respond to acute treatment or if side effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol, the calcium channel blocker flunarizine, several 5-HT antagonists and amitriptyline. Recently antiepileptic drugs (valproic acid, gabapentin, topiramate) were evaluated for the prophylaxis of migraine. The use of botulinum-toxin is under investigation.     

硝酸甘油型实验性偏头痛大鼠模型行为症状学评价

目的 对硝酸甘油型实验性偏头痛动物模型行为症状学进行系统的评价。方法应用硝酸甘油型实验性偏头痛动物模型，采用持续时间分段计数的方法，通过空白对照和药物反证治疗进行系统的评价。结果空白组始终未出现行为症状表现(耳红、挠头、爬笼)；模型组与治疗组均于3min以后出现行为症状表现，药物组对大鼠行为症状表现有明显干预作用。结论硝酸甘油型实验性偏头痛大鼠模型行为症状学评价是观察治疗偏头痛药物疗效的较为全面客观、且能量化的一项合理指标。     

Ergotamine: its use in the treatment of migraine and its complications.

This paper gives a review of the use of ergotamine in the treatment of migraine and discusses its side effects and the treatment of possible complications. It is concluded that ergotamine is an effective and valuable substance in the treatment of acute attacks of migraine. However, ergotamine remains a potentially dangerous substance, its possible side effects being multiple and in some cases very serious. In view of the important adverse effects, the further study of other molecules effective in the treatment of acute migraine attacks is warranted.     

Neurobiology of chronicization

In the past few years, research on chronicization of headache has focussed primarily on migraine, even though there are other types of primary headache that over time can turn into chronic forms. Only a minority of migraine sufferers will develop a chronic condition, with attacks that are likely to vary in their clinical features. As a result, in chronic migraine the specific diagnostic criteria for this headache type do not always exhibit the typical features of migraine. Among the factors that play a major role in favouring chronicization are a high frequency of migraine attacks since the beginning, overuse of symptomatic medication and onset of depression or arterial hypertension. Several neurophysiology, biochemistry and functional neuroimaging studies suggest that chronic migraine may be associated with structural, functional and metabolic changes in the brain, especially involving the brainstem.     

Prevalence and indirect costs of headache in a Brazilian Company

Employees from a Brazilian oil company research centre (n = 993) were interviewed on the occurrence of headache during a 30 days period. Headache prevalence was 49.8%, with a mean frequency of 4.3 +/- 7.0 attacks per month, lasting 12.2 +/- 21.4 hours each. According to the International Headache Society diagnostic criteria, migraine (5.5%), episodic tension-type headache (26.4%), chronic tension-type headache (1.7%) and headaches not fulfilling the criteria for such disorders (16.2%) were observed. Women suffered comparatively more headache and specifically migraine than men. The pain interfered with work productivity in 10% of the subjects, corresponding to 538.75 hours off. According to an indirect costs estimation for each headache, the company may loose up to US$125.98 per employee annually. Since among headaches migraine has the highest indirect cost, migraine prevention and treatment is particularly important at the working environment. Migraine frequency may be prevented to a large extent, resulting on positive effects in both the quality of life and productivity. The cost-benefit ratio clearly favours therapeutic and preventive programs against chronic headaches.     

Prophylactic treatments of migraine

Prophylactic treatment is mainly intended to reduce the frequency of migraine attacks. It is usually proposed to patients who suffer from two or more attacks per month. It should also be considered in patients who suffer from less frequent, but prolonged, disabling attacks with a poor response to abortive treatment, and who consider that their quality of life is reduced between attacks. Excessive intake of acute medication, more than twice a week, is a strong indication for prophylactic treatment. In order to obtain a good compliance to treatment, the patient must be informed of the expected efficacy of the drugs, and of their most frequent side effects. Thus, the choice of a prophylactic drug is made together with the patient. Based on the results of published controlled trials, the main prophylactic drugs are some betablockers, methysergide, pizotifene, oxetorone, flunarizine, amitriptyline, NSAIDs, and sodium valproate. Some less evaluated drugs such as aspirin, DHE, indoramine, verapamil, may be useful. Other substances such as riboflavin and new antiepileptic dugs are being evaluated. The choice of the drug to start with depends on several considerations. The first step is to make sure that there are no contra indications, and no possible interaction with the abortive medications. Then, possible side effects will be taken into account, for example, weight gain is a problem for most young women and patients who practice sports may not tolerate betablockers. Associated pathologies have to be checked. For example, a hypertensive migraine sufferers may benefit from betablockers; in a patient who suffers both from migraine and tension type headaches or from depression, amitriptyline is the first choice drug. The type of migraine should also be considered; for instance, in frequent attacks with aura, aspirin is recommended and betablockers avoided. In most cases, prophylaxis should be given as monotherapy, and it is often necessary to try successively several drugs before finding the most appropriate one. Doses should be increased gradually, in order to reach the recommended daily dose, only if tolerance permits. The treatment efficacy has to be assessed after 2 or 3 months, during which the patient must keep a headache diary. If the drug is judged ineffective, an overuse of symptomatic medications should be checked, as well as a poor compliance, either of which may be responsible. In case of a successful treatment, it should be continued for 6 or 12 months, and then, one should try to taper off the dose in order to stop the treatment or at least to find the minimum active dose. Relaxation, biofeedback, stress coping therapies, acupuncture are also susceptible to be effective in migraine prophylaxis.     

Sumatriptan and ergotamine overuse and drug-induced headache: a clinicoepidemiologic study.

Drug-induced headache, particularly ergotamine-induced headache, is a common problem in migraine treatment. Some case reports suggest that even the new serotonergic antimigraine drugs such as sumatriptan can lead to overuse and subsequent drug-induced headache. We performed a controlled study to identify the rate of sumatriptan overuse and sumatriptan-induced headache and compared it to the rate of ergotamine overuse and ergotamine-induced headache. Two thousand sixty-five consecutive heachache patients, all experienced in intake of sumatriptan (n = 631) or ergotamine (n = 620), were enrolled over a three-year study period. The rates of overuse and drug-induced headache and the clinical features of the subgroups were compared. Risk factors for sumatriptan overuse were identified. The rates of ergotamine and sumatriptan overuse were 14.2% and 3.5%, respectively (p < 0.001). Drug-induced headache could be found more frequently in cases of ergotamine overuse than in cases of sumatriptan overuse (68% versus 32%; p < 0.01). Development of sumatriptan overuse was most common in patients with previous drug-induced headache (68%), combined headache as the primary headache type (45%), and subcutaneous application of sumatriptan (45%). We conclude that sumatriptan intake can lead to overuse and subsequent drug-induced headache. The risk for overuse and drug-induced headache is significantly lower than in patients with ergotamine intake. This might be caused in part by the relatively short period of sumatriptan availability on the market. The new generation of serotonin-1B/D-receptor agonists in the treatment of headache should have a potential for overuse similar to that of traditional headache drugs.     

Analgesic-induced chronic headache: long-term results of withdrawal therapy

Summary Headache characteristics are described in 139 patients with chronic daily or almost daily headaches due to regular intake of analgesics and the short- and long-term results of drug withdrawal. Drug-induced headache was described as dull, diffuse, and band-like, and usually started in the early morning. The mean duration of the original headache (migraine or tension headache) was 25 years; regular intake of drugs and chronic daily headache had started 10 and 6 years prior to withdrawal therapy, respectively. Patients took an average of 34.6 tablets or analgesic suppositories or antimigraine drugs per week containing 5.8 different substances. The drugs most often used were caffeine (95%), ergotalkaloids (89%), barbiturates (64%), and spasmolytics, paracetamol, and pyrazolone derivates (45%–46%). A total of 103 patients (68 migraine, 35 tension or combination headache) were available for interviews at a mean time interval of 2.9 years after an inpatient drug withdrawal programme. Chronic headache had disappeared or was reduced by more than 50% in two-thirds of the patients. Positive predictors for successful treatment were migraine as primary headache, chronic headache lasting less than 10 years, and regular intake of ergotamine. Drug intake was significantly reduced and patients used single substances more often. Patients who originally suffered from migraine, superimposed on the daily headache, also experienced a significant improvement in the frequency of the migraines and their intensity. Migraine prophylaxis through beta-blocking agents and calcium channel antagonists was more efficient after drug-withdrawal therapy.     

Ergot of rye-the first specific for migraine.

Over the past decade the various triptan derivatives have been accepted as the most effective available agents for relieving migraine attacks. Prior to that, for a period of half a century, ergotamine was the only 'specific' available for this purpose. In 1918, Stoll had isolated it from the various alkaloids present in extracts of the sclerotia of the fungus Claviceps purpurea (ergot), which grow on rye and, to a lesser extent, on other grasses. By 1925 ergotamine was beginning to be used to treat migraine attacks. However, as ergotamine was present in extracts of ergot, which had been used to treat migraine first in Italy in 1862, and then by Edward Woakes (1868) in England, and after him by Albert Eulenburg in Germany (1883), the drug had actually come into unrecognised use for the disorder more than half a century before ergotamine itself was known to exist. Unfortunately, because of ergotamine's chemical and pharmacokinetic properties, extracts of ergot of rye were incapable of producing consistent therapeutic results, so that general acceptance that the first specific substance for migraine treatment existed had to wait until pure ergotamine was available for administration.     

Lysine-acetylsalicylic acid in acute migraine attacks

Vasoconstrictive agents have been widely used in the treatment of migraine. These types of drugs have various side effects and are not suitable for many patients. Due to nausea or vomiting, nonoral treatment is often required, but only a few nonvasoconstrictive drugs exist in a parenteral form and are suitable for the treatment of acute migraine in the emergency setting. In a randomized, double-blind, crossover trial we evaluated the efficacy of 1,000 mg lysine-acetylsalicylic acid i.v. (LAS) compared to 0.5 mg ergotamine s.c. in 56 patients (112 attacks) with acute migraine. To gain further insight into the possible role of vasoconstriction, blood flow velocities (BFV) were measured in intra- and extracranial arteries using duplex sonography and transcranial Doppler sonography. Both agents were equally potent in relieving headache. Intravenous LAS resulted in a significantly faster relief and had fewer side effects. LAS had no effect on BFV. Ergotamine increased BFV in the middle cerebral artery only. No correlation was found between changes in BFV and the relief of headache. This is the first trial to compare the intravenous formulation of LAS in the treatment of migraine with another antimigraine medication and suggests that it is an effective and safe drug for the parenteral treatment of acute migraine attacks.     

Evidence-based medicine in migraine prevention

Migraine headache is a chronic, painful, disabling and potentially progressive, condition primarily occurring in early and middle adulthood. For many patients, daily activities are impaired by the sudden and unpredictable occurrence of migraine attacks. In recent years, significant progress has been made in the field of migraine treatment. For the acute treatment of migraine attacks, 5-hydroxytryptophan(1B/D) agonists (so called triptans), were the most innovative development, successfully aborting attacks in less than 1 h. The search for innovative drugs usable for migraine prevention, however, was less successful, mainly due to the lack of reliable and predictive animal models. Recently, neuromodulators such as valproic acid and topiramate, initially developed as anticonvulsants, have been shown in large clinical trials to be effective in the prevention of migraine. As for the acute treatment of migraine attacks more than 10 years ago, large clinical trial programs are now setting new standards for evidence-based medicine in migraine prevention. This review summarizes the current options in migraine prevention with special emphasis on clinical trial design and new developments such as topiramate.     

Cluster headache and chronic paroxysmal hemicrania: current therapy

In acute attacks of cluster headache (CH), the mainstays of treatment are inhalation of pure oxygen (due to lack of any side effects), ergotamine aerosol, and intranasal application of local anaesthetics. The following treatments have hitherto been recommended for the prevention of attacks: young patient with first manifestation-methysergide; middle aged patient with episodic or chronic CH-steroids; older patient with history of resistance to therapy-lithium. These guidelines have been superceded as a result of the demonstration of the efficacy of several other drugs which have reduced side effects. This increased variety of treatments also reduces the importance of clinical differentiation between episodic and chronic cluster headache. Today, the drugs of first choice for treatment of episodic cluster headache are steroids or calcium channel blockers like verapamil, replacing methysergide which is now drug of second choice. In chronic CH, verapamil and lithium are normally prescribed, steroids-possibly in combination with one of the other drugs-are regarded as drugs of second choice. Another possibility, used with increasing frequency, is valproate acid, and the experimental drug budipine may be a further alternative in therapy resistant patients. There is no convincing role for invasive surgical procedures, particularly in the light of the increased number of effective drugs. The treatment of choice for chronic paroxysmal hemicrania is indometacin, although individual patients may respond to salicylates, naproxene, prednisone and ergotamine.     

Neuroimaging features of whole‐brain functional connectivity predict attack frequency of migraine

Migraine is a chronic neurological disorder characterized by attacks of moderate or severe headache accompanying functionally and structurally maladaptive changes in brain. As the headache days/month is often measured by patient self‐report and tends to be overestimated than actually experienced, the possibility of using neuroimaging data to predict migraine attack frequency is of great interest. To identify neuroimaging features that could objectively evaluate patients' headache days, a total of 179 migraineurs were recruited from two data center with one dataset used as the training/test cohort and the other used as the validating cohort. The guidelines for controlled trials of prophylactic treatment of chronic migraine in adults were used to identify the frequency of attacks and migraineurs were divided into low (MOl) and high (MOh) subgroups. Whole‐brain functional connectivity was used to build multivariate logistic regression models with model iteration optimization to identify MOl and MOh. The best model accurately discriminated MOh from MOl with AUC of 0.91 (95%CI [0.86, 0.95]) in the training/test cohort and 0.79 in the validating cohort. The discriminative features were mainly located within the limbic lobe, frontal lobe, and temporal lobe. Permutation tests analysis demonstrated that the classification performance of these features was significantly better than chance. Furthermore, the indicator of functional connectivity had a higher odds ratio than behavioral variables with implementing a holistic regression analysis. The current findings suggested that the migraine attack frequency could be distinguished by using machine‐learning algorithms, and highlighted the role of brain functional connectivity in revealing underlying migraine‐related neurobiology.