sumatriptan, Imitrex
Role of tension receptors in dyspeptic patients with hypersensitivity to gastric distention.

Tack J, Caenepeel P, Corsetti M, Janssens J.

Department of Internal Medicine, University Hospital Gasthuisberg, University of Leuven, Belgium. Jan.Tack med.kuleuven.ac.be

BACKGROUND & AIMS: Studies in health have shown that tension-sensitive mechanoreceptors mediate sensitivity to gastric distention. A role for these mechanoreceptors in perception or symptoms in hypersensitive functional dyspepsia (FD) has not been established. Tension-sensitive mechanoreceptors are activated during phasic contractions and inactivated during gastric relaxation. The aim of the present study was to investigate whether hypersensitive FD patients perceive spontaneous changes in fundic wall tension and whether fundus-relaxing drugs decrease sensitivity to gastric distention and meal-related symptoms. METHODS: Fifty patients were selected after a barostat study established gastric hypersensitivity. In 12 patients, an intragastric balloon was inflated with a fixed volume just below perception thresholds and patients were asked to indicate changes in perception on a keypad, and the relationship between perception and contractions was analyzed. In 20 patients, we studied the influence of the fundus-relaxing drug sumatriptan on sensitivity to gastric distention. In, respectively, 10 and 8 patients, we studied the influence of the fundus-relaxing drugs sumatriptan and clonidine on meal-related symptoms. RESULTS: The majority of patients had a statistically significant association between perception and phasic isovolumetric contractions. Pretreatment with sumatriptan increased both pressures and volumes needed to induce first perception and discomfort. Pretreatment with sumatriptan and clonidine both significantly decreased meal-induced symptoms. CONCLUSIONS: Patients with hypersensitivity to gastric distention perceive isovolumetric phasic contractions of the proximal stomach. Fundus-relaxing drugs decrease sensitivity to gastric distention and decrease meal-induced symptoms in these patients. The findings are compatible with involvement of tension mechanoreceptors in symptom generation in hypersensitive FD.

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sumatriptan, Imitrex
Long-term tolerability of sumatriptan nasal spray in adolescent patients with migraine.

Natarajan S, Jabbour JT, Webster CJ, Richardson MS.

Department of Pediatric Neurology, Le Bonheur Children's Hospital, Memphis, TN, USA.

OBJECTIVE: This 1-year, open-label, multicenter study was designed to assess the long-term tolerability and efficacy of sumatriptan nasal spray 20 mg in adolescent patients with migraine. METHODS: A prospective, multicenter, open-label study was conducted in patients aged 12 to 17 years who were allowed to treat an unlimited number of migraines at severe, moderate, or mild pain intensity with sumatriptan nasal spray for up to 1 year. All patients started the study at the 20-mg dose of sumatriptan nasal spray. Dose could be adjusted downward to 5 mg at the discretion of the investigator to optimize therapy. RESULTS: A total of 484 adolescent migraineurs treated 4676 migraines with sumatriptan nasal spray 20 mg (3593 during the first 6 months and 1083 during the second 6 months). A total of 3940 migraines and 699 migraines were treated with one and two 20-mg doses of sumatriptan nasal spray, respectively. Only 10 patients (treating 42 migraines) took the 5-mg dose of sumatriptan nasal spray. The overall percentage of migraines treated with either one 20-mg dose or one, two, or three 20-mg doses with at least 1 drug-related adverse event was 19%. The most common specific drug-related adverse event was unpleasant taste, reported in 17% of migraines. No other single drug-related adverse event was reported in more than 1% of migraines over the 1-year treatment period. When unpleasant taste was excluded from the adverse-event tabulations, the percentages of migraines with at least 1 drug-related adverse event after one or one, two, or three 20-mg doses declined to 4% and 3%, respectively. No patient experienced any drug-related changes in 12-lead ECGs, vital signs, or nasal assessments; and no clinically meaningful changes in clinical laboratory values were observed. Across all migraines with evaluable efficacy data (n=4334), headache relief was reported in 43% of migraines at 1 hour and in 59% at 2 hours after dosing with sumatriptan nasal spray 20 mg. Of the 2561 migraines with headache relief 2 hours postdose, headache recurrence was reported within 24 hours of initial dosing in 7% of migraines. None of the efficacy or tolerability results varied as a function of time in the study (ie, first 6 months vs. second 6 months). CONCLUSION: Sumatriptan nasal spray 20 mg is generally well tolerated and may be beneficial during long-term use by adolescent migraineurs ages 12 to 17 years.

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sumatriptan, Imitrex
MIGRAINE TREATMENT.

[No authors listed]

Wenzel R, Dortch M, Cady R, Loland JH, Diamond S. Migraine headache misconceptions: barriers to effective care. Pharmacotherapy. 2004;24:638-648. Migraine headaches affect 12% of the adult population in the United States and cause a significant economic loss due to decreased workplace productivity. Although interactions between pharmacists and individuals with headache are common, few pharmacists receive adequate training regarding migraine therapy. We refute several misconceptions that hinder effective care, such as that migraine is a vascular disease, triptans cause rampant cardiac-related morbidity and even mortality, a best oral triptan exists, sinus and tension headaches are prevalent, and migraine is a minor economic problem. Our pathophysiologic understanding demonstrates that migraine is a neurologic process of the trigeminovascular system, of which vascular effects are secondary. This process can result in a myriad of clinical signs and symptoms, often leading to a misdiagnosis of sinus or tension headache. The last decade's experience with triptans in more than half a billion people worldwide reveals a benign adverse-effect profile, particularly when taken early in an attack. Published reports and real-world experiences illustrate that these drugs do not merit fears of triptan-induced cardiac consequences in appropriately selected individuals. Society's productivity loss due to migraine is measured in billions of dollars. Restoring a patient's ability to function normally is now recognized as the primary treatment goal, not merely relieving pain. Thus, the overreliance on "pain killer" drugs such as butalbital-containing products and the continued underutilization of migraine-specific drugs need to be addressed. Opportunities exist for pharmacists and other health care providers to dispel continually propagated migraine misconceptions and familiarize themselves with advances in therapy. Such actions will benefit patients, the health care system, and society as a whole. Comment: This is a marvelous review for residents and primary care practitioners.-Stewart J. Tepper This is a thought provoking article which deserves to be widely discussed. It contains many home truths which should have considerable impact for health care practitioners and will provide useful ammunition for patient groups and headache physicians battling to access resources for headache patients. We reached similar conclusions following our U.K. population survey of headache treatment and health care utilization. Undoubtedly, pharmacists and other health care professionals can act as important conduits to facilitate the prompt effective treatment of headache.-David S. Millson Apfel CC, Korttila K, Abdalla M, Kerger H, Turan A, Vedder I, Zernak C, Danner K, Jokela R, Pocock SJ, Trenkler S, Kredel M, Biedler A, Sessler DI, Roewer N, IMPACT Investigators. a factorial trial of six interventions for the prevention of postoperative nausea and vomiting. N Engl J Med. 2004;350:2441-2451. Background: Untreated, one-third of patients who undergo surgery will have postoperative nausea and vomiting. Although many trials have been conducted, the relative benefits of prophylactic antiemetic interventions given alone or in combination remain unknown. Methods: We enrolled 5199 patients at high risk for postoperative nausea and vomiting in a randomized, controlled trial of factorial design that was powered to evaluate interactions among as many as three antiemetic interventions. Of these patients, 4123 were randomly assigned to 1 of 64 possible combinations of six prophylactic interventions: 4 mg of ondansetron or no ondansetron; 4 mg of dexamethasone or no dexamethasone; 1.25 mg of droperidol or no droperidol; propofol or a volatile anesthetic; nitrogen or nitrous oxide; and remifentanil or fentanyl. The remaining patients were randomly assigned with respect to the first four interventions. The primary outcome was nausea and vomiting within 24 hours after surgery, which was evaluated blindly. Results: Ondansetron, dexamethasone, and droperidol each reduced the risk of postoperative nausea and vomiting by about 26%. Propofol reduced the risk by 19%, and nitrogen by 12%; the risk reduction with both of these agents (ie, total intravenous anesthesia) was thus similar to that observed with each of the antiemetics. All the interventions acted independently of one another and independently of the patients' baseline risk. Consequently, the relative risks associated with the combined interventions could be estimated by multiplying the relative risks associated with each intervention. Absolute risk reduction, though, was a critical function of patients' baseline risk. Conclusions: Because antiemetic interventions are similarly effective and act independently, the safest or least expensive should be used first. Prophylaxis is rarely warranted in low-risk patients, moderate-risk patients may benefit from a single intervention, and multiple interventions should be reserved for high-risk patients. Comment: We do not know the mechanism of postop nausea, but it is likely to be both medication-induced and central, with potential central generators being nucleus tractus solitariuus and medullary area postrema. Both dopamine and serotonin are clearly involved, and probably Substance P, and we also do not know the relation between migrainous nausea and iatrogenic nausea. Although ondansetron, a 5-HT3-receptor antagonist was included in the randomization, aprepitant, the Substance P/NK1 antagonist antinauseant, synthesized by Richard Hargreaves and team, was not in the study. I included this article as food for thought: which of these medications should we use for our migraine patients, and should we combine multiple medications? I believe a randomized controlled trial of antinauseants alone in treatment of migraine nausea is in order.-Stewart J. Tepper I agree with Dr. Tepper that a randomized comparator trial is urgently needed for treatment of nausea in migraine. I was a little puzzled to see fentanyl and remifentanil described as potential antinausea agents. I would have assumed they are less effective or may actually cause nausea as predicted by their pharmacology. The early studies with ondansetron suggested a potential role in the acute treatment of migraine. However, later work using an early headache classifications and trial designs failed to confirm efficacy (Ferrari MD. 5-HT3-receptor antagonists and migraine. J Neurol. 1991;238:S53-S56). Perhaps the newer antinauseants deserve revisiting given recent developments with the IHS classification and trial designs.-David S. Millson Dodick DW, Martin V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia. 2004;24:417-424. Triptans are the treatment of choice for acute migraine. While seemingly a homogenous group of drugs, results from a meta-analysis reveal significant differences in efficacy and tolerability among oral triptans. The incidence of drug-related central nervous system (CNS) side-effects with some triptans is as high as 15% and may be associated with functional impairment and reduced productivity. The occurrence of adverse events associated with triptans in general, and CNS side-effects in particular, may lead to a delay in initiating or even avoidance of an otherwise effective treatment. Potential explanations for differences among triptans in the incidence of CNS side-effects may relate to pharmacological and pharmacokinetic differences, including receptor binding, lipophilicity, and the presence of active metabolites. Of the triptans reviewed, at clinically relevant doses, almotriptan 12.5 mg, naratriptan 2.5 mg, and sumatriptan 50 mg had the lowest incidence of CNS side-effects, while eletriptan 40 and 80 mg, rizatriptan 10 mg, and zolmitriptan 2.5 and 5 mg had the highest incidence. The most likely explanations for the differences in CNS side-effects among triptans are the presence of active metabolites and high lipophilicity of the parent compound and active metabolites. Eletriptan, rizatriptan, and zolmitriptan have active metabolites, while lipophilicity is lowest for almotriptan and sumatriptan. If CNS side-effects are a clinically relevant concern in the individual patient, use of a triptan with a low incidence of CNS side-effects may offer the potential for the earlier initiation of treatment and more effective outcomes. Comment: This article raises more questions than it answers. CNS penetration and liphophilicity do indeed go hand in hand as described by Professor Peter Goadsby in his review (Goadsby P. A triptan too far? J Neurol Neurosurg Psychiatry. 1999;66:121). However, this relationship is questionable in relation to naratriptan which is at least as liphophilic as zolmitriptan and rizatriptan. For naratriptan the FDA mandated a maximum daily dose of 5 mg due to concerns relating to CNS toxicity with higher doses. This also explains why the subcutaneous formulation was abandoned. I do not believe that active metabolites contribute significantly to CNS activity unless they accumulate (which is not the case). Triptan metabolites are usually less liphophilic generated by first pass through the liver (in many cases N-demethylation) which renders them more water soluble and enhances renal elimination. CNS side-effects are also related to onset of action with a trade-off for increased efficacy within 30 minutes with oral formulations of eletriptan, rizatriptan, and zolmitriptan versus the slower onset of naratriptan and frovatriptan. Other factors predicting CNS penetration relate to uptake and competition for the P-gp phospho glycoprotein pump which facilitates the exclusion of lipophilic drugs from the CNS and for which eletriptan is a substrate.-David S. Millson Sender J, Bradford S, Watson D, Lipscombe S, Rees T, Manley R, Dowson AJ. Setting up a Specialist Headache Clinic in primary care: general practitioners with a special interest in headache. Headache Care. 2004;1:165-171. Part of the National Health Service modernization process is to develop General Practitioners with Special Interest (GPwSI) services for intermediate care. Management of headache is currently poor in the United Kingdom due to a lack of trained health care professionals, patients not accessing care, and a reliance on ineffective medications. This warrants the development of GPwSI in headache services. The Royal College of General Practitioners has produced a framework document for the development of an intermediate care service for headache. While this describes what needs to be present in such a service, it does not address the practicalities of implementing it. This article provides organizational and practical guidance for setting up such a service. The majority of headache patients can be managed by multidisciplinary GP- or GPwSI-based care teams located in Primary Care Trusts. Relatively few patients need to referred to secondary care services. The processes of headache management are the same for the whole case mix, involving initial screening, diagnosis, assessment of severity, prescription of therapies tailored to the individual patient's needs, and proactive follow-up. However, the successful implementation of such services poses significant economic and professional challenges to both health care providers and physicians that must be overcome for this program to be successful. Comment: As an American who travels to the United Kingdom a bit, and counts many British as friends, let me try to summarize how this works. The UK National Health Service (NHS) is hierarchical, and specialists are limited in number and often difficult to access for general practitioners (GPs), especially in the hinterlands. Since GPs provide the majority of care in the United Kingdom, control has been placed regionally in Primary Care Trusts run by primary care doctors. A provision has been instituted to allow GPs with special interest in particular specialties to train to provide care in place of specialists, to reduce the burden of referrals to the overtaxed specialists. These GPs with Special Interest (GPwSIs, pronounced "gypsies") have the potential to give outstanding and badly needed care, and headache is an obvious need. The training would be similar to what Dr. Andy Dowson has championed with his Migraine in Primary Care Advisors (MIPCA) in the United Kingdom, and Roger Cady and the Primary Care Network (PCN) provides to primary care practitioners in the United States, but longer and with more bureaucratic documentation. In the United States, certified headache fellowships exist, and we do not distinguish between the training of the doctors at onset-any interested licensed physician can do a headache fellowship. US qualifying Headache Boards, in the works, may also be allowed for licensed physicians who have completed certified fellowships.-Stewart J. Tepper Sang CN, Ramadan NM, Wallihan RG, Chappell AS, Freitag FG, Smith TR, Silberstein SD, Johnson KW, Phebus LA, Bleakman D, Ornstein PL, Arnold B, Tepper SJ, Vandenhende F. LY293558, a novel AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute migraine. Cephalalgia. 2004;24:596-602. Glutamatergic hyperactivity is implicated migraine pathogenesis. Also, LY293558, an alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate (KA) receptor antagonist, is effective in preclinical models of migraine. We therefore tested LY293558 in acute migraine. We conducted a randomized, triple-blind, parallel-group, double-dummy, multicenter trial of 1.2 mg/kg intravenous (IV) LY293558, 6 mg subcutaneous (SC) sumatriptan, or placebo in the treatment of acute migraine. The primary efficacy variable was the headache response rate, ie, headache score improvement from moderate/severe at baseline to mild/none at 2 hour. Of 45 enrolled patients, 44 patients (20:24 [M:F]; mean age +/- SD = 40 +/- 9 years) completed the study. Response rates were 69% for LY293558 (P= .017 vs. placebo), 86% for sumatriptan (P < .01 vs. placebo), and 25% for placebo. LY293558 and sumatriptan were superior to placebo (P < .01 for all comparisons) on all other measures of improvement in pain and migraine-associated symptoms. Fifteen percent of patients who took LY293558 reported adverse events (AEs) (n = 2; 1 mild, 1 severe). Fifty-three percent of patients who took sumatriptan (n = 8; 7 mild, 1 moderate) and 31% of those who received placebo reported AEs (n = 5; 4 mild, 1 severe). The efficacy and safety results of LY293558 in this small migraine proof of concept trial, together with supportive preclinical data, provide evidence for a potential role of nonvasoactive AMPA/KA antagonists in treating migraine. Larger trials are needed to further test the hypothesis. Comment: This is a seminal proof of concept study for the first AMPA/KA antagonist demonstrating potential efficacy approaching that of subcutaneous (SC) sumatriptan in acute migraine. I would be intrigued to know if the adverse events (AEs) relating to SC sumatriptan were perceived by patients with prior triptan experience (difficult to avoid in the United States!) and may have allowed them to identify treatment. The important next step must be to dose range the new agent and to identify either a rapidly acting oral formulation or parenteral route (eg, intranasal, transdermal). This small scale efficacy trial, if confirmed for a nonvasoactive AMPA/KA antagonist, may pave the way for an alternative to the triptans. -David S. Millson.

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sumatriptan, Imitrex
Cluster headache: symptomatic treatment.

Torelli P, Manzoni GC.

Headache Centre, Section of Neurology, Department of Neuroscience, University of Parma, Via Gramsci 14, I-43100 Parma, Italy. paolatorelli libero.it

The clinical management of cluster headache (CH) attacks requires a symptomatic treatment that is rapidly effective in resolving or significantly reducing symptoms. First-choice drugs for the symptomatic treatment of CH are subcutaneous sumatriptan at a dose of 6 mg and 100% oxygen inhalation at a rate of 7 l/min for no more than 15 min. Sumatriptan acts by suppressing pain and the accompanying autonomic phenomena, with no substantial differences in its mechanism of action between episodic and chronic CH. The drug can be used for prolonged periods without loss of efficacy or safety and its side-effects are generally mild or moderate. Oxygen inhalation has a number of advantages over drug therapy: it is free from side-effects, has no contraindications--unlike sumatriptan, it can be used in patients with cardiac, cerebral or peripheral vascular disease and with kidney, liver or lung disease--acts rapidly and can be administered several times a day. Its disadvantages are that it is scarcely practical and may induce a "rebound effect". Sumatriptan nasal spray, zolmitriptan and dihydroergotamine nasal spray are scarcely effective. After the introduction of sumatriptan, ergotamine tartrate has been relegated to a secondary role in the symptomatic treatment of CH. Among other non-drug and topical drug treatment options, hyperbaric oxygen therapy and the intranasal application of 10% cocaine hydrochloride and 10% lidocaine in the sphenopalatine fossa have also proved effective.

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sumatriptan, Imitrex
In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

Wilding IR, Clark D, Wray H, Alderman J, Muirhead N, Sikes CR.

Pharmaceutical Profiles, Ltd, Nottingham, United Kingdom.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

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sumatriptan, Imitrex
Daily sumatriptan for detoxification from rebound.

Drucker P, Tepper S.

From the University of Washington School of Medicine, Seattle.

Medications which provide symptomatic relief from headache can transform episodic migraine into chronic daily headache by propagating the daily headache, causing "rebound." It is possible to restore the episodic migraine pattern by using an inpatient course of intravenous dihydroergotamine. This study was undertaken to explore whether it was possible to use oral sumatriptan in the outpatient setting as a bridge to detoxification for patients with chronic daily headache due to medication overuse. All patients had previously met International Headache Society (IHS) criteria for episodic migraine and currently had greater than 15 days of headache per month for greater than 1 month. These patients were advised to take 25 mg sumatriptan by mouth three times a day for 10 days or until they were headache-free for 24 hours. Results reveal that of the 26 patients who started the protocol, 58% had reverted to an episodic migraine pattern at 1 month, and 69% were no longer having chronic daily headache at 6 months. This study demonstrates that it is possible to detoxify patients with rebound headaches using oral sumatriptan during the withdrawal period in an outpatient setting.

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sumatriptan, Imitrex
MIGRAINE EPIDEMIOLOGY, CLINICAL SYMPTOMS, AND TREATMENT.

[No authors listed]

Thomas E, Boardman H, Ogden H, Millson D, Croft P. Advice and care for headaches: who seeks it, who gives it?Cephalalgia. 2004;24:740-752. Using data from a cross-sectional survey and a prospective record linkage study, the aims of this study were to (i) determine sources of advice and care for headaches in a population survey of adults and (ii) investigate prospectively the influences of headaches on general practice consultation in a 12-month follow-up of the responders to the population survey. A population-based cross-sectional survey was mailed to 4885 adults (aged >/=18 years) with an adjusted response rate of 56% (n = 2662). The main outcome measures of interest were (i) self-report advice and care-seeking in the survey, (ii) consultation with general practitioner for headache and for other conditions in 12-month period subsequent to the survey. Reporting a recent GP consultation for headache was associated with younger age (mean: 46 vs 48 years), female gender (68% vs 60%), and greater headache severity as measured by frequency, pain, and associated disability. The most common sources of advice and care in the past were GPs (27%), opticians (21%), and pharmacists (8%). Consultations for headache were not common in the 12 months following the survey (n = 144); however, those reporting a recent headache were almost four times more likely to consult subsequently with a headache than those who did not (relative risk; 95% CI: 3.7; 1.9, 7.0). Recent reporting of headache was also associated with an increased risk of consulting for mental disorders (1.7; 1.2, 2.6), diseases of the digestive (1.6; 1.1, 2.3) and respiratory system (1.4; 1.1, 1.8), and a decreased risk of consulting for circulatory diseases (0.8; 0.7, 1.0). Only a minority of headache sufferers consults their GP, regardless of severity, with opticians and pharmacists being other important sources of information. Headache appears to have an additional impact upon GP workload through increased rates of consultations for nonheadache conditions among headache sufferers. The interesting findings regarding rates of consultation for digestive and circulatory conditions among headache sufferers may be linked to the use of headache medication. Comment: A fascinating study, in that it not only discusses with whom UK headache patients seek care, but also their comorbid complaints, and ties in the comorbidity and primary headache disorder -Stewart J. Tepper, MD Dowson AJ, Tepper SJ, Baos V, Baudet F, D'Amico D, Kilminster S. Identifying patients who require a change in their current acute migraine treatment: the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire. Curr Med Res Opin. 2004;20:1125-1135. Background: Currently available measures of the efficacy of acute migraine medications are not frequently used in primary care. They may be too burdensome and complicated for routine use. Objectives: To design and test a new, easy-to-use, four-item assessment tool, the Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire for use by clinicians, to quickly evaluate how a recently prescribed acute medication is working, and to identify patients who require a change of their current acute treatment. Methods: A 27-item Migraine-ACT questionnaire was developed by an international advisory board of headache specialists. Questions were formulated in four domains: headache impact, global assessment of relief, consistency of response, and emotional response. All these are clinically important measures of migraine severity and treatment outcome. All questions were dichotomous and answered by "yes" or "no." Patients (n = 185) attending secondary care headache clinics who were diagnosed with migraine according to International Headache Society criteria entered a multinational, prospective, observational study to investigate the test-retest reliability and construct validity of the 27-item Migraine-ACT. Patients completed the Migraine-ACT on two occasions, separated by a 1-week interval, and test-retest reliability was assessed by Pearson product moment and Spearman rank measures. Construct validity was assessed by correlating patients' answers to the 27-item Migraine-ACT with those to other questionnaires (individual domains and total scores) conceptually related to it; the Short-Form 36 quality-of-life questionnaire (SF-36), the Migraine Disability Assessment (MIDAS) questionnaire, and the Migraine Therapy Assessment Questionnaire (MTAQ). Discriminatory t-tests were used to identify the four Migraine-ACT questions (one in each domain) which discriminated best between the domains of the SF36, MIDAS, and MTAQ. These four items constituted the final four-item Migraine-ACT. Results: The test-retest reliability of the 27 Migraine-ACT questions ranged from good to excellent, and correlation coefficients were highly significant for all items. The consistency of reporting the yes and no answers was also excellent. Correlations of Migraine-ACT items with SF-36 and MIDAS items and SF-36, MIDAS, and MTAQ total scores indicated that the following were the most discriminating items, in the respective four domains, and constitute the final Migraine-ACT questionnaire: Consistency of response: Does your migraine medication work consistently, in the majority of your attacks? Global assessment of relief: Does the headache pain disappear within 2 hours? Impact: Are you able to function normally within 2 hours? Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities? The four-item Migraine-ACT was shown to be highly reliable (Spearman/Pearson measure r= 0.82). The individual questions, and the total four-item Migraine-ACT score, showed good correlation with items of the SF-36, MIDAS, and MTAQ questionnaires, particularly with the total MTAQ and SF-36 scores. Conclusions: The four-item Migraine-ACT questionnaire is an assessment tool for use by primary-care physicians to identify patients who require a change in their current acute migraine treatment. It is brief and simple to complete and score, and has demonstrated reliability, accuracy, and simplicity. Migraine-ACT can therefore be recommended for everyday clinical use by clinicians. Comment: Dowson et al have developed a useful tool with which to assess the clinical efficacy of acute migraine treatments. Migraine-ACT does seem to be a simple tool to apply at the coalface of clinical practice in primary care. They report good test-retest reliability with construct validity and have focused in on four key items (representing four domains) from a possible 27 questions. Might this become a new gold standard for use in migraine clinical trials?-David S. Millson, MD Goldstein JA, Massey KD, Kirby S, Gibson M, Hettiarachchi J, Rankin AJ, Jackson NC. Effect of high-dose intravenous eletriptan on coronary artery diameter. Cephalalgia. 2004;24:515-521. The goal of this study was to evaluate the coronary vasoconstrictive effects of high doses of eletriptan compared with a standard dose of sumatriptan. Patients with no clinically significant coronary artery disease were randomized to receive high-dose intravenous eletriptan (n = 24) versus a standard dose of sumatriptan (n = 18; 6 mg subcutaneously) versus placebo (n = 18). Serial angiograms were obtained. The primary noninferiority analysis found equivalence between the mean maximum change in left anterior descending coronary artery diameter for eletriptan, -22%[95% confidence interval (CI) -26, -19], and sumatriptan, -19% (95% CI -22, -16). The change due to placebo was -16% (95% CI -20, -12). No individual cases of clinically significant vasoconstriction were observed. The results confirm that eletriptan has a broad cardiovascular safety margin, with plasma concentrations comparable to three to five times the C(max) of an oral 80-mg dose associated with modest vasoconstriction equivalent to standard therapeutic doses of sumatriptan. Comments: A very reassuring study on the cardiovascular effects of eletriptan at massively supratherapeutic doses, administered intravenously to boot. And the data on sumatriptan are also reassuring. This study, which was suggested by the FDA, is well worth reading in its entirety.-Stewart J. Tepper, MD I agree with Dr. Tepper this is reassuring data for the cardiovascular safety of eletriptan, with subcutaneous sumatriptan as a positive control showing comparable lack of vasoconstriction. Whether this makes the higher dose of eletriptan (80 mg orally) any more acceptable as a starting dose remains to be seen given its drug interaction profile. Unfortunately, clinicians rarely know the "true status" of coronary disease in their patients prior to exposure to a triptan and will still need to apply the cautious template warnings recommended by FDA, which have served us all very well in maintaining the excellent safety profile of the triptans thus far.-David S. Millson, MD Kolodny A, Polis A, Battisti WP, Johnson-Pratt L, Skobieranda F, on behalf of the Rizatriptan Protocol 052 Study Group. Comparison of rizatriptan 5 mg and 10 mg tablets and sumatriptan 25 mg and 50 mg tablets. Cephalalgia. 2004;24:540-546. This randomized, double-blind, two-attack, placebo-controlled, crossover study explored the efficacy and tolerability of rizatriptan 10 mg compared with sumatriptan 50 mg as well as rizatriptan 5 mg compared with sumatriptan 25 mg in the acute treatment of migraine. Following randomization to one of six possible treatment sequences, patients (n = 1447) treated two sequential attacks of moderate or severe intensity separated by at least 5 days. Patients assessed pain severity, migraine-associated symptoms, and functional disability at 0.5, 1, 1.5, and 2 hours post-treatment. Compared with placebo, all treatments were effective. On the primary endpoint of time to pain relief, rizatriptan 10 mg was not statistically different from sumatriptan 50 mg [odds ratio (OR) 1.10, P= .161], and rizatriptan 5 mg was statistically superior to sumatriptan 25 mg (OR 1.22, P= .007). In general, rizatriptan 10 and 5 mg treatment resulted in improvement compared with the corresponding doses of sumatriptan on measures of pain severity, migraine symptoms, and functional disability, and the 5-mg dose reached statistical significance on almost all measures. All treatments were generally well tolerated. Comments: Merck did three rizatriptan-sumatriptan comparison studies. The first two were: Tfelt-Hansen P, Teall J, Rodriguez F, Giacovazzo M, Paz J, Malbecq W, Block GA, Reines SA, Visser WH. Oral rizatriptan versus oral sumatriptan: a direct comparative study in the acute treatment of migraine. Rizatriptan 030 Study Group. Headache. 1998;38:748-755 and Goldstein J, Ryan R, Jiang K, Getson A, Norman B, Block GA, Lines C. Headache. 1998;38:737-747. The current study, completed years ago and always available by request from Merck all these years, is the third. The endpoint of time to pain relief was made difficult to interpret by inclusion as successes patients who obtained pain relief, and then had recurrence in less than 2 hours, which swirled as controversy when these studies were initially presented. In addition, as Dr. Marek Gawel pointed out in a review of these studies (Gawel M, Wiebe S. Evidence-based analysis of a migraine treatment drug comparison trial. Cephalalgia. 2000;20 Suppl 2:33-38), there was an asymmetry in comparison groups, in that patients were required to be rizatriptan, but not sumatriptan naive, although that bias does not clearly cut one way or another. Nonetheless, symmetry of comparison groups is most important in comparative studies.-Stewart J. Tepper, MD The delayed publication of this study is a cause for concern. Why has it taken so long to reach the light of day? Given the failure to show robust evidence of superiority for rizatriptan 10 mg versus sumatriptan 50 mg, one is tempted to speculate that commercial factors have influenced dissemination of results which may have been at variance with other marketing messages at time of launch. A recent independent [2004] review of this study published on the internet by the Canadian Evidence based Practice Centre commented: Another (Merck Study #052) has never been published. Because this study has not been published, the adequacy of randomization and of other aspects of the study design cannot be assessed. Some results from this trial were reported in a meta-analysis (Ferrari 2002). Sumatriptan 50 mg and rizatriptan 5 mg were similar in pain relief and pain-free responses at 2 hours. Sumatriptan had a small advantage in 24-hour sustained response which did not reach statistical significance (6%, CI: 1 to 13), Rizatriptan 5 mg was associated with significantly fewer adverse events (12%, CI: 4 to 20). In the same trial, sumatriptan 25 mg was indistinguishable from rizatriptan 10 mg on all efficacy measures, and was indistinguishable from rizatriptan 5 mg on all measures except for time to relief. (Helfand M, Peterson K. Oregon Evidence-based Practice Center, Oregon Health & Science University, page 60/120. http://www.ohsu.edu/drugeffectiveness/reports/documents/Triptans_Updated_Final_Report_1.pdf. Accessed on 29th August 2004) -David S Millson, MDCook AJ, Roberts DA, Henderson MD, Van Winkle LC, Chastain DC, Hamill-Ruth RJ. Electronic pain questionnaires: a randomized, crossover comparison with paper questionnaires for chronic pain assessment. Pain. 2004;110:310-317. Electronic questionnaires for pain assessment are becoming increasingly popular. There have been no published reports to establish the equivalence or psychometric properties of common pain questionnaires administered via desktop computers. This study compared responses to paper (P) and touch screen electronic (E) versions of the Short-Form McGill Pain Questionnaire (SF-MPQ), and Pain Disability Index (PDI), while examining the role of computer anxiety and experience, and evaluating patient acceptance. In a randomized, crossover design, 189 chronic pain patients completed P and E versions of the SF-MPQ and PDI, and self-ratings of anxiety, experience, relative ease, and preference. Psychometric properties were highly similar for P and E questionnaires. For the SF-MPQ, 60% or more of subjects gave equivalent responses on individual descriptors and PPI scale, with 80% rating within +/-1 point for an 11-point VAS. Correlations for the SF-MPQ scales ranged from 0.68 to 0.84. For the PDI, 60% or more of subjects responded within +/-1 point on individual questions, and the total score correlation was 0.67. Comparison of mean difference scores revealed no significant differences between modes for any of the questionnaire items or scores. Anxiety and experience scores showed no significant associations through correlations and high/low comparisons. Although nearly half of the subjects reported no computer training, anxiety ratings were low, and considerably more subjects rated the E questionnaires as easier and preferred. Findings are consistent with test-retest reliability data, and support the validity and acceptance of electronic versions of the SF-MPQ and PDI. Comment: In research, we are increasingly using computers to gather clinical data, but it turns out no one has asked whether they work as well as paper gathering techniques. This study suggests that it is fine to continue the electronic revolution in data collection.-Stewart J. Tepper, MD Pringsheim T, Gooren L. Migraine prevalence in male to female transsexuals on hormone therapy. Neurology. 2004;63:593-594. Migraine prevalence is three times higher in women than men, suggesting that sex hormones may be involved in migraine generation. To further understand the relationship between migraine and sex hormones, we assessed male to female transsexuals (MFTs) using antiandrogens to suppress male sex characteristics and estrogens to induce female sex characteristics for the presence of headache. Compared with The Netherlands' population data, the migraine prevalence of 26% in MFTs is similar to the prevalence of 25% in genetic females and significantly greater than the prevalence of 7.5% in men. Thirty-one percent of patients in the GEM study with migraine had migraine with aura. In our study, 54% of MFTs with migraine or probable migraine headache endorsed visual phenomena before the onset of their headaches in contrast to 2 of 22 (9%) with tension headache. This is interesting given observations on the relationship between high estrogen states and aura. Patients developing migraine aura while using estrogen replacement therapy have been described in which reducing the estrogen dose was associated with the loss of aura. Similarly, when migraine develops for the first time during pregnancy, it is significantly more likely to be migraine with aura. The higher frequency of aura symptoms in MFTs may be related to the high doses of estrogens used. Possible explanations for the prevalence of migraine in MFTs taking hormone therapy include structural differences in the transsexual brain (a female-sized bed nucleus of the stria terminalis has been found in MFTs) that migraine headache is part of the female gender role, or that the stresses of gender reassignment are triggering headache. However, the authors speculate that the prevalence of migraine in MFTs on hormonal therapy is more likely related to the effect of antiandrogen and estrogen therapy on nitric oxide (NO). NO is a known migraine trigger and has a role in mediating nociceptive transmission in migraine. Circulating NO originates mainly from the vascular endothelium. NO levels are influenced by estrogen, which stimulates NO synthesis. Estrogen decreases vascular tone by its effect on NO, which causes endothelium-dependent vasodilation. Antiandrogen treatment in MFTs increases circulating NO levels by 72%. Estrogen treatment in MFTs has been shown to improve endothelial (NO)-dependent vasodilation in the forearm resistance circulation. These physiologic changes in circulating NO and endothelial-dependent vasodilation related to the use of estrogens and antiandrogens may contribute to the generation of migraine in this unique group of patients. In conclusion, MFTs taking hormonal therapy have similar rates of migraine as genetic females. Because this is a small and uncontrolled study, follow-up evaluation of this result is recommended with established baseline headache histories and examination by a neurologist to confirm the diagnosis. Lipton RB, Bigal ME, Steiner TJ, Silberstein SB, Olesen J. Classification of primary headaches. Neurology. 2004;63:427-435. Given the range of disorders that produce headache, a systematic approach to classification and diagnosis is an essential prelude to clinical management. For the last 15 years, the diagnostic criteria of the International Headache Society (IHS) have been the accepted standard. The second edition of The International Classification of Headache Disorders (January 2004) reflects our improved understanding of some disorders and the identification of new disorders. Neurologists who treat headache should become familiar with the revised criteria. Like its predecessor, the second edition of the IHS classification separates headache into primary and secondary disorders. The four categories of primary headaches include migraine, tension-type headache, cluster headache and other trigeminal autonomic cephalalgias, and other primary headaches. There are eight categories of secondary headache. Important changes in the second edition include a restructuring of these criteria for migraine, a new subclassification of tension-type headache, introduction of the concept of trigeminal autonomic cephalalgias, and addition of previously unclassified primary headaches. Several disorders were eliminated or reclassified. In this article, the authors present an overview of the revised IHS classification, highlighting the primary headache disorders and their diagnostic criteria. They conclude by presenting an approach to headache diagnosis based upon these criteria. Comment: A worthwhile stop on your way to perusing the full International Classification of Headache Disorders II available in Cephalalgia 2004;24(Supplement 1).-Stewart J. Tepper, MD Afridi SK, Kaube H, Goadsby PJ. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain. 2004;110(3):675-680. Studying attacks of migraine is considerably hampered by its fundamentally episodic nature. Developing approaches to triggering migraine reliably is important for advancing understanding of the disorder by facilitating its study. Based on the work of the Copenhagen Group, we administered an intravenous infusion of 0.5 mug/kg/min glyceryl trinitrate (GTN) to 44 migraineurs, 23 migraine without aura, 21 migraine with aura, and to 12 healthy controls. We sought to characterize the GTN-induced migraine in terms of the clinical features of the attacks and reproducibility of triggering, and included a nonmigraine control group for the purpose of comparing any effects to exclude an ordering effect. Of the 44 patients administered GTN, 33 had a migraine attack fulfilling International Headache Society criteria. Thirty-two attacks were of migraine without aura and one of migraine with aura. Twelve patients described typical premonitory symptoms, which have not been previously documented with GTN-induced migraine. A repeat attack was triggered in all subjects but one. In one case, a visual aura was also triggered both times. Our study shows that GTN-induced triggering is common in our patients, and remarkably reproducible. The data will facilitate the use of the GTN model in studies requiring extensive planning, such as brain imaging, or where preventive questions are at issue. We also report the first patient with a reproducible GTN-triggered migraine with aura. Comment: This study is further confirmation of Professor Jes Olesen's theory that nitric oxide is the final common pathway in migraine, and that GTN can serve as a vehicle for its production, resulting in delayed migraine. What is new and exciting is the description of triggering of premonitory symptoms, and of migraine with aura.-Stewart J. Tepper, MD.

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