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Migraine is caused by hyperactivity of the trigeminovascular system, where trigeminal ganglia (TG) play an important role. This hyperactivity might originate from an underfunctional GABAergic system in TG. To investigate this possibility, we adapted a mouse model of migraine by inducing migraine-like grimaces in male mice via repeated injections of nitroglycerin (NTG, 10 mg/kg, i.p.), once every 2 days, for up to 5 sessions. Migraine-like facial pain scores were measured using the mouse grimace scale. Repeated NTG treatments in mice caused significant increases in migraine-like grimaces that were aborted and prevented by two anti-migraine agents sumatriptan and topiramate, respectively. After 5 sessions of NTG injections, the GABA-synthesizing enzyme, 65-kDa glutamate decarboxylase (GAD65), but not the GABA transporter 1 (GAT1) or the α6 subunit-containing GABAA receptors (α6GABAARs), was downregulated in mouse TG tissues. Taking advantage of the unaffected TG α6GABAAR expression in NTG-treated mice, we demonstrated that an α6GABAAR-selective positive allosteric modulator (PAM), DK-I-56-1, exhibited both abortive and prophylactic effects, comparable to those of sumatriptan and topiramate, respectively, in this migraine-mimicking mouse model. The brain-impermeable furosemide significantly prevented the effects of DK-I-56-1, suggesting its peripheral site of action, likely via preventing α6GABAAR modulation in TG. Results suggest that a decreased GABA synthesis caused by the reduced GAD65 expression in TG contributes to the trigeminovascular activation in this repeated NTG-induced migraine-mimicking model and that the unaltered α6GABAARs in TG are potential targets for migraine treatment. Thus, α6GABAAR-selective PAMs are potential anti-migraine agents for both abortive and preventive therapies.

The use of the efficient drug delivery systems in combinatorial or multi-drug treatment of complicated diseases for effective and target-specific delivery of therapeutic agents necessitates the use of the fast and reliable analytical techniques to reveal the true release profiles of the investigated drugs. The knowledge about the release kinetics of the drugs from different substrates and the effective parameters on this process can be obtained by mathematical modeling of release profiles which is a difficult and cost-effective task in multi-drug delivery processes because of the difficulty in the simultaneous determination of multiple release profiles. In this study, a kinetic-spectrophotometric analytical methodology has been proposed for the simultaneous determination of release profiles of Sumatriptan and Naproxen, two widely used drugs in migraine treatment which use MCR-ALS for the decomposition of the release data matrices. The obtained release profiles have been subjected to mathematical modeling for further determination of release mechanisms. It has been shown that the MCR-ALS effectively decomposes the data matrices (more than 97% of explained variance) and Korsmeyer–Peppas and Ritger–Peppas models can well describe the release behavior of drugs from the investigated substrate (R2 > 0.99 for both compounds and acceptable low SSE values).

Hepatic clearance may be uptake rate limited by organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1). While comparison of OATP activity has been investigated across species, little has been reported for OCT1. Additionally, while data on interspecies transporter expression in the liver exist, quantitative comparison of these transporters in multiple tissues is lacking. In the current research, the pharmacokinetics of OCT1 substrates (sumatriptan and metformin) were assessed in Oct knockout rats for comparison with previous Oct1/2-/- mice data and OCT1 pharmacogenetics in humans. Effect of OCT1 inhibitors verapamil and erlotinib on OCT1 substrate liver partitioning was also evaluated in rats. Expression of 18 transporters, including Oatps and Octs, in 9 tissues from mice and rats was quantitated using nanoLC/MS-MS, along with uptake transporters in hepatocytes from 5 species. Interspecies differences in OCT1 activity were further evaluated via uptake of OCT1 substrates in hepatocytes with corresponding in vivo liver partitioning in rodents and monkey. In Oct1-/- rats, sumatriptan hepatic clearance and liver partitioning decreased; however, metformin pharmacokinetics were unaffected. OCT1 inhibitor coadministration decreased sumatriptan liver partitioning. In rodents, Oatp expression was highest in the liver, although comparable expression of Oatps in other tissues was determined. Expression of Octs was highest in the kidney, with liver Oct1 expression comparably lower than Oatps. Liver partitioning of OCT1 substrates was lower in rodents than in monkey, in agreement with the highest OCT1 expression and uptake of OCT1 substrates in monkey hepatocytes. Species-dependent OCT1 activity requires consideration when translating preclinical data to the clinic.

Background Transient receptor potential ankyrin 1 (TRPA1) channels may have a role in migraine as some substances known to cause headache activate the channel. In the craniovascular system such activation causes a calcitonin gene-related peptide (CGRP)-dependent increase in meningeal blood flow. TRPA1 channels in the endothelium of cerebral arteries cause vasodilation when activated. The headache preventive substance feverfew inhibits activation of TRPA1 channels. In this study we aim to compare and characterize the effect of the TRPA1 agonist allyl isothiocyanate (AITC) on the diameter of rat dural and pial arteries in vivo. Methods The genuine closed-cranial window technique in rats was used to examine changes in dural and pial artery diameter and mean arterial blood pressure (MABP) after intracarotid infusion of AITC. Blockade experiments were performed by intravenous infusion of olcegepant, HC-030031, sumatriptan or capsazepine immediately after infusion of AITC, in four different groups of rats. Results AITC caused a significant dilation of dural arteries, which was inhibited by HC-030031, olcegepant and sumatriptan, but not by capsazepine. In pial arteries AITC caused a significant dilation, which was not inhibited by any of the pre-treatments, suggesting a poor penetration of the blood-brain barrier or autoregulation due to dimethyl sulfoxide (DMSO) mediated decrease in MABP during HC-030031 infusion. AITC did not cause a significant change in MABP. Conclusion AITC causes dilation of dural arteries via a mechanism dependent on CGRP and TRPA1 that is sensitive to sumatriptan. AITC causes a small but significant dilation of pial arteries.

Ischemic heart disease is a leading cause of death on a global scale, placing major socio-economic burdens on health systems worldwide. Myocardial ischaemia and reperfusion (I/R)-induced tissue injury is associated with alteration in activity of inflammatory system and nitric oxide pathway. Sumatriptan, which is mainly used to relieve migraine headache, has recently been shown to exert anti-inflammatory properties. In this study, we aimed to assess the possible cardioprotective effect of sumatriptan in a rat model of I/R injury. Male Wistar rats were subjected to 30-min ligation of left anterior descending coronary artery and 120-min reperfusion. Animals were randomly divided into five groups: (1) Sham (2) I/R (3) I/R treated with sumatriptan (0.3 mg/kg i.p.) 20 min after induction of I/R rats, (4) GR127935 (a selective antagonist of 5-HT1B/D serotonin receptors; 0.3 mg/kg) 20 min after induction of I/R, and (5) GR127935 (0.3 mg/kg) 15 min before administration of sumatriptan. Post-infarct treatment with sumatriptan increased left ventricular function, which was damaged in I/R animal's heart. Sumatriptan (0.3 mg/kg) decreased lipid peroxidation, CK-MB and lactate dehydrogenase levels; tumor necrosis factor concentration; and Nf-ҡB' protein production. Treatment with sumatriptan significantly increased the endothelial nitric oxide synthase (eNOS) expression consequences nitric oxide metabolites' level in I/R rats. Also, injection of sumatriptan remarkably decreased myocardial tissue injury assessed by histopathological study. These findings suggest that sumatriptan may attenuate I/R injury via modulating the inflammatory responses and endothelial NOS activity. But therapeutic index of sumatriptan is narrow according to the result of this study.

Background The commercial formulation of sumatriptan nasal spray is an effective option for migraine patients requiring or preferring a non-oral route of drug administration, but its utility is limited by poor absorption and tolerability issues. DFN-02, a new formulation of sumatriptan 10 mg nasal spray, is co-formulated with a permeation enhancer that gives it pharmacokinetics comparable to subcutaneous sumatriptan. As reported previously, DFN-02 was significantly better than placebo on multiple efficacy endpoints at 2 h postdose, including pain freedom, absence of the most bothersome symptom, and pain relief, and its safety and tolerability profiles were excellent. Objective The objective of this study was to assess the efficacy of acute treatment of migraine with DFN-02, including its effect on migraine-related functional disability and patient satisfaction with treatment. Methods This was a multicenter, randomized, double-blind, placebo-controlled efficacy and safety study of DFN-02 in adults with episodic migraine. Functional disability and subject satisfaction with treatment were prespecified endpoints, assessed in real-time by subjects, using an electronic diary. Results In total, 107 subjects were randomized. DFN-02 was significantly superior to placebo for the reduction in functional disability score from predose level at 2 h after treatment (− 1.2 vs. − 0.6, p

Background Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) induces headache in healthy volunteers but the precise mechanisms by which PACAP38 leads to headache are unclear. We investigated the headache preventive effect of sumatriptan and ketorolac on PACAP38-induced headache in healthy volunteers. In addition, we explored contribution of vascular mechanisms to PACAP38-induced headache using high resolution magnetic resonance angiography. Methods Thirty-four healthy volunteers were divided in two groups (A and B) and received infusion of PACAP38 (10 picomol/kg/min) over 20 min. Group A was pretreated with intravenous sumatriptan (4 mg) or ketorolac (30 mg) 20 min before infusion of PACAP38. Group B received infusion of sumatriptan or ketorolac as post-treatment 90 min after infusion of PACAP38. In both experiments, we used a randomized, double-blind, cross-over design. We recorded headache characteristics and circumference of extra-intracerebral arteries. Results We found no difference in AUC (0–6 h) of PACAP38-induced headache in group A, pretreated with sumatriptan or ketorolac (p = 0.297). There was no difference between sumatriptan and ketorolac in PACAP38-induced circumference change (AUCBaseline-110 min) of MMA (p = 0.227), STA (p = 0.795) and MCA (p = 0.356). In group B, post-treatment with ketorolac reduced PACAP38-headache compared to sumatriptan (p p = 0.039) and MMA (p = 0.015) but not of MCA (p = 0.981) compared to ketorolac. In an explorative analysis, we found that pre-treatment with sumatriptan reduced PACAP38-induced headache compared to no treatment (AUC0-90min). Conclusions Post-treatment with ketorolac was more effective in attenuating PACAP38-induced headache compared to sumatriptan. Ketorolac exerted its effect without affecting PACAP38-induced arterial dilation, whereas sumatriptan post-treatment attenuated PACAP38-induced dilation of MMA and STA. Pre-treatment with sumatriptan attenuated PACAP38-induced headache without affecting PACAP38-induced arterial dilation. Our findings suggest that ketorolac and sumatriptan attenuated PACAP38-induced headache in healthy volunteers without vascular effects. Trial registration Clinicaltrials.gov (NCT03585894). Registered 13 July 2018

In this work, we developed a coarse-grained model of sumatriptan suitable for extensive molecular dynamics simulations. First, we confirmed the interfacial distribution of this drug in bilayers through cryogenic transmission electron microscopy and small-angle X-ray scattering techniques, as was predicted by our previous atomistic simulations. Based on these simulations, we developed a coarse-grained model for sumatriptan able to reproduce its overall molecular behavior, captured by atomistic simulations and experiments. We then tested the sumatriptan model in a micellar environment along with experimental characterization of sumatriptan-loaded micelles. The simulation results showed good agreement with photon correlation spectroscopy and electrophoretic mobility experiments performed in this work. The particle size of the obtained micelles was comparable with the simulated ones; meanwhile, zeta-potential results suggest adsorption of the drug on the micellar surface. This model is a step forward in the search for a suitable drug-delivery system for sumatriptan. Fil: Wood, Irene. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Albano, Juan Manuel Ricardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina Fil: Filho, Pedro L. O.. Universidade de Sao Paulo; Brasil Fil: Couto, Veronica Muniz. Universidade Estadual de Campinas; Brasil Fil: Farias, Marcelo A. de. Ministério da Ciência, Tecnologia, Inovações e Comunicações. Centro Nacional de Pesquisa em Energia e Materiais; Brasil Fil: Portugal, Rodrigo V.. Ministério da Ciência, Tecnologia, Inovações e Comunicações. Centro Nacional de Pesquisa em Energia e Materiais; Brasil Fil: de Paula, Eneida. Universidade Estadual de Campinas; Brasil Fil: Oliveira, Cristiano L. P.. Universidade de Sao Paulo; Brasil Fil: Pickholz, Mónica Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Física de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Física de Buenos Aires; Argentina

Cluster headache is characterized by severe, unilateral headache attacks of orbital, supraorbital or temporal pain lasting 15-180 min accompanied by ipsilateral lacrimation, rhinorrhea and other cranial autonomic manifestations. Cluster headache attacks need fast-acting abortive agents because the pain peaks very quickly; sumatriptan injection is the gold standard acute treatment. First-line preventative drugs include verapamil and carbolithium. Other drugs demonstrated effective in open trials include topiramate, valproic acid, gabapentin and others. Steroids are very effective; local injection in the occipital area is also effective but its prolonged use needs caution. Monoclonal antibodies against calcitonin gene-related peptide are under investigation as prophylactic agents in both episodic and chronic cluster headache. A number of neurostimulation procedures including occipital nerve stimulation, vagus nerve stimulation, sphenopalatine ganglion stimulation and the more invasive hypothalamic stimulation are employed in chronic intractable cluster headache.

Purpose: Monoamine oxidases (MAOs) are non-CYP enzymes that contribute to systemic elimination of therapeutic agents, and localized on mitochondrial membranes. The aim of the present study was to validate quantitative estimation of metabolic clearance of MAO substrate drugs using human liver microsomes (HLMs). Methods: Three MAO substrate drugs, sumatriptan, rizatriptan and phenylephrine, as well as four CYP substrates were selected, and their disappearance during incubation with HLMs or mitochondria (HLMt) was measured. Metabolic clearance (CL) was then calculated from the disappearance curve. Results: CL obtained in HLMs for sumatriptan and a typical MAO substrate serotonin was correlated with that obtained in HLMt among ten human individual livers. Hepatic intrinsic clearance (CLint,vitro) estimated from CL in HLMs was 14–20 and 2–5 times lower than in vivo hepatic intrinsic clearance (CLint,vivo) obtained from literature for MAO and CYP substrates, respectively. Utilization of HLMs for quantitatively assessing metabolic clearance of MAO substrates was further validated by proteomics approach which has revealed that numerous proteins localized on inner and outer membranes of mitochondria were detected in both HLMs and HLMt. Conclusion: CLint,vitro values of MAO substrate drugs can be quantitatively estimated with HLMs and could be used for semi-quantitative prediction of CLint,vivo values. © 2017 Springer Science+Business Media New York, Embargo Period 12 months

The cardioprotective effects of remote hind limb preconditioning (RIPC) are well known, but mechanisms by which protection occurs still remain to be explored. Therefore, the present study was designed to investigate the role of TRPV and CGRP in adenosine and remote preconditioning-induced cardioprotection, using sumatriptan, a CGRP release inhibitor and ruthenium red, a TRPV inhibitor, in rats. For remote preconditioning, a pressure cuff was tied around the hind limb of the rat and was inflated with air up to 150 mmHg to produce ischemia in the hind limb and during reperfusion pressure was released. Four cycles of ischemia and reperfusion, each consisting of 5 min of inflation and 5 min of deflation of pressure cuff were used to produce remote limb preconditioning. An ex vivo Langendorff's isolated rat heart model was used to induce ischemia reperfusion injury by 30 min of global ischemia followed by 120 min of reperfusion. RIPC demonstrated a significant decrease in ischemia reperfusion-induced significant myocardial injury in terms of increase in LDH, CK, infarct size and decrease in LVDP, +dp/dtmax and -dp/dtmin. Moreover, pharmacological preconditioning with adenosine produced cardioprotective effects in a similar manner to RIPC. Pretreatment with sumatriptan, a CGRP release blocker, abolished RIPC and adenosine preconditioning-induced cardioprotective effects. Administration of ruthenium red, a TRPV inhibitor, also abolished adenosine preconditioning-induced cardioprotection. It may be proposed that the cardioprotective effects of adenosine and remote preconditioning are possibly mediated through activation of a TRPV channels and consequent, release of CGRP.

Purpose The aim of this study is to evaluate the detection rate of almotriptan, eletriptan, frovatriptan, sumatriptan, rizatriptan, and zolmitriptan in the hair of migraineurs taking these drugs; the degree of agreement between type of self-reported triptan and triptan found in hair; if the concentrations in hair were related to the reported cumulative doses of triptans; and whether hair analysis was able to distinguish occasional use from the overuse of these drugs. Methods Out of 300 headache patients consecutively enrolled, we included 147 migraine patients who reported to have taken at least one dose of one triptan in the previous 3 months; 51 % of the patients overused triptans. A detailed pharmacological history and a sample of hair were collected for each patient. Hair samples were analyzed by liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS) by a method that we developed. Results All the triptans could be detected in the hair of the patients. The agreement between type of self-reported triptan and type of triptan found in hair was from fair to good for frovatriptan and zolmitriptan and excellent for almotriptan, eletriptan, sumatriptan, and rizatriptan (P

Sumatriptan succinate (SS) is a selective serotonin receptor agonist used for the treatment of migraine attacks, suffering from extensive first-pass metabolism and low oral bioavailability (∼14%). The aim of this work is to compare the performance of different ready-made co-processed platforms (Pharmaburst®, Prosolv ODT®, Starlac®, Pearlitol Flash®, or Ludiflash®) in the formulation of SS sublingual orodispersible tablets (ODTs) using direct compression technique. The prepared SS ODT formulae were evaluated regarding hardness, friability, simulated wetting time, and in vitro disintegration and dissolution tests. Different mucoadhesive polymers—HPMC K4M, Carbopol®, chitosan, or Polyox®—were tested aiming to increase the residence time in the sublingual area. A pharmacokinetic study on healthy human volunteers was performed, using LC/MS/MS assay, to compare the optimum sublingual formula (Ph25/HPMC) with the conventional oral tablet Imitrex®. Results showed that tablets prepared using Pharmaburst® had significantly (p

The intranasal formulation of zolmitriptan, a selective serotonin 5-HT1B/1D agonist, was recently approved by the US Food and Drug Administration for the treatment of acute migraine in pediatric patients 12 years of age or older. This article summarizes the efficacy and tolerability of zolmitriptan (Zomig(®)) nasal spray (NS) in acute migraine in this patient group. Zolmitriptan NS 5 mg was more effective in relieving headache pain than placebo in two double-blind studies in pediatric patients 12-17 years of age with acute migraine. Furthermore, zolmitriptan NS 2.5 and 5 mg effectively relieved photophobia and phonophobia, and was associated with a faster return to normal daily activities than placebo. Zolmitriptan NS is rapidly absorbed from the nasal mucosa and is associated with a fast onset of action, with one study showing a significant difference versus placebo with regard to headache response 15 min after administration. In both trials, zolmitriptan NS was generally well tolerated, with no serious adverse events. In conclusion, zolmitriptan NS provides rapid, effective and generally well tolerated treatment of acute migraine in pediatric patients 12 years of age or older and may be of particular benefit for those with nausea or not easily able to swallow tablets.

The aim of this report is to increase awareness of a possible association between cranial nerve paresis and the use of sumatriptan in migraine sufferers, particularly in patients who have additional vascular risk factors. We describe a series of three cases where third nerve paresis developed in patients who were treated with the oral form of sumatriptan. All of the patients had a clear history of repetitive migraine headache and none of them had previous third nerve paresis. Among a variety of medications for the treatment of migraine, there are some drugs with vasoconstrictive effects, particularly triptans. These drugs may be a contributing factor for microvascular damage of the cranial nerves and other organs.

Background The MAST Study is a longitudinal, cross-sectional survey study of US adults with migraine. These analyses were conducted to estimate rates of acute medication overuse (AMO) and determine associations of AMO with individual and headache characteristics. Methods Eligible respondents had ICHD-3-beta migraine, reported ≥3 monthly headache days (MHDs) in the past 3 months, ≥1 MHD in the past 30 days, and currently took acute headache medication. AMO was defined according to ICHD-3-beta thresholds for monthly days of medication taking when diagnosing medication overuse headache. Results Eligible respondents (N = 13,649) had a mean age of 43.4 ± 13.6 years; most were female (72.9%) and Caucasian (81.9%). Altogether, 15.4% of respondents met criteria for AMO. Compared with those not overusing medications, respondents with AMO were significantly more likely to be taking triptans (31.3% vs 14.2%), opioids (23.8% vs 8.0%), barbiturates (7.8% vs 2.7%), and ergot alkaloids (3.1% vs 0.6%) and significantly less likely to be taking NSAIDs (63.3% vs 69.8%) (p

Animal models of migraine-like pain enabling ongoing study of behaviour typically involve the systemic administration of chemical vasodilators or dural administration of inflammatory algogens. However, neither method mediates prolonged effects on behavior indicative of enduring pathophysiological changes occurring within dural or trigeminal pain circuits. We generated successive generations of a unique inbred rat strain, spontaneous trigeminal allodynia (STA) rats, previously reported to exhibit an episodic migraine-like behavioural phenotype. We show that both male and female STA rats display robust and sustained reductions in periorbital thresholds to cutaneous mechanical stimulation. Otherwise, the general behavior (e.g. locomotor, grooming) of these rats appeared normal. In female STA rats, the mechanical hypersensitivity was confined to the cephalic region, manifested after puberty through adolescence, and was sustained into adulthood recapitulating the clinical manifestation of migraine. We exploited this hitherto unidentified chronic phenotype to show that the migraine-specific drugs sumatriptan (5-HT1B/1D receptor agonist) and olcegepant (CGRP receptor antagonist) could completely reverse cephalic hypersensitivity using a within subject cross-over paradigm. Our findings indicate that STA rats actually possess a phenotype indicative of migraine chronicity which is exquisitely sensitive to migraine therapeutics. This unique strain could prove to be an invaluable resource in preclinical migraine drug discovery.

Migraine affects up to 25% of women of reproductive age. In the majority of these women, migraine improves progressively during pregnancy, but symptoms generally recur shortly after delivery. As suboptimally treated migraine in pregnancy could have negative consequences for both mother and fetus, the primary aim of clinicians should be to provide optimal treatment according to stage of pregnancy, while minimising possible risks related to drug therapy. Nonpharmacological approaches are always first-line treatment, and should also be used to complement any required drug treatment. Paracetamol is the preferred drug for acute treatment throughout pregnancy. If paracetamol is not sufficiently effective, sporadic use of sumatriptan can be considered. NSAIDs such as ibuprofen can also be used under certain circumstances, though their intake in the first and third trimesters is associated with specific risks and contraindications. Preventive treatment should only be considered in the most severe cases. In women contemplating pregnancy, counselling is essential to promote a safe and healthy pregnancy and postpartum period for the mother and child, and should involve a dialogue addressing maternal concerns and expectations about drug treatment. This Review summarizes current evidence of the safety of the most common antimigraine medications during pregnancy and breastfeeding, and provides treatment recommendations for use in clinical practice.

Background Migraine is an expensive condition impacting on the economically active sector of the population. Given the expense of anti-migraine medicine, it is important to monitor the impact of generic prescribing and therapeutic substitution. Objective The primary aim was to analyse the prescribing patterns and cost of anti-migraine medicines to determine the impact of generic prescribing and prescribing changes over time. Method A retrospective drug utilisation study was conducted on South African private sector medical insurance claims data for 2011. Results A total of 797 patients received 1583 anti-migraine medicines during 2011. The majority of patients (70.14 %) were females. The average age of patients was 41.61 (SD = 14.91) years. Clonidine was the most frequently prescribed (49.21 % of prescribing frequency; 25.70 % of cost), followed by the triptans [selective serotonin (5-HT1B/1D)-receptor agonists] (27.98 % of prescribing frequency; 45.92 % of cost). Five triptans were prescribed. The average cost per sumatriptan prescription was the lowest (the only triptan with generic equivalents). Rizatriptan was the most frequently prescribed triptan (18.51 % of prescribing frequency; 29.15 % of cost). Conclusion The results were generally in agreement with previous South African studies. The impact of the introduction of newer triptans and of generic equivalents on prescribing patterns was clear.

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 given intratracheally have rarely been well explored. We aimed to verify the effect of Imigran, which acts on the tracheal smooth muscle directly in vitro. We examined the effectiveness of Imigran on isolated rat tracheal smooth muscle by testing: (1) effect on tracheal smooth muscle resting tension; (2) effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic; (3) effect of the drugs on electrically induced tracheal smooth muscle contractions. The results indicated that the addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. The addition of Imigran at doses of 10(-5) M or above elicited a significant relaxation response to 10(-6) M methacholine-induced contraction. Imigran could inhibit electrical field stimulation-induced spike contraction. It also had a minimal effect on the basal tension of trachea as the concentration increased. The study indicated high concentrations of Imigran could cause bronchodilation to reduce asthma attacks not only by blocking parasympathetic tone, but also by directly antagonizing the effect of cholinergic receptors.

Randomized clinical trials have demonstrated that the efficacy of a fixed-dose single-tablet combination containing sumatriptan and naproxen sodium (S/NS) was greater than either of its individual components. Simplifying drug regimens (e.g., via a fixed-dose combination) has been shown to improve “real-world” outcomes by reducing pill burden and treatment regimen complexity, improving adherence, and reducing healthcare resource use and associated costs; however, no studies assessing such outcomes have been conducted to date for the acute treatment of migraine. To assess migraine-related healthcare resource use and associated costs for subjects prescribed S/NS vs. subjects prescribed single-entity oral triptans (SOTs) within a managed care population in the USA. In this retrospective analysis of administrative claims data from July 1, 2008 to December 31, 2009 (IMS LifeLink), subjects meeting the following criteria were selected: one or more pharmacy claim(s) for either S/NS or SOT (index date), aged 18–64 years; at least one migraine diagnosis, and continuous enrollment in the 6 months prior to and post the index date. The study population was subsequently stratified for two analyses: triptan-naive (triptan naive in the 6-month period prior to the index date) and triptan-switch (triptan user in the 6-month period prior to the index date and switching to another triptan). Subjects prescribed S/NS were propensity-score matched with subjects prescribed SOT (triptan-naive analysis: 1:3; triptan-switch analysis: 1:1) to assess differences in healthcare resource use and associated costs (2009 US$) between the S/NS and SOT groups. Results from the triptan-naive and triptan-switch analyses suggest that subjects prescribed S/NS are likely to have similar healthcare resource use patterns as those either newly initiated on an SOT or switching SOTs, as measured by migraine medication use, migraine-related healthcare resource use, and all-cause healthcare resource use. One exception was the observed increased use of opioids in the SOT group compared with the S/NS group (change in mean number of tablets pre-index vs. post-index, S/NS vs. SOT; triptan-naive analysis: 8.6 vs.18.3, p = 0.045; triptan-switch analysis: −8.2 vs. 17.7; p = 0.120). Total costs from the triptan-naive analysis indicated that the S/NS group had lower migraine-related (US$744 vs. US$820; p = 0.067) and all-cause healthcare costs (US$4,391 vs. US$4,870; p = 0.040) when compared with the SOT group, driven by savings in medical costs (migraine-related: US$252 vs. US$380; p = 0.001; all-cause: US$3,023 vs. US$3,599; p = 0.014). However, no significant differences were observed for total costs from the triptan-switch analysis (migraine-related healthcare costs, S/NS vs. SOT: US$1,159 vs. US$1,117; p = 0.929; all-cause healthcare costs: US$5,128 vs. US$4,788; p = 0.381). Study results suggest similar healthcare resource use patterns and associated costs when comparing S/NS and SOT across a triptan-naive and triptan-experienced population. While the current study focuses on direct medical costs, future studies should extend beyond such a perspective to explore functional status, productivity, and health-related quality of life and satisfaction, attributes not captured in administrative claims data, but nonetheless important treatment goals.

Neurogenic dural vasodilation has been demonstrated to play an important role in migraine. 5-HT(7) receptors have been found on trigeminal nerve endings and middle meningeal arteries and demonstrated involved in the dilatation of meningeal arteries. The aim of the present study was to demonstrate whether 5-HT(7) receptors are involved in neurogenic dural vasodilation in migraine. The neurogenic dural vasodilation model of migraine was used in this study. Unilateral electrical stimulation of dura mater was performed in anesthetized male Sprague-Dawley rats. Animals were pretreated with selective 5-HT(7) receptor agonist AS19, 5-HT(7) receptor antagonist SB269970, 5-HT1B/1D receptor agonist sumatriptan, or vehicles. Blood flow of the middle meningeal artery (MMA) was measured by a laser Doppler flowmetry. AS19 significantly increased the basal and stimulated blood flows of the middle meningeal artery following electrical stimulation of dura mater, and its effect was dose dependent at the early stage. SB269970 and sumatriptan significantly reduced the basal and stimulated blood flows of middle meningeal artery. The present study demonstrates for the first time that 5-HT(7) receptors are involved in neurogenic dural vasodilation evoked by electrical stimulation of dura mater and maybe of relevance in the pathophysiology and treatment of migraine.

Migraine is number seven in WHO's list of all diseases causing disability and the third most costly neurological disorder in Europe. Acute attacks are treatable by highly selective drugs such as the triptans but there is still a huge unmet therapeutic need. Unfortunately, drug development for headache has almost come to a standstill partly because of a lack of valid animal models. Here we review previous models with emphasis on optimal characteristics of a future model. In addition to selection of animal species, the method of induction of migraine-like changes and the method of recording responses elicited by such measures are crucial. The most naturalistic way of inducing attacks is by infusion of endogenous signaling molecules that are known to cause migraine in patients. The most valid response is recording of neural activity in the trigeminal system. The most useful headache related responses are likely to be behavioral, allowing multiple experiments in each individual animal. Distinction is made between acute and prophylactic models and how to validate each of them. Modern insight into neurobiological mechanisms of migraine is so good that it is only a question of resources and efforts that determine when valid models with ability to predict efficacy in migraine will be available.

In this work, we report a molecular dynamics simulations study of protonated sumatriptan (pSMT) in a fully hydrated bilayer of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidyl-choline at the fluid lamellar phase. The simulations were carried out at three different drug/lipid stoichiometries, 1:75, 1:10 and 1:3, under NPT conditions. Our results show partition of pSMT between the lipid head-water interphase and water phase. The main interactions that stabilized the systems were hydrogen bonds, salt bridges and cation-π. Besides, pSMT molecules have no access to the hydrophobic region of the bilayer at the studied concentrations. From an atomistic point of view, this work could contribute to the discussion of drug-membrane interactions regarding the limitation of sumatriptan to cross the blood-brain barrier.

The sumatriptan iontophoretic transdermal system (ZECUITY®) [hereafter referred to as sumatriptan TDS] is the first transdermal treatment for migraine to be approved by the US FDA. This article reviews the available pharmacologic properties of sumatriptan TDS and its clinical efficacy and tolerability for the acute treatment of adult patients with migraine with or without aura. Sumatriptan, a selective 5-hydroxy-tryptamine receptor subtype 1 (5-HT₁) agonist, is presumed to exert its therapeutic effect on migraine patients by binding to the 5-HT(1B/1D) receptors on intracranial blood vessels and sensory nerves of the trigeminal system, resulting in cranial vessel constriction and the inhibition of the release of pro-inflammatory neuropeptides and plasma extravasation. In a well designed, phase III clinical trial, sumatriptan TDS was shown to be more effective than placebo at treating a single migraine attack, with significantly more sumatriptan TDS than placebo recipients being headache pain free and nausea free at 2 hours. These data were supported by a long-term, repeat-use study over 12 months. Additionally, sumatriptan TDS was generally well tolerated in clinical trials; the most common adverse events were application-site reactions. The sumatriptan TDS formulation avoids the gastrointestinal tract, and has a controlled, sustained delivery, allowing for patients with migraine-associated nausea and vomiting to receive treatment without the risk of inconsistent absorption or avoidance of tablet use (associated with oral delivery of the drug in these patients). Moreover, it may offer a useful alternative to the nasal spray or subcutaneous sumatriptan formulations. However, definitive conclusions on the comparative efficacy and tolerability of sumatriptan TDS versus other sumatriptan formulations or other migraine drugs are not as yet possible, and data from comparative trials would be of great interest. Sumatriptan TDS is a useful addition to the treatment options available to migraine patients.

A fixed-dose combination of sumatriptan/naproxen sodium (Treximet(®)) has been approved in the US for the acute treatment of migraine in adults. In two randomized trials, sumatriptan/naproxen sodium demonstrated significantly better efficacy than sumatriptan alone, naproxen sodium alone, or placebo as late-intervention therapy for a single migraine episode in adults, as assessed by co-primary efficacy endpoints evaluating pain and other migraine-related symptoms, as well as health-related quality of life (HR-QOL) endpoints. In four other randomized trials, the drug combination was also effective as early intervention in adults with migraine (including those with menstrual migraine and dysmenorrhoea, or those with poor response or intolerance to triptan therapy) according to various pain-related primary efficacy and HR-QOL endpoints. Data from longer-term, non-randomized studies support these findings, and the drug combination appears to be beneficial in patients with migraine and cutaneous allodynia. In clinical trials, sumatriptan/naproxen sodium was generally well tolerated, with an overall tolerability profile similar to that of sumatriptan. The most common adverse events were in line with those expected for sumatriptan and naproxen sodium. Current data indicate that sumatriptan/naproxen sodium is a useful option in the treatment of adult migraine.

To assess the differences in the cost-effectiveness of oral triptan therapy for migraines among European countries. A cost-effectiveness analysis of triptan therapy for migraine was conducted from a health-care payer perspective in four European countries (France, Italy, Spain and the UK). The study included those orally administered triptans available in all of these countries (almotriptan, brand-name sumatriptan, generic sumatriptan, zolmitriptan), and it was performed using a decision-tree model that incorporated costs of the drugs and probabilities associated with the possible events and outcomes. Average cost-effectiveness ratios were calculated in two different scenarios. The average cost-effectiveness ratio showed wide variations across the different countries, these differences being up to 131 % (almotriptan), 77 % (brand-name sumatriptan), 153 % (generic sumatriptan) and 77 % (zolmitriptan). Generic sumatriptan was the most cost-effective drug analysed in the studied countries. Caution must be taken when trying to transfer conclusions of pharmacoeconomics studies on migraines even in neighbouring countries. This cross-country variability is a concern for decision-makers and also for the elaboration of international recommendations and clinical practice guidelines.

Migraine is a common disease in children and adolescents. The incidence of migraine has increased alarmingly in the general population during recent decades. Migraine causes considerable individual suffering and impaired quality of life. Therefore, appropriate management is essential. In this article, the treatment of acute migraine in children and adolescents will be reviewed. Only a few randomized controlled studies have been published and high placebo rates are a major problem for proving superiority of active drugs. Generally, acetaminophen (paracetamol) and ibuprofen are accepted as drugs of first choice, even though the evidence is poor for the former and limited for latter. Among 14 studies on triptans in adolescents, 9 showed some superiority over placebo with respect to pain relief and pain freedom, and among 6 studies in children, 5 suggest some superiority over placebo. Sumatriptan nasal spray and zolmitriptan nasal spray have been approved for adolescents in Europe; almotriptan has been approved for adolescents in the USA, as has rizatriptan for patients aged 6-17 years. A recent study demonstrated the efficacy of a fixed combination of sumatriptan and naproxen in adolescents with migraine. In conclusion, evidence for the pharmacological treatment of acute migraine in children is very poor and evidence for adolescents is better but still limited.

Sumatriptan, a drug widely used to alleviate migraine headaches, has several somatosensory adverse effects, including tactile allodynia. To understand whether sumatriptan affects sensory and affective circuitries simultaneously, we investigated the responses of 12 healthy volunteers to electrical stimuli after infusion with either sumatriptan or saline. Using a double-blind crossover study design, we used functional magnetic resonance imaging (fMRI) to measure brain activation in different areas during electrical stimulation. The visual analog scale (VAS) and short-form McGill pain questionnaire (SF-MPQ) were used to rate stimulation-evoked sensations and affections after drug administration. VAS rating, SF-MPQ, and block fMRI were all performed in each subject during sumatriptan and saline injection. Echo-planar imaging sequences were used to determine the whole-brain blood oxygenation level-dependent signal of the entire brain. Our results showed that sumatriptan predominantly activated regions in the medial pain system and smaller regions in the lateral pain system. These regions included the secondary somatosensory cortex (SII), anterior insular cortex, orbitofrontal cortex, medial thalamus, cerebellar supravermis, dentate nucleus, and the majority of the anterior cingulate cortex (ACC). In contrast, activation following saline administration was observed primarily in the lateral pain system, including the primary sensory cortex, lateral SII, posterior insular cortex, anterior ACC, and lateral thalamus. Importantly, we found that VAS ratings and MPQ scores were increased after sumatriptan infusion, but not after saline administration. Our fMRI, VAS, and SF-MPQ findings suggest that sumatriptan plays a significant role in the affective dimension of pain and a minor role related to sensory discrimination.

Accurate, sensitive, and precise high performance thin layer chromatographic (HPTLC) methods were developed and validated for the determination of sumatriptan and zolmitriptan in presence of their degradation products. Sumatriptan was separated from its degradation products and analyzed on TLC silica gel 60 F254 plates using chloroform–ethyl acetate–methanol–ammonia (4:3:3:0.1, v/v) as a developing system followed by densitometric measurement of the bands at 228 nm. Zolmitriptan was determined using chloroform–ethyl acetate–methanol–ammonia (3:3:3:1, v/v) as a developing system followed by densitometric measurement at 222 nm. The methods were validated over a range of 0.5–4 μg/spot for sumatriptan and 0.5–3 μg/spot for zolmitriptan. The proposed methods were successfully applied for the determination of the studied drugs in bulk powder and in their pharmaceutical formulations.

Background This research sought to further validate the rat nitroglycerin (NTG) migraine model by comparing the effects of single versus recurrent NTG episodes on behavioral endpoints that mirror ICHD-3 diagnostic criteria for migraine, and to determine if the altered behavioral endpoints are reduced after administration of sumatriptan. Methods Separate cohorts of rats were administered NTG (10 mg/kg/2 ml) or saline (Experiment 1: single injection; Experiment 2: repeated injections; Experiment 3: repeated injections with sumatriptan [0.0, 0.3 and 1.0 mg/kg/ml] rescue. Behavioral endpoints were assessed 2 h after final NTG administration and included time in light/dark chambers for photophobia and activity, pain facial ratings, and cool (5 °C) and warm (46 °C) tail dip. Results The first two experiments demonstrated that repeated (n = 5) but not single NTG injections produced photophobia, decreased activity, and yielded less weight gain than saline injections. Experiment 3 showed that sumatriptan attenuated hypoactivity, reduced facial expressions of pain, and reversed weight alterations in a dose-dependent manner. Conclusions These findings identify numerous clinical homologies of a recurrent NTG rat migraine model that may be useful for screening novel pharmacotherapies.

Pure menstrual migraine (PMM) and menstrually related migraine (MRM) are difficult challenges in migraine management. Triptans are a class of highly selective serotonin receptor agonists, which interfere with the pathogenesis of migraine and are effective in relieving the associated neurovegetative symptoms. In recent years triptans have been extensively proposed for the treatment of severe, disabling, and recurrent perimenstrual migraine attacks. This review summarizes the different levels of recommendations for the use of triptans in the treatment of perimenstrual migraine. This review is also intended to offer an updated reasonable guide to physicians treating perimenstrual migraine in daily practice.

There are many categories and individual types of headache and most have a variety of treatment protocols, while a few are best treated by just one medication. This paper will concentrate on acute care medications for migraine and discuss some new and future acute care treatments. There is not much to discuss about prevention, except that onabotulinumtoxinA has been approved for prevention of chronic migraine. Cluster headache will also be discussed, as there are some future treatments for acute care and prevention being studied at present. For the acute care of migraine in the US, we have seven triptans by tablet plus other routes and one non steroidal anti-inflammatory medication approved by the FDA that is currently available (Cambia brand of buffered diclofenac potassium for oral solution). There are several other acute care medications in various stages of development and there are three new methods of administering a triptan and others under investigation. The optimal acute care therapy for migraine should be faster, easier to use and more efficient with fewer adverse events than what is currently available. What follows is a brief review of the status in development for five of the many new acute care medications being investigated: the CGRP antagonist tablet telcagepant, the sumatriptan iontophoretic patch Zelrix, sumatriptan powder for use in the OptiNose apparatus, dihydroergotamine for oral inhalation (Levadex), civamide nasal solution for prevention of episodic cluster headache (Civanex) and sphenopalatine ganglion stimulation for acute cluster attacks in chronic cluster headaches. Other future treatments that will not be discussed include transcranial magnetic stimulation, a 5-HT(1F) agonist named alniditan, large conductance calcium-activated potassium channel openers, glial modulators or other medications and devices in early stages of development.

To test the hypothesis that calcitonin gene-related peptide (CGRP) modulates brain activity, we investigated the effect of intravenous CGRP on brain activity in response to a visual stimulus. In addition, we examined if possible alteration in brain activity was reversed by the anti-migraine drug sumatriptan. Eighteen healthy volunteers were randomly allocated to receive CGRP infusion (1.5 μg/min for 20 min) or placebo. In vivo activity in the visual cortex was recorded before, during and after infusion and after 6 mg subcutaneous sumatriptan by functional magnetic resonance imaging (3 T). 77% of the participants reported headache after CGRP. We found no changes in brain activity after CGRP (P = 0.12) or after placebo (P = 0.41). Sumatriptan did not affect brain activity after CGRP (P = 0.71) or after placebo (P = 0.98). Systemic CGRP or sumatriptan has no direct effects on the BOLD activity in visual cortex. This suggests that in healthy volunteers both CGRP and sumatriptan may exert their actions outside of the blood–brain barrier. Electronic supplementary material The online version of this article (doi:10.1007/s10194-011-0415-4) contains supplementary material, which is available to authorized users.

Menstrual migraine (MM) is often reported to be more severe and more resistant to treatment than other migraines. Nevertheless, initial treatment should be the same as for any migraine. When results of acute therapy are incomplete or unsatisfactory, preventive strategies are warranted, including both pharmacologic preventives and careful adherence to lifestyle modifications. Where MM differs from other attacks is in its predictable timing and discrete precipitants. These differences allow for unique preventive strategies that target either the timing of the attacks or their hormonal precipitants. Nonspecific MM strategies-those that do not address the hormonal mechanism-include scheduled dosing of nonsteroidal anti-inflammatory drugs (NSAIDs) or triptans throughout the menstrual window. NSAIDs are a good choice when there is comorbid dysmenorrhea and allow for treatment of breakthrough headaches with triptans. Both strategies require that the timing of MM is highly predictable. Specific strategies for MM are those that reduce or eliminate the premenstrual decline in estradiol that predictably precipitates attacks. These include continuous or extended-cycle dosing of combined hormonal contraceptives (CHCs). A number of common gynecologic comorbidities argue for early adoption of these treatments, as CHCs effectively treat dysmenorrhea, menorrhagia, ovarian cysts, endometriosis, and irregular cycles. In the author's experience, hormonal preventives are the best approach for most women whose menstrual attacks are resistant to acute therapy. They afford the greatest therapeutic benefit in prevention while treating common comorbidities and allowing for acute treatment with triptans when needed.

A needle-free device for delivering a 6 mg fixed dose of sumatriptan into subcutaneous tissues has been developed and approved for the acute treatment of migraine and cluster headache in the US and some EU countries. In a pivotal registration study in healthy adult volunteers, a single dose of needle-free subcutaneous sumatriptan 6 mg demonstrated bioequivalence to a single dose of traditional, needle-based subcutaneous sumatriptan 6 mg when delivered into the abdomen or the thigh, but not the arm. In a noncomparative, multicentre, phase IV study, the administration of (one or two doses of) needle-free subcutaneous sumatriptan 6 mg consistently provided rapid and sustained relief from migraine pain and associated symptoms during the treatment of up to four migraine attacks over a period of up to 60 days among current triptan users. Moreover, the use of needle-free subcutaneous sumatriptan was associated with a significant improvement in treatment satisfaction in these patients who were less than 'very satisfied' with their usual symptomatic therapy. Needle-free subcutaneous sumatriptan was generally well tolerated in the phase IV study. Although the overall adverse event profile of the needle-free delivery system was similar to that previously reported for the needle-based delivery system, it was associated with a numerically higher incidence of administration/injection-site reactions in clinical trials that enrolled healthy adult volunteers.

To predict the success of an analgesic drug we have suggested a bibliometric indicator, the Top Journals Selectivity Index (TJSI) (Kissin, Scientometrics, 86:785---795, 2011). It represents the ratio (as %) between the number of all types of articles on a particular drug in the top 20 biomedical journals and the number of articles on that drug in all (>5,000) journals covered by Medline over the first 5 years after a drug's introduction. For example, the highest TJSI score among analgesics was that of sumatriptan, the most successful drug for the treatment of migraine. The aim of this study was to demonstrate that TJSI may be used not only in the field of analgesics, but also for various other categories of drugs. The study tested two hypotheses. First, the difference between the most successful and less successful drugs in any pharmacological class can be reliably detected by TJSI. Second, drugs with TJSI indicators as high as that of sumatriptan can be found among other pharmacological classes as well. Drugs from various pharmacological classes approved by the Federal Drug Administration (FDA) during the 10-year period, 1980---1989, were used in this study. Two groups of 10 drugs were selected to test the first hypothesis. One group included the most successful (breakthrough) drugs; the other included less successful drugs matched with the breakthrough drugs according to mechanism of action. The difference between the two groups was compared using three publication indices: the TJSI, the number of all types of articles on a drug in journals presented by Medline (AJI), and the number of articles covering only randomized controlled trials (RCT). It was found that TJSI can detect the difference between the two groups of drugs better than the two other indices. TJSI detected the difference between a breakthrough drug and its less successful counterpart at least 69% of the time with 95% confidence. With the other two indices the difference was not distinguishable from random chance. Some of the breakthrough drugs (zidovudine, omeprazole, lovastatin) have TSJIs as high or even higher than that of sumatriptan (19.2 vs. 23.0, 21.4, and 20.6, respectively). In conclusion, TJSI can be useful not only in the field of analgesics, but also with drugs belonging to other pharmacological classes.

The indomethacin/prochlorperazine/caffeine fixed combination (Difmetré®) combines the NSAID indomethacin with the phenothiazine antiemetic prochlorperazine and caffeine. It is currently available as two oral (effervescent tablet and coated tablet) and two rectal (suppository and low-dose suppository) formulations. Oral and rectal formulations of indomethacin/prochlorperazine/caffeine were effective and generally well tolerated in the treatment of migraine and episodic tension-type headache (TTH) in adult patients participating in randomized, multicentre, active-comparator controlled studies. For the most part, the efficacy of oral indomethacin/prochlorperazine/caffeine did not significantly differ from that of oral sumatriptan in patients with migraine and oral nimesulide in patients with episodic TTH. With rectal administration, indomethacin/prochlorperazine/caffeine was, in general, significantly more effective than sumatriptan in patients with migraine. Thus, oral and rectal formulations of indomethacin/prochlorperazine/caffeine provide a further option in the acute treatment of migraine and in the treatment of episodic TTH in adult patients.

Naratriptan 2.5 mg is now an over-the-counter drug in Germany. This should increase the interest in drug. The GSK Trial Register was searched for published and unpublished double-blind, randomised, controlled trials (RCTs) concerning the use of naratriptan in migraine. Only 7 of 17 RCTs are published in full. Naratriptan 2.5 mg is superior to placebo for acute migraine treatment in 6 RCTs, but inferior to sumatriptan 100 mg and rizatriptan 10 mg in one RCT each. This dose of naratriptan has no more adverse events than placebo. Naratriptan 1 mg b.i.d. has some effect in the short-term prophylactic treatment of menstruation-associated migraine in 3 RCTs. In 2 RCTs, naratriptan 2.5 mg was equivalent to naproxen sodium 375 mg for migraine-related quality of life. Naratriptan 2.5 mg (34% preference) was superior to naproxen sodium 500 mg (25% preference). Naratriptan 2.5 mg is better than placebo in the acute treatment of migraine. The adverse effect profile of naratriptan 2.5 mg is similar to that of placebo. The efficacy of naratriptan 2.5 mg versus NSAIDs is not sufficiently investigated. Naratriptan, when available OTC is a reasonable second or third choice on the step care ladder in the acute treatment of migraine.

The objective of this study is to analyse our experience in the treatment of refractory chronic migraine (CM) with onabotulinumtoxinA (BTA) and specifically in its effects over disabling attacks. Patients with CM and inadequate response or intolerance to oral preventatives were treated with pericranial injections of 100 U of TBA every 3 months. The dose was increased up to 200 U in case of no response. The patients kept a headache diary. In addition, we specifically asked on the effect of BTA on the frequency of disabling attacks, consumption of triptans and visits to Emergency for the treatment of severe attacks. This series comprises a total of 35 patients (3 males), aged 24–68 years. All except three met IHS criteria for analgesic overuse. The number of sessions with BTA ranged from 2 to 15 (median 4) and nine (26%) responded (reduction of >50% in headache days). However, the frequency of severe attacks was reduced to an average of 46%. Oral triptan consumption (29 patients) was reduced by 50% (from an average of 22 to 11 tablets/month). Those six patients who used subcutaneous sumatriptan reduced its consumption to a mean of 69% (from 4.5 to 1.5 injections per month). Emergency visits went from an average of 3 to 0.4 per trimester (−83%). Six patients complained of mild adverse events, transient local cervical pain being the most common. Although our data must be taken with caution as this is an open trial, in clinical practice treatment of refractory CM with BTA reduces the frequency of disabling attacks, the consumption of triptans and the need of visits to Emergency, which makes this treatment a profitable option both clinically and pharmacoeconomically.

The present work focuses on the preparation and evaluation of lecithin organogel system of thermoreversible polymer pluronic F127, which would enhance the stability and absorption of sumatriptan succinate across the skin. Formulations were developed with and without co-surfactant (pluronic F127). The prepared organogels were evaluated for its appearance, organoleptic characteristics, and feel upon application, homogeneity, occlusivenes, washability, pH, viscosity, spreadability, gel transition temperature of formulations. The formulations were also evaluated for drug content, in vitro drug diffusion properties and skin irritation testing. In vivo evaluation of formulations was carried out by hot plate and writhing test method, and finally the optimized formulation was subjected to stability studies. The developed formulations were easily washable, smooth in feel, and showed no clogging which indicate superior texture of system. Formulation, containing pluronic showed greater spreadability and higher drug diffusion rate as compared to pluronic free organogel. Drug content of organogel formulations was in the range of 94–97%. The pH of the formulations was 6.48 ± 0.5 and 6.98 ± 0.1, reflecting no risk of skin irritation. Pluronic not only enhances the stability of organogel by increasing the viscosity (from 6,541 ± 234.76 to 7,826 ± 155.65 poise) but also increases the release of drug from 67.39 ± 1.53% to 74.21 ± 1.7%. The sumatriptan exhibits higher and long lasting antinociceptive effect as indicated by the persistent increase in reaction time in hot plate and inhibited abdominal contraction in acetic acid-induced writhing test (p

Migraine headaches frequently occur in the pediatric population, with a prevalence of 3% in children 2-7 years of age, 4-11% in children 7-11 years of age, and 8-23% in children 11 years of age and older. Migraine without aura is more than twice as common as migraine with aura in children. Headaches are the third leading cause of emergency room referrals and rank in the top five health problems of children. The 2004 American Academy of Neurology's treatment parameter for migraine in children and adolescents recommended that nasal sumatriptan be considered for acute treatment; however, data were lacking to make a decision regarding the available oral triptans at that time. The more recently released European guidelines discuss three different triptans for use in children but no specific triptan was recommended. Currently, six of the seven available triptans have been studied for efficacy and safety in the pediatric population; however, only a few well controlled clinical studies have been conducted. Sumatriptan has the most available data on outcomes in general, with nasal sumatriptan showing the most positive results. Nasal sumatriptan is approved in children older than 12 years of age in Europe. Oral sumatriptan does not show any clinical benefit versus placebo in children. Rizatriptan and zolmitriptan have conflicting efficacy and safety data, with most studies favoring the use of oral rizatriptan and nasal zolmitriptan. Almotriptan is the first triptan to obtain a US FDA indication in adolescents with migraines lasting 4 or more hours. This approval was based upon two studies, one large clinical trial and one very small, open-label, pilot study. At this time, there are insufficient data to recommend naratriptan and eletriptan for first- or second-line use in pediatric patients with migraines. There are currently no efficacy data for frovatriptan in pediatric patients, which limits its use in this population. Adverse effects of triptans and pharmacokinetic data in children and adolescents are similar to those in adults. The triptan class should be considered as an acute treatment option for children and adolescents with migraines, although their use is mostly 'off-label'. Of the available triptans, there are more positive efficacy data for sumatriptan and zolmitriptan nasal sprays, and rizatriptan and almotriptan tablets than for the other triptans.

Although we have several acute care medications for the treatment of migraine, we are always looking for new medications to treat our patients. Patients often say that their headaches are not under optimal control and would be happy to try another medication. Patients look for faster onset of relief, more complete relief, no recurrent headache and no adverse events. This article will cover some new and some anticipated acute care products, CGRP antagonists, sumatriptan by iontophoretic patch, sumatriptan by needle-free injections, DHE by oral inhalation and diclofenac potassium in a sachet. Botulinum toxin therapy, although a preventive measure, will be mentioned at the end.

Migraineurs often do not use acute migraine-specific medications. Patient-reported satisfaction with triptans is modest. Patients are generally interested in obtaining more rapid and complete symptom relief. The role of trigeminal vascular activation may explain why some patients fail to respond to current treatment. Novel formulations of currently available acute migraine treatments have been developed, with improved clinical outcomes, response times, and pain-free rates. Currently available effective, novel, acute migraine therapies include needle-free injectable sumatriptan and effervescent diclofenac. Orally inhaled dihydroergotamine is a new treatment modality. These novel formulations may help patients achieve desirable outcomes, including faster and more complete relief, more consistent response, and improved drug tolerability.

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.

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity, sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions. During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation (weekly frequency of attacks decrease >50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).

Triptans (serotonin 5-HT(1B/1D) receptor agonists) such as frovatriptan have been shown to be highly effective and well tolerated in the treatment of patients with acute migraine. However, the large number of available triptans has led to the issue of how best to decide which triptan should be prescribed at an individual patient level. This review focuses on frovatriptan and highlights parameters that affect oral triptan choice, discusses the results of several open-label clinical and post-marketing surveillance studies of frovatriptan, and compares these naturalistic data with those from similar studies of other oral triptans. Efficacy data obtained from these trials are used to compare costs of treating migraine with frovatriptan and other oral triptans in four European countries. Studies of triptans in migraine have used several outcomes deemed important to patients, including complete pain relief, absence of recurrence, rapid onset of action, no side effects, restoration of functional ability, improvements in quality of life, and cost. In contrast to indirect evidence from some individual randomized, double-blind studies, results from open-label naturalistic studies and a meta-analysis of 31 placebo-controlled efficacy studies suggest that frovatriptan is associated with a lower rate of migraine recurrence than with other triptans in a real-world clinical setting (17% for frovatriptan 2.5 mg vs 23-40% for other triptans in the meta-analysis). It is likely that this may be due to the terminal elimination half-life of this agent (about 26 hours), which is longer than that of other triptans. Naturalistic studies indicate that the long duration of action of frovatriptan appears to confer other benefits such as greater patient satisfaction, with over 90% of patients and doctors rating frovatriptan therapy as 'very good' or 'good'. The cost of treatment with different triptans based on the number of tablets required per episode varies widely in each of the four countries analysed (Great Britain Pound 4.95-7.98 in France, Great Britain Pound 6.78-12.58 in Germany, Great Britain Pound 4.32-9.73 in the UK and Great Britain Pound 6.69-10.36 in Italy, based on lowest possible costs for branded versions in 2008) due to differences in both the acquisition costs of these agents and in the headache recurrence rates. Frovatriptan compares favourably with other available triptans with regard to cost per migraine attack on this basis, although head-to-head studies are required to confirm these data. The low rate of headache recurrence with frovatriptan compared with other oral triptans, and the associated lower treatment costs, deserve consideration when choosing an oral triptan for the treatment of patients with acute migraine.

Recurrence was first recognised as a clinical problem in 1989 with the advent of sumatriptan. The history of recurrence in early sumatriptan randomised clinical trials is described. Recurrence has been ascribed to patient-dependent factors but experience with ergot alkaloids suggested that recurrence can also be treatment-dependent. Possible mechanisms for recurrence are discussed.

Although medication costs make up one of the smallest portions of the overall expense of headache care, it is the segment of expense that often impacts the patient most directly. The advent of triptans marked a major advance in migraine therapy, but their high cost has limited their widespread use. Four options can be considered as potential means to reduce the cost of triptans. These include compulsory licensing, exclusive contracting, over-the-counter -availability, and the introduction of generic triptans. Each method impacts the consumer, third-party payer, or pharmaceutical company in a different manner.