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Background The efficacy of triptans as the main acute treatment strategy for migraine headache at the population-wide level needs to be understood to inform clinical decision-making. We summarise key trends in triptan use using more than 25 years of Danish nationwide data. Methods We conducted a nationwide register-based cohort study based on all Danish residents with access to public healthcare between 1 January 1994 and 31 October 2019 and summarise informative trends of all purchases of triptans in Denmark in the same period. Complete purchase records of Sumatriptan, Naratriptan, Zolmitriptan, Rizatriptan, Almotriptan, Eletriptan, and Frovatriptan were used. Findings Over a 25-year period, triptan use increased from 345 to 945 defined daily doses (DDD) per 1000 inhabitants per year and the yearly prevalence of triptan use increased from 5.17 to 14.57 per 1000 inhabitants. Between 2014 and 2019, 12.3% of the Danish migraine population purchased a triptan. Following their initial purchase, 43% of patients had not repurchased triptans within 5 years. At most, 10% of patients indicating triptan discontinuation tried more than one triptan. The prevalence of triptan overuse, defined as having purchased at least 20 DDDs of triptans per month for 3 consecutive months, increased in parallel with the prevalence of triptan use, prevalent in 56 of every 1000 triptan users every year between 2014 and 2019. Interpretation In a cohort with access to free clinical consultations and low medication costs, we observed low rates of triptan adherence, likely due to disappointing efficacy and/or unpleasant side effects rather than economic considerations. Triptan success continues to be hindered by poor implementation of clinical guidelines and high rates of treatment discontinuance.

Objective To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks. Methods A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study. Results Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( p = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( p = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( p

Aim Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments. Methods A “two-hit” hyperalgesic priming strategy was used to induce vulnerability to a normally subthreshold challenge with umbellulone, a transient receptor potential ankyrin 1 (TRPA1) activator, in uninjured female and male C57BL/6 mice. Priming (i.e. the first hit) was induced by three consecutive daily episodes of restraint stress; repeated umbellulone was also evaluated for potential priming effects. Sixteen days after the first restraint stress, mice received inhalational umbellulone (i.e. the second hit) to elicit migraine-like pain. Medications currently used for acute or preventive migraine therapy including propranolol (a beta blocker) and sumatriptan (5HT1B/D agonist), as well as olcegepant, an experimental calcitonin gene related peptide (CGRP) receptor antagonist and nor-Binaltorphimine (nor-BNI), an experimental long-acting kappa opioid receptor (KOR) antagonist, were investigated for their efficacy to block priming and prevent or reverse umbellulone-induced allodynia in primed animals. To assess migraine-like pain, cutaneous allodynia was determined by responses to periorbital or hindpaw probing with von Frey filaments. Results Repeated restraint stress, but not umbellulone exposure, produced transient cutaneous allodynia that resolved within 16 d. Restraint stress produced long-lasting priming that persisted beyond 16 d, as demonstrated by reinstatement of cutaneous allodynia following inhalational umbellulone challenge. Pretreatment with propranolol or nor-BNI prior to restraint stress prevented both transient cutaneous allodynia and priming, demonstrated by a lack of umbellulone-induced cutaneous allodynia. Following establishment of restraint stress priming, olcegepant, but not propranolol or nor-BNI, prevented umbellulone-induced cutaneous allodynia. When administered 1 h after umbellulone, sumatriptan, but not olcegepant, reversed umbellulone-induced cutaneous allodynia in restraint stress-primed rats. Conclusion We have developed a novel injury-free model with translational relevance that can be used to study mechanisms relevant to migraine-like pain and to evaluate novel acute or preventive treatments. Restraint stress priming induced a state of vulnerability to a subthreshold stimulus that has been referred to as “latent sensitization”. The development of latent sensitization could be prevented by blockade of stress pathways with propranolol or with a kappa opioid receptor antagonist. Following establishment of latent sensitization, subthreshold stimulation with umbellulone reinstated cutaneous allodynia, likely from activation of meningeal TRPA1-expressing nociceptors. Accordingly, in restraint stress-primed animals, sumatriptan reversed umbellulone-induced cutaneous allodynia, supporting peripheral sites of action, while propranolol and nor-BNI were not effective. Surprisingly, olcegepant was effective in mice with latent sensitization when given prior to, but not after, umbellulone challenge, suggesting time-dependent contributions of calcitonin gene-related peptide receptor signaling in promoting migraine-like pain in this model. Activation of the calcitonin gene-related peptide receptor participates in initiating, but has a more limited role in maintaining, pain responses, supporting the efficacy of small molecule calcitonin gene-related peptide antagonists as preventive medications. Additionally, the effectiveness of sumatriptan in reversal of established pain thus suggests modulation of additional, non-calcitonin gene-related peptide receptor-mediated nociceptive mechanisms. Kappa opioid receptor antagonists may represent a novel preventive therapy for stress-related migraine.

Background Migraine patients want acute treatment to provide complete relief of the migraine attack within 30 minutes. Traditionally, “speed of onset of effect” is evaluated by estimating the time-point for first statistical separation of drug and placebo. The estimated onset of effect can be a few percent difference of patients being pain free in very large randomised, controlled trials. This difference, however, can be clinically irrelevant. Methods Placebo-controlled randomised, controlled trials with pain freedom results from 30 min to 2–4 hours were retrieved from the literature. For each time-point, the therapeutic gain (drug minus placebo) (TG) was calculated. Therapeutic gain for being pain free of 5% was chosen for the definition of “onset of action”, since this is approximately 1/3 of the 16% TG and 1/4 of 21% of TG for sumatriptan 50 mg and 100 mg, respectively. Results A total of 22 time-effect curves based on randomised, controlled trials were analysed. Based on the “onset of action” of 5% pain freedom, the evaluated drugs and administration forms can be classified as follows: i) Early time to onset, ≤30 min (three randomised, controlled trials); ii) medium time to onset, 60 min (nine randomised, controlled trials); iii) delayed time to onset, 90–120 min (10 randomised, controlled trials). Conclusion Only three non-oral administration forms with a triptan (subcutaneous sumatriptan and nasal zolmitriptan) resulted in an “onset of action” at ≥30 min; in the future, early onset of action should be a priority in the development of new drugs or new administration-forms for the treatment of acute migraine attacks.

Introduction Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. Methods We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. Results Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38–90) vs. 100 (60–120) minutes ( p = 0.028), 4 (2.5–5) vs. 3 (2–4) attacks/day ( p = 0.024). No other difference was found. Conclusions In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

Background Ubrogepant, a small-molecule calcitonin gene-related peptide receptor antagonist, was recently approved as an oral medication for the acute treatment of migraine. This study aimed to determine whether ubrogepant shows efficacy in a preclinical model of migraine-like pain and whether repeated oral administration of ubrogepant induces latent sensitization relevant to medication overuse headache in rats. Methods A “two-hit” priming model of medication overuse headache was used. Female Sprague-Dawley rats received six oral doses of sumatriptan 10 mg/kg over 2 weeks to induce latent sensitization (i.e. “priming”). Cutaneous allodynia was measured periodically over 20 days in the periorbital and hindpaw regions using von Frey filaments. The rats were then subjected to a 1-hour bright light stress challenge on two consecutive days. At the start of the second bright light stress exposure, oral sumatriptan 10 mg/kg, oral ubrogepant 25, 50, or 100 mg/kg, or vehicle was administered; thereafter, cephalic and hindpaw sensory thresholds were monitored hourly over 5 hours to determine the efficacy of ubrogepant in reversing bright light stress-induced cutaneous allodynia. A dose of ubrogepant effective in the medication overuse headache model (100 mg/kg) was then selected to determine if repeated administration would produce latent sensitization. Rats were administered six oral doses of ubrogepant 100 mg/kg, sumatriptan 10 mg/kg (positive control), or vehicle over 2 weeks, and cutaneous allodynia was evaluated regularly. Testing continued until mechanosensitivity returned to baseline levels. Rats were then challenged with bright light stress on days 20 and 21, and periorbital and hindpaw cutaneous allodynia was measured. On days 28 to 32, the same groups received a nitric oxide donor (sodium nitroprusside 3 mg/kg, i.p.), and cutaneous allodynia was assessed hourly over 5 hours. Results Sumatriptan elicited cutaneous allodynia in both cephalic and hindpaw regions; cutaneous allodynia resolved to baseline levels after cessation of drug administration (14 days). Sumatriptan priming resulted in generalized and delayed cutaneous allodynia, evoked by either bright light stress (day 21) or nitric oxide donor (day 28). Ubrogepant dose-dependently blocked both stress- and nitric oxide donor-induced cephalic and hindpaw allodynia in the sumatriptan-induced medication overuse headache model with a 50% effective dose of ∼50 mg/kg. Unlike sumatriptan, ubrogepant 100 mg/kg in repeated effective doses did not produce cutaneous allodynia or latent sensitization. Conclusions Both ubrogepant and sumatriptan demonstrated efficacy as acute medications for stress- and nitric oxide donor-evoked cephalic allodynia in a preclinical model of medication overuse headache, consistent with their clinical efficacy in the acute treatment of migraine. However, in contrast to sumatriptan, repeated treatment with ubrogepant did not induce cutaneous allodynia or latent sensitization. These studies suggest ubrogepant may offer an effective acute treatment of migraine without risk of medication overuse headache. Trial Registration Number: Not applicable

Objectives The authors have previously tried to develop a model for the testing of novel drug candidates for migraine, using the headache and migraine provoking agent cilostazol. Previous studies have used sumatriptan tablets as the validating drug, but they were not sufficiently effective. In this study we test the effect of subcutaneous sumatriptan on cilostazol induced headache in patients with migraine without aura. Method Thirty patients with migraine without aura received 200 mg cilostazol on two different study days. The induced headache was treated with subcutaneous sumatriptan in a randomized, double-blind cross-over design. The patients filled out a self-reported headache questionnaire until 12 h after cilostazol. Results All 30 patients experienced headache (range 3–10) on both study days and the headache fulfilled the criteria for a migraine-like attack in 73% on the sumatriptan day and in 77% on the placebo day. Sumatriptan injection reduced the headache score 2 h after treatment ( p = 0.003). The difference between headache intensity on the sumatriptan day and the placebo day was significant at both 2 h ( p = 0.01) and 4 h ( p = 0.0007) after treatment. Conclusion Subcutaneous sumatriptan reduces cilostazol induced headache in migraine patients. The cilostazol model may be useful as a tool to test the potential of new anti-migraine drugs. Trial registration: The study is registered on clinicaltrials.gov (NCT03422796).

Introduction Females are thought to have increased risk of developing post-traumatic headache following a traumatic head injury or concussion. However, the processes underlying this susceptibility remain unclear. We previously demonstrated the development of post-traumatic headache-like pain behaviors in a male rat model of mild closed head injury, along with the ability of sumatriptan and an anti-calcitonin-gene-related peptide monoclonal antibody to ameliorate these behaviors. Here, we conducted a follow-up study to explore the development of post-traumatic headache-like behaviors and the effectiveness of these headache therapies in females subjected to the same head trauma protocol. Methods Adult female Sprague Dawley rats were subjected to a mild closed head injury using a weight-drop device (n = 126), or to a sham procedure (n = 28). Characterization of headache and pain related behaviors included assessment of changes in cutaneous cephalic and extracephalic tactile pain sensitivity, using von Frey monofilaments. Sensitivity to headache/migraine triggers was tested by examining the effect of intraperitoneal administration of a low dose of glyceryl trinitrate (100 µg/kg). Treatments included acute systemic administration of sumatriptan (1 mg/kg) and repeated systemic administration of a mouse anti-calcitonin gene-related peptide monoclonal antibody (30 mg/kg). Serum levels of calcitonin gene-related peptide were measured at baseline and at various time points post head injury in new cohorts of females (n = 38) and males (n = 36). Results Female rats subjected to a mild closed head injury developed cutaneous mechanical hyperalgesia, which was limited to the cephalic region and was resolved 4 weeks later. Cephalic pain hypersensitivity was ameliorated by treatment with sumatriptan but was resistant to an early and prolonged treatment with the anti-calcitonin gene-related peptide monoclonal antibody. Following the resolution of the head injury-evoked cephalic hypersensitivity, administration of glyceryl trinitrate produced a renewed and pronounced cephalic and extracephalic pain hypersensitivity that was inhibited by sumatriptan, but only partially by the anti-calcitonin gene-related peptide treatment. Calcitonin gene-related peptide serum levels were elevated in females but not in males at 7 days post head injury. Conclusions Development of post-traumatic headache-like pain behaviors following a mild closed head injury, and responsiveness to treatment in rats is sexually dimorphic. When compared to the data obtained from male rats in the previous study, female rats display a prolonged state of cephalic hyperalgesia, increased responsiveness to a headache trigger, and a poorer effectiveness of an early and prolonged anti-calcitonin gene-related peptide treatment. The increased risk of females to develop post-traumatic headache may be linked to enhanced responsiveness of peripheral and/or central pain pathways and a mechanism independent of peripheral calcitonin gene-related peptide signaling.

Objective To evaluate whether intraganglionic calcitonin gene-related peptide induced differential migraine-like responses in male and female rats. Methods Calcitonin gene-related peptide was injected in the trigeminal ganglion of male and female rats followed by assessment of periorbital mechanical allodynia with von Frey hairs. The influence of systemic treatment with sumatriptan or intraganglionic treatment with minocycline and propentofylline was determined on the calcitonin gene-related peptide-induced mechanical allodynia in male and female rats. One additional group was exposed to an aversive light 24 h after calcitonin gene-related peptide priming, followed by evaluation of periorbital mechanical threshold, and another group was tested in the elevated-plus maze. Results Intraganglionar calcitonin gene-related peptide-induced periorbital mechanical allodynia in female (0.5 to 6 h) and male rats (0.5 to 4 h). Systemic sumatriptan briefly attenuated the mechanical allodynia, but intraganglionar minocycline or propentofylline injection was effective only in male rats. Calcitonin gene-related peptide induced photic sensitivity in female and male rats (lasting 4 h and 1 h, respectively), as well as anxiety-like behavior. Conclusions Intraganglionar calcitonin gene-related peptide may play a major role in migraine-like responses, including periorbital mechanical allodynia, light sensitivity and anxiety like-behavior. Female rats are likely to be more susceptible to calcitonin gene-related peptide effects and a better understanding of the sexual dimorphism in calcitonin gene-related peptide signaling may help to improve migraine therapy.

Background Loss of conditioned pain modulation/diffuse noxious inhibitory controls has been demonstrated in patients with migraine and medication overuse headache. We hypothesized that exposure to acute migraine medications may lead to dysregulation of central pain modulatory circuits that could be revealed by evaluating diffuse noxious inhibitory controls and that prior noxious stimulus is required for a loss of the diffuse noxious inhibitory control response in rats exposed to these medications. Methods Rats were “primed” by continuous infusion of morphine or one of two doses of sumatriptan. Diffuse noxious inhibitory control was evaluated at the end of drug-priming (day 7) and again after sensory thresholds returned to baseline (day 21). The Randall-Selitto hindpaw pressure test was used as the test stimulus and forepaw capsaicin injection served as the conditioning stimulus. Results Morphine-primed rats showed opioid-induced hyperalgesia accompanied by a loss of diffuse noxious inhibitory controls on day 7. Sumatriptan-primed rats did not develop hyperalgesia or loss of diffuse noxious inhibitory controls on day 7. Morphine-primed and high-dose sumatriptan-primed rats only had a loss of diffuse noxious inhibitory control on day 21 if they received a capsaicin injection on day 7. Conclusions Prolonged exposure to migraine treatments followed by an acute nociceptive stimulation caused long-lasting alterations in descending pain modulation, shown by a loss of diffuse noxious inhibitory controls. Morphine was more detrimental than sumatriptan, consistent with clinical observations of higher medication overuse headache risk with opioids. These data suggest a mechanism of medication overuse headache by which migraine medications combined with repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of future migraine attacks as well as risk of medication overuse headache.

Background There are cases in the headache literature described as “cluster-migraine,” but none of stereotyped cases of cluster headache evolving into status migrainosus. We believe this is the first documented case of “cluster-status migrainosus”. Case A 54 year-old female hospital administrator presented with headaches with a unique periodicity and semiology that were acutely responsive to high-flow oxygen. She experienced cluster headache attacks every Thursday morning at 3–4 am, which would evolve into status migrainosus lasting through Sunday evening. These attacks were preceded by prodromal depressed mood changes and fluid retention, and later followed by postdromal euphoria and auto-diuresis. These attacks initially occurred every other week and progressed to weekly attacks for 1.5 years. These headaches did not respond to trials of propanolol, sodium valproate, topiramate, amitriptyline, gabapentin, and carbamazepine for preventive treatment or to oral sumatriptan and butalbital-acetaminophen-caffeine for acute treatment. We started her on high-flow 100% oxygen for cluster headache, which successfully aborted greater than 80% of her weekly cluster headache attacks and prevented them from evolving into status migrainosus. Conclusion We believe this is the first case of “cluster-status migranosus” described in the medical literature. High-flow oxygen both aborted the cluster headaches and prevented the ensuing status migrainosus.

Introduction Research in development of new migraine therapeutics is hindered by the lack of suitable, predictive animal models. Cilostazol provokes headache in healthy humans and migraineurs by increasing intracellular cAMP levels. We aimed to investigate whether cilostazol could provoke headache-like behaviours and c-fos expression in rats. In order to evaluate the predictive validity of the model, we examined the response to the migraine specific drug sumatriptan. Methods The effect of cilostazol (125 mg/kg p.o.) in female Sprague Dawley rats was evaluated on a range of spontaneous behavioural parameters, light sensitivity and mechanical sensitivity thresholds. We also measured c-fos expression in the trigeminal nucleus caudalis. Results Cilostazol increased light sensitivity and grooming behaviour. These manifestations were not inhibited by sumatriptan. Cilostazol also induced c-fos expression in the trigeminal nucleus caudalis. Furthermore, trigeminal – but not hind paw hyperalgesia was observed. Conclusion The altered behaviours are suggestive of cilostazol induced headache with migraine-like features, but not specific. The presence of head specific hyperalgesia and the c-fos response in the trigeminal nucleus caudalis imply that the model involves trigeminal nociception. The model will be useful for studying mechanisms related to the cAMP pathway in headache, but its predictive properties appear to be more limited due to the lack of response to sumatriptan.

ObjectiveAfter sumatriptan was approved by the Food and Drug Administration in 1992, triptans became first-line anti-migraine therapies. Rapidly rising triptan expenditures, however, led payers, including Medicaid, to implement cost-containment policies. We describe triptan utilization and reimbursement trends in Medicaid.MethodsUsing national summary files for outpatient drug utilization, utilization and expenditure data from 1993 to 2013 were extracted and summed for all triptan national drug codes reimbursed by Medicaid. Data were collected separately for tablets, injections and sprays.ResultsThe number of triptan prescriptions increased from 87,348 in 1993 to 0.9 million in 2004; fell to 0.4 million in 2009; rose to 1 million in 2011; and rose 1.2 million in 2013. In 2013, Medicaid spent $96.8 million on triptans: 74.4%, 18.4% and 7.2% for tablets, injections and sprays, respectively. Average reimbursement per prescription was $54 for tablets, $351 for injections and $235 for sprays in 2013. From 1993 to 2013, sumatriptan was the most widely prescribed among the triptans.ConclusionsThe substantial increase in triptan prescriptions from 2009 to 2011, without being convincingly explained by either rising migraine prevalence or rising Medicaid enrollment, is suggestive of reduced access to these medications prior to 2009. Cost-containment policies may have inadvertently prevented Medicaid migraineurs from obtaining appropriate pharmacotherapy.Prior presentationsAn earlier version of this paper was presented as a poster at the Annual Meeting of the International Society for Pharmacoeconomics and Outcomes Research, Philadelphia, PA, May 2015, where it received a finalist award.

Cortical spreading depolarization is a metabolically costly phenomenon that affects the brain in both health and disease. Following severe stroke, subarachnoid hemorrhage, or traumatic brain injury, cortical spreading depolarization exacerbates tissue damage and enlarges infarct volumes. It is not known, however, whether spreading depolarization also occurs in the retina in vivo. We report now that spreading depolarization episodes are generated in the in vivo rat retina following retinal vessel occlusion produced by photothrombosis. The properties of retinal spreading depolarization are similar to those of cortical spreading depolarization. Retinal spreading depolarization waves propagate at a velocity of 3.0 ± 0.1 mm/min and are associated with a negative shift in direct current potential, a transient cessation of neuronal spiking, arteriole constriction, and a decrease in tissue O2 tension. The frequency of retinal spreading depolarization generation in vivo is reduced by administration of the NMDA antagonist MK-801 and the 5-HT(1D) agonist sumatriptan. Branch retinal vein occlusion is a leading cause of vision loss from vascular disease. Our results suggest that retinal spreading depolarization could contribute to retinal damage in acute retinal ischemia and demonstrate that pharmacological agents can reduce retinal spreading depolarization frequency after retinal vessel occlusion. Blocking retinal spreading depolarization generation may represent a therapeutic strategy for preserving vision in branch retinal vein occlusion patients.

Background A model for the testing of novel anti-migraine drugs should preferably use healthy volunteers for ease of recruiting. Isosorbide-5-mononitrate (5-ISMN) provokes headache in healthy volunteers with some migraine features such as pulsating pain quality and aggravation by physical activity. Therefore, this headache might respond to sumatriptan, a requirement for validation of any model. The hypothesis of the present study was that sumatriptan is effective in 5-ISMN-induced headache in healthy individuals. Methods In a double-blind, randomised, crossover design, 30 healthy volunteers of both sexes received 5-ISMN 60 mg on two separate days, each day followed by oral self-administered placebo or sumatriptan 50 mg. Headache response and accompanying symptoms were registered in a questionnaire by the participants themselves. Results 5-ISMN induced a reproducible headache in all 30 participants. The headache had several migraine-like features in all participants and 20 individuals developed a migraine-like attack. Median peak headache score was 5 on both experimental days ( p = 1.00). There was no reduction, but instead an increase in headache intensity 2 hours after sumatriptan ( p = 0.003). Difference in area under the headache score curve (AUC) 0–4 hours between sumatriptan and placebo was not significant ( p = 0.30). Conclusion 5-ISMN is a very powerful inducer of migraine-like headache in healthy individuals but the headache does not respond to sumatriptan. The model is not useful for future drug testing.

Background Migraine-tic syndrome was first reported in 2004 in a 44-year-old woman who had concomitant symptoms of both typical trigeminal neuralgia and migraine. We report here two further cases of migraine-tic syndrome and speculate on the relevance of this condition to the pathophysiology of headache. Case reports A 43-year-old woman presented with typical trigeminal neuralgia symptoms that preceded the onset of migraine headache; both headache types responded to treatment with sumatriptan. A 35-year-old woman presented with trigeminal neuralgia that consistently followed the onset of migraine headache. The former aspect responded to baclofen, but the migraine headache required treatment with amitriptyline. Discussion These two patients provide further support for the presence of an overlap syndrome of migraine-tic. We suggest that there is a common pathway for trigeminal neuralgia and migraine.

Background In most pharmacokinetic studies, the oral absorption of drugs is impaired during migraine attacks but exceptions occur. A study on gastric emptying using gastric scintigraphy indicated that gastric stasis also occurs interictally in migraine. These studies were reviewed critically. Results In seven studies, mainly investigating NSAIDs and analgesics, the early absorption of the drugs during 112 migraine attacks was delayed. The absorption of sumatriptan is usual in therapeutic doses, and rizatriptan was normal during 131 migraine attacks. The interictal gastric stasis observed using gastric emptying scintigraphy (GES) with solids ( n = 13) could not be confirmed in a larger study ( n = 27) using the same method. Also gastric emptying measured with GES with liquids ( n = 7) and epigastric impedance ( n = 64) was normal outside migraine attacks. Conclusions and possible clinical implications Drug absorption is not generally impaired during migraine attacks. Gastric emptying is most likely normal in the majority of migraine patients outside attacks. Prokinetic and antiemetic drugs such as metoclopramide and domperidone should not be routinely combined with oral analgesics or oral triptans. If, however, nausea is severe or vomiting occurs, treatment with an antiemetic with proven efficacy on the nausea of migraine can be indicated.

Cyclic vomiting syndrome (CVS) is characterized by episodic vomiting and shares similarities with migraine headache. Guidelines recommend using triptans as abortive therapy in CVS, but there are limited data on its efficacy. Methods: We thus sought to characterize sumatriptan use and performed a cross-sectional study of adults with CVS episodes within the previous 6 months. Questionnaires about demographics, clinical characteristics, and response to sumatriptan (defined as >50% reduction in symptoms) were administered via e-mail. We investigated differences between responders and nonresponders, using χ 2 and Student’s t test. Results: Of 101 participants (age 41 ± 15 years, 74% female, 83% Caucasian), 39 (38%) used sumatriptan during their last CVS attack. Most reported an improvement in nausea (55%), vomiting (59%), and abdominal pain (43%) within 2 h and at 24 h (67%, 73%, and 67%) respectively. Eighteen (46%) reported that sumatriptan helped them avoid emergency department visits and 20 (51%) avoided being hospitalized. Nonresponse to sumatriptan was associated with depression ( p = 0.01), current cannabis use ( p = 0.02), use of benzodiazepines ( p = 0.04), and opioids (0.02) during an episode. No serious side effects were noted. Conclusions: Sumatriptan use reduced symptoms of CVS but did not abort them. Prospective studies to determine its independent effects are needed.

Background Migraine headache is a neurological disorder affecting millions worldwide. However, little is known about the mechanisms contributing to migraine. Recent genome-wide association studies have found single nucleotide polymorphisms in the gene encoding transient receptor potential channel M8. Transient receptor potential channel M8 is generally known as a cold receptor but it has been implicated in pain signaling and may play a role in migraine pain. Methods In order to investigate whether transient receptor potential channel M8 may contribute to the pain of migraine, the transient receptor potential channel M8 activator icilin was applied to the dura mater using a rat behavioral model of headache. Cutaneous allodynia was measured for 5 hours using Von Frey filaments. Results : Dural application of icilin produced cutaneous facial and hind paw allodynia that was attenuated by systemic pretreatment with the transient receptor potential channel M8-selective antagonist AMG1161 (10 mg/kg p.o.). Further, the anti-migraine agent sumatriptan (0.6 mg/kg s.c.) or the non-selective NOS inhibitor L-NAME (20 mg/kg i.p.) also attenuated allodynia when given as a pretreatment. Conclusions These data indicate that transient receptor potential channel M8 activation in the meninges produces behaviors in rats that are consistent with migraine and that are sensitive to pharmacological mechanisms known to have efficacy for migraine in humans. The findings suggest that activation of meningeal transient receptor potential channel M8 may contribute to the pain of migraine.

Background Dihydroergotamine (DHE) and sumatriptan are contraindicated in patients with cardiovascular disease because of their vasoconstricting properties, which have originally been explored in proximal coronary arteries. Our aim was to investigate DHE and sumatriptan in the proximal and distal coronary artery, middle meningeal artery and saphenous vein. Methods Blood vessel segments were mounted in organ baths and concentration response curves for DHE and sumatriptan were constructed. Results In the proximal coronary artery, meningeal artery and saphenous vein, maximal contractions to DHE (proximal: 8 ± 4%; meningeal: 32 ± 7%; saphenous: 52 ± 11%) and sumatriptan (proximal: 17 ± 7%; meningeal: 61 ± 18%, saphenous: 37 ± 8%) were not significantly different. In the distal coronary artery, contractions to DHE (5 ± 2%) were significantly smaller than those to sumatriptan (17 ± 9%). At clinically relevant concentrations, mean contractions to DHE and sumatriptan were below 3% in proximal coronary arteries and below 6% in distal coronary arteries. Contractions in the meningeal artery and saphenous vein were higher (7%–38%). Conclusions Contractions to DHE in distal coronary arteries are smaller than those to sumatriptan, while at clinical concentrations they both induce only slight contractions. In meningeal arteries contractions to DHE and sumatriptan are significantly larger, showing their cranioselectivity. Contractions to DHE in the saphenous vein are higher than those in the arteries, confirming its venous contractile properties.

Background There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line. Methods A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses. Results Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention. Interpretation We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

Background: Migraine therapy with sumatriptan may cause adverse side effects like pain at the injection site, muscle pain, and transient aggravation of headaches. In animal experiments, sumatriptan excited or sensitized slowly conducting meningeal afferents. We hypothesized that sumatriptan may activate transduction channels of the “irritant receptor,” the transient receptor potential ankyrin type (TRPA1) expressed in nociceptive neurons. Methods: Calcium microfluorometry was performed in HEK293t cells transfected with human TRPA1 (hTRPA1) or a mutated channel (TRPA1-3C) and in dissociated trigeminal ganglion neurons. Membrane currents were recorded in the whole-cell patch clamp configuration. Results: Sumatriptan (10 and 400 µM) evoked calcium transients in hTRPA1-expressing HEK293t cells also activated by the TRPA1 agonist carvacrol (100 µM). In TRPA1-3C-expressing HEK293t cells, sumatriptan had hardly any effect. In rat trigeminal ganglion neurons, sumatriptan, carvacrol, and the transient receptor potential vanillod type 1 agonist capsaicin (1 µM) generated robust calcium signals. All sumatriptan-sensitive neurons (8% of the sample) were also activated by carvacrol (14%) and capsaicin (48%). In HEK293-hTRPA1 cells, sumatriptan (100 µM) evoked outwardly rectifying currents, which were almost completely inhibited by the TRPA1 antagonist HC-030031 (10 µM). Conclusion: Sumatriptan activates TRPA1 channels inducing calcium inflow and membrane currents. TRPA1-dependent activation of primary afferents may explain the painful side effects of sumatriptan.

Objective The objective of this article is to evaluate the efficacy and tolerability of two doses of oral sumatriptan vs placebo in the acute treatment of migraine in children and adolescents. Background Currently, there is no approved prescription medication in Japan for the treatment of migraine in children and adolescents. Methods This was a multicenter, outpatient, single-attack, double-blind, randomized, placebo-controlled, parallel-group study. Eligible patients were children and adolescents aged 10 to 17 years diagnosed with migraine with or without aura (ICHD-II criteria 1.1 or 1.2) from 17 centers. They were randomized to receive sumatriptan 25 mg, 50 mg or placebo (1:1:2). The primary efficacy endpoint was headache relief by two grades on a five-grade scale at two hours post-dose. Results A total of 178 patients from 17 centers in Japan were enrolled and randomized to an investigational product in double-blind fashion. Of these, 144 patients self-treated a single migraine attack, and all provided a post-dose efficacy assessment and completed the study. The percentage of patients in the full analysis set (FAS) population who report pain relief at two hours post-treatment for the primary endpoint was higher in the placebo group than in the pooled sumatriptan group (38.6% vs 31.1%, 95% CI: −23.02 to 8.04, p = 0.345). The percentage of patients in the FAS population who reported pain relief at four hours post-dose was higher in the pooled sumatriptan group (63.5%) than in the placebo group (51.4%) but failed to achieve statistical significance ( p = 0.142). At four hours post-dose, percentages of patients who were pain free or had complete relief of photophobia or phonophobia were numerically higher in the sumatriptan pooled group compared to placebo. Both doses of oral sumatriptan were well tolerated. No adverse events (AEs) were serious or led to study withdrawal. The most common AEs were somnolence in 6% (two patients) in the sumatriptan 25 mg treatment group and chest discomfort in 7% (three patients) in the sumatriptan 50 mg treatment group. Conclusions There was no statistically significant improvement between the sumatriptan pooled group and the placebo group for pain relief at two hours. Oral sumatriptan was well tolerated.

Objective Probable migraine is a common, disabling migraine subtype fulfilling all but one of the diagnostic criteria for migraine. This study was conducted to evaluate the efficacy and tolerability of sumatriptan/naproxen sodium for the acute treatment of probable migraine without aura. Methods Patients treated a headache of probable migraine without aura when pain was moderate or severe with sumatriptan/naproxen sodium ( n = 222 intent-to-treat (ITT)) or placebo ( n = 221 ITT/complete case analysis a ) in this randomized, double-blind, parallel-group study. Results Sumatriptan/naproxen sodium was more effective than placebo with respect to the co-primary efficacy endpoints two-hour pain-free response (29% sumatriptan/naproxen sodium vs 11% placebo, p Conclusion Sumatriptan/naproxen sodium is effective in the acute treatment of probable migraine as demonstrated by higher rates of freedom from pain and restoration of function.

Objective: Efficacy and tolerability profiles of Treximet [sumatriptan/naproxen sodium combination tablet (SNC)] have been established in clinical trials but have to date been virtually unstudied in pragmatic research. The primary objective of this study was to compare the overall satisfaction of SNC to its monotherapy components, S/N [one 100 mg Imitrex tablet (S) and two Aleve (naproxen sodium) 220 mg tablets, total dose 440 mg (N)] administered concomitantly using the Patient Perception of Migraine Questionnaire –Revised (PPMQ-R). Methods: Adults with migraine ( n = 50) without ‘medication overuse headache’ were treated for up to 18 migraine attacks per 3-month study period with study medication; SNC during one study period and S/N during the other study period. For all endpoints, differences between treatments were compared with paired t tests. Results: The percentage of patients reporting satisfied/very satisfied for Overall Satisfaction of SNC versus S/N (primary endpoint) was 85% versus 72% respectively ( p = 0.054). For Overall Effectiveness, the results were 82% for SNC versus 73% for S/N ( p = 0.159); and for Overall Side Effects the results were 86% for SNC versus 69% for S/N ( p = 0.005). Mean PPMQ-R scores reflect greater satisfaction with SNC than S/N for Total score and for each of four subscales. The difference between SNC and S/N was significant for the Ease of Use subscale ( p = 0.004) and met the criterion of being clinically meaningful for both the Total score and Ease of Use. SNC did not differ from S/N with respect to pain-free response 2 h post dose, pain relief 2 h post dose, sustained 24 h pain-free response, or sustained 24 h pain relief. Conclusion: Although the primary endpoint only just failed, the results of this pragmatic outcomes study demonstrate SNC to have benefits over its concomitantly administered components in the acute treatment of migraine.

Introduction If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE’s antimigraine effect, which is the subject of this review, has only rarely been mentioned. Methods Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time. Findings Subcutaneous DHE 1 mg was inferior to subcutaneous sumatriptan 6 mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2 mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (Tmax = 12 min). Conclusion DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE.

When drug therapy is necessary and cannot be avoided during a pregnancy, the decision of what drug therapy is best may be difficult for the health care provider because the vast majority of drugs are classified as Pregnancy Category C. This classification indicates that information regarding the risk to the fetus is unknown. For ethical reasons, pregnant women are not included in drug studies, so most decisions regarding the safety of a particular drug are based on animal studies, available cases reports, or are theoretical and are based on pharmacokinetic properties. Fortunately, with the development of Pregnancy Registries, more information has been collected, analyzed, and is available regarding the safety of drugs during pregnancy. These registries have expanded in recent years allowing better determination of fetal safety for triptans and antiepileptic drugs (AEDs). The information assists health care providers in selecting optimal therapy for women seeking pregnancy or those already pregnant. This review presents the most recent information for the treatment and prophylaxis of migraines and seizures during pregnancy.

Objective: The study was carried out to assess the efficacy and tolerability of rizatriptan orally disintegrating tablet (ODT) for treating acute migraine in patients who are non-responders to sumatriptan. Background: Many migraineurs report dissatisfaction with sumatriptan efficacy. It is unclear whether sumatriptan 100 mg non-responders will respond to other triptans. Methods: This was a randomized, placebo-controlled, double-blind study in adults with >1-year history of ICHD-II (International Classification of Headache Disorders, second edition) migraine who reported that they generally do not respond to sumatriptan (≥50% unsatisfactory response). In the baseline phase, participants treated a single moderate/severe migraine attack with open-label generic sumatriptan 100 mg. Those who continued to experience moderate/severe pain at two hours post-dose were eligible to enter the double-blind treatment phase, during which participants treated three migraine attacks in crossover fashion (two with rizatriptan 10-mg ODT, one with placebo) after being randomly assigned to one of three treatment sequences (1 : 1 : 1 ratio). The primary endpoint was two-hour pain relief. Results: A total of 102 (94%) participants treated at least one study migraine. Pain relief at two hours was significantly greater with rizatriptan compared with placebo (51% vs. 20%, p Conclusion: Rizatriptan 10-mg ODT was superior to placebo at providing two-hour pain relief and two-hour pain freedom in the treatment of acute migraine in those who do not respond to sumatriptan 100 mg. Rizatriptan was generally well tolerated in this population.

The ability of tonabersat to relieve the symptoms of migraine attacks with or without aura was evaluated in a randomized, double-blind, placebo-controlled, multicentre, parallel-group study. Patients received 20 or 40 mg of tonabersat, or 50 mg of sumatriptan (positive control), or placebo at the onset of a moderate or severe attack. Headache intensity, relief and recurrence were recorded for 24 h after dosing. On the basis of primary or secondary efficacy measures, tonabersat did not provide a clinically or statistically significant advantage over placebo. Tonabersat generally was well tolerated and had no effect on vital signs, electrocardiogram recordings or laboratory values. The lack of efficacy may be a function of the slow absorption of tonabersat. As a consequence of slow absorption, daily administration of tonabersat as prophylaxis for migraine attacks is under investigation in ongoing studies.

Two identical randomized, placebo-controlled, crossover studies were conducted to evaluate consistency of response to sumatriptan/naproxen sodium 85/500 mg (S/NS) over four attacks in adults with migraine. Patients were instructed to treat within 1 h of pain onset while pain was mild. Co-primary end-points were pain-free response at 2 h (2hPF) and 24-h sustained pain-free response (24hSPF) calculated as percentages of all attacks. In Study 1, 570 patients treated 1693 attacks with S/NS and 424 with placebo. In Study 2, 565 patients treated 1678 attacks with S/NS and 422 with placebo. Compared with placebo, S/NS conferred higher 2hPF rates (Study 1: S/NS 52%, placebo 25%; Study 2: S/NS 50%, placebo 20%; both P < 0.001) and higher 24hSPF rates (Study 1: S/NS 37%, placebo 17%; Study 2: S/NS 34%, placebo 12%; both P < 0.001). 2hPF was reported in at least two of the first three S/NS-treated attacks in 55.0% of patients in Study 1 and 52.1% of patients in Study 2. 24hSPF was reported in at least two of the first three S/NS-treated attacks in 35.7% of patients in Study 1 and 32.6% of patients in Study 2. The incidences of any adverse event and of specific adverse events were low and generally similar between S/NS and placebo.

The aim was to examine pharmacological treatment of migraine patients admitted to a tertiary care pain clinic. A retrospective review of 100 consecutive migraine patients admitted to The Wasser Pain Management Centre was conducted. Patients included met the 2nd Edition of the International Classification of Headache Disorders criteria for diagnosis of migraine. Data were collected with regard to nicotine and alcohol consumption, family history of migraine headaches, other pain diagnoses and pharmacological treatment. Twenty-two per cent of these patients were male as opposed to 78% female. The mean age of patients admitted for migraine was 43.4 years. Of the patients admitted, 48% had tried at least one triptan in the past and only 31% were actively using triptan(s). The most commonly used triptan in the past had been sumatriptan, whereas the most common triptan used on admission was rizatriptan. Opiate use was much more prevalent; 72% of admitted patients were using an opiate and 27% used multiple opiates. A significant number of patients had not yet been tried on a triptan despite meeting the diagnostic criteria for migraine and having significant disability. More education of the general medical community may be beneficial in implementing a stratified care approach to migraine management.

We successfully treated 2 pediatric cases of abdominal pain-related functional gastrointestinal disorder with sumatriptan. When 9 years old, patient 1 developed periodic abdominal pain that was intractable to medication and remitted spontaneously. She was diagnosed with abdominal migraine, categorized as H2c in the Rome III criteria for functional gastrointestinal disorders. At age 12, intranasal sumatriptan relieved her pain, and her attacks halted 2 years later. Patient 2 was a 9-year-old girl diagnosed with attention-deficit hyperactivity disorder (ADHD), who began to have intermittent abdominal pain of variable severity, which sometimes restricted daily activity. She was diagnosed with childhood functional abdominal pain syndrome, categorized as H2d1 using the Rome III criteria. Intranasal sumatriptan also relieved her pain. These cases suggest that the mechanism of pain in abdominal pain-related functional gastrointestinal disorders is similar to that of migraine, with probable central hypersensitivity, at least in a subset of cases.

Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is ‘a clean drug’, methylergometrine is ‘a relatively dirty drug’ with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.

Cluster headache belongs to the trigeminal autonomic cephalgias. Clinically, it is characterized by attacks of severe pain localized orbitally, supraorbitally or temporally, lasting for 15–180 min and occuring from once every other day to eight times a day. The attacks are associated with one or more of the following: conjunctival injection, lacrimation, nasal congestion, rhinorrhoea, forehead and facial sweating, miosis, ptosis and eyelid oedema (1). Attacks occur in series (so-called cluster periods or bouts) that are usually separated by remission periods lasting for months or years. In chronic cluster headache (CCH) substantial remission periods are lacking. Mean age at onset is 20–40 years and, for unknown reasons, 80% of patients are male. Treatment usually consists of drug therapy. Agents used for acute therapy are inhalation of high-flow oxygen, sumatriptan subcutaneous injection or nasal spray and zolmitriptan nasal spray. For transitional or short-term prophylaxis, corticosteroids and ergotamine derivatives are used. The cornerstone of maintenance prophylaxis is verapamil, but lithium and methysergide may also be used. Some patients respond to melatonin or topiramate (2). Nevertheless, there are a significant percentage of patients with CCH that do not experience satisfactory pain relief with drug therapy alone. In the last years new invasive techniques have emerged, and operational criteria have been proposed to define pharmacologically intractable headache (3). Case report

Usually limited information about the frequency of migraine episodes is derived from acute migraine trials. However, the design of some studies is such that they also provide relevant information about the attack frequency without the bias associated with patient expectations of treatment effect between attacks during prophylaxis trials. Using clinical data from repeated migraine attacks treated with placebo, naratriptan 2.5 mg or sumatriptan 100 mg, we show that attack and interictal periods can be described by a random probability distribution. Based on a gamma distribution, the mean interval between attacks was estimated to be 24 (17-34) days for placebo, 23 (18-29) days for naratriptan 2.5 mg and 22 (17-28) for sumatriptan 100 mg. These findings suggest that the interictal interval is not affected by abortive treatment with triptans. Interpretation of these results may be limited by the study type, yet the method represents a new tool for the evaluation of disease dynamics and treatment effect in the prophylaxis of migraine.

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OBJECTIVE: To report and evaluate available data on the use of serotonin 5-HT1 agonists (triptans) during pregnancy. DATA SOURCES: A PubMed search, limited to English-language articles on human subjects, was conducted (1990–December 2007) using the search terms pregnancy, migraine, and the individual triptan drug names. In addition, the manufacturers of all 7 available triptans were contacted regarding the existence of a pregnancy registry for their drug(s) and the availability of registry reports. STUDY SELECTION AND DATA EXTRACTION: All retrospective and prospective studies reporting on pregnancy outcomes after the use of a triptan were included and critically evaluated. Data from all available manufacturer-sponsored pregnancy registries were also included. DATA SYNTHESIS: Safe and effective treatment of migraine during pregnancy is imperative. Data involving sumatriptan and, to a lesser extent, naratriptan and rizatriptan, exist primarily regarding exposure in the first trimester. These data show no significant differences in congenital malformations or poor pregnancy outcomes when compared with expected rates in the general population or with the observed rates in control subjects. There is very little information regarding exposure in middle and late pregnancy. CONCLUSIONS: Sumatriptan appears to be a safe treatment alternative for pregnant women who experience new-onset or worsened migraines in the first trimester. Further observation is needed prior to recommending its use in later trimesters. Based upon available data, the other agents in this class cannot be recommended for use during pregnancy at this time.

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the Food and Drug Administration's (FDA) medWatch program (800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.

Background: There is evidence to suggest that the midbrain periaqueductal grey (PAG) has a role in migraine and the actions of the anti-migraine drug sumatriptan. In the present study we examined the serotonergic modulation of GABAergic and glutamatergic synaptic transmission in rat midbrain PAG slices in vitro. Results: Serotonin (5-hydroxytriptamine, 5-HT, IC50 = 142 nM) and the selective serotonin reuptake inhibitor fluoxetine (30 μM) produced a reduction in the amplitude of GABAA-mediated evoked inhibitory postsynaptic currents (IPSCs) in all PAG neurons which was associated with an increase in the paired-pulse ratio of evoked IPSCs. Real time PCR revealed that 5-HT1A, 5-HT1B, 5-HT1D and 5-HT1F receptor mRNA was present in the PAG. The 5-HT1A, 5-HT1B and 5-HT1D receptor agonists 8-OH-DPAT (3 μM), CP93129 (3 μM) and L694247 (3 μM), but not the 5-HT1F receptor agonist LY344864 (1 – 3 μM) inhibited evoked IPSCs. The 5-HT (1 μM) induced inhibition of evoked IPSCs was abolished by the 5-HT1B antagonist NAS181 (10 μM), but not by the 5-HT1A and 5-HT1D antagonists WAY100135 (3 μM) and BRL15572 (10 μM). Sumatriptan also inhibited evoked IPSCs with an IC50 of 261 nM, and reduced the rate, but not the amplitude of spontaneous miniature IPSCs. The sumatriptan (1 μM) induced inhibition of evoked IPSCs was abolished by NAS181 (10 μM) and BRL15572 (10 μM), together, but not separately. 5-HT (10 μM) and sumatriptan (3 μM) also reduced the amplitude of non-NMDA mediated evoked excitatory postsynaptic currents (EPSCs) in all PAG neurons tested. Conclusion: These results indicate that sumatriptan inhibits GABAergic and glutamatergic synaptic transmission within the PAG via a 5-HT1B/D receptor mediated reduction in the probability of neurotransmitter release from nerve terminals. These actions overlap those of other analgesics, such as opioids, and provide a mechanism by which centrally acting 5-HT1B and 5-HT1D ligands might lead to novel anti-migraine pharmacotherapies.

Thirty to forty percent of migraineurs do not respond to any given triptan treatment. We identified clinical variables that significantly predict therapeutic non-response and evaluated the efficacy of eletriptan (20, 40 and 80 mg) and sumatriptan (100 mg) vs. placebo in a subgroup of patients with all predictor variables. First-attack data were pooled from 10 randomized, double-blind, placebo-controlled migraine trials ( n = 8473). Multivariate regression analyses identified three significant baseline predictors of failure to achieve 2-h pain-free response: severe headache pain, presence of photophobia/phonophobia and presence of nausea. Time of dosing following headache onset did not influence 2-h pain-free response. Among patients with all three risk factors ( n = 2010; 24± of total sample), 2-h pain-free response was significantly higher in patients receiving all three doses of eletriptan or sumatriptan vs. placebo (all P< 0.01). Thus, eletriptan and sumatriptan are efficacious in difficult-to-treat patients at high risk for non-response to triptans.

Studies performed in selected populations show that the use of triptans for migraine is low. Our study was aimed at establishing patterns of triptan utilization in a large community using the drug prescription database of a regional Health Authority in Italy. In a population of 224 065 residents, 0.55% received at least one prescription of triptans in 1 year: 77.9% were female and 22.1% male. Oral dosage forms accounted for 94% of prescriptions. About 60% of patients received a single prescription (containing one or two packages) of one triptan in 1 year. Age distribution showed that 7% of patients were aged >65 years. They received 14% of packages, prevalently sumatriptan and zolmitriptan (the two triptans with the longest commercialization in Italy); 5.7% of patients received 40% of packages. Moreover, 3.2% of triptans users received >120 dosage units in the year in the form of tablets (>10 single doses/month), and were potential triptan abusers. Our data indicate suboptimal treatment of migraine patients and also incorrect treatment of some patients (potential triptans abusers, the elderly).

If treatment-emergent central nervous system (CNS) symptoms following triptan therapy represent direct pharmacological effects of the drug, they should occur independent of response to active drug. However, if they represent unmasking of neurological symptoms of the migraine attack after pain is relieved, they should be more common in responders both to active drug and to placebo. To explore this issue, we evaluated the relationship between the CNS adverse events and treatment response following triptan or placebo treatment. We used pooled data from seven double-blind, placebo-controlled trials involving eletriptan 20 mg (E20, n = 402), eletriptan 40 mg (E40, n = 1870), eletriptan 80 mg (E80, n = 1393), sumatriptan 100 mg (S100, n = 275) and placebo (Pbo, n = 1024). Somnolence was more prevalent among 2 h headache responders than non-responders for all treatments, including E80 (8.8% vs. 5.0%; P < 0.05), E40 (6.4% vs. 5.0%; NS), E20 (4.0% vs. 2.0%; NS), S100 (4.7% vs. 3.2%; NS) and Pbo (7.6% vs. 3.0%; P < 0.05). Similarly, the incidence of asthenia was higher among patients who responded to treatment compared with those who did not respond to E80 (15.2% vs. 7.8%; P < 0.05), E40 (6.5% vs. 3.6%; P < 0.05), E20 (6.5% vs. 1.0%; P < 0.05), S100 (10.1% vs. 4.7%; NS) and Pbo (4.4% vs. 2.7%; NS). The generally higher rates of somnolence and asthenia in patients who respond to treatment suggests that these treatment-emergent neurological symptoms may represent the unmasking of CNS symptoms associated with the natural resolution of a migraine attack, rather than simply representing drug-related side-effects. The rate of somnolence in placebo responders is comparable to that in responders to E40 and E80, indicating that somnolence is related, at least in some important part, to headache relief and not treatment.

A young woman had typical cluster headache attacks and a pituitary mass lesion. The headache attacks resolved after transsphenoidal resection of the tumour, which was diagnosed as a granulomatous inflammation. The association between cluster headache and granulomatous enlargement of the pituitary gland has never been described before. This case reinforces the growing evidence that even in typical cases of cluster headache, neuroimaging is mandatory to exclude structural lesions.

A temporary sensitization of central trigeminal neurones in migraine patients during acute attacks has been described in previous studies using the electrically evoked nociceptive blink reflex. The cornea is innervated by small myelinated A-delta and unmyelinated C-fibres only. Stimulation with air puffs activates peripheral nociceptors and allows the investigation of peripheral trigeminal nerve structures. Our objective was to investigate whether corneal reflex examinations with air puff stimulation detect abnormalities in migraineurs during their pain-free interval and if the corneal reflex may be modulated by the administration of an oral triptan. After validation of the nociceptive air puff technique by investigating the corneal reflexes before and after a local anaesthesia of the cornea, we recorded corneal reflexes in 25 migraineurs during their pain-free period and 25 healthy controls before and after the oral administration of 100 mg sumatriptan in a randomized, placebo-controlled, crossover study. Baseline response areas under the curve (AUCs) and latencies of the R2 components of the corneal reflexes did not show any significant differences between patients and controls. Patients did not show any significant differences regarding their headache and non-headache side. The use of an oral triptan had no significant influence on latencies or AUCs in both patients and controls. Our data suggest that there is no facilitation of the trigeminal system in the headache-free interval among patients with migraine. The stable corneal reflexes after the oral administration of 100 mg sumatriptan suggest that there was no inhibition of the trigeminal system, both in patients during their headache-free period and in healthy controls.

The purpose of the study was to develop a mouse model to study trigeminovascular mechanisms using intravital microscopy on a closed cranial window. In addition, we studied exogenous and endogenous calcitonin gene-related peptide (CGRP)-mediated vasodilation in dural arteries. Arteries in C57BL/6Jico mice were constricted with endothelin-1, which reduced the baseline diameter by 65-75%. Subsequently, vasodilation was induced by α-CGRP, capsaicin or transcranial electrical stimulation of perivascular trigeminal nerves in the absence or presence of different concentrations of BIBN4096BS or sumatriptan. Both α-CGRP and capsaicin induced vasodilation in preconstricted arteries. Transcranial electrical stimulation also induced current-dependent relaxation of dural arteries with 100 μA producing maximal dilation in the control group. BIBN4096BS blocked the responses evoked by ä-CGRP and capsaicin, as well as electrical stimulation, whereas sumatriptan attenuated only vasodilation induced by electrical stimulation. This model is likely to prove useful in dissecting elements of the trigeminovascular system and for exploring pathophysiological aspects of migraine, especially in future studies using transgenic mice with mutations relevant to those observed in patients with migraine.

Clinical and experimental data suggest that ergotamine compounds and triptans may contribute to vascular events such as myocardial infarction and stroke. The role of blood cell aggregation in this context is, however, not clarified. We aimed to evaluate the impact of different acute antimigraine compounds on platelet and erythrocyte aggregation in a human ex vivo experimental design. In 20 healthy subjects without migraine and in 20 healthy subjects with migraine without aura, platelet and erythrocyte aggregation were measured before and after intake of placebo, acetylsalicylic acid, ergotamine tartrate, zolmitriptan and sumatriptan. Platelet aggregation was measured by the so-called platelet reactivity index. Erythrocyte aggregation was measured by photometric assessment in an aggregometer. Ergotamine tartrate induced a significant increase of platelet aggregation, whereas acetylsalicylic acid induced a significant decrease in both subject groups. After placebo, after sumatriptan and after zolmitriptan, no significant changes of platelet aggregation were noted. Erythrocyte aggregation was affected by neither compound. We can conclude that platelet aggregation, but not erythrocyte aggregation, is increased after intake of ergotamine tartrate. This may in part contribute to vascular side-effects of this compound. Acetylsalicylic acid and the triptans appeared to be safe with respect to platelet and erythrocyte aggregation.

This study explored the association between headache response and return to functioning, and identified migraine-associated symptoms related to functional status and acceptability of migraine treatment as reported by patients. Data from migraineurs enrolled in the active arms of a randomized, double-blind, parallel group, placebo-controlled, clinical trial were analysed. The relationships between headache response and functional response, and clinical factors and treatment acceptability were assessed using X2 tests of proportions and logistic regressions. A greater proportion of patients with headache response at 0.5 h were functioning at 0.5, 1 and 2 h compared with patients who did not attain a headache response at 0.5 h ( P < 0.0001). These patients also were more likely to find their treatment acceptable ( P < 0.05). The results suggest a direct temporal relationship among the key determinants of migraine resolution. Rapid headache response is associated with faster return to functioning; rapid headache and functional responses are significant attributes of treatment acceptability.

Over the years the paradigm of treating early during the migraine attack has become well established in clinical practice. It is also recommended that the 5-HT1B/1D agonists be administered early during the migraine attack for efficacy. This is because it has been proposed that most migraineurs are less responsive to delayed treatment, owing to the development of central sensitization of the pain transmission. The main objective of this prospective, cross-over study at a specialist clinic was to evaluate if these recommendations should also apply to the subcutaneous formulation of sumatriptan. Results are based on 20 adult International Headache Society migraineurs. Two attacks ( n = 40) were treated with 6 mg subcutaneous sumatriptan as early as possible after the onset of migraine headache and two attacks ( n = 40) as late as the patients could bear. The median intra-individual difference between the two strategies in time from first occurrence of pain to injection was 5.7 h and the median intra-individual difference in pain intensity at the time of injection was 29 visual analogue units. No significant differences were found in time to freedom from pain, pain severity at 1 and 2 h, area under the curves from injection to pain free or in headache recurrence after injection. At the end of the study, most of the patients claimed that their medication was as effective when given early as when given late in the course of the attack. The discrepancy between our present findings and retrospective analyses of trials on oral triptans probably has more to do with the less disturbed pharmacokinetics early during the migraine attack than with central sensitization. Consequently, we recommend nonoral formulations of triptans, which do not necessarily have to be administered early during the migraine attack to provide efficacy. In conclusion, it is reassuring for migraineurs that it is worthwhile taking their medication in an appropriate formulation even if they have not been able to do so early in the course of the attack.