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Chronic orofacial pain disorders are common debilitating conditions, affecting the trigeminal system. Its underlying pathophysiological mechanisms are still unclear and the therapy is often unsatisfactory, therefore, preclinical models are crucial to identify the key mediators and novel treatment options. Complete Freund's adjuvant (CFA)-induced orofacial inflammatory allodynia/hyperalgesia is commonly used in rodents, but it has not been validated with currently used drugs. Here we tested the effects of the adjuvant analgesic/antiepileptic voltagegated Na+ channel blocker complex mechanism of action topiramate in comparison with the gold standard antimigraine serotonin 5-HT1B/D receptor agonist sumatriptan in this model. CFA was injected subcutaneously into the right whisker pad of male Sprague-Dawley rats (250-300 g), then mechanonociceptive threshold values were investigated with von Frey filaments (3, 5, and 7 days after CFA injection). Effects of topiramate (30 mg/kg per os) and sumatriptan (1 mg/kg subcutaneous) on the adjuvantinduced chronic inflammatory orofacial allodynia were investigated 60, 120, and 180 min after the treatments each day. To determine the optimal concentration for drug effect analysis, we tested the effects of two different CFA-concentrations (1 and 0.5 mg/mL) on mechanonociceptive thresholds. Both concentrations of CFA induced a chronic orofacial allodynia in 60% of all rats. Although, higher CFA concentration induced greater allodynia, much more stable threshold reduction was observed with the lower CFA concentration: on day 3 the thresholds decreased from 18.30 g to approximately 11 g (low) and 5 g (high), respectively, however a slight increase was observed in the case of higher CFA concentration (on days 5, 7, and 11). In all investigation days, topiramate showed significant anti-allodynic effect comparing the pre and post drug dose and comparing the vehicle treated to the drug treated groups. Sumatriptan also caused a significant threshold increase compared to pre dose thresholds (day 3) and also showed a slight anti-allodynic effect compared to the vehicle-treated group (day 3 and 5). In the present study CFA-induced chronic orofacial allodynia was reversed by topiramate in rats validating the model with the adjuvant analgesic. Other than establishing a validated orofacial pain-related syndrome model in rats, new ways are opened for the repurposing of topiramate. [ABSTRACT FROM AUTHOR]

Introduction: Migraine is a debilitating, neurological disorder, characterized by episodes of ipsilateral headache, often associated with symptoms such as nausea, vomiting, vertigo, and other sensory symptoms. The role of commonly used triptans (5 HT1B/1D agonists) – rizatriptan and sumatriptan – is very scarcely explored in Indian population with migraine. Thus, this study was done to assess the efficacy and tolerability of 10 mg oral rizatriptan versus 50 mg oral sumatriptan for the treatment of acute moderate-to-severe migraine. Materials and Methods: A total of 113 migraine patients attending the neurology outpatient department were enrolled in our study. The efficacy parameters included in our study were pain relief, pain free at 2 h, and sustained pain-free response in both the groups. Adverse drug reactions, if any, were recorded as a measure of tolerability. Results: Overall rizatriptan showed superior efficacy in terms of pain relief at 2 h (71.92% vs. 60.71%) with a statistically significant difference at 1.5 h (P = 0.0084) and 2 h (P = 0.0099) and complete abolition of headache (pain free) at all the four time points spaced 30 min apart (43.85% vs. 26.78%). Twenty-four hours sustained pain-free response was also more in the rizatriptan group (63.42% vs. 47.06%) as compared to that in the sumatriptan group. The frequency of adverse effects was seen more in the sumatriptan group (83.89%) than those receiving rizatriptan (49.68%). Conclusions: Rizatriptan 10 mg was found to be more efficacious and tolerable as compared to sumatriptan 50 mg. [ABSTRACT FROM AUTHOR]

Introduction and purpose Migraine is a common disease mostly affecting women. It has a huge influence on patients' life strongly decreasing its quality by cause of repetitive headache episodes and often comes with unpleasant and burdensome symptoms like photophobia, nausea or vomiting. This article focuses on migraine treatment, especially on new drugs. Primary drugs used in migraine attacks are non-steroid anti-inflammatory drugs (NSAI) and triptans. Because of their side effects and impact on internal organs, these substances are often contraindicated or inefficient. The same applies to triptans, which cannot be used by patients with cardiovascular diseases. Due to the need of a new migraine treatment path development, new remedies have been found, bringing hope for patients who could not use prior options. They are divided into two groups: ditans (lasmiditan), which are 5-HT1F serotonin receptor agonists and gepants (ubrogepant, rimegepant, atogepant and zavegepant), which are CGRP receptor antagonists. A summary of the current state of knowledge is intended to increase the awareness of physicians and patients when selecting the appropriate treatment. Material and methods The following review was based on articles obtained from the PubMed and Google Scholar databases. Key search terms included migraine, ditans, gepants, migraine treatment. Conclusions Drugs described in this study clearly show the new pathway of migraine treatment and prevention. They are safer and show more benefits than substances currently used. They can also be used in wider range of patients with conditions marked as contraindications for current schemes. However more research is still needed to fully describe their characteristics. [ABSTRACT FROM AUTHOR]

1-(3-(2-(Dimethylammonio)ethyl)-1H-indol-5-yl)-N-methylmethanesulfonamide succinate (sumatriptan succinate, HSum+·HSucc−) is a serotonin receptor agonist used to treat migraines. By the recrystallization of this substance from ethanol, its hemi(ethanol solvate), HSum+·HSucc−·0.5EtOH, was obtained. The solid was characterized by X-ray diffraction and FT-IR spectroscopy. In HSum+·HSucc−·0.5EtOH, solvent molecules link succinate anions into infinite O–H...O bonded chains, which are further connected by N–H...O interactions with cations into H-bonded layers. [ABSTRACT FROM AUTHOR]

Background: Migraine and vestibular migraine are disorders associated with a heightened motion sensitivity that provoke symptoms of motion-induced nausea and motion sickness. VM affects (3% of adults in the USA and affects three-fold more women than men. Triptans (selective serotonin receptor agonists) relieve migraine pain but lack efficacy for vertigo. Murine models of photophobia and allodynia have used injections of calcitonin gene-related peptide (CGRP) or other migraine triggers, such as sodium nitroprusside (SNP), to induce migraine sensitivities in mice to touch and light. Yet, there is limited research on whether these triggers affect motion-induced nausea in mice, and whether migraine blockers can reduce these migraine symptoms. We hypothesized that systemic delivery of CGRP or SNP will increase motion sickness susceptibility and motion-induced nausea in mouse models, and that migraine blockers can block these changes induced by systemically delivered CGRP or SNP. Methods: We investigated two measures of motion sickness assessment [motion sickness index (MSI) scoring and motion-induced thermoregulation] after intraperitoneal injections of either CGRP or SNP in C57BL/6J mice. The drugs olcegepant, sumatriptan and rizatriptan were used to assess the efficacy of migraine blockers. Results: MSI measures were confounded by CGRP’s effect on gastric distress. However, analysis of tail vasodilatations as a surrogate for motion-induced nausea was robust for both migraine triggers. Only olcegepant treatment rescued tail vasodilatations. Conclusions: These preclinical findings support the use of small molecule CGRP receptor antagonists for the treatment of motion-induced nausea of migraine, and show that triptan therapeutics are ineffective against motion-induced nausea of migraine [ABSTRACT FROM AUTHOR]

Aim: Evidence from mouse models suggests that brain serotonergic pathways control blood glucose. We hypothesized that sumatriptan (5HT1B‐receptor agonist) would alter glucose homeostasis in humans. Materials and Methods: We conducted a two‐visit random‐order double‐blinded placebo‐controlled cross‐over trial in 10 overweight adults that were otherwise healthy. Participants received sumatriptan (single dose, 100 mg) or placebo before undergoing a 60‐min intravenous glucose tolerance test, followed by a 120‐min hyperinsulinaemic euglycaemic clamp. Results: Glucose excursion was greater during intravenous glucose tolerance test with sumatriptan compared with placebo [iAUC0‐60 min 316 (268‐333) vs. 251 (197‐319) min/mmol/L p =.047]. This was probably explained by a combination of reduced circulating insulin levels [iAUC0‐10 min 1626 (1103‐2733) vs. 2336 (1702‐3269) min/pmol/L, p =.005], reduced insulin sensitivity [M/I‐value 2.11 (1.15, 4.05) vs. 3.03 (1.14, 4.90) mg/kg/min per pmol/L, p =.010] and glucose effectiveness [SG 0.17 (0.12, 0.21) vs. 0.22 (0.18, 0.65)/min, p =.027]. Conclusions: 5HT1B receptors have a glucoregulatory role in humans, probably acting on insulin secretion, insulin sensitivity and glucose effectiveness. [ABSTRACT FROM AUTHOR]

Rizatriptan (RZT) is an efficient anti-migraine drug which belongs to the class of selective 5 HT (1B/1D) serotonin receptor agonists. Nevertheless, RZT elicits several adverse effects and RZT nasal sprays have a limited half-life, requiring repeated doses that could cause patient noncompliance or harm to the nasopharynx and cilia. The current research aimed to develop orally disintegrating films (ODFs) of RZT employing maltodextrin (MTX) and pullulan (PUL) as film-forming polymers, as well as propylene glycol (PG) as a plasticizer. The ODFs were prepared by solvent casting method (SCM). The technique was optimized using Box–Behnken design (BBD), contemplating the ratios of PUL: MTX and different levels of PG (%) as factor variables. The influence of these factors was systematically analyzed on the selected dependent variables, including film thickness, disintegration time (D-time), folding endurance (FE), tensile strength (TS), percent elongation (%E), moisture content (%), and water uptake (%). In addition, the surface morphology, solid state analysis, drug content uniformity (%), drug release (%), and pH of the RZT-ODFs were also studied. The results demonstrated a satisfactory stable RZT-ODFs formulation that exhibited surface homogeneity and amorphous RZT in films with no discernible interactions between the model drug and polymeric materials. The optimized film showed a rapid D-time of 16 s and remarkable mechanical features. The in vitro dissolution kinetics showed that 100% RZT was released from optimized film compared to 61% RZT released from conventional RZT formulation in the initial 5 min. An animal pharmacokinetic (PK) investigation revealed that RZT-ODFs had a shorter time to achieve peak plasma concentration (Tmax), a higher maximum plasma concentration (Cmax), and area under the curve (AUC0−t) than traditional oral mini capsules. These findings proposed a progressive approach for developing anti-migraine drugs that could be useful in reducing the complications of dysphagia in geriatric and pediatric sufferers. [ABSTRACT FROM AUTHOR]

Background: Medication overuse is a significant issue that complicates the treatment of headache disorders. The most effective medications for the acute treatment of migraine all have the capacity to induce medication overuse headache (MOH). Novel acute migraine-specific treatments are being developed. However, because the mechanism(s) underlying medication overuse headache are not well understood, it is difficult to predict whether any particular acute medication will induce MOH in susceptible individuals. LY573144 (lasmiditan), a 5-HT1F receptor agonist, has recently been shown to be effective in the acute treatment of migraine in phase 3 trials. The aim of this study is to determine whether frequent administration of lasmiditan induces behaviors consistent with MOH in a pre-clinical rat model.Methods: Sprague Dawley rats were administered six doses of lasmiditan (10 mg/kg), sumatriptan (10 mg/kg), or sterile water orally over 2 weeks and cutaneous allodynia was evaluated regularly in the periorbital and hindpaw regions using von Frey filaments. Testing continued until mechanosensitivity returned to baseline levels. Rats were then submitted to bright light stress (BLS) or nitric oxide (NO) donor administration and were again evaluated for cutaneous allodynia in the periorbital and hindpaw regions hourly for 5 hours.Results: Both lasmiditan and sumatriptan exhibited comparable levels of drug-induced cutaneous allodynia in both the periorbital and hindpaw regions, which resolved after cessation of drug administration. Both lasmiditan and sumatriptan pre-treatment resulted in cutaneous allodynia that was evoked by either BLS or NO donor.Conclusions: In a pre-clinical rat model of MOH, oral lasmiditan, like sumatriptan, induced acute transient cutaneous allodynia in the periorbital and hindpaw regions that after resolution could be re-evoked by putative migraine triggers. These results suggest that lasmiditan has the capacity to induce MOH through persistent latent peripheral and central sensitization mechanisms. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The purpose of the Research to Practice column is to review and critique current research articles that directly affect the practice of the advanced practice nurse (APN) in the emergency department. This review examines the findings of M. Oskoui et al. (2019) from their article, "Practice guideline update summary: Acute treatment of migraine in children and adolescents: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society." The authors completed an extensive literature review and created eight recommendations for the acute treatment of pediatric migraine focusing on medication selection, dosing, patient education, and patient counseling. By applying the evidence-based guidelines presented in this study, the urgent care or emergency department APN can confidently recognize and treat acute migraine symptoms and reduce patient risks from unnecessary testing and overuse of acute migraine medications. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to establish a pharmacodynamic model to quantitatively compare the efficacy characteristics of seven kinds of triptans and their different dosage forms in the treatment of acute migraines. Methods: Clinical studies of triptans in the treatment of acute migraines were comprehensively searched in the public databases. Pharmacodynamic models were established to describe the dose-effect and time-course of each kind of triptan for the proportion of patients who became pain free or had pain relief. Results: A total of 92 articles involving 47,376 subjects were included in the analysis. After eliminating the placebo effect, oral eletriptan (40 mg) had the highest efficacy among all oral drugs at the maximum approved dose, and the proportion of patients who became pain free and had pain relief were 30.9% and 37.9% at 2 h, respectively. However, oral naratriptan (2.5 mg) had the lowest efficacy, and the proportion of patients who became pain free and had pain relief was 10.3% and 21.6% at 2 h, respectively. The efficacy of subcutaneous administration was significantly higher than that of oral administration, and the efficacy of nasal spray administration was comparable to that of oral administration. Regarding the dose-effect, the efficacy of the sumatriptan nasal spray significantly increased within the FDA (Food and Drug Administration)-approved dose range. When the dose was increased from 5 to 20 mg of sumatriptan nasal spray, the proportion of patients who became pain free and had pain relief increased by 16.8% and 18.3% at 2 h, respectively. Regarding the time-course, the time of onset of subcutaneous sumatriptan (6 mg) was the fastest, and the fraction of patients who were pain free at 2 h accounted for 90.6% of that at 4 h. Conclusions: This study evaluated the efficacy characteristics of seven kinds of triptans and their different dosage forms. The present findings provide necessary quantitative information for migraine medication guidelines. [ABSTRACT FROM AUTHOR]

The medications in use for treating migraine are directed either towards inhibiting the characteristic migraine pain or towards preventing it from occurring. In this pursuit, ergotamine and sumatriptan class of 5-HT1B receptor agonists have been proved to be extremely effective. Further research into this field led us to design cyanopyridone derivatives that were synthesized through cyclization of 2-cyano-N-phenylacetamides with malonitrile and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. The synthesized cyanopyridones analogs, when docked with active site of 5-HT1B receptor, showed better binding affinity compared to standard antimigraine medications. Additionally, in silico ADME prediction for drug-likeness and pharmacokinetics revealed that all compounds are safer and can be used as antimigraine medicine. The structure of the synthesized compounds has been elucidated on the basis of spectral analysis. [ABSTRACT FROM AUTHOR]

Objectives: Sumatriptan (Imigran) is a potent and highly selective 5‐HT1 receptor agonist often used in treating acute migraine. Intranasal sumatriptan is well absorbed and is generally effective in relieving headache. However, the effects of Imigran on human nasal mucosa have rarely been well explored, to verify the effect of Imigran, which act on human nasal mucosa directly in vitro. Design and participants: We examined the effectiveness of Imigran on human nasal mucosa by testing: (i) effect on human nasal mucosa resting tension; (ii) effect on contraction caused by 10−6 mol/L methoxamine as a sympathetic mimetic; and (iii) effect of the drugs on electrically induced on human nasal mucosa contractions. Results: The results indicated that addition of methoxamine to the incubation medium caused the nasal mucosa to contract in a dose‐dependent manner. Addition of Imigran at doses of 10−4 mol/L elicited a significant relaxation response to 10−6 mol/L methoxamine‐induced contraction. Imigran could not inhibit electrical field stimulation‐induced spike contraction. It also had a minimal effect on the basal tension of nasal mucosa as the concentration increased. Conclusions: The study indicated that high concentrations of Imigran had a significant spasmolytic effect by antagonising α‐adreoceptors and nasal obstruction could not be released in the patient combined with acute migraine and stuffy nose by concomitant α‐adrenergic agonist nasal spray plus Imigran nasal spray. [ABSTRACT FROM AUTHOR]

Amongst the side effects of triptans, a substantial percentage of patients experience injection site pain and tenderness, the underlying mechanism of which is unknown. We found that the dose range from 10 fg to 1000 ng (intradermal) of sumatriptan induced a complex dose-dependent mechanical hyperalgesia in male rats, with distinct peaks, at 1 pg and 10 ng, but no hyperalgesia at 1 ng. In contrast, in females, there was 1 broad peak. The highest dose (1000 ng) did not produce hyperalgesia in either sex. We evaluated the receptors mediating sumatriptan hyperalgesia (1 pg, 1 and 10 ng). In males, the injection of an antagonist for the serotonin (5-HT) receptor subtype 1B (5-HT 1B ), but not 5-HT 1D , markedly inhibited sumatriptan (1 pg)-induced hyperalgesia, at 10 ng a 5-HT 1D receptor antagonist completely eliminated hyperalgesia. In contrast, in females, the 5-HT 1D , but not 5-HT 1B , receptor antagonist completely blocked sumatriptan (1 pg and 10 ng) hyperalgesia and both 5-HT 1B and 5-HT 1D receptor antagonists attenuated hyperalgesia (1 ng) in females, which is GPR30 estrogen receptor dependent. While selective 5-HT 1D or 5-HT 1B , agonists produce robust hyperalgesia in female and male rats, respectively, when co-injected the hyperalgesia induced in both sexes was attenuated. Mechanical hyperalgesia induced by sumatriptan (1 pg and 10 ng) is dependent on the G-protein α i subunit and protein kinase A (PKA), in IB4-positive and negative nociceptors. Understanding the mechanisms responsible for the complex dose dependence for triptan hyperalgesia may provide useful information for the design of anti-migraine drugs with improved therapeutic profiles. [ABSTRACT FROM AUTHOR]

Objective A review of treatment options for menstrual migraine. Background Migraine affects ∼30 million people in the US. A subset of female migraineurs have migraines that are mainly associated with menstruation. Menstrual migraine (MM) is divided into pure MM and menstrually related migraine. Pure MM attacks occur only with menstruation and have a prevalence of 1%. Menstrually related migraine has a prevalence of 6-7%, and occurs both during menstruation as well as during the rest of the cycle. MM is usually without aura and is more severe, longer lasting, and more resistant to treatment due to the effects of ovarian hormones, specifically estrogen. MM treatment is divided into acute, short-term prophylaxis, and daily prevention. The best-studied acute treatments are triptans. For short-term prophylaxis, triptans, non-triptans, or combinations are used. Some preventive medications may be used daily to prevent MM. Many anti-epileptic medications used in migraine prevention can affect the efficacy of oral contraceptives and hormonal treatments, so caution is indicated when these are used. Methods PubMed, Scopus, Cochrane, and Embase were searched for MM and treatments. Results Many randomized, placebo-controlled, prospective studies have evaluated the efficacy of sumatriptan, rizatriptan, naratriptan, zolmitriptan, and almotriptan in MM. Reviewing numerous studies with statistically significant results, rizatriptan has the best overall evidence for acute treatment of MM, ranging from pain-free responses of 33-73% at 2 hours. Sumatriptan and rizatriptan have shown similar efficacies of 61-63% in terms of 2 hour pain freedom. Rizatriptan showed sustained pain relief between 2 and 24 hours with an efficacy of 63% and sustained pain freedom for MM between 2 and 24 hours with an efficacy of 32%. For short-term prevention of MM, there were four randomized controlled trials for frovatriptan taken twice daily, one trial for zolmitriptan taken three times daily, and two studies for naratriptan taken twice daily, all of which showed statistically significant results. Among studies on non-triptans for short-term prevention of MM, magnesium, estrogen, naproxen sodium, and dihydroergotamine all had statistically significant results. Many antiepileptic medications taken for prevention of MM can cause enzyme induction affecting oral contraceptives (OCs) and hormonal treatments to different degrees. Topiramate has the least effect on OCs at doses below 200 mg/day. Lamotrigine noticeably decreases oral contraceptive levels; however, the evidence for it as a preventive medication is not strong. Conclusion MM can be very difficult to treat. For acute treatments, rizatriptan has the best overall evidence. For short-term prevention, frovatriptan, zolmitriptan, or naratriptan, as well as magnesium, estrogen, naproxen sodium, or dihydroergotamine may be useful. [ABSTRACT FROM AUTHOR]

Background The development of novel migraine therapies has been slow, in part because of the small number of clinically relevant animal models. We have recently developed a new mouse model of chronic migraine using chronic intermittent nitroglycerin, a known human migraine trigger. The objective of this study was to validate this model by testing known and potential migraine-preventive treatments. Methods Migraine therapies were administered to male and female mice for 11 days. On day 3, mice were tested with nitroglycerin every second day for nine days. Basal and nitroglycerin-evoked mechanical hypersensitivity was evaluated using von Frey filaments. Results Chronic intermittent nitroglycerin produced acute hyperalgesia with each administration, and progressive and sustained basal hypersensitivity. The established preventive migraine therapy propranolol effectively blocked the development of acute and chronic nitroglycerin-induced hyperalgesia, while valproate had no effect. Potential migraine-preventive therapies were also tested: Amiloride inhibited nitroglycerin-induced acute and chronic hyperalgesia; while memantine was ineffective. We also tested the acute migraine therapy sumatriptan, which did not alter nitroglycerin-induced hyperalgesia, but instead resulted in acute and chronic hyperalgesia similar to that observed following nitroglycerin administration. Conclusions This study establishes the chronic nitroglycerin model as an additional screening tool to test novel migraine-preventive therapies. [ABSTRACT FROM AUTHOR]

Objectives/Background We herein investigated the role of polymorphisms in calcitonin gene-related peptide ( CGRP)-related genes looking at the association of rs3781719 ( T > C) in the calcitonin gene-related polypeptide-alpha ( CALCA) gene and of rs3754701 ( T > A) and rs7590387 ( C > G) at the receptor activity modifying 1 ( RAMP 1) locus with triptan response in patients with migraine without aura ( MwoA). In addition, their role was evaluated as risk factors for transformation of episodic migraine into medication overuse headache ( MOH). The CGRP has a central role in the pathogenesis of migraine; however, little information is currently available concerning the role of polymorphisms in CGRP-related genes as determinants of clinical response to anti-migraine drugs or as risk factors for migraine chronification. Methods Genotyping was conducted retrospectively by real-time polymerase chain reaction allelic discrimination assay in 219 patients with MwoA and 130 with MOH in whom migraine was the primary headache type. Gene variants association was evaluated by logistic regression analysis adjusted by confounding factors. The threshold of statistical significance was set according to the total number of polymorphisms analyzed in the current study and in previous publications arising from overlapping datasets. Results No evidence of association was found between the three polymorphisms tested and triptan response in MwoA patients. Conversely, carriers of RAMP 1 rs7590387 GG displayed a lower risk of episodic migraine transformation into MOH (vs C allele carriers, odds ratio [ OR]: 0.27, 95% confidence interval [ CI]: 0.13-0.57, P = 0.0002; threshold of significance set at P < 0.0029). When genotype distribution for RAMP 1 rs7590387 was compared between healthy controls (n = 209) and MOH patients, carriers of rs7590387 GG were found at lower risk of developing MOH ( OR: 0.43, 95% CI: 0.22-0.85, P = 0.011). Conclusion These results suggest that RAMP 1 rs7590387 may have a role in the transformation of episodic migraine into MOH. [ABSTRACT FROM AUTHOR]

Objectives To monitor for a signal of major teratogenicity by determining the risk of all birth major defects following in utero exposure to sumatriptan, naratriptan, and the sumatriptan/naproxen sodium combination product (tablets marketed in the United States as Treximet [GlaxoSmithKline, Research Triangle Park, NC, USA]), and to monitor for unusual patterns of defects that might suggest teratogenicity. Background The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to anti-migraine drugs in pregnancy is likely. The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry captured data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. Methods In this primarily prospective, observational study, health care professionals from anywhere in the world enrolled, on a voluntary basis, women exposed to sumatriptan, naratriptan, or the sumatriptan/naproxen sodium combination product during their pregnancies. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The proportion of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. Results The registry enrolled 680 evaluable exposed pregnant women, which resulted in 689 infants and fetuses (outcomes). Of these outcomes, 626 were exposed to sumatriptan, 57 were exposed to naratriptan (seven were exposed to both sumatriptan and naratriptan), and six were exposed to the sumatriptan/naproxen sodium combination product. Twenty outcomes with major birth defects were reported among 528 outcomes exposed in the first trimester to sumatriptan. The estimated risk of major birth defects following first-trimester sumatriptan exposure is 4.2% (20/478 [95% confidence interval [ CI] 2.6%-6.5%]). Among 52 first-trimester exposures to naratriptan, major birth defects were reported in one outcome, an infant with exposure to both sumatriptan and naratriptan [birth defect risk of 2.2% (1/46 [95% CI 0.1%-13.0%]). No major defects were reported among the five outcomes with first-trimester exposure to the sumatriptan/naproxen sodium combination products. Conclusions The Sumatriptan, Naratriptan, and Treximet Pregnancy Registry detected no signal of teratogenicity associated with major birth defects for sumatriptan. This finding is consistent with results from other observational studies using a variety of control groups. Enrollment in the registry was insufficient to permit definitive conclusions of the risks associated with naratriptan or sumatriptan/naproxen sodium tablets, or to assess the risk of individual birth defects in any of the products studied. Low enrollment and high rates of loss to follow up within the registry over an extended period of time led the registry's scientific advisory committee to conclude that continuation of the registry beyond its 16 years would offer little additional power to rule out more moderate increases in the risk of birth defects. Data from the other ongoing surveillance sources constitute an important element of post-marketing surveillance of these medications. The lack of a signal of major teratogenicity with sumatriptan across these several sources of data is encouraging. [ABSTRACT FROM AUTHOR]

Trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, and rhinorrhea ( SUNCT). Conventional pharmacological therapy can be successful in the majority of trigeminal autonomic cephalalgias patients. Most cluster headache attacks respond to 100% oxygen inhalation, or 6 mg subcutaneous sumatriptan. Nasal spray of sumatriptan (20 mg) or zolmitriptan (5 mg) are recommended as second choice. The bouts can be brought under control by a short course of corticosteroids (oral prednisone: 60-100 mg/day, or intravenous methylprednisolone: 250-500 mg/day, for 5 days, followed by tapering off the dosage), or by long-term prophylaxis with verapamil (at least 240 mg/day). Alternative long-term preventive medications include lithium carbonate (800-1600 mg/day), methylergonovine (0.4-1.2 mg/day), and topiramate (100-200 mg/day). As a rule, paroxysmal hemicrania responds to preventive treatment with indomethacin (75-150 mg/day). A short course of intravenous lidocaine (1-4 mg/kg/hour) can reduce the flow of attacks during exacerbations of SUNCT. Lamotrigine (100-300 mg/day) is the preventive drug of choice for SUNCT. Gabapentin (800-2700 mg/day), topiramate (50-300 mg/day), and carbamazepine (200-1600 mg/day) may be of help. [ABSTRACT FROM AUTHOR]

Cluster headache pain is very intense, usually increases in intensity very rapidly from onset, and attacks are often frequent. These clinical features result in significant therapeutic challenges. The most effective pharmacological treatment options for acute cluster attack include subcutaneous sumatriptan, 100% oxygen, and intranasal zolmitriptan. Subcutaneous or intramuscular dihydroergotamine and intranasal sumatriptan are additional options. Transitional therapy is applicable mainly for patients with high-frequency (>2 attacks per day) episodic cluster headache, and options include short courses of high-dose oral corticosteroids, dihydroergotamine, and occipital nerve blocks with local anesthetic and steroids. Prophylactic therapy is important both for episodic and chronic cluster headache, and the main options are verapamil and lithium. Verapamil is drug of first choice but may cause cardiac arrhythmias, and periodic electrocardiograms ( EKGs) during dose escalation are important. Many other drugs are also in current use, but there is an insufficient evidence base to recommend them. [ABSTRACT FROM AUTHOR]

Abstract: The selective 5-HT1 receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5-HT1 receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca2+ transients. Pre-application of the 5-HT1 antagonist GR 127935 or the selective 5-HT1D antagonist BRL 15572 prevented inhibition while the selective 5-HT1B antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT1D receptor subtype. Sumatriptan inhibition of the action potential evoked Ca2+ signaling was mediated selectively through N-type Ca2+ channels. Although the T-type Ca2+ channel accounted for a greater proportion of the Ca2+ signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca2+ channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5-HT1 receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine. [Copyright &y& Elsevier]

Objective.- To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydroergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings. Methods.- MEDLINE was searched using the terms 'migraine' and 'emergency,' and 'therapy' or 'treatment.' Reports from emergency department and urgent care settings that involved all routes of medication delivery were included. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.- Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well as rizatriptan. Effectiveness varied widely, even when the pain-free and pain-relief statistics were evaluated separately. As these medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan administration. Multiple studies compared triptans with anti-emetics, dopamine antagonists, and non-steroidal anti-inflammatory drugs. The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed. While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and phonophobia. Conclusions.- Although there are relatively few studies involving health-care provider-administered triptans or DHE for acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single agents with each other. [ABSTRACT FROM AUTHOR]

Subcutaneous sumatriptan is an effective treatment for pain from acute migraine headache, and can be used in patients with known migraine syndrome and in patients with primary headaches when secondary causes have been excluded. In limited comparative trials, subcutaneous sumatriptan performed in a manner comparable with oral eletriptan and intravenous metoclopramide, was superior to intravenous aspirin and intramuscular trimethobenzamidediphenhydramine, and was inferior to intravenous prochlorperazine for pain relief. The most common side effects seen with subcutaneous sumatriptan are injection site reactions and triptan sensations. As with all triptans, there is a risk of rare cardiovascular events with subcutaneous sumatriptan and its use should be limited to those without known cerebrovascular disease and limited in those with known cardiovascular risk factors and unknown disease status. In studies of patient preference and tolerability, the subcutaneous formulation has a faster time of onset and high rate of efficacy when compared with the oral formulation, but the oral formulation appears to be better tolerated. It is important to consider the needs of the patient, their past medical history, and what aspects of migraine treatment are most important to the patient when considering treatment of acute migraine or primary headache. Subcutaneous sumatriptan is a good first-line agent for the treatment of pain from acute migraine headaches and primary headaches. [ABSTRACT FROM AUTHOR]

A double-blind, randomized, parallel study was done to compare sumatriptan, ergotamine, naproxen and rizatriptan in 40 outpatients treating a single migraine attack of moderate to severe intensity. Among these groups, significantly more number of patients had headache relief at 2 hours postdose in naproxen and rizatriptan group as compared to ergotamine. Naproxen, rizatriptan and sumatriptan were better than ergotamine in causing freedom from the associated symptoms of nausea, vomiting, photophobia and phonophobia at 2 hour postdose. Naproxen, rizatriptan and sumatriptan were also efficacious in causing functional normalization at 2 hours postdose as compared to ergotamine. The overall results of the study suggest that naproxen is as efficacious as triptan group of drugs but better than ergotamine group in treatment of moderate-severe acute migraine attack. It is more cost effective than triptans and also a well tolerated drug [ABSTRACT FROM AUTHOR]

Migraine is a common type of headache and its most severe attacks are usually treated with triptans, the efficacy of which is extremely variable. Several SNPs in genes involved in metabolism and target mechanisms of triptans have been described. To define an association between genetic profile and triptan response, we classified a migrainous population on the basis of triptan response and characterized it for polymorphisms in the genes coding for monoamine oxidase A, G protein β3 and the cytochrome CYP1A2. Analysis of the association between genotypic and allelic frequencies of the analyzed SNPs and the grade of response to triptan administration showed a significant correlation for MAOA uVNTR polymorphism. Further stratification of patients in abuser and non-abuser groups revealed a significant association with triptan overuse and, within the abusers, with drug response to the CYP1A2*1F variant. [ABSTRACT FROM AUTHOR]

Summary: Migraine is a common, multisymptom disorder that can severely impact the daily activities of migraineurs. Triptans (primarily sumatriptan) are the most commonly prescribed treatment for migraine and are considered a relatively safe and effective initial therapy. Unfortunately, current sumatriptan formulations (i.e., oral, nasal, subcutaneous) may be associated with limitations that can result in patients' delaying or avoiding treatment. For oral formulations, these limitations include difficulty in taking an oral medication due to the nausea and vomiting that often accompany migraine, and inconsistent absorption, whereas nasal and subcutaneous formulations may be associated with low bioavailability and an undesirable rate of adverse events, respectively. An alternative to current formulations is transdermal drug delivery, particularly iontophoresis. Transdermal delivery has several advantages over current formulations, including avoidance of the gastrointestinal tract, controlled and sustained delivery, and convenient administration. This article reviews the in vitro, in vivo, and preclinical data supporting the use of iontophoresis for the delivery of sumatriptan, as well as the recent clinical data for Zelrix (NuPathe Inc., Conshohocken, PA), an iontophoretic sumatriptan patch currently in phase III development for the treatment of migraine. [ABSTRACT FROM AUTHOR]

( Headache 2010;50:249-255) Background.— The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after Tmax = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. Objective.— The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. Methods.— Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at Tmax, 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). Results.— The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of Cmax). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC0-10h was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. Conclusions.— There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan. [ABSTRACT FROM AUTHOR]

Sumatriptan succinate is an agonist for a vascular 5-hydroxytryptamine (5-HT)1 receptor subtype (probably a member of the 5-HT1D family). It does not have significant affinity for the remaining 5-HT receptors. It does not have affinity for alpha1, alpha2 or beta-adrenergic, dopamine1, dopamine2, muscarinic or benzodiazepine receptors. The objective of the study was to evaluate the in vitro transnasal absorption of sumatriptan succinate through sheep nasal mucosa and to determine its in vitro permeation behavior from various formulations containing penetration enhancers. In this study four different thermoreversible gel formulations designed for nasal delivery of sumatriptan succinate were formulated. The formulations were prepared by using a poly(oxythylene) poly(oxypropylene) block copolymer (Pluronic F 127) based gel along with different permeation enhancers and a pluronic lecithin organogel base. The effect of different concentrations of sodium glycocolate, EDTA and transcutol on in vitro nasal diffusion of sumatriptan succinate was studied. The best permeation profile was obtained with a formulation containing transcutol at a concentration of 0.005% w/w. Pluronic lecithin organogel showed good gelling properties at a concentration in the 20% range. [ABSTRACT FROM AUTHOR]

Objective.— This study evaluated the pharmacokinetic and tolerability profiles of Zelrix™ (NuPathe Inc., Conshohocken, PA, USA), the novel formulation of sumatriptan (formerly known as NP101). Background.— Migraine is an episodic headache disorder characterized by a combination of neurological, gastrointestinal, and autonomic symptoms. Gastrointestinal disturbances, including nausea, vomiting, and gastric stasis are common and can result in significant impact on treatment. Triptans are 5-hydroxytriptanime1B/1D agonists that work on the trigeminal nerve that is activated during migraine. All triptans approved for use in the US are currently available as oral formulations; however, this may not be the ideal route of administration for many migraineurs. Sumatriptan is also available as a nasal spray and subcutaneous (sc) injection. Therefore, the need to develop improved methods for noninvasive parenteral delivery of triptans remains high. Methods.— This was a Phase I, single-center, open-label, crossover study that assessed the pharmacokinetic properties of a single dose of sumatriptan delivered using an iontophoretic transdermal patch in comparison with oral, injection, and nasal delivery. Subjects were healthy male and female volunteers who received each of 5 treatments: sumatriptan 100 mg oral tablets, sumatriptan 6 mg sc, sumatriptan 20 mg nasal spray, Zelrix I (transdermal patch with 3 g of gel solution delivering 6 mg of sumatriptan transdermally), or Zelrix II (transdermal patch containing 2.6 g of gel solution delivering 6 mg of sumatriptan). Results.— The Cmax for Zelrix was reduced to 30% and 28% of the sumatriptan sc dose, thereby reducing the risk of triptan-like sensations associated with high peak plasma concentrations. Plasma concentrations for Zelrix I and Zelrix II were intermediate between those for oral and nasal sumatriptan doses tested. Transdermal patch delivery of sumatriptan to the systemic circulation reached plasma concentrations of 10 ng/mL within about 30 minutes. The mean drug delivery of Zelrix I and II was 6.11 mg (confidence intervals [CI] 5.33-6.88) and 6.09 mg (CI 5.52-6.66), respectively. The AUC0-inf was approximately 99% for the Zelrix I patch and 100% for the Zelrix II patch as compared with sumatriptan 6 mg sc dose. Both doses of sumatriptan transdermal patches were well tolerated. Skin reactions at the patch site were mild and erythema resolved in most subjects within 48-72 hours. Conclusions.— The results from this study show that sumatriptan administration using a novel iontophoretic transdermal technology delivers plasma levels within the range for nasal spray, tablet, and injectable sumatriptan. Zelrix I and II were well tolerated and adverse events were mild and transient. Transdermal delivery of sumatriptan using the SmartRelief iontophoretic technology may prove beneficial for a large segment of the migraine population based upon fast, consistent delivery of drug and avoidance of common gastrointestinal disturbances associated with migraine. [ABSTRACT FROM AUTHOR]

Abstract: The in vitro inhibitory effects and in silico docking energies of 18 compounds with respect to Aquaporin 4 (AQP4) were investigated. More than half of the compounds tested showed inhibitory activity in the in vitro functional assay and included the 5-HT1B/1D agonists sumatriptan, and rizatriptan. Moreover, the observed inhibitory activity of the compounds used in this study at 20μM showed a strong correlation with their in silico docking energies, r 2 =0.64, which was consistent with that found in previous studies. The AQP4 inhibitory IC50 values of three compounds, 2-(nicotinamido)-1,3,4-thiadiazole, sumatriptan and rizatriptan, were subsequently found to be 3, 11, and 2μM, respectively. [Copyright &y& Elsevier]

Abstract: Sumatriptan and the other triptan drugs target the serotonin receptor subtypes1B, 1D, and 1F (5-HT1B/D/F), and are prescribed widely in the treatment of migraine. An anti-migraine action of triptans has been postulated at multiple targets, within the brain and at both the central and peripheral terminals of trigeminal “pain-sensory” fibers. However, as triptan receptors are also located on “pain-sensory” afferents throughout the body, it is surprising that triptans only reduce migraine pain in humans, and experimental cranial pain in animals. Here we tested the hypothesis that sumatriptan can indeed reduce non-cranial, somatic and visceral pain in behavioral models in mice. Because sumatriptan must cross the blood brain barrier to reach somatic afferent terminals in the spinal cord, we compared systemic to direct spinal (intrathecal) sumatriptan. Acute nociceptive thresholds were not altered by sumatriptan pre-treatment, regardless of route. However, in behavioral models of persistent inflammatory pain, we found a profound anti-hyperalgesic action of intrathecal, but not systemic, sumatriptan. By contrast, sumatriptan was completely ineffective in an experimental model of neuropathic pain. The pronounced activity of intrathecal sumatriptan against inflammatory pain in mice raises the possibility that there is a wider spectrum of therapeutic indications for triptans beyond headache. [Copyright &y& Elsevier]

The marketing of sumatriptan, a selective serotonin (5-HT) 1B/1D agonist, first of the class of triptans, has increased the therapeutic options for the treatment of migraine attacks. However, almost one third of patients in clinical trials fail to have headache relief after oral administration of sumatriptan. To evaluate whether the interindividual differences in the clinical response following oral administration of sumatriptan are due to differences in its pharmacokinetics. We compared the pharmacokinetics of sumatriptan after oral (100 mg) and subcutaneous (6 mg) administration in two age- and gender-matched groups: ten subjects (group A) with satisfactory response and ten (group B) with unsatisfactory response to oral sumatriptan. Patients were studied during headache-free intervals. Blood samples were taken serially from baseline to 360 min after oral administration and from baseline to 180 min after subcutaneous injection. Sumatriptan plasma concentrations were determined by high-performance liquid chromatography (HPLC) with an electrochemical detector. Following oral dosing, patients of group A absorbed sumatriptan significantly faster and achieved early plasma levels significantly higher than patients of group B. The systemic exposure to sumatriptan during the first 2 h, which are the most important for rapid onset of action and for antimigraine efficacy, was significantly greater in group A than in group B ( P < 0.001, Student’s t test for independent data). On the other hand, after subcutaneous injection of sumatriptan, the profile of the curves was similar in all patients, and there were no differences in pharmacokinetics between group A and group B. The slow rate and low extent of absorption of the drug during the first 2 h after dosing observed in patients of group B could explain their unsatisfactory response to oral sumatriptan. [ABSTRACT FROM AUTHOR]

Abstract: Activation of the 5-HT1B/D receptor inhibits cerebrovascular neurogenic inflammation (NI). The aim of this study was to determine if the 5-HT1B/D receptor agonist sumatriptan can also inhibit NI in other regions of the body. NI was assessed by measuring plasma extravasation (PE) and changes in blood flow in the rat hindpaw. Sumatriptan was administered locally (20μl, 50 or 100nM, s.c.) into the dorso-medial region of one hindpaw. The other paw was pre-treated with vehicle (20μl of 0.9% saline) and served as a control. NI was induced after treatment with sumatriptan/vehicle by injecting capsaicin (15μl, 1%, s.c.) into each paw or by electrically stimulating the saphenous nerve (4Hz, 30s). Sumatriptan administered locally or systemically (300μg/kg, i.v.) significantly reduced saphenous nerve and capsaicin-induced PE and vasodilation. The systemic and local inhibitory actions of sumatriptan are mediated by the 5-HT1B/D receptor as pre-treatment with the 5-HT1B/D antagonist GR127935 (GR; 15μl, 1μM, s.c. or 0.2μmol/kg, i.v.) completely blocked the inhibitory effect of sumatriptan on capsaicin-induced vasodilation and reduced the inhibitory effect of sumatriptan on capsaicin and electrically induced-PE. Neither PE induced by local injection of substance P (SP) (20pmol, 20μl, s.c.) nor vasodilation induced by local CGRP injection was affected by pre-treatment with sumatriptan. These findings indicate that both local and systemic activation of the 5-HT1B/D receptor by sumatriptan reduce NI induced by nerve stimulation or capsaicin presumably by inhibiting neuropeptide release. 5-HT1B/D receptor agonists may be useful for the treatment of non-trigeminal pain conditions involving NI. [Copyright &y& Elsevier]

Abstract: The anti-migraine drug sumatriptan often induces unpleasant somatosensory side effects, including a dislike of being touched. With a double-blind cross-over design, we studied the effects of sumatriptan and saline on perception (visual analogue scale) and cortical processing (functional magnetic resonance imaging) of tactile stimulation in healthy subjects. Soft brush stroking on the calf (n =6) was less pleasant (p <0.04) and evoked less activation of posterior insular cortex in the sumatriptan compared to the saline condition. Soft brushing activated pain processing regions (anterior insular, lateral orbitofrontal, and anterior cingulate cortices, and medial thalamus) only in the sumatriptan condition, whereas activation of somatosensory cortices was similar in both conditions. Soft brush stroking on the palm (n =6) was equally pleasant in both conditions. One possible mechanism for the activation of pain processing regions by brush stroking is sensitization of nociceptors by sumatriptan. Another possibility is inhibition of a recently discovered system of low-threshold unmyelinated tactile (CT) afferents that are present in hairy skin only, project to posterior insular cortex, and serve affective aspects of tactile sensation. An inhibition of impulse transmission in the CT system by sumatriptan could disinhibit nociceptive signalling and make light touch less pleasant. This latter alternative is consistent with the observed reduction in posterior insular cortex activation and the selective effects of stimulation on hairy compared to glabrous skin, which are not explained by the nociceptor sensitization account. [Copyright &y& Elsevier]

Abstract: Background: Headache associated with menses is often not formally diagnosed. Objectives: The goal of this study was to evaluate patients with menstrual headache who had never previously been diagnosed with migraine and assign 1988 International Headache Society (IHS) diagnoses to their menstrual headaches. Secondary objectives included evaluation of the treatment efficacy of newly diagnosed menstrually related migraine (MRM) with sumatriptan 100 mg and patient satisfaction with sumatriptan versus satisfaction with previous therapy. Methods: Patients were recruited via advertisement in a local daily newspaper, and headache diagnosis and eligibility criteria of respondents were assessed by telephone. During telephone screening, IHS criteria for headache were applied to symptoms described by patients as menstrual headache. Those with previously undiagnosed headaches who fulfilled criteria for migraine without or with aura (IHS 1.1 or 1.2) and all inclusion/exclusion criteria at visit 1 were provided with sumatriptan 100 mg to treat 1 MRM. Patients were instructed to treat their next MRM as early as possible after the onset of headache. A treatment diary was provided with study medication for documentation of headache pain severity and associated symptoms; time of treatment and response at 30, 60, and 90 minutes and at 2, 4, 24, and 48 hours posttreatment; medication for persistence or recurrence; adverse effects; and onset of menstrual cycle. In analysis, headache response was defined as a reduction in pretreatment head pain from moderate or severe to mild or no pain. Results: A total of 153 patients responded to an advertisement seeking menstrual headache sufferers. After the preliminary screening by telephone, 105 patients were assigned IHS diagnoses based on reported symptoms associated with their menstrual headache. Overall, 63% (66/105) fulfilled criteria for IHS 1.1 (migraine without aura), 12% (13/105) met criteria for IHS 1.2 (migraine with aura), and 5% (5/105) met criteria for IHS 1.7 (migrainous disorder). Of the 79 patients meeting the criteria for IHS 1.1 or 1.2, 45 patients were enrolled. Thirty-nine (mean age, 34.8 years; mean duration of experiencing menstrual headaches, 11.1 years) of the 45 patients treated 1 MRM with sumatriptan 100 mg per protocol (6 patients were lost to follow-up or withdrew consent). Headache response was reported by 70% of patients at 2 hours and 86% at 4 hours. The pain-flee response after treatment at the moderate or severe phase occurred in 41% of patients at 2 hours and in 61% at 4 hours. All 39 patients reported previous use of nonsteroidal anti-inflammatory medications for acute treatment of headache; in addition, 1 of the 39 also took acetylsalicylic acid/caffeine/butalbital, 1 took acetaminophen/caffeine/butalbital, 1 took ketorolac, and 1 took acetaminophen plus codeine. In terms of patient satisfaction, 69% of patients were satisfied with sumatriptan versus 15% of patients who were satisfied with their previous therapy. Conclusions: Seventy-five percent of women with previously undiagnosed menstrual headaches met diagnostic criteria for migraine in this small sample. Two hours after treatment with sumatriptan 100 rag, 70% of patients with headaches treated at moderate to severe pain had a pain relief response (reduction to mild or no pain). [Copyright &y& Elsevier]

AbstractBackground:Maternal treatment with the 5-HT2Areceptor antagonist ketanserin (KT) in pre-eclamptic patients is associated with a high placental transmission of KT, resulting in pharmacologically active levels of KT in the umbilical cord artery (UCA) and the neonate. Prolonged exposure to a 5-HT receptor antagonist may influence the functionality of foetal 5-HT receptors and compromise foetal development. Objective:To study whether exposure to KT influences the characteristics of foetal 5-HT receptors, functional studies were performed on 5-HT2Aand 5-HT1B/1Dreceptors in UCA from pre-eclamptic patients treated with KT. Methods:UCAs were obtained, immediately after delivery, from pre-eclamptic patients (n = 7), treated antenatally with intravenous KT. Pre-eclamptic patients (n = 13), not treated with KT (non-KT), were included as a control group. Segments of UCA were prepared and mounted in tissue baths and isometric force changes were determined. Cumulative concentration response curves to 5-HT and to the 5-HT1B/1D receptor agonist sumatriptan were constructed in the absence or presence of the 5-HT2Areceptor antagonist KT or the 5-HT1B/1Dreceptor antagonist GR125743, respectively. Results:All UCA segments showed contractile responses to both 5-HT and sumatriptan, and the concentration response curves showed a rightward shift with increasing concentrations of KT and GR125743, respectively, indicating the presence of functional 5-HT2Aand 5-HT1B/1Dreceptors in the foetal tissue. No significant differences were found in maximum response (Emax)(expressed in percent of response on 100 mMKCl) or potency (pEC50) of 5-HT in both groups (Emax= 141 ± 7.7, pEC50= 7.67 ± 0.26 in KT-treated group and Emax= 162 ± 12.6, pEC50= 7.69 ± 0.14 in non-KT treated group, respectively). No significant differences were found in the potency of the antagonist KT in both study groups (pKb= 7.65 ± 0.31 in KT group and 7.46 ± 0.17 in non-KT group, respectively). Similarly, with sumatriptan, no significant differences were found between KT-treated patients and non-KT treated patients (Emax= 142 ± 16.2 and 140 ± 14.7, respectively, pEC50= 6.17 ± 0.37 and 6.41 ± 0.28 respectively, pKbof GR125743 = 7.83 ± 0.48 and 8.43 ± 0.29, respectively). Conclusion:Foetal exposure to KT in pre-eclamptic patients does not seem to influence the functional characteristics of 5-HT2Aand 5-HT1B/1Dreceptors in the UCA.Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]