When should triptans be taken during a migraine attack?

The common strategy to treat a migraine attack as soon as it begins, made for classical acute antimigraine treatments such as ergotamine and analgesics, has not been transposed to the triptans. The recommendation to delay triptan intake until headache intensity is at least moderate is merely a habit generated by the protocol used in triptan trials and a nonvalidated attempt to reduce costs. It is also favoured by the few studies suggesting that sumatriptan is less effective when given early in an attack, especially during the aura phase. Recent retrospective analyses of small numbers of 'protocol violators' in controlled trials of sumatriptan suggest that the drug is more efficient when taken while the headache is mild. Pain-free responses and therapeutic gains over aspirin (acetylsalicylic acid)-metoclopramide or ergotamine-caffeine combinations were increased under these conditions. The available circumstantial evidence is reviewed and discussed. Before any conclusion can be drawn and recommendation made, results are awaited from randomised controlled trials specifically addressing whether or not triptans are more efficient in mild headache. Meanwhile, there seems to be no medical reason to withhold treatment of a mild headache with a triptan as long as triptan intake does not exceed 1 or 2 doses per week. Most mild headaches in patients with migraine appear indeed to be mild migraine attacks, even when the headache characteristics are those of tension-type headache.     

Advances in pharmacological treatment of 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 non-steroidal anti-inflammatory 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 with serotonin (5-HT_1B/D) agonists (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 show only 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 three 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 anti-epileptic drugs (valproic acid, gabapentin, topiramate) were evaluated for the prophylaxis of migraine. The use of botulinum toxin is under investigation.     

Headache due to antimigraine 5HT1 receptor agonists

(1) Like other analgesics and antimigraine drugs, the 5HT1 receptor agonists, or triptans, can cause a self-sustaining headache syndrome. (2) Headache due to 5HT1 receptor agonists should be suspected when a patient presents with an increased frequency of migraine or non migraine headache associated with daily intake of such drugs. Withdrawal usually leads to the disappearance of those headaches that are due to the drug, or at least a reduction in their frequency.     

Medication overuse headache: a focus on analgesics, ergot alkaloids and triptans.

Medication overuse headache (MOH, formerly known as drug-induced headache) is a well known disorder following the frequent use of analgesics or any other antiheadache drug including serotonin 5-HT(1B/D) agonists (triptans). Recent studies suggest clinical features of MOH depend on the substance class that has been overused. The delay between the frequent intake of any antiheadache drug and daily headache is shortest for triptans (mean 1.7 years), longer for ergot alkaloids (mean 2.7 years) and longest for analgesics (mean 4.9 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate within 6 months after successful withdrawal is about 30% and increases steadily up to 50% after 5 years.     

Part I: what do patients really need and want from migraine treatment?

Migraine is characterised by recurrent episodes of head pain, often accompanied by other symptoms, such as nausea and vomiting. In addition to migraine impairing a patient's ability to function normally during an attack, fear of the next attack can detract from quality of life between attacks. Of those migraineurs who consult a physician for headache, the minority are prescribed migraine-specific triptans and many are dissatisfied with current therapy. Clinical trials have shown that triptans are capable of providing rapid and effective relief of headache pain, which is what patients primarily desire from acute migraine therapies. Patients generally prefer to administer acute migraine therapies orally, but conventional tablets do not suit all patients and situations. Some patients dislike swallowing tablets, nausea can make swallowing difficult and can be exacerbated by fluid intake, and attacks can easily strike when fluids are not readily available, especially as many young migraineurs lead busy, active lives. Patients need a treatment that enables any migraine attack to be treated promptly and effectively in any given situation. Tablets that dissolve rapidly on the tongue without a requirement for extra fluid intake are a popular alternative to conventional tablets, allowing discreet, convenient and early treatment of migraine anywhere and anytime it strikes. Several triptans are currently on the market in conventional tablet form, but some are available in other formulations, such as orally disintegrating tablets or nasal sprays, making it possible to prescribe rapidly effective migraine treatments in formulations that suit individual patient preferences, lifestyles and attack characteristics.     

Frovatriptan review

Frovatriptan belongs to the triptan compounds used for the acute treatment of migraine. Its affinity for the migraine-specific serotonin 5HT1B-receptors is highest in the class. Its long half-life in plasma (26 h) and metabolism by multiple pathways are unique characteristics among the triptans. These features can translate into long duration of action and low risk of interactions with other drugs. Frovatriptan has been effective and well tolerated over a wide range of doses in randomised, double-blind, placebo-controlled acute migraine trials and long-term, open-label trials. The 2.5-mg dose is recommended for both efficacy and a favourable side effect profile for acute migraine treatment. Frovatriptan has the lowest headache recurrence rate of all the triptans. Frovatriptan was better tolerated than sumatriptan in a head-to-head comparison study. Frovatriptan could make its mark especially in slowly progressing migraine attacks and in attacks that are highly predictable. For example, for the short-term prophylaxis of menstrual migraine, frovatriptan is the triptan of first choice.     

Frovatriptan review

Frovatriptan belongs to the triptan compounds used for the acute treatment of migraine. Its affinity for the migraine-specific serotonin 5HT_1B-receptors is highest in the class. Its long half-life in plasma (26 h) and metabolism by multiple pathways are unique characteristics among the triptans. These features can translate into long duration of action and low risk of interactions with other drugs. Frovatriptan has been effective and well tolerated over a wide range of doses in randomised, double-blind, placebo-controlled acute migraine trials and long-term, open-label trials. The 2.5-mg dose is recommended for both efficacy and a favourable side effect profile for acute migraine treatment. Frovatriptan has the lowest headache recurrence rate of all the triptans. Frovatriptan was better tolerated than sumatriptan in a head-to-head comparison study. Frovatriptan could make its mark especially in slowly progressing migraine attacks and in attacks that are highly predictable. For example, for the short-term prophylaxis of menstrual migraine, frovatriptan is the triptan of first choice.     

Menstrual migraine: a review of hormonal causes, prophylaxis and treatment

Migraine in some women is associated with changes in sex hormone levels. Many women suffer from increased frequency of migraine around the time of menses. Menstrual migraine (MM) may be more severe than migraine that occurs at other times of the cycle. The pathogenesis of MM is probably related to declining estrogen levels after exposure to high levels of the hormone for several days. The acute treatment of MM is similar to that of non-menstrually-related attacks. 5-HT(1B/1D) agonists (triptans), ergots, NSAIDs, or combination analgesics may be used, although the response to some drugs may not be as robust as that of non-menstrual attacks. Women who suffer from frequent or debilitating MM attacks may benefit from perimenstrual prophylaxis that can be either hormonal or non-hormonal.     

Menstrual migraine: a review of hormonal causes,prophylaxis and treatment

Migraine in some women is associated with changes in sex hormone levels. Many women suffer from increased frequency of migraine around the time of menses. Menstrual migraine (MM) may be more severe than migraine that occurs at other times of the cycle. The pathogenesis of MM is probably related to declining estrogen levels after exposure to high levels of the hormone for several days. The acute treatment of MM is similar to that of non-menstrually-related attacks. 5-HT_1B/1D agonists (triptans), ergots, NSAIDs, or combination analgesics may be used, although the response to some drugs may not be as robust as that of non-menstrual attacks. Women who suffer from frequent or debilitating MM attacks may benefit from perimenstrual prophylaxis that can be either hormonal or non-hormonal.     

The use of triptans in the management of menstrual migraine

Many women experience headaches, including migraine, in association with their menstrual cycles. Although definitions vary, menstrual migraine generally refers to migraine without aura that occurs within several days prior to and several days after the onset of menses.Although menstrual migraine has been reported to be more difficult to treat than other types of migraines, there is no evidence from controlled clinical trials to support this assertion. Thus, the pharmacological treatment of menstrual migraine should be similar to that of other types of migraines, except with respect to the use of hormonal manipulations to treat menstrual migraine.Serotonin 5-HT(1B/1D) receptor agonists (triptans) are effective for the acute treatment of both menstrual and non-menstrual migraines. When used as acute therapy, a triptan should be administered early, when the headache is still mild in severity. Ideally, an acute therapy will provide rapid and complete pain relief with no disability. Some patients may require preventive therapy for menstrual migraine based on suboptimal response to an adequate trial of acute therapy. Patient diaries that record headache onset, relationship to the menstrual cycle and treatment response through three complete cycles will allow accurate prediction of the onset of menstrual migraine; this information is also needed to make decisions about timing of intermittent preventive therapy. The goals of intermittent preventive therapy are to reduce the frequency, duration and intensity of menstrual migraine attacks.Clinical studies show that triptans are effective when used as either acute therapy or as intermittent preventive therapy for menstrual migraine. Sumatriptan and zolmitriptan have been evaluated in prospective, randomised, controlled trials for acute treatment. Retrospective analyses and open-label studies also support the use of other triptans as acute therapy. In addition, sumatriptan, frovatriptan, naratriptan and zolmitriptan have been evaluated as intermittent preventive therapy in prospective studies. Thus, data from clinical studies indicate that triptans are effective for the treatment of menstrual migraine.     

Acute treatment of migraines

Migraine is a prevalent and disabling brain disorder that costs billions of dollars annually in direct healthcare costs, and school and work absenteeism and presenteeism. The objective of acute treatment is a cost-effective, rapid restoration of functional ability, with minimal recurrence and adverse effects. The acute treatment of migraine includes specific drugs, which currently all have vasoconstrictive effects (dihydroergotamine and triptans), and nonspecific drugs that include paracetamol (acetaminophen), combination analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), dopamine antagonists, narcotics and corticosteroids. NSAIDs have both peripheral and central effects on reversing migraine, and so may represent the best alternative for patients who cannot use triptans and ergots due to vascular contraindications. Narcotics and habituating medications should be avoided in the acute treatment of migraine, as the risk for transformation to chronic daily headache is excessively high at a relatively infrequent rate of exposure.     

Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines

INTRODUCTION: Migraine is a multifactorial neurovascular disorder characterized by recurrent episodes of disabling pain attacks, accompanied with gastrointestinal, neurological systems dysfunction. The pharmacologic treatment of migraine is classically divided in the management of the acute attack and preventive strategies. Acute treatments consist of triptan, ergot, opioid, antiemetic and NSAIDs. AREAS COVERED: This article discusses pharmacodynamics and pharmacokinetics of zolmitriptan . The data were obtained by searching the following keywords in MEDLINE: zolmitriptan, pharmacokinetics, pharmacodynamics, triptans, migraine, menstrual-related migraine, cluster headache, relatively to the period 1989 - 2012. EXPERT OPINION: Zolmitriptan has been considered effective treatment in the acute phase of migraine, menstrual-related migraine and cluster headache attacks. Pharmacokinetic parameters may vary as a consequence of gender differences, inter- and intra-subjects variability and delivery system. Zolmitriptan was developed with the aim of obtaining a lipophilic compound in order to be more rapidly absorbed and centrally active. Pharmacologically, pharmacokinetic parameters are responsible for its wide efficacy and the limited adverse effect profile.     

Olcegepant, a non-peptide CGRP1 antagonist for migraine treatment

Olcegepant is the first potent and selective non-peptide antagonist of the calcitonin gene-related peptide 1 (CGRP1) receptor, a key modulator in neurogenic inflammatory pain. Under development by Boehringer Ingelheim GmbH, olcegepant is an intravenously formulated treatment for acute attacks of migraine. In preclinical studies, olcegepant attenuated arterial dilation induced by CGRP or electrical stimulation. In a phase II clinical trial, olcegepant reduced the severity of headache in 60% of migraine sufferers and met secondary endpoints including headache-free rate and rate of sustained response. Only mild-to-moderate transient adverse events were observed, with no adverse cardiovascular symptoms reported. The compound appears to be an effective anti-migraine medication that is well tolerated and does not display the vasoconstrictive effect that precludes the use of triptans and dihydroergotamine in certain patients. For a successful marketing of olcegepant, larger clinical trials and the development of an effective oral formulation will be necessary.     

Efficacy and tolerability of zolmitriptan oral tablet in the acute treatment of menstrual migraine

OBJECTIVE: To determine the efficacy and tolerability of zolmitriptan 2.5 mg oral tablet as an acute treatment for menstrual migraine attacks. METHODS: This was a two-phase, multicentre, randomised, double-blind, placebo-controlled, parallel-group outpatient study (Phase I is reported here). The study was conducted at 27 sites in the USA. Eligible women were randomised (1 : 1) to receive either zolmitriptan 2.5 mg oral tablet or placebo, and instructed to acutely treat up to two menstrual migraine attacks per menstrual period for up to three menstrual cycles with a single dose of study medication. Menstrual migraine was operationally defined as an attack occurring within the time period of 2 days prior to the expected onset of menses to 5 days after the onset of menses. Participants were asked to treat migraine headaches of moderate or severe intensity only that occurred >24 hours after the end of the last migraine attack and that had not been acutely treated with other medications. Information regarding each migraine attack was recorded by patients in treatment diary cards. The primary efficacy variable was 2-hour headache response (defined as a 2-point drop on a 4-point scale) for all attacks treated. Secondary variables included 1- and 4-hour headache response rate; 1-, 2- and 4-hour headache response based on a 100 mm visual analogue scale (VAS); pain-free rate at 1, 2 and 4 hours; use of escape medication; the proportion of patients with recurrence within 24 hours of initial treatment; and tolerability. RESULTS: The intention-to-treat population comprised 334 patients (zolmitriptan [n = 174]; placebo [n = 160]). Patients treated 625 attacks with zolmitriptan and 529 attacks with placebo. Twice as many patients who took zolmitriptan achieved a 2-hour headache response compared with placebo recipients (65.7% vs 32.8%; p < 0.0001). Furthermore, a significantly higher headache response was observed with zolmitriptan than placebo at all timepoints assessed. Significantly more zolmitriptan recipients were pain-free 2 hours post-dose compared with placebo recipients (p < 0.0001). The use of escape medication was considerably lower in zolmitriptan recipients (42.6% vs 71.3%; p < 0.0001). Based on the reduction in VAS score of > or = 30 mm from baseline, significantly more zolmitriptan recipients achieved headache response compared with placebo recipients at 1, 2 and 4 hours post-dose (all p < 0.0001). Recurrence was reported in 29.1% of zolmitriptan-treated attacks versus 45.1% of placebo-treated attacks (p = 0.0009), with median time to recurrence of 8.5 and 4.0 hours, respectively. Zolmitriptan was well tolerated. CONCLUSION: Oral zolmitriptan is effective and well tolerated for the acute treatment of menstrual migraine attacks. The results are similar to those seen with zolmitriptan in studies of the general migraine population.     

Novel migraine therapy with calcitonin gene-regulated peptide receptor antagonists

Primary headaches, for example, migraine and cluster headaches represent the most prevalent neurological disorders, affecting up to 15-20% of the adult population. There is a clear association between head pain and the release of calcitonin gene-related peptide (CGRP). In this review the role of CGRP in human cranial circulation is described and the role for specific CGRP antagonism elucidated. It is well known that triptans (5-HT(1B/1D) agonist) alleviate headache in part through normalisation of CGRP levels. The central role of CGRP in migraine pathophysiology has resulted in the development of small-molecule CGRP antagonists with no cardiovascular side effects. Such compounds have high selectivity for human CGRP receptors and are efficacious in the relief of acute migraine attacks. Research indicates that they effect the abluminal side of the blood-brain barrier and that they are not vasoconstrictive, providing a new dimension in therapy.     

New therapeutic target in primary headaches - blocking theCGRP receptor

The primary headaches are among the most prevalent neurological disorders, afflicting up to 16% of the adult population. The associated pain originates from intracranial blood vessels that are innervated by sensory nerves storing several neurotransmitters. In primary headaches, there is a clear association between the headache and the release of calcitonin gene-related peptide (CGRP), but not other neuronal messengers. The specific purpose of this review is to describe CGRP in the human cranial circulation and to elucidate a possible role for a specific antagonist in the treatment of primary headaches. Acute treatment with administration of a 5-HT(1B/1D) agonist (triptan) results in alleviation of the headache and normalisation of the CGRP level. The mechanism of action of triptans involves vasoconstriction of intracranial vessels and a presynaptic inhibitory effect of sensory nerves. The central role of CGRP in migraine and cluster headache pathophysiology has led to the search for small-molecule CGRP antagonists, which are predicted to have fewer cardiovascular side effects in comparison to the triptans. The initial pharmacological profile of such a group of compounds has recently been disclosed. These compounds have high selectivity for human CGRP receptors and are reportedly efficacious in the relief of acute attacks of migraine.     

Medication overuse headaches – what is new?

Patients suffering from frequent migraine attacks or chronic tension-type headache are at risk of developing drug-induced headache (now called ‘medication overuse headache’ [MOH]) as described by the new classification of the International Headache Society. This headache entity is caused by frequent use of antiheadache compounds (non-opioid analgesics, ergot alkaloids, 5-HT agonists, combined preparations with caffeine or codeine) for more than 15 days/month. Most patients, however, use the medication daily. The standard therapy of MOH is withdrawal therapy (mostly under in-patient conditions) followed by prophylactic treatment of the primary headache. The relapse rate reaches up to 40% within 1 year after a previously successful withdrawal therapy. The pathophysiology of MOH remains to be determined and, consequently, therapy has been driven by experience rather than by scientific hypotheses. The identification of predictors for both medication overuse and relapse after successful withdrawal should improve prevention and therapy in the future. Several medical (e.g., class of overused drugs) and psychological (e.g., standard of performance) predictors were recently identified. Medication overuse in headache patients is based on multiple factors with physical, social and psychological impact. In view of the high prevalence and relapse rate, it is necessary to establish a structured post-treatment programme for patients after the acute withdrawal phase, which considers the predictors for relapse.     

Taking the negative view of current migraine treatments: the unmet needs

Acute migraine treatment is given to abolish ongoing attacks, while prophylactic migraine treatment is given on a daily basis to prevent the occurrence of migraine attacks as far as possible. The majority of migraine patients do not use the specific acute anti-migraine drugs, the triptans. Thus, only 10% (Denmark) to 35% (France) of migraine patients use triptans. This is most likely due to relatively low efficacy. Thus, in randomized controlled trials (RCTs) pain freedom after 2 hours ranges from 12% (frovatriptan 2.5?mg) to 40% (rizatriptan 10?mg). For prophylactic treatment (propranolol, valproate, topiramate) a response (at least a 50% reduction in migraine frequency) is observed in 40-50%. In addition, prophylactic treatment is hampered by adverse events and withdrawals. There is a need for new acute anti-migraine drugs and targets are already available and there are more to come. It has been estimated that approximately 2% of the adult population need prophylactic treatment because of frequent migraine attacks. For prophylactic migraine drugs there is an even greater need for new drugs than for acute drug treatment.