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One-year tolerability and efficacy of sumatriptan nasal spray in adolescents with migraine: results of a multicenter, open-label study.

OBJECTIVE: The objective of this study was to determine the 1-year tolerability and efficacy of sumatriptan nasal spray (NS) at doses of 5, 10, and 20 mg for the treatment of acute migraine in adolescents. METHODS: This was a prospective, multicenter, open-label, 1-year, multiple-attack study. Adolescents (aged 12-17 years) with a > or =6-month history of migraine with or without aura, 2 to 8 moderate or severe migraines per month, and a typical migraine duration of > or =4 hours were eligible for participation. After initial treatment with sumatriptan 10 mg, the dose could be adjusted down to 5 mg or up to 20 mg at the investigator's discretion to optimize tolerability or efficacy. Patients could treat an unlimited number of moderate or severe migraine attacks, provided there was a 24-hour headache-free period between treated attacks and a 2-hour period between doses of sumatriptan NS. A second dose of sumatriptan NS was available for headache recurrence 2 to 24 hours after initial treatment; no more than 2 doses could be used within a 24-hour period. Adverse events, vital signs, electrocardiographic and physical findings, and laboratory variables were assessed. Headache response (reduction of moderate/severe predose pain to mild/no pain) and pain-free response (reduction of moderate/severe predose pain to no pain) were reported by patients 2 hours after dosing. RESULTS: A total of 437 patients treated > or =1 migraine; 3272 total attacks were treated, with 3675 drug exposures (mean, 1.1 dose/attack). Patients had a mean age of 14.1 years, 91% were white, and 53% were female. Seven patients used the 5-mg dose; meaningful conclusions concerning this dose could not be made. Drug-related adverse events were reported in 33% of attacks with the 10-mg dose and 31% with the 20-mg dose; most were related to taste disturbance. Adverse events did not increase with a second dose or over time. Four percent (16/437) of patients withdrew due to drug-related adverse events. One serious adverse event, a facial-nerve ischemic event (10-mg dose), was considered drug related. No drug-related changes in vital signs or electrocardiographic findings were observed. Headache response 2 hours after dosing was reported by 76% of patients taking the 10-mg dose and 72% of those taking the 20-mg dose. Pain-free response 2 hours after dosing was reported by 43% and 40% of patients in the 10- and 20-mg groups, respectively. CONCLUSIONS: Based on these results, sumatriptan NS at doses of 10 and 20 mg was well tolerated and effective in the 1-year treatment of multiple migraine attacks in adolescents.

Administration, Intranasal↗

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

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

Adolescent↗

Sumatriptan, 5-HT(1D) receptors and obsessive-compulsive disorder.

BACKGROUND: After considering the effects of 5-HT receptor agonists with different binding profiles on the symptoms of obsessive-compulsive disorder (OCD), Zohar and Kindler hypothesized that the 5-HT(1D) receptor was implicated in this disorder's pathophysiology. METHODS: We explored the 5-HT(1D) hypothesis in a 5-day, random, double-blind, placebo-controlled trial of oral sumatriptan 100 mg/day in medication-free adults with OCD. We hypothesized that sumatriptan, a 5-HT(1D) agonist, would diminish 5-HT release, thereby worsening OCD symptoms. We further hypothesized that by beginning to desensitize 5-HT(1D) receptors, sumatriptan pretreatment would promote a faster response or an increased likelihood of response to subsequent treatment with a selective serotonin reuptake inhibitor. RESULTS: The five sumatriptan subjects' OCD symptom worsening, as measured by the Yale-Brown scale ( upward arrow 17.6% (S.D. 14.6)), was significant when compared to the slight symptom decrease in the five placebo subjects ( downward arrow 5.2% (S.D. 4.9), P<0.015). The sumatriptan group did not exhibit a faster response or greater likelihood of response to a 90-day, open label trial of paroxetine. CONCLUSIONS: Longer term studies of the effects of 5-HT(1D) agonists on OCD symptoms are indicated. Zolmitriptan, a potent 5-HT(1D) receptor agonist with better penetration of the blood-brain barrier, may be a preferred challenge agent.

Adolescent↗

Sumatriptan absorption from different regions of the human gastrointestinal tract.

Sumatriptan exhibits low oral bioavailability partly due to presystemic metabolism, which may vary with regional differences in metabolic activity throughout the gastrointestinal tract. This study evaluated sumatriptan absorption in humans after administration orally and by oroenteric tube into the jejunum and cecum. Because the site of cecal administration varied, pharmacokinetic parameters for sumatriptan and its major metabolite were compared statistically only after oral and jejunal administration. One-half of the oral dose was recovered in the urine as parent (3%) and metabolite (46%). Sumatriptan was absorbed throughout the gastrointestinal tract; absorption was similar after oral and jejunal administration, and less after cecal administration. The metabolite AUC and the AUC ratio (metabolite/parent) were significantly lower after jejunal compared to oral administration; the AUC ratio was two-fold lower after cecal administration. Results suggest that presystemic metabolism of sumatriptan varies throughout the gastrointestinal tract and/or regional differences exist in the absorption of metabolite formed within the gastrointestinal tract.

Administration, Oral↗

5-HT1-receptor agonist sumatriptan modifies gastric size after 500 ml of water in dyspeptic patients and normal subjects.

Sumatriptan, a 5-HT1-receptor agonist has been shown to delay gastric emptying of liquids and solids in humans. However, no data are available of the effect of sumatriptan on gastric adaptation after distension with liquids and on symptoms induced by gastric distension. In 23 normal subjects and 30 dyspeptic patients with normal upper gastrointestinal endoscopy and real-time ultrasonography, the transverse gastric proximal and distal area and sagittal axis of the proximal stomach were determined by real-time ultrasonography and computed tomography after 500 ml of water. The area was determined by real-time ultrasonography and computed tomography twice at times 48 hr apart. Thirty minutes before real-time ultrasonography, placebo or sumatriptam were give subcutaneously in a double-blind fashion. Epigastric pain, bloating, heartburn, and nausea were also monitored through an intensity score from zero to 10 performed during the test. In six dyspeptic patients, the gastric distension was performed also with real-time ultrasonography and computed tomography after placebo and hyoscine butyl-bromide, a quaternary anticholinergic agent. Real-time ultrasonography and computed tomography demonstrated that after sumatriptan there is a reduction in proximal and distal transverse area and an increase in the sagittal axis of the proximal stomach. Hyoscine butyl-bromide increased all gastric measurements. Among the symptoms evaluated, only nausea was significantly reduced by sumatriptan (P < 0.01). Sumatriptan modifies gastric size, with a reduction in the transverse section and an increase of the sagittal axis of the proximal stomach and improves the nausea induced by gastric distension in dyspeptic patients.

Adult↗

Involvement of 5-HT1B and 5-HT1D receptors in sumatriptan mediated vasocontractile response in rabbit common carotid artery.

1. In this study we examined the involvement of 5-HT(1B) and 5-HT(1D) receptors in the vasocontractile response induced by 5-HT(1B/D)-receptor agonist sumatriptan in rabbit common carotid artery (CCA). 2. Immunoblotting experiments using specific antisera against 5-HT(1B) or 5-HT(1D) receptors revealed the presence of one weak (at 93 kD for 5-HT(1B) or at 105 kD for 5-HT(1D)) and one strong band (at 46 kD for 5-HT(1B) or at 52 kD for 5-HT(1D)) in CCA. 3. Sumatriptan-mediated vasocontractile response was antagonized by SB216641 with an apparent pKb value of 8.6, which was consistent with its affinity for 5-HT(1B) receptor. Antagonism by BRL15572 was weak and calculated apparent pKb (6.0) value was consistent with its affinity for 5-HT(1B) subtype (but not for 5-HT(1D) subtype). This result indicates insignificant or no involvement of 5-HT(1D) receptor in the vasocontractile response. 4. The vasocontractile response induced by sumatriptan was highly sensitive to pertussis toxin treatment of CCA. Nicardipine, a calcium channel blocker, also potently antagonized vasocontractile response induced by sumatriptan. 5. 5-HT, but not sumatriptan, stimulated inositol phosphate accumulation in CCA. 6. These results indicate that stimulation of 5-HT(1B) subtype activate a pertussis toxin (PTX) sensitive G protein (Go/Gi) and mediate vasocontraction, in which L-type voltage dependent calcium channels are involved.

Animals↗

Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors.

AIMS: We compared the vasoconstrictor effects of 5-HT with those of the selective 5-HT1B/1D-receptor agonists sumatriptan and rizatriptan in human isolated cranial (middle meningeal) arteries. In addition selective 5-HT1B- or 5-HT1D-receptor antibodies were used in combination with semiquantitative immunohistochemical techniques to compare the levels of expression of these receptors in human middle meningeal and coronary arteries. METHODS: Middle meningeal and coronary arteries were obtained (with consent) from either neurosurgical patients or donor hearts, respectively. Segments of middle meningeal artery were mounted in organ baths for isometric recording and cumulative concentration-effect curves to 5-HT, rizatriptan and sumatriptan were obtained. Frozen fresh sections of middle meningeal and coronary arteries were subjected to standard immunohistochemical techniques using specific 5-HT1B- or 5-HT1D-receptor primary antibodies and a radiolabelled secondary antibody. Data were subjected to analysis of variance (ANOVA) and nonlinear regression analysis. RESULTS: 5-HT, rizatriptan and sumatriptan were potent vasoconstrictors in human isolated middle meningeal artery (EC50 values=32, 90 and 71 nM, respectively). A significantly higher level of 5-HT1B-receptor immunoreactivity was detected in middle meningeal artery compared with coronary artery (ANOVA, F=7.95, DF=1,4, P<0.05). CONCLUSIONS: Rizatriptan and sumatriptan act selectively to cause vasoconstriction in human isolated middle meningeal artery and are 10-fold more potent than in human coronary artery. The higher level of expression of 5-HT1B-receptors in middle meningeal compared with coronary artery provides a pharmacological basis for the craniovascular selectively of both rizatriptan and sumatriptan.

Adult↗

Zolmitriptan versus sumatriptan for the acute oral treatment of migraine: a randomized, double-blind, international study.

This randomized, double-blind, parallel-group study compared the efficacy and tolerability of zolmitriptan (2.5 or 5 mg) and sumatriptan (50 mg) in the acute oral treatment of up to six moderate-to-severe migraine attacks. The intention to treat (ITT) population comprised of 1522 patients: 500 treated with zolmitriptan 2.5 mg (2671 attacks), 514 with zolmitriptan 5 mg (2744 attacks) and 508 with sumatriptan 50 mg (2693 attacks). Overall, the 2-h headache response rates in these groups were 62.9, 65.7 and 66.6%, respectively. There were no statistically significant differences between sumatriptan 50 mg and zolmitriptan 2.5 mg (P = 0.12) or 5 mg (P = 0.80). Approximately 40% of patients in each group reported a 2-h headache response in > or = 80% of attacks. There were no statistically significant differences between the groups in the rates of headache response at 1 h (zolmitriptan 2.5 mg 36.9%, zolmitriptan 5 mg 39.5% and sumatriptan 50 mg 38.0%) or 4 h (70.3, 72.9 and 72.2%, respectively) or in the rates of meaningful migraine relief at 1, 2 or 4 h or sustained (24-h) pain relief. All treatments were well tolerated. In conclusion, zolmitriptan (2.5 or 5 mg) proved similarly efficacious compared with sumatriptan (50 mg), both in terms of response rates and consistency across attacks.

Administration, Oral↗

Extracellular recordings of membrane potential from guinea-pig isolated trigeminal ganglion: lack of effect of sumatriptan.

The aim of this study was to investigate the effect of the anti-migraine drug and selective 5-HT1 receptor agonist, sumatriptan, on membrane potential of guinea-pig isolated trigeminal ganglion. Ganglia were divided into three longitudinally, placed in two-compartment baths and the d.c. potential between compartments was recorded extracellularly. Drugs were applied to the Krebs superfusion fluid of one compartment. KCl (3 mmol/l) and GABA (0.1 mmol/l) caused depolarization (0.30 +/- 0.05 and 0.55 +/- 0.08 mV respectively, n = 11-19). 5-HT (1-10 mumol/l) caused small depolarizations (0.06 +/- 0.02 mV, n = 8) but sumatriptan (0.1-10 mumol/l) had no effect on trigeminal ganglion membrane potential. Collagenase pretreatment, to enhance desheathing, or modification of the composition of the Krebs solution failed to reveal any effect of sumatriptan. These data provide no evidence to suggest that sumatriptan inhibits neurotransmission in trigeminal ganglion. However, 5-HT1 receptors may be present in insufficient numbers in the trigeminal ganglion to elicit a change in membrane potential. Further studies are required to investigate the effect of sumatriptan at the level of the sensory nerve terminals within the intracranial vasculature, where 5-HT1 receptors may be concentrated.

Animals↗

The safety of sumatriptan in asthmatic migraineurs.

A recent report has questioned the safety of sumatriptan in asthmatic migraineurs. To investigate this, we have reviewed the sumatriptan clinical trial safety database of over 75 completed trials. Within the clinical trial database, 375 asthmatic patients were identified who treated 1214 migraine attacks with sumatriptan. The incidence and nature of adverse events in the asthmatic patient subgroup who received sumatriptan was similar to that in the complete clinical trial population. Six reports of asthma were recorded as adverse events, but only one case was classified by the investigator as related to treatment. There is no clinical or pharmacological evidence to suggest that the safety profile of sumatriptan is altered in asthmatic patients compared to other migraine sufferers.

Asthma↗

Self-treatment of acute migraine with subcutaneous sumatriptan using an auto-injector device: comparison with customary treatment in an open, longitudinal study.

In a multicenter open longitudinal clinical trial where 479 patients suffering from migraine with or without aura were recruited, patients treated at home one to three migraine attacks with their customary treatment, and subsequently, over a 3-month period, one to three migraine attacks with 6 mg sumatriptan sc using an autoinjector. The headache response to customary treatment was 19% at 1 h and 30.5% at 2 h, and was not significantly different when only attacks treated "adequately" according to accepted treatment recommendations were considered: 16% at 1 h and 35% at 2 h. In contrast, 69% and 82% of patients treated with 6 mg sumatriptan sc had mild headache or no headache at 1 and 2 h respectively, regardless of migraine type or duration of symptoms prior to treatment. Other migraine symptoms (nausea, vomiting, photo- and phonophobia) were effectively treated with sumatriptan. Recurrence of migraine was observed in 31% of patients and was well controlled by a second injection of sumatriptan. It is concluded that 6 mg sumatriptan sc, self-administered using an autoinjector, is well tolerated and more effective than most currently used acute treatments for migraine in a population of severely affected patients consulting a neurologist.

Acute Disease↗

Introduction of a novel self-injector for sumatriptan. A controlled clinical trial in general practice.

A novel self-injector for the administration of subcutaneous sumatriptan in the treatment of migraine attacks was tested in 138 patients recruited by family physicians in Denmark: 108 patients completed the initial double-blind, crossover part of the study. Sumatriptan 6 mg s.c. was significantly better than placebo at 30, 60, 90 and 120 min after injection in relieving moderate or severe headache to mild or none as well as relieving any headache to none. At 60 min after injection, the treatment response rate was 61% for sumatriptan and 6% for placebo. During the following open-phase trial of four attacks treated with sumatriptan, treatment response rates were 68-74%. During the total of 538 attacks treated, 12 attempts at using the self-injector failed. In the double-blind and open phases, 81% and 90% of patients respectively found the device easy or very easy to use. Adverse effects were benign and short-lasting, but led seven patients to discontinue the study. In conclusion, subcutaneous sumatriptan administered with a novel self-injector is an effective treatment for migraine compared to placebo in patients treated by their family physician.

Adult↗

Human isolated coronary artery contraction to sumatriptan: a post hoc analysis.

A post hoc analysis was performed on concentration response curves to sumatriptan in 62 human isolated coronary arteries. We determined whether donor-related clinical characteristics (age, sex, cause of death) and properties of the coronary artery (functional endothelial integrity, muscle mass) were related to the potency and efficacy of sumatriptan in contracting the human isolated coronary artery. The efficacy of sumatriptan was inversely related to the functional integrity of the vessel endothelium. Thus, contrary to expectation, coronary artery constriction to sumatriptan seems to be more pronounced in patients with nondiseased coronary arteries where the endothelium is intact. Nevertheless, in view of the high coronary reserve in these patients, myocardial ischemia after the use of sumatriptan is unlikely to occur, whereas in patients with coronary artery disease even a small contraction may be deleterious.

Adult↗

Comparison of the efficacy of zolmitriptan and sumatriptan: issues in migraine trial design.

In this international, multicentre, double-blind, placebo-controlled, single attack study, 'triptan naive' migraine patients were randomized in an 8:8:1 ratio to receive zolmitriptan 5 mg, sumatriptan 100 mg or placebo. The all-treated analysis included 1058 patients who took study medication. The primary endpoint, complete headache response, was reported by 39%, 38% and 32% of patients treated with zolmitriptan, sumatriptan and placebo, respectively, with no significant difference between treatment groups. In patients with moderate headache at baseline, complete response was significantly greater following zolmitriptan than after placebo (48% vs. 27%; P=0.01); there was no significant difference between sumatriptan and placebo groups (40% vs. 27%). In patients with severe baseline headache (where a greater reduction in headache intensity is required for a headache response), there was no significant difference between any groups in complete headache response rates. For secondary endpoints, active treatment groups were significantly superior to placebo for: 1-, 2- and 4-h headache response (e.g. 2-h headache response rates: zolmitriptan 59%; sumatriptan 61%; placebo 44%; P < 0.01 vs. placebo); pain-free response rates at 2 and 4 h; alleviation of nausea and vomiting; use of escape medication and restoration of normal activity. The incidence of adverse events was similar between zolmitriptan and sumatriptan groups but was slightly lower in the placebo group. The lack of difference between active treatments and placebo for complete response probably reflects the high placebo response obtained, which is probably a result of deficiencies in trial design. For example, the randomization ratio may result in high expectation of active treatment. Thus, while ethically patient exposure to placebo should be minimized, this must be balanced against the scientific rationale underpinning study design.

Adolescent↗

An open preference study with sumatriptan 50 mg and zolmitriptan 2.5 mg in 100 migraine patients.

Understanding factors influencing patients' preference will improve guidance to make rational choices in expanded symptomatic migraine treatment. The objective of this open-label, cross-over study was to explore patients' preferences for sumatriptan 50 mg vs. zolmitriptan 2.5 mg tablets, focusing on factors influencing this preference. One hundred consecutive migraine patients attending our clinics were asked to treat three attacks with each medication and then fill out a preference questionnaire. Ninety-four migraineurs completed the trial and 42 (44%, 95% CI 34-58%) reported that they preferred zolmitriptan 2.5 mg over sumatriptan 50 mg tablets and 27 (29%, 20-38%) preferred sumatriptan 50 mg. The remaining 25 (27%, 18-36%) did not show any preference. For the initial treatment of the attacks, there were more patients needing just one tablet of zolmitriptan 2.5 mg compared with sumatriptan 50 mg (67 vs. 39%). The reasons for preference among those 69 patients who had shown preference for either of the two triptans were: a faster onset of action (speed of onset) (73%), a longer duration of the effects (39%), fewer adverse events (35%) and lower price (13%). Only one-quarter of the studied migraine population thought that sumatriptan 50 mg and zolmitriptan 2.5 mg were equivalent, which suggests that most migraine patients differentiate between triptans. A faster onset of action (speed of onset) was the most important reason for preference.

Adult↗

The effect of sumatriptan on brain monoamines in rats.

Clinical data suggests that sumatriptan is effective in the acute treatment of migraine. The vascular effects of the drug have been invoked to explain this antimigraine efficacy. However, the effect of sumatriptan on brain monoamines has not previously been investigated. In order to study these hypothetical effects, we administered the drug to 24 male rats, subcutaneously, at three doses (0.3, 0.6, and 0.9 mg/kg of body weight), and 30 minutes later, all animals were decapitated. Dopamine, serotonin, and their metabolites 3,4 dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid, and homovanillic acid concentrations were measured in the frontal cortex, hypothalamus, striatum, and hippocampus, by high performance liquid chromatography. Plasma concentrations of the drug were also determined. The control group was treated with NaCl 0.9%, given subcutaneously. Sumatriptan, at the dose of 0.3 mg/kg did not alter the brain monoamine concentrations; however, at the dose of 0.6 mg/kg, sumatriptan decreased serotonin concentration in the hypothalamus and increased the turnover of dopamine and serotonin in the hypothalamus and striatum, while at the dose of 0.9 mg/kg, it augmented only the turnover of serotonin in the hypothalamus. No dose-dependent effect of the drug was found. This subcortical antidopaminergic and antiserotoninergic effect of sumatriptan may be involved in its antimigraine action.

3,4-Dihydroxyphenylacetic Acid↗

Sumatriptan-nonresponders: a survey in 366 migraine patients.

Sumatriptan, notably after subcutaneous administration, is highly effective in the acute treatment of migraine in the majority of patients. The response is consistent within patients and over time. To determine risk factors for nonresponse to sumatriptan, we compared clinical characteristics in responders and nonresponders and, within patients, between attacks with and without response. We found no differences at the strict level of significance (P < 0.001 because of multiple comparisons), but only tendencies for differences (0.001 < P < 0.05) in either the subcutaneous or oral groups. In the subcutaneous group, nonresponders had a higher body mass index, migraine onset at an earlier age, and, most importantly, they treated their migraine attacks earlier. In the oral group, nonresponders had attacks associated with more severe vomiting and photophobia, more often went to sleep or rest, and more frequently experienced initial worsening of the headache after sumatriptan administration. Within patients, no differences were found between attacks with and without response. In conclusion, we found few, if any, clinically relevant risk factors for nonresponse to sumatriptan. Administration of sumatriptan too early was the strongest indicator and should be avoided.

Administration, Oral↗

Using pretreatment quality of life perceptions to predict response to sumatriptan in migraineurs.

Quality of life perceptions vary for individuals with similar medical conditions and reflect disease impact. When correlated with subsequent response to treatment, such data may contribute useful insights in understanding the determinants of therapeutic effectiveness in selected medical conditions. Two hundred thirty-five migraine patients never previously treated with injectable sumatriptan completed a Short Form-36 questionnaire before receiving a supervised test dose and a prescription for the medication. Medical records were examined to determine the number of comorbid conditions, headache characteristics (age at onset, headache frequency, duration of disease, aura, association with menses, unilaterality, and emesis), and documentation of sumatriptan's effect in relieving migraine during 12 months of follow-up. Logistic regression was used to identify patient- and disease-specific features most closely associated with the dependent variable, clinical response. One hundred eighty-four patients (78%) reported both relief of symptoms and continued usage of sumatriptan. Patients who experienced emesis with headaches (OR = 2.05 [1.07, 3.91]) and those with higher pretreatment Physical Functioning scores (OR = 3.27 [1.28, 8.37]) were more likely to respond to sumatriptan. Response to sumatriptan therapy was associated with specific pretreatment quality of life domains and headache features. These results may be useful in improving the efficiency of disease management strategies for patients with migraine.

Adult↗