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PubMed1998

A practical guide to the management and prevention of migraine.

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. Mild migraine attacks are treated with antiemetics followed by analgesics such as aspirin (acetylsalicylic acid), paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are treated by antiemetics combined with ergotamine or dihydroergotamine. Sumatriptan, a specific serotonin 5-HT1B/D receptor agonist, is used if attacks do not respond to ergotamine or if intolerable adverse effects occur. The new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profile from sumatriptan, but this translates into only minor differences in efficacy, headache recurrence and adverse effects. Migraine prophylaxis should be implemented when more than 3 attacks occur per month, if attacks do not respond to acute treatment or if the adverse effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine. Drugs less effective or those with unpleasant adverse effects are the serotonin receptor antagonists (pizotifen, methysergide and lisuride), dihydroergotamine, cyclandelate, NSAIDs, valproic acid (sodium valproate) and amitriptyline. The efficacy of aspirin or magnesium is still under evaluation.

Analgesics↗

PubMed2002

Rizatriptan: an update of its use in the management of migraine.

UNLABELLED: Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2 to 4%). CONCLUSION: Rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest rizatriptan should be considered as a first-line treatment option in the management of migraine.

Administration, Oral↗

PubMed2001

Clinically significant drug interactions with agents specific for migraine attacks.

The drugs which provide specific relief from migraine attacks, the ergopeptides (ergotamine and dihydroergotamine) and the various 'triptans' (notably sumatriptan), are often prescribed for persons already taking various migraine preventative agents, and sometimes drugs for other indications. As a result, migraine-specific drugs may become involved in drug-drug interactions. The migraine-specific drugs all act as agonists at certain subclasses of serotonin (5-hydroxytryptamine; 5-HT) receptor, particularly those of the 5-HT1D subtype, and produce vasoconstriction through these receptor-mediated mechanisms. The oral bioavailabilities of these drugs, particularly those of the ergopeptides, are often incomplete, due to extensive presystemic metabolism. As a result, if migraine-specific agents are coadministered with drugs with vasoconstrictive properties, or with drugs which inhibit the metabolism of the migraine-specific agents, there is a risk of interactions occurring which produce manifestations of excessive vasoconstriction. This can also occur through pharmacodynamic mechanisms, as when ergopeptides or triptans are coadministered with methysergide or propranolol (although a pharmacokinetic element may apply in relation to the latter interaction), or if one migraine-specific agent is used shortly after another. When ergopeptide metabolism is inhibited by the presence of macrolide antibacterials, particularly troleandomycin and erythromycin, the resultant interaction can produce ergotism, sometimes leading to gangrene. Similar pharmacokinetic mechanisms, with their vasoconstrictive consequences, probably apply to combination of the ergopeptides with HIV protease inhibitors (indinavir and ritonavir), heparin, cyclosporin or tacrolimus. Inhibition of triptan metabolism by monoamine oxidase A inhibitors, e.g. moclobemide, may raise circulating triptan concentrations, although this does not yet seem to have led to reported clinical problems. Caffeine may cause increased plasma ergotamine concentrations through an as yet inadequately defined pharmacokinetic interaction. However, a direct antimigraine effect of caffeine may contribute to the claimed increased efficacy of ergotamine-caffeine combinations in relieving migraine attacks. Serotonin syndromes have been reported as probable pharmacodynamic consequences of the use of ergots or triptans in persons taking serotonin reuptake inhibitors. There have been two reports of involuntary movement disorders when sumatriptan has been used by patients already taking loxapine. Nearly all the clinically important interactions between the ergopeptide antimigraine agents and currently marketed drugs are likely to have already come to notice. In contrast, new interactions involving the triptans are likely to be recognised as additional members of this family of drugs, with their different patterns of metabolism and pharmacokinetics, are marketed.

Drug Interactions↗

PubMed2002

Spotlight on rizatriptan in migraine.

Rizatriptan is an orally active serotonin 5-HT(1) receptor agonist that potently and selectively binds to 5-HT(1B/1D) subtypes. Earlier clinical trials demonstrated that rizatriptan 5 or 10mg is more effective than placebo at providing pain relief and a pain-free state, relieving associated symptoms of migraine, normalising functional ability and improving patient quality of life, and showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recently, rizatriptan 10mg was shown to be more effective than zolmitriptan 2.5mg or naratriptan 2.5mg at producing a pain-free state 2 hours postdose. Furthermore, compared with naratriptan, significantly more patients who received rizatriptan were pain free or had pain relief from 1 hour onwards. The number of patients with normal functional ability at 2 hours was significantly higher after rizatriptan than after naratriptan or zolmitriptan. Rizatriptan was also generally more effective than zolmitriptan or naratriptan at relieving migraine-associated symptoms. Rizatriptan is generally well tolerated, and adverse events are usually mild and transient. The most common adverse events associated with rizatriptan in recent randomised trials were asthenia/fatigue, dizziness, somnolence and nausea. There was a trend towards a lower incidence of adverse events with rizatriptan compared with zolmitriptan (31.2 vs 38.8%). However, rizatriptan was associated with a significantly higher incidence of adverse events than naratriptan (39 vs 29%). The incidence of chest pain was similar after the administration of rizatriptan, zolmitriptan or naratriptan (2-4%). In conclusion, rizatriptan is an effective drug for the acute treatment of moderate or severe migraine. Oral rizatriptan 5 and 10mg have shown greater efficacy than placebo in providing pain relief, an absence of pain, relief from associated symptoms, normal functional ability and an improvement in patient quality of life. Earlier results showed that rizatriptan provides faster freedom from pain and reduces nausea to a greater extent than oral sumatriptan. More recent studies have shown that rizatriptan 10mg provides faster pain relief and a higher percentage of patients with an absence of pain and normal functional ability at 2 hours than naratriptan 2.5mg or zolmitriptan 2.5mg. The efficacy of rizatriptan is retained when used in the long term, and the drug is generally well tolerated. Although well designed studies comparing rizatriptan with almotriptan, eletriptan and frovatriptan would further define the position of rizatriptan, current data suggest that rizatriptan should be considered as a first-line treatment option in the management of migraine.

Animals↗

PubMed2005

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.

Clinical Trials as Topic↗

PubMed2006

Migraine in children and adolescents: a guide to drug treatment.

Migraine is a common disorder in children and adolescents, with a prevalence of 5 and 10%, respectively. Some patients may have recognisable factors that trigger or aggravate migraine attacks, such as flickering or bright lights, strong smells and noise, and where possible these should be avoided. It is also wise to maintain a lifestyle where children receive regular meals and get sufficient sleep. If used, acute pharmacological treatment should be given at the onset of an attack, followed by a rest or sleep. According to recent literature, paracetamol (acetaminophen) and ibuprofen can be recommended for the acute treatment of migraine attacks in children and adolescents, and sumatriptan nasal spray can be recommended for adolescents. The oral formulation of sumatriptan has not shown efficacy in paediatric patients, and the subcutaneous injection, although somewhat effective, is not an ideal formulation for this patient group. There are too few data on the efficacy of the other 'triptans' to recommend their use in children and adolescents. There are less data on the use of prophylactic drugs in paediatric patients. In systematic studies, only flunarizine, which is not available in many countries, and propranolol have been found to be effective. A pilot placebo-controlled study suggests that topiramate might also be effective. Several other agents are commonly used to prevent migraine attacks in children (e.g. amitriptyline, valproic acid [sodium valproate]) despite a lack of robust research into their efficacy.

Adolescent↗

PubMed2007

Use of the sustained pain-free plus no adverse events endpoint in clinical trials of triptans in acute migraine.

OBJECTIVE: To assess the relationship between the sustained pain free (SPF) and adverse event (AE) rates associated with six oral serotonin 5-HT(1B/1D) receptor agonists (triptans) used for the treatment of acute migraine, employing data from a previous meta-analysis (that included almotriptan, eletriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan, but not frovatriptan) in order to provide a rationale for the use of the rate of patients who are SPF plus no AE (SNAE) as an endpoint in trials of medications for acute migraine. BACKGROUND: The attributes of drug treatment for acute migraine that are most important to people who experience them are complete pain relief, lack of recurrence, rapid onset and lack of AEs. The endpoints used to assess therapy for acute migraine do not always address these elements. METHODS: The relationship between SPF and AE rates was explored using nonparametric regression techniques, and the box-plot method was used to identify outliers. The estimated SNAE rate for each triptan was calculated with and without assuming independence between efficacy and tolerability. RESULTS: At the level of the individual agent, there was a significant relationship between the efficacy and tolerability of each triptan, with the exception of almotriptan 12.5 mg, which had an AE rate approximately 30% lower than would be expected, and eletriptan 20 mg, which had an AE rate approximately 20% higher than would be expected, on the basis of their efficacy. Almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest base-case values for SNAE, respectively, and both qualified statistically as outliers to the distribution of SNAE values obtained with the other triptans. The probability that each triptan was superior to the reference agent (sumatriptan 100 mg) in terms of SNAE was calculated across all possible values (at the level of the individual patient) for the relationship between efficacy and tolerability. Again, almotriptan 12.5 mg and eletriptan 20 mg had the highest and lowest values for their SNAE rates, respectively, and almotriptan 12.5 mg qualified statistically as an outlier from the distribution of the probabilities obtained for the other triptans. CONCLUSION: This analysis determined that higher SPF rates were strongly associated with higher AE rates, with the notable exception of almotriptan 12.5 mg, which had a lower than expected AE rate, resulting in the highest SNAE rate of the included triptans and doses. SNAE is a useful measure that can be used to discriminate between therapies and this endpoint incorporates the attributes that are most relevant to patient satisfaction with treatment. We recommend calculation of the SNAE rate at the level of the individual patient in future clinical trials of medication for the treatment of acute migraine to facilitate selection of a treatment for acute migraine that offers the best chance for effective management.

Acute Disease↗

PubMed1997

Autoradiographic localization of 5-HT1E and 5-HT1F binding sites in rat brain: effect of serotonergic lesioning.

5-carboxamidotryptamine (5-CT)-insensitive binding sites labelled by [3H]5-hydroxytryptamine (5-HT) in the presence of 100 nM 5-CT and 100 nM mesulergine, were examined by semi-quantitative autoradiography in rat brain. Under these conditions most of the labelled sites correspond to 5-HT1E and 5-HT1F sites. The 5-CT-insensitive binding is located mainly in cortical layer V, caudate-putamen, interpeduncular nucleus and claustrum. In cortex and caudate-putamen, a large proportion of 5-CT-insensitive sites is displaced by 250 nM sumatriptan and can be attributed to the presence of 5-HT1F receptors. A low, but significant, level of displacement by sumatriptan was observed in the choroid plexus. Lesions of serotonergic neurones by intracerebroventricular 5,7-dihydroxytryptamine injection does not significantly modify the densities of 5-HT1E or 5-HT1F binding sites. Our findings suggest that the 5-HT1F receptor has a limited distribution in rat brain, mainly located on non-serotonergic neurones.

Animals↗

PubMedDate not supplied

Comparative tolerability of oral 5-HT1B/1D agonists.

OBJECTIVES: To compare the relative tolerability of 5-HT1B/1D agonists and to investigate the relationships (if any) among systemic exposure, lipophilicity, and clinical tolerability for 5-HT1B/1D agonists. METHODS: Post hoc correlations were sought among the following variables: absolute dose (= administered dose x oral bioavailability), Cmax, LogDpH7.4 (LogD), frequencies of all, neurological and dizziness/somnolence/drowsiness adverse events, adjusted for corresponding placebo-associated frequencies. RESULTS: For effective doses of all drugs with available data, absolute dose-response relationships exist for adverse event frequencies. The overall rank order of the frequency of adverse events was as follows: naratriptan < sumatriptan = rizatriptan < zolmitriptan. With the exception of eletriptan, 5-HT1B/1D agonists exhibit correlations between absolute dose, Cmax (R = 0.97), and LogD (R = 0. 71). For neurological and dizziness/somnolence/drowsiness adverse event frequencies, the overall rank order was sumatriptan < naratriptan < rizatriptan < zolmitriptan. Neither LogD nor absolute dose size predicted adverse event frequencies. CONCLUSIONS: Triptans may be distinguished in terms of their tolerability. Effectiveness, absolute dose size, and lipophilicity are related for the 5-HT1B/1D agonists considered here, except eletriptan. Adverse event frequencies cannot be predicted from in vitro measures of lipophilicity, in vivo estimates of absolute bioavailability, dose size, or any combination of these variables. Since these drugs are all agonists at 5-HT1B/1D receptors in the low nanomolar range, but differ in their tolerability profiles, adverse effects are not likely to be mediated through 5-HT1B/1D receptors. Drugs of this class must be studied individually and on a reasonably large scale in clinical development programs.

Administration, Oral↗

PubMedDate not supplied

[Cost effectiveness of treatment with triptanes in Spain].

INTRODUCTION: Migraine is a very common disorder and frequent cause of consultation of the neurologist. The triptanes have been a great advance in the treatment of migraine attacks. At present it is the treatment of choice in severe attacks of migraine, but it is more expensive than the other drugs used for this. Taking into account the greater efficacy and the saving in direct and indirect costs which may be due to treatment with triptanes, its use may not only be effective but also efficient. OBJECTIVE: To analyze the cost effectiveness of the triptanes sold in Spain (sumatriptan, naratriptan, zolmitriptan, rizatriptan, almotriptan). MATERIAL AND METHODS: We analyzed the efficacy, therapeutic gain and number of different triptanes needed for treatment. We evaluated the cost of multiplying the result of the number needing treatment by the price of each unit of the drug. The results are expressed in pesetas and in euros. RESULTS: Rizatriptan gave the best results and was the cheapest triptan, followed by sumatriptan and zolmitriptan. When criteria of efficacy were used, naratriptan was the most expensive triptan, in spite of being the cheapest per unit. CONCLUSIONS: In chronic, recurrent disorders such as migraine, when the cost of treatment using triptans is assessed, one has not only to evaluate the cost per unit but also to introduce other parameters such as the efficacy of the drug, which is one of the most important.

Cost-Benefit Analysis↗

PubMed2002

Almotriptan: a review of pharmacology, clinical efficacy, and tolerability.

OBJECTIVE: This article summarizes preclinical and clinical data for almotriptan. METHODS: Almotriptan has been evaluated in more than 3,500 acute migraine patients in phase 2 and 3 double-blind, randomized trials and in 1,500 patients in long-term open-label trials. RESULTS: Controlled clinical trials show that almotriptan 12.5 mg is significantly more effective than placebo. These results are observed across different endpoints examined, including pain relief at 2 hours, pain-free outcome at 2 hours, recurrence rate, use of escape medication, and sustained pain-free outcome. The onset of pain relief is observed as early as 30 minutes after administration. Results from a multiple-attack study show that almotriptan maintains a consistency of response across 3 attacks, and results from long-term studies confirm that patients continue to respond to almotriptan for up to 1 year. Results from 2 comparative studies show that almotriptan 12.5 mg has comparable efficacy to sumatriptan 50 or 100 mg, but almotriptan has a superior tolerability profile. Early use of almotriptan results in a higher proportion of patients achieving pain relief or complete freedom from pain. CONCLUSIONS: Because almotriptan has a tolerability profile comparable to that of placebo, it may be more acceptable for early administration. The incidence of treatment-related adverse events with almotriptan is comparable to that of placebo and significantly lower than recorded with sumatriptan. In addition, almotriptan has a low incidence of chest symptoms, an adverse event associated with triptan use. Because of its comparable efficacy and superior tolerability profile, almotriptan offers a potential improvement over existing triptans for the treatment of acute migraine.

Clinical Trials, Phase II as Topic↗

PubMed1992

Characterization of the contractile serotonergic receptor in guinea pig trachea with agonists and antagonists.

5-Hydroxytryptamine (5-HT)2 receptors can be partially characterized by their sensitivity to ketanserin blockade and increase in phosphoinositide turnover upon stimulation. Previously, the contraction of guinea pig trachea to 5-HT was shown to be antagonized by the 5-HT2 receptor antagonists ketanserin and LY53857. However, 5-HT did not dramatically increase phosphoinositide turnover in guinea pig trachea, suggesting that the contractile receptor may be different from the classically defined 5-HT2 receptor. The present in vitro studies better characterize this receptor, using diverse serotonergic agonists and antagonists to profile in more detail the contractile serotonergic receptor in guinea pig trachea. With regard to agonists, the 5-HT2 receptor agonists DOI and alpha-methyl-5-HT contracted guinea pig trachea with greater potency than quipazine, 5-methoxytryptamine, 5-carboxamidotryptamine, 8-hydroxy-2-(di-N-propylamino)tetralin and 2-methyl-5-HT. Sumatriptan and 1-(3-chlorophenyl)-piperazine (10 nM-100 microM) were inactive as agonists. A strong correlation between agonist potency (EC50) and reported 5-HT receptor binding affinities was found for both the 5-HT1C (r = 0.890) and 5-HT2 (r = 0.831) receptor. Ketanserin, spiperone, ritanserin, LY53857, 1-napthylpiperazine, 1-(3-chlorophenyl)-piperazine, rauwolscine, ICS 205-930, cyanopindolol and sumatriptan all blocked 5-HT-induced contractions in guinea pig trachea. As occurred with agonist potencies, strong correlations were found between reported 5-HT1C (r = 0.814) and 5-HT2 (r = 0.912) receptor binding affinities in brain membranes and apparent dissociation constants (KB) for the 10 antagonists of 5-HT induced contraction in guinea pig trachea.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗

PubMed1992

Dihydroergotamine: a review of its use in the treatment of migraine and other headaches.

Dihydroergotamine has been one of the main drugs used in the treatment of migraine for greater than 40 years. The recent introduction of the more selective 5-HT antagonist sumatriptan will challenge the place of dihydroergotamine in migraine therapy and indicates the need to review the evidence for the use of dihydroergotamine. Although there is little evidence from double-blind clinical trials, dihydroergotamine does appear to be effective in the treatment of acute attacks and in the prevention of migraine. Its place in treatment is in cases where simple analgesics alone or in combination with other agents fail to provide relief. Further studies are necessary to compare dihydroergotamine with sumatriptan for acute migraine and with beta-blockers in prophylaxis to determine its future role in migraine therapy.

Dihydroergotamine↗

PubMed2005

[The role of triptans and analgesics for primary headache treatment].

Primary headache especially migraine is very common disorder. The mainstay in the acute treatment of migraine is triptans (sumatriptan, zolmitriptan, eletriptan, naratriptan) and analgesics or NSAIDs. However, it is still unclear the appropriate usage of triptans and analgesics or NSAIDs for migraine treatment. Mild attacks may be managed with analgesics or NSAIDs while severe disabling ones usually respond better to specific antimigraine drugs, triptans. Analgesics or NSAIDs administration is always plagued with the potential of subsequent drug induced headache phenomenon. Therefore usage of analgesics or NSAIDs should be restricted only for young and typical type patients with migraine. As triptan medication method corresponding to various life style, in addition to tablet formulation, there are subcutaneous injector and nasal spray formulation in sumatriptan, rapid melt tablet formulation in zolmitriptan (rapimelt) and naratriptan (rapidisk). These different type of formulation are valuable for patient's needs.

Analgesics↗

PubMed2006

[Clinical use of triptans in the management of migraine].

The discovery of the triptans (selective serotonin agonists 5HT(1B/1D), with 7 compounds (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan) soon available (5 in France: sumatriptan, naratriptan, eletriptan, zolmitriptan and almotriptan), was a considerable step forward in the acute treatment of migraine. Although randomized clinical studies have demonstrated their significant efficacy, triptans have still to be accepted into the clinical practice of some prescribing practitioners. Rather than attempting to highlight clinically insignificant differences between the triptans, efforts need to be focused on the optimal use of these drugs in clinical practice. This review therefore aims at answering questions related to the efficacy of triptans, recurrence of attacks after use, safety and tolerability, drug interactions and the cost of triptans in clinical use. Triptans are effective and well-tolerated drugs in the acute treatment of migraine attacks, and are the most cost-effective migraine therapy in patients with severe symptoms. Triptans should therefore be considered as first-line therapy in a stratified strategy, ensuring 'right treatment first time' for patients with severe migraine. Moreover, although very few studies have been conducted to date, clinical experience shows that a non-responder to one triptan may well benefit from another triptan, or even the same compound via a different route of administration.

Clinical Trials as Topic↗

PubMed1989

Headache: classification, mechanism and principles of therapy, with particular reference to migraine.

The sensation of pain derived from intracranial and extracranial blood vessels is conveyed to the central nervous system chiefly by the trigeminal nerve, with first order neurones terminating in the nucleus caudalis of the spinal trigeminal tract and an area lateral to the dorsal horn of the spinal cord at the second cervical segment. The evoked discharge of second order neurons can be suppressed by activation of the endogenous pain control system or, in about one third of cases, by the local application of ergot derivatives or the serotonin (5HT1) agonist sumatriptan (GR43175). Stimulation of brainstem structures such as locus ceruleus, raphe nuclei and the trigeminal system induce changes in the cerebral and extracranial circulations of the experimental animal that mimic those of migraine with aura (classical migraine). Clinical and laboratory observations have led to a neural hypothesis for migraine in which changes in hypothalamic function (an 'internal clock') and reactions to stress or excessive afferent stimuli are thought to initiate brainstem activity, causing secondary vascular changes and release of inhibition of the trigeminal pain pathways to cause headache. Painful distension of cranial blood vessels may contribute the throbbing component to migraine headache. Migraine is associated with a lowered level of platelet serotonin that is thought to reflect monoamine depletion in brainstem nuclei. Migraine headache can be precipitated by reserpine, which releases serotonin from body stores, and relieved by the intravenous infusion of serotonin. The new 5HT1 agonist sumatriptan promises to have the beneficial effects of serotonin without the side-effects that limited its clinical use.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1995

Effect of alpha adrenergic agonist on the rabbit ear artery contraction to serotonin: enhanced response mediated by serotonergic1-like receptors.

The effect of methoxamine or phenylephrine (PHE) on the contractile response of the rabbit ear artery to serotonin was assessed by using isolated arterial rings mounted in tissue baths for the measurement of isometric force development. A contractile threshold concentration of methoxamine or PHE (10-30 nM) shifted the serotonin concentration-response curve to the left by approximately 200-fold. Neither mechanical removal of the vascular endothelium nor chemical denervation had any effect on the alpha agonist-amplified response of ear artery to serotonin. Although the response to serotonin in the absence of the alpha agonist was mediated primarily by alpha-1 adrenergic receptors, prazosin did not block the amplified response to serotonin. Ketanserin (10 nM), ritanserin (50 nM) and MDL 72222 (1 microM) also had no effect on the amplified response, ruling out the involvement of serotonergic (5-HT)2 and 5-HT3 receptors. However, methiothepin (3 nM) and 1-(1-naphthyl)piperazine (10 and 100 nM) blocked the PHE-amplified contraction of ear artery to serotonin. When the contractile response of ear artery to 5-carboxamidotryptamine was measured in the presence of a threshold concentration of alpha agonist, the concentration-response curve was shifted 8300-fold to the left. The amplified response to 5-carboxyamidotryptamine was insensitive to 10 nM ketanserin, but was blocked by 3 nM methiothepin. Sumatriptan, a selective 5-HT1 agonist, failed to induce vasoconstriction in the absence of a threshold concentration of alpha agonist. However, in the presence of PHE, sumatriptan induced a concentration-dependent contraction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Cocaine inhibits GABA release in the VTA through endogenous 5-HT.

The ventral tegmental area (VTA) is thought to be involved in the addictive properties of many drugs, including cocaine. It has been hypothesized that cocaine exerts its actions in the VTA by blocking the reuptake of dopamine released from the dendrites of the A10 dopamine neurons, thus prolonging the actions of dopamine at D2 autoreceptors. However, cocaine also blocks the reuptake of the other monoamines, including serotonin (5-HT). Using intracellular recordings from midbrain dopamine neurons in a brain slice preparation, we have found that cocaine (0.1-10 microM) inhibited the GABAB IPSP in a dose-dependent manner. This effect was observed in the presence of the D2 dopamine receptor antagonists sulpiride (1 microM) and eticlopride (0.1 microM). 5-HT mimicked this effect, as did the selective 5-HT1D receptor agonist sumatriptan and the 5-HT-releasing agent fenfluramine. The actions of both 5-HT and cocaine were attenuated by the 5-HT1C/D antagonist metergoline. Pretreatment of slices with the 5-HT-depleting agent p-chloroamphetamine (pCA; 10 microM) abolished the inhibition of the GABAB IPSP by cocaine but failed to affect the actions of sumatriptan. We conclude that cocaine acts to modulate the GABA input to A10 dopamine neurons via inhibition of the 5-HT transporter, increasing the concentration of 5-HT at presynaptic 5-HT1D receptors. These actions of cocaine were apparent at lower concentrations than those required to act via inhibition of the dopamine transporter. This reduction of inhibitory synaptic input into the VTA would be expected to attenuate the GABA-mediated feedback inhibition from the nucleus accumbens, thus leading to increased activation of dopamine neurons.

Animals↗