Dihydroergotamine, ergotamine, methysergide and sumatriptan - basic science in relation to migraine treatment

The 5-hydroxytryptamine (5-HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5-HT(1B) , 5-HT(1D) , and 5-HT(1F) receptors. Ergotamine, dihydroergotamine, and methysergide, as well as the "triptan" sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these four drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in reliving the symptoms of a migraine attack.     

Comparative effects of the antimigraine drugs sumatriptan and ergotamine on the distribution of cardiac output in anaesthetized pigs

The haemodynamic effects of sumatriptan, a 5-HT1-like receptor agonist, and ergotamine, an agonist at alpha-adrenergic, dopamine as well as 5-HT receptors, were compared using intracardiac injection of radioactive microspheres of different sizes in anaesthetized pigs. Ergotamine (0.02 mg.kg-1) and sumatriptan (0.3 mg.kg-1) decreased systemic vascular conductance and cardiac output. Only ergotamine raised arterial blood pressure. Both sumatriptan and ergotamine decreased arteriovenous anastomotic, but not capillary, blood flow in the head and body skin. Arteriovenous and capillary blood flow in the dura mater and nasal mucosa and capillary blood flow in the brain, kidneys, adrenals, intestine, heart, spleen and muscle remained unchanged. However, kidney conductance was decreased by both drugs, spleen conductance by sumatriptan and heart, liver and adrenal conductances were decreased by ergotamine. Thus, both sumatriptan and ergotamine constricted arteriovenous anastomoses in the skin, but not in the dura mater or nasal mucosa. Ergotamine constricted the vasculature more than sumatriptan, although both drugs may differentially decrease vascular conductances in some organs.     

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.     

Patterns of lamotrigine use in daily clinical practice during the first 5 years after introduction in the Netherlands

OBJECTIVE: Follow-up data on the long-term effectiveness (efficacy and tolerability) of lamotrigine are limited. A useful though crude measure for effectiveness in daily clinical practice is the treatment retention rate determined from drug dispensing data. This study describes the baseline characteristics, the usage patterns and the retention rate of this antiepileptic drug (AED) in a population-based cohort of lamotrigine users in the Netherlands during the first 5 years after its registration in 1995. Data from this cohort are compared with those from the initial randomized clinical trials (RCTs) in patients with refractory epilepsy. METHODS: This retrospective cohort study used dispensing data from community pharmacies. Baseline characteristics and usage patterns were evaluated for first time users of lamotrigine in this study. Usage patterns were characterized as continued, add-on or discontinued use during the patient observation time window. Cox regression analysis was used to explore possible relationships between baseline characteristics and specific usage patterns defined. The baseline characteristics and discontinuation rates in this cohort study were compared with RCT data reported in medical literature. RESULTS: A total of 3598 lamotrigine users were identified. The mean age of the population was 39 years and 54% were female. On average, patients used two other AEDs at the start of lamotrigine therapy and approximately 6% of the patients had no history of prior AED use. The discontinuation rate was 25% after 1 year, and approximately 32% at the end of the 5-year study. Addition of another drug or discontinuation was seen in more than half of the population 3 years after the start of therapy. Concurrent use of valproic acid was associated with a better retention rate. Absence of AED history, use of antidepressants, or use of migraine abortive drugs resulted in an increased likelihood of discontinuing lamotrigine. The population from RCTs differed from the study cohort with respect to age, concurrent use of AEDs and length of follow-up. CONCLUSION: Data from RCTs cannot easily be extrapolated to daily clinical practice. In this large, observational study, lamotrigine therapy failed in a considerable number of patients, although the mean retention rate was better than previously reported by others. Population-based linkage of health care records can be used to further clarify the effectiveness of lamotrigine.     

Responsiveness of non-IHS migraine and tension-type headache to sumatriptan

In a long-term efficacy and satiety study, 424 patients were treated with sumatriptan (6 mg sc) for 1,904 migraine attacks. The patients were diagnosed with migraine based on IHS criteria but individual migraine attacks treated in the study were physician diagnosed; not necessarily required to meet IHS criteria. A re-analysis of the treatment response to open label sumatriptan (6 mg sc) indicated that 43 patients had treated at least one migraine that fulfilled IHS criteria for tension-type headache. Analysis of this population revealed they treated 232 headaches. Of these headaches, 114 were classified per IHS criteria as migraine; 76 as tension-type; and 42 as. non-IHS migraine (not classifiable as IHS migraine or IHS tension-type headache). Of the 114 migraines a positive response to sumatriptan occurred in 109 (96%) cases; of the 76 tension-types, 73 responded to sumatriptan (97%); of the 42 non-IHS migraine, 40 (95%) responded to sumatriptan. An equivalent response to sumatriptan among three diagnostic groups of headache supports the concept of a common biologic mechanism involving 5HT₁ receptors that spans a range of clinical presentations.     

Ergotamine abuse: Results of ergotamine discontinuation, with special reference to the plasma concentrations

Twenty-three patients suffering from continuous headache linked with habitual daily use of ergotamine tartrate were studied. Their headaches were classified clinically, and possible side effects of ergotamine medication, plasma levels of ergotamine, and occurrence of withdrawal symptoms after discontinuation of drug abuse were recorded. Seventeen of the patients were clinically diagnosed as suffering from "ergotamine headache", and seven of them complained of coldness in the extremities. Plasma ergotamine levels were measured by using a radioimmunoassay. In almost half of the patients the 1 h plasma levels after the daily dose were below the detection limit of the procedure (0.12 ng/ml). The duration and severity of the withdrawal symptoms did not correlate with the doses and plasma levels of ergotamine. In only 4 of the 21 patients who were followed up for 3 to 6 months did headache symptoms not improve after ergotamine withdrawal. The results indicate that even small (0.5–1.0 mg/day) doses of ergotamine tartrate taken regularly may cause continuous headache symptoms and withdrawal symptoms after discontinuation.     

Effectiveness of nasal sumatriptan in 5- to 12-year-old children

OBJECTIVE: To assess the tolerability and effectiveness of nasal sumatriptan in the treatment of migraine in 5- to 12-year-old children. BACKGROUND: Although headaches are a common disorder and occur in up to 10.6% of children, many of the new migraine abortive agents have not been well evaluated in this population. It has recently been reported that nasal sumatriptan is effective in the treatment of migraine in adolescents. In younger children, it is yet to be characterized. In addition, many children have significant amounts of vomiting with their migraines, limiting their use of oral medications. DESIGN AND METHODS: Children with headache were evaluated by a child neurologist, child psychologist, and pediatric nurse practitioner. Clinical and International Headache Society diagnoses were established for each child. Patients with headaches that were either unresponsive to oral medications or had significant vomiting were treated with nasal sumatriptan. Initial administration and tolerability were performed in the Headache Center at Cincinnati's Children's Hospital Medical Center. Patients or their parents were contacted to assess the overall effectiveness of nasal sumatriptan after home administration. RESULTS: Ten patients aged between 5 and 12 years (mean, 9.9 years) received either a 5-mg (n = 2) or 20-mg (n = 8) dose of sumatriptan. All 10 patients had a clinical diagnosis of migraine; 7 met the International Headache Society criteria for migraine. The mean age of headache onset was 6.6 years. A total of 57 headaches were treated; 47 (82.5%) responded to sumatriptan. Of the patients who treated headaches, the mean number of headaches treated was 5.2, while the mean number of responsive headaches was 4.3. One patient had no response, 2 patients had a 50% response, and 6 patients had 100% response to the nasal sumatriptan. Three patients reported persistent "bad taste." CONCLUSIONS: This report demonstrates that nasal sumatriptan may be effective in aborting migraine in young children (aged 5 to 12 years). It also suggests that there may be subgroups for which it works well. This information suggests that double-blind, placebo-controlled studies are necessary to determine the overall effectiveness of nasal sumatriptan in this age group.     

Placebo-controlled clinical trials with ergotamine in the acute treatment of migraine

Although oral ergotamine alone or in combination with caffeine is widely used for the acute treatment of migraine, there is little evidence that it is significantly more effective than placebo. There are no placebo-controlled data to support the use of aerosol or suppository formulations. In addition, the recommended doses of ergotamine cannot be justified. Each formulation of ergotamine now should be tested in clinical studies performed according to the IHS criteria for trial design and in migraine patients fulfilling the diagnostic criteria of the IHS. Until these clinical data are available, no dear recommendations can be given for the use of ergotamine in the acute treatment of migraine.     

Early migraine intervention with sumatriptan 100 mg in patients with a history of nonresponse to sumatriptan 50 mg: an open-label, prospective study of multiple attacks

Background

Early treatment with sumatriptan tablets (50 and 100 mg) has been shown to be effective in retrospective and prospective study designs. Despite the efficacy of sumatriptan 50 mg and early intervention, however, some patients continue not to respond completely to this dose. New evidence with a scientific basis for early intervention suggests that some patients may need to treat early to prevent the establishment of central sensitization. Also, patients cite complete pain relief as the most important attribute of a migraine medication.

Objective

The primary objective of this study was to determine the 2-hour efficacy of sumatriptan 100 mg in achieving complete pain relief in patients with a history of nonresponse to sumatriptan 50 mg in an early-intervention treatment paradigm. Secondary end points included complete pain relief at 4 hours, consistency of complete relief in at least 2 of 3 attacks, sustained complete relief over 24 hours, satisfaction with the 100-mg dose, and relief of associated symptoms.

Methods

This open-label, prospective study was conducted at the Wesley Headache Clinic (Memphis, Tennessee). Male and female patients between the ages of 18 and 65 years who fulfilled International Headache Society classification criteria for migraine, and who had a documented history of nonresponse to sumatriptan 50 mg at 2 hours after dosing when treating in the early, mild-pain phase in at least 2 of 3 migraine attacks were eligible for the study. Patients were instructed to receive one 100-mg sumatriptan tablet at the earliest sign of pain, while still mild, in 3 subsequent migraine attacks. After each treated attack, patients were to record a detailed diary entry.

Results

Twenty patients (17 women, 3 men; mean age, 44 years) treated all 3 migraines during the early, mild-pain phase and completed the study. Of the 60 attacks treated, 48 (80%) were pain free at 2 hours, 56 (93%) were pain free at 4 hours, and 45 (75%) were pain free at 2 hours and continued to be pain free at 24 hours (sustained pain-free response). Sumatriptan 100 mg was well tolerated; none of the patients reported any adverse events.

Conclusions

In this study of migraineurs with a history of nonresponse to sumatriptan 50 mg at 2 hours after dosing in the early, mild-pain phase of migraine, increasing the dose of sumatriptan from 50 mg to 100 mg in the early-intervention paradigm, in most attacks complete pain relief was achieved for up to 24 hours. Because patients have indicated that becoming pain free was their therapeutic goal, based on the results of this study, physicians may want to consider increasing the dose of sumatriptan to 100 mg at the first sign of pain if the patient has consistently not responded to sumatriptan 50 mg in the early-intervention model.     

The early use of ergotamine in migraine. Edward Woakes' report of 1868, its theoretical and practical background and its international reception

Although ergot had been used in obstetrics for several centuries, it was proposed for the treatment of migraine only in the 19th century. The British ENT-surgeon Edward Woakes (1837-1912) recommended ergot as a vasoconstricting agent for migraine and other neurogenic conditions associated with vasodilatation in 1868. He subscribed to the theory of vasodilatation by sympathetic deficit, presented in the early 1850s by Brown-Séquard and Claude Bernard. Du Bois-Reymond proposed vasoconstriction by sympathetic overactivity as the cause of migraine in 1860; Brown-Séquard opposed this in favour of vasodilatation. Vasodilatation due to sympathetic deficit in migraine was again supported by M?llendorf, with clinical evidence, in 1867. Woakes' paper of 1868 introduced ergot as a vasoconstrictor for the same condition. Reception abroad was prompt. A German version appeared in 1869, and Eulenburg cited Woakes in his textbook of 1871. Eulenburg presented the use of ergot for migraine as a routine measure in the second edition of his textbook in 1878, and in a paper published in 1883. The method was internationally accepted, but it became really popular only after the isolation of pure ergotamine in 1918, resulting in the first reliable compounds with stable properties and predictable effects. Contrary to Woakes' theory, in the early 20th century ergot was used for migraine because of its well-documented adrenolytic properties, as migraine was by then again believed to be a sympathotonic and vasospastic condition.     

Eletriptan for the treatment of migraine in patients with previous poor response or tolerance to oral sumatriptan

To determine the tolerability and efficacy of eletriptan in patients who had discontinued oral sumatriptan due to lack of efficacy or intolerable adverse events (AEs) during previous clinical treatment (not a controlled trial). Eletriptan is a potent, selective 5-HT1B/1D receptor agonist with beneficial pharmacokinetic properties compared with sumatriptan. In a double-blind, parallel group, placebo-controlled multicentre study, patients with and without aura (n = 446) were randomized to 40 mg eletriptan (E40, n = 188), 80 mg eletriptan (E80, n = 171) or placebo (n = 87) for treatment of up to three migraine attacks. Two-hour headache response, based on first-dose, first-attack data, was 59% for eletriptan 40 mg, 70% for eletriptan 80 mg, and 30% for placebo (P < 0.0001 for both doses of eletriptan vs. PBO; P < 0.05 for E80 vs. E40). Onset of action was rapid, with 1-h headache response rates significantly superior for E40 and E80 vs. placebo (40%, 48%, 15%; P < 0.0005). Both E40 and E80 were significantly superior to placebo, based on first-dose, first-attack data, for 2-h pain-free response (35%, 42%, and 7%; P < 0.0001). Both E40 and E80 demonstrated significant consistency of response, with headache relief rates at 2 h on at least two of three attacks in 66% and 72% vs. 15% on placebo (P < 0.001). AEs were mild to moderate in severity and dose related. The most commonly reported AEs included nausea, vomiting, asthenia, and chest symptoms. E40 and E80 produce an effective response in patients who had previously discontinued treatment with sumatriptan due to lack of efficacy or side-effects.     

A comparative trial of zolmitriptan and sumatriptan for the acute oral treatment of migraine

OBJECTIVE: This randomized, double-blind, parallel group multicenter study compared response rates and tolerability of zolmitriptan with sumatriptan in the acute treatment of migraine. METHODS: A sample consisting of 1445 outpatients with an established diagnosis of migraine was randomized to zolmitriptan, 2.5 mg or 5 mg, or sumatriptan, 25 mg or 50 mg. Patients took 1 tablet for moderate/severe migraine and a second identical tablet, if necessary, for recurrent headache of moderate/severe intensity 4 to 24 hours after the initial dose. Up to six attacks were treated during a 6-month period. The primary outcome measure was headache response 2 hours after the initial dose. Secondary end points included 1-hour and 4-hour headache response and pain relief over 24 hours. RESULTS: A headache response at 2 hours was noted in 67.1% of patients taking zolmitriptan, 2.5 mg, and 64.8% of those taking zolmitriptan, 5 mg, versus 59.6% of patients taking sumatriptan, 25 mg, and 63.8% of those taking sumatriptan, 50 mg. At 2 and 4 hours, the differences between zolmitriptan, 2.5 mg, and sumatriptan, 25 mg, were statistically significant (odds ratio=1.49 and 1.67, respectively; both P<.001). Statistically significant differences between zolmitriptan, 2.5 mg, and sumatriptan, 50 mg, were seen at 2 and 4 hours post dose (odds ratio=1.21 and 1.23, respectively; both P<.05). At 1 hour post dose, the headache response rate for zolmitriptan, 2. 5 mg, was numerically higher than response rates for sumatriptan, 25 mg and 50mg (odds ratio=1.16, odds ratio=1.06, though they failed to reach statistical significance; P=.061, P=.461 respectively). Differences between zolmitriptan, 5 mg, and sumatriptan, 25 mg, were statistically significant at 1, 2, and 4 hours (odds ratio=1.43, 1. 46, and 1.78, respectively; all P<.001) and at 1 and 4 hours versus sumatriptan, 50 mg (odds ratio=1.28, P=.002; odds ratio=1.29, P=.012, respectively). Although not statistically significant at 2 hours, more patients responded to zolmitriptan, 5 mg, than to sumatriptan, 50 mg (odds ratio=1.16, P=.064). Patients receiving zolmitriptan, 2. 5 mg or 5 mg, achieved more pain relief over 24 hours than patients receiving sumatriptan, 25 mg (odds ratio=1.47, and 1.54 respectively, both P<.001) or sumatriptan, 50 mg (odds ratio=1.17, P=.021; odds ratio=1.22, P=.005, respectively). All treatments were well tolerated. CONCLUSIONS: Zolmitriptan, 2.5 mg and 5 mg, was at least as effective as sumatriptan, 25 mg or 50 mg, for all parameters studied. Zolmitriptan, 2.5 mg, was significantly more effective than sumatriptan, 50 mg, in terms of headache response at 2 and 4 hours. Patients taking zolmitriptan were significantly more likely to have pain relief over 24 hours than those taking sumatriptan.     

Treatment of nonresponders to oral sumatriptan with zolmitriptan and rizatriptan: a comparative open trial

In order to study the effect of zolmitriptan and rizatriptan in oral sumatriptan nonresponders (defined as lack of response in three or more of five attacks), 56 patients were studied in an open trial in a crossover fashion. Both zolmitriptan, 5 mg, and rizatriptan, 10 mg, were effective in the majority of sumatriptan nonresponders. The response to rizatriptan, 10 mg, appeared to be better than to zolmitriptan, 5 mg. Approximately 19% of sumatriptan nonresponders remained nonresponders to both zolmitriptan and rizatriptan.     

CNS effects of sumatriptan and rizatriptan in healthy female volunteers

This study investigates the CNS effects of sumatriptan and rizatriptan, with temazepam as an active comparator, in healthy female volunteers. Sixteen volunteers completed a randomized, double-blind, crossover study and on four separate occasions received either 100 mg sumatriptan, 20 mg rizatriptan or 20 mg temazepam. The main parameters were eye movements, EEG, body sway, visual analogue scales and a cognitive test battery. Rizatriptan and sumatriptan decreased saccadic peak velocity by 18.3 (95% CI: 5.7, 30.8) and 15.0 (2.2, 27.9) degrees/sec, respectively, about half the decrease induced by temazepam (35.0 (22.1, 47.8) degrees/sec). Body sway increased (30% for rizatriptan (16%, 45%) and 14% for sumatriptan (1%, 27%), respectively). Temazepam caused larger, similar effects. In contrast to temazepam, sumatriptan and rizatriptan decreased reaction times of recognition tasks and increased EEG alpha power (significant for sumatriptan, 0.477 (0.02, 0.935). Therapeutic doses of sumatriptan and rizatriptan caused CNS effects indicative of mild sedation. For EEG and recognition reaction times the effects were opposite to temazepam, indicating central stimulation.     

A within-patient comparison of subcutaneous and oral sumatriptan in the acute treatment of migraine in general practice

This study compared, for the first time in the United Kingdom, the efficacy and safety of oral 100 mg and subcutaneous 6 mg sumatriptan within a patient for the acute treatment of migraine. The patient's preference for the two formulations of sumatriptan were also recorded. The study was a multicentre, randomized, open, crossover design with an optional open parallel group extension. Individual attacks were treated with one formulation only. Over 10% of patients who treated attack 1 in both treatment periods of the crossover phase reported headache relief with each formulation at 4 h. Only 3% of patients failed to respond to at least one of the formulations at this time point. At the end of the crossover phase patient preference for the injection more than doubled from the pretreatment level in those patients who were previously naive to sumatriptan. During the optional phase of the study, 38% of patients chose to treat some attacks with oral and some with subcutaneous sumatriptan. The main reason for choosing injection was speed of relief, whilst convenience was the major reason for the use of the tablet.     

Preference comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg tablet in migraine

OBJECTIVE: To compare the proportion of patients who prefer rizatriptan orally disintegrating tablet (ODT) 10-mg to sumatriptan 50-mg tablet. BACKGROUND: Migraineurs express treatment preference based on a variety of attributes including the speed of pain relief and medication formulation. Rizatriptan ODT is an orally disintegrating formulation of rizatriptan, a selective 5-HT1B/1D receptor agonist. This study was conducted to determine patient preference between rizatriptan ODT 10-mg and sumatriptan 50-mg tablet for the acute treatment of migraine. METHODS: This was a multicenter, randomized, open-label, two-period crossover study conducted in the United States with 524 enrolled patients. Patients treated a single moderate or severe headache in each treatment period. Patients treated one migraine with either rizatriptan ODT 10-mg or sumatriptan 50-mg tablet, then treated a second migraine with the alternate therapy. Patients completed diary assessments at baseline, and 30, 45, 60, 90, and 120 minutes postdose and rated headache severity on a 4-point scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). At the final study visit following treatment of their second migraine, patients expressed preference for one of the two study medications by completing an interviewer-administered Global Preference Question and then responded to a self-administered series of questions to capture their most important reason for preferring one study medication over the other. Safety measurements were recorded through standard adverse experience reporting. RESULTS: Three hundred eighty-six patients treated two migraine attacks. For those patients who expressed a preference for either rizatriptan ODT or sumatriptan (n = 374), the percentage of patients who preferred rizatriptan ODT 10-mg (57%, n = 213) was significantly greater than those who preferred sumatriptan 50-mg tablet (43%, n = 161) (P<.01). For those patients who treated two migraine attacks and had drug severity measures for both attacks (n = 384), a significantly greater percentage of patients reported pain relief after taking rizatriptan ODT than sumatriptan at the 45- and 60-minute time points (38% versus 29% and 58% versus 49%, respectively) (P<.01). In addition, a significantly greater percentage of patients taking rizatriptan ODT reported a pain-free status at the 60- and 120-minute time points (23% versus 17% [P<.05] and 60% versus 52% [P<.01], respectively). Both rizatriptan ODT and sumatriptan were well tolerated. CONCLUSIONS: A significantly greater proportion of patients preferred rizatriptan ODT 10-mg to sumatriptan 50-mg tablet for the acute treatment of migraine. Efficacy and safety data are consistent with the preference findings.     

Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group

Rizatriptan is a potent, oral, 5-HT1B/1D agonist with more rapid absorption and higher bioavailability than oral sumatriptan. It was postulated that this would result in more rapid onset of effect. This randomized, double-blind, triple-dummy, parallel-groups study compared rizatriptan 5 mg, rizatriptan 10 mg, sumatriptan 100 mg, and placebo in 1268 outpatients treating a single migraine attack. Headache relief rates after rizatriptan 10 mg were consistently higher than sumatriptan at all time points up to 2 hours, with significance at 1 hour (37% versus 28%, P = 0.010). All active agents were significantly superior to placebo with regard to headache relief and pain freedom at 2 hours (P < or = 0.001). The primary efficacy endpoint of time to pain relief through 2 hours demonstrated that, after adjustment for age imbalance, rizatriptan 10 mg had earlier onset than sumatriptan 100 mg (P = 0.032; hazard ratio 1.21). Rizatriptan 10 mg was also superior to sumatriptan on pain-free response (P = 0.032), reduction in functional disability (P = 0.015), and relief of nausea at 2 hours (P = 0.010). Significantly fewer drug-related clinical adverse events were reported after rizatriptan 10 mg (33%, P = 0.014) compared with sumatriptan 100 mg (41%). We conclude that rizatriptan 10 mg has a rapid onset of action and relieves headache and associated symptoms more effectively than sumatriptan 100 mg.     

Resolution of concentration-response differences in onset of effect between subcutaneous and oral sumatriptan

OBJECTIVE: To investigate whether the concentration-response relationships for onset of effect of oral and subcutaneous (s.c.) sumatriptan differ, and if so, then to explore whether a single model for the onset of effect can nonetheless be found for multiple dose sizes and both routes of administration. METHODS: Active and placebo response rates and mean plasma concentrations were collected from the literature for 0 < or =t < or = 2 hours. Plasma concentration-response relationships were plotted. Logarithmic models for the onset of effect (ie, active response rates), characterized by convexity factor A and location parameter B were constructed from the same data. RESULTS: The concentration-response relationships for s.c. and oral sumatriptan are qualitatively different. A single logarithmic model for the onset of effect provides good estimates of observed response rates during the first 2 hours post-dose for multiple dose sizes after both oral and s.c. routes of administration. The precision of this model resides in both its variables. Location parameters for this model differ for similar absolute doses by the two routes of administration. However, curve convexity (representing rate of onset of effect) is related to absolute dose (and hence plasma concentration) in the same way for sumatriptan tablets and injections. CONCLUSIONS: No simple plasma concentration-response relationship exists that is sufficiently robust to apply to both s.c. and oral sumatriptan. There are separate pharmacokinetic-pharmacodynamic relationships for rate of onset and extent of effect. The design of exploratory clinical trials for new acute therapies for migraine may be more efficient when these factors are considered, and these factors may help to describe the gap between experimental and ordinary clinical environments.