A multicenter, open-label, long-term safety and tolerability study of DFN-02, an intranasal spray of sumatriptan 10 mg plus permeation enhancer DDM, for the acute treatment of episodic migraine.

BackgroundDFN-02 is a novel intranasal spray formulation composed of sumatriptan 10 mg and a permeation-enhancing excipient comprised of 0.2% 1-O-n-Dodecyl-β-D-Maltopyranoside (DDM). This composition of DFN-02 allows sumatriptan to be rapidly absorbed into the systemic circulation and exhibit pharmacokinetics comparable to subcutaneously administered sumatriptan. Rapid rate of absorption is suggested to be important for optimal efficacy. The objective of this study was to evaluate the safety and tolerability of DFN-02 (10 mg) in the acute treatment of episodic migraine with and without aura over a 6-month period based on the incidence of treatment-emergent adverse events and the evaluation of results of clinical laboratory tests, vital signs, physical examination, and electrocardiograms.MethodsThis was a multi-center, open-label, repeat-dose safety study in adults with episodic migraine with and without aura. Subjects diagnosed with migraine with or without aura according to the criteria set forth in the International Classification of Headache Disorders, 2nd edition, who experienced 2 to 6 attacks per month with fewer than 15 headache days per month and at least 48 headache-free hours between attacks, used DFN-02 to treat their migraine attacks acutely over the course of 6 months.ResultsA total of 173 subjects was enrolled, 167 (96.5%) subjects used at least 1 dose of study medication and were evaluable for safety, and 134 (77.5%) subjects completed the 6-month study. A total of 2211 migraine attacks was reported, and 3292 doses of DFN-02 were administered; mean per subject monthly use of DFN-02 was 3.6 doses. Adverse events were those expected for triptans, as well as for nasally administered compounds. No new safety signals emerged. Dysgeusia and application site pain were the most commonly reported treatment-emergent adverse events over 6 months (21% and 30.5%, respectively). Most of the treatment-emergent adverse events were mild. There were 5 serious adverse events, all considered unrelated to the study medication; the early discontinuation rate was 22.5% over the 6-month treatment period.ConclusionDFN-02 was shown to be well tolerated when used over 6 months to treat episodic migraine acutely

Triptans and CGRP blockade - impact on the cranial vasculature

The trigeminovascular system plays a key role in the pathophysiology of migraine. The activation of the trigeminovascular system causes release of various neurotransmitters and neuropeptides, including serotonin and calcitonin gene-related peptide (CGRP), which modulate pain transmission and vascular tone. Thirty years after discovery of agonists for serotonin 5-HT1B and 5-HT1D receptors (triptans) and less than fifteen after the proof of concept of the gepant class of CGRP receptor antagonists, we are still a long way from understanding their precise site and mode of action in migraine. The effect on cranial vasculature is relevant, because all specific anti-migraine drugs and migraine pharmacological triggers may act in perivascular space. This review reports the effects of triptans and CGRP blocking molecules on cranial vasculature in humans, focusing on their specific relevance to migraine treatment

The effect of weight, body mass index, age, sex, and race on plasma concentrations of subcutaneous sumatriptan: a pooled analysis.

Objective/backgroundFactors such as body size (weight and body mass index [BMI]), age, sex, and race might influence the clinical response to sumatriptan. We evaluated the impact of these covariates on the plasma concentration (Cp) profile of sumatriptan administered subcutaneously.MethodsWe conducted three pharmacokinetic studies of subcutaneous sumatriptan in 98 healthy adults. Sumatriptan was administered subcutaneously (236 administrations) as either DFN-11 3 mg, a novel 0.5 mL autoinjector being developed by Dr. Reddy's Laboratories; Imitrex(®) (Sumatriptan) injection 3 mg or 6 mg (6 mg/0.5 mL); or Imitrex STATdose 4 mg or 6 mg (0.5 mL). Blood was sampled for 12 hours to determine sumatriptan Cp. Maximum Cp (Cmax), area under the curve during the first 2 hours (AUC0-2), and total area under the curve (AUC0-∞) were determined using noncompartmental methods. Post hoc analyses were conducted to determine the relationship between these exposure metrics and each of body weight, BMI, age, sex, and race (categorized as white, black, or others).ResultsBoth weight and BMI correlated negatively with each exposure metric for each treatment group. Across all treatment groups, AUC0-2 for subjects with BMI less than or equal to median value was 1.03-1.12 times the value for subjects with BMI more than median value. For subjects with BMI less than or equal to median value receiving DFN-11, median AUC0-2 was slightly less than that for subjects with BMI more than median value receiving Imitrex 4 mg and larger than that for subjects with BMI more than median value receiving Imitrex 3 mg. Results were similar for the other exposure metrics and for weight. Exposure was higher in women than in men, which can be attributed in part to differences in weight. There was no relationship between exposure and age. For DFN-11, AUC0-2 and AUC0-∞ were lower in nonwhites compared with whites; the ratio of median values was 0.84 and 0.89, respectively. A similar, nonstatistically significant, trend was observed in the other products (ratio of median values ranging from 0.84 to 0.89).ConclusionWeight and BMI appear to be important covariates for sumatriptan exposure: subjects with lower values for either metric of body size have higher systemic exposure compared with subjects with higher values. Additional studies are required to determine if doses of subcutaneous sumatriptan may be adjusted based on BMI for comparable efficacy and a potentially improved tolerability profile

Eletriptan in the management of acute migraine. An update on the evidence for efficacy, safety, and consistent response

Migraine is a multifactorial, neurological and disabling disorder, also characterized by several autonomic symptoms. Triptans, selective serotonin 5-HT1B/1D agonists, are the first-line treatment option for moderate-to-severe headache attacks. In this paper, we review the recent data on eletriptan clinical efficacy, safety, and tolerability, and potential clinically relevant interactions with other drugs. Among triptans, eletriptan shows a consistent and significant clinical efficacy and a good tolerability profile in the treatment of migraine, especially for patients with cardiovascular risk factors without coronary artery disease. It shows the most favorable clinical response, together with sumatriptan injections, zolmitriptan and rizatriptan. Additionally, eletriptan shows the most complex pharmacokinetic/dynamic profile compared with the other triptans. It is metabolized primarily by the CYP3A4 hepatic enzyme and therefore the concomitant administration of CYP3A4-potent inhibitors should be carefully evaluated. A relatively low risk of serotonin syndrome is given by the co-administration with serotoninergic drugs. No clinically relevant interaction has been found with drugs used for migraine prophylactic treatment or other acute drugs, with the exception of ergot derivatives that should not be co-administered with eletriptan

Cluster headache management and beyond

The therapeutic management of cluster headache is based on a very stable triad of drugs. Acute treatment has, in subcutaneous sumatriptan, its gold standard if compared to pure oxygen or indomethacin. Preventative treatment is based on verapamil at high doses (≥ 360 mg) and is a gold standard if compared to lithium carbonate or topiramate. Transitional treatments, based on the short-term use of corticosteroids with either systemic or local administration (GON), can be useful for the suppression of most resistant cluster periods, but with a well-known carry-over phenomenon related to the length of the cluster period itself. The role of invasive or noninvasive neuromodulation approaches must still be determined on a large scale; therefore, its use is not recommended as of yet. Lifestyle changes, including alcohol avoidance during the active phase of the disease, sleep hygiene and use of vasodilation drugs, should be carefully considered and the patients should be fully informed

Up to date on the use of triptans for child and adolescent migraine: “the state of the art”

The introduction of triptans, in the early 1990s, has improved the therapy for acute migraine attack, offering a new quality of life for those patients who suffer from this disabling neurological disorder. Epidemiological data point out that about 10% of school–age children suffer from migraine, with a progressive increase in incidence and prevalence up to the threshold of adulthood. The increase in extent and prevalence of migraine from the years of growth stresses the importance of the application and adjustment of ad hoc therapeutic (either pharmacological or not) and diagnostic measures. Indeed, the peculiar neurobiological and psychological aspects which are typical of an “evolving” organism preclude the use, by simple “transposition” or “proportion”, of the knowledge acquired from adult–targeted studies. That requires the implementation of studies to analyze the specific responses of children and adolescents to the triptans. To date, the studies on such issues are absolutely insufficient to draw definitive conclusions and indications for the use of triptans for child and adolescent migraineurs

Migraine: Diagnosis, treatment and understanding c1960-2010

seminar transcriptThere are around eight million migraine sufferers in the UK today. This Witness Seminar looked at the last 50 years of research into the diagnosis and treatment of the condition and the changing attitudes of the medical profession towards this debilitating disorder. Chaired by Dr Mark Weatherall, the participants, some of whom were also migraine sufferers, included neurologists and pharmacologists, representatives from patient organizations such as Migraine Action and the Migraine Trust, and GPs and headache nurses. The discussion covered the vascular and neuronal theories of migraine, the early treatment with ergotamine, analgesics and antiemetics, and investigations into the importance of 5-HT. It then moved on to examine the scientific research behind the development of the triptans during the 1980s and impact of their introduction in the early 1990s. More recent treatments, such as the use of Botox (botulinum toxin), were also considered. Other topics included the development of headache classification and diagnostic criteria for migraine; the support for migraine sufferers such as headache clinics, specialist headache nurses, and charities; and the reason why, despite the number of sufferers and its high socio-economic cost, there is often little interest in migraine and research attracts limited fundin

Sumatriptan effects on morphine-induced antinociceptive tolerance and physical dependence: The role of nitric oxide

Sumatriptan, a 5HT (5-hydroxytryptamine)1B/1D receptor agonist, showed neuroprotection in different studies. The aim of the present study was to investigate the effect of sumatriptan on morphine-induced antinociceptive tolerance and physical dependence. We also investigated the possible role of nitric oxide (NO) on sumatriptan effects. Tolerance was induced by morphine injection (50, 50, 75 mg/kg) three times daily for five days. Antinociceptive latency after acute and chronic treatment with sumatriptan (0.001, 0.01, 0.1 and 1 mg/kg) was measured by hot plate test in morphine-dependent animals. To investigate the possible involvement of NO, different isoforms of nitric oxide synthase (NOS) inhibitors including L-NAME, aminoguanidine and 7-nitroindazole were co-administered with sumatriptan. Nitrite level in mice hippocampus was quantified by Griess method. To examine the role of sumatriptan on physical dependence, three parameters of withdrawal signs were recorded after injection of naloxone (4 mg/kg). Acute treatment with sumatriptan (0.01, 0.1 and 1 mg/kg) attenuated the antinociceptive tolerance (P < 0.001). Chronic injection of sumatriptan (0.001, 0.01 and 0.1 mg/kg), as well, decreased the antinociceptive tolerance (P < 0.001). Moreover, co-administration of NOS inhibitors prevented the effects of sumatriptan. Sumatriptan significantly increased the level of nitrite only after chronic administration. Sumatriptan administration showed no alteration in naloxone-precipitated withdrawal signs. Acute and chronic administration of sumatriptan attenuated morphine antinociceptive tolerance; at least in chronic phase via nitrergic pathway. Our data did not support beneficial effects of sumatriptan on morphineinduced physical dependence in mice

Induction of chronic migraine phenotypes in a rat model after environmental irritant exposure

Air pollution is linked to increased emergency department visits for headache and migraine patients frequently cite chemicals or odors as headache triggers, but the association between air pollutants and headache is not well understood. We previously reported that chronic environmental irritant exposure sensitizes the trigeminovascular system response to nasal administration of environmental irritants. Here, we examine whether chronic environmental irritant exposure induces migraine behavioral phenotypes. Male rats were exposed to acrolein, a transient receptor potential channel ankyrin-1 (TRPA1) agonist, or room air by inhalation for 4 days before meningeal blood flow measurements, periorbital cutaneous sensory testing, or other behavioral testing. Touch-induced c-Fos expression in trigeminal nucleus caudalis was compared in animals exposed to room air or acrolein. Spontaneous behavior and olfactory discrimination was examined in open-field testing. Acrolein inhalation exposure produced long-lasting potentiation of blood flow responses to a subsequent TRPA1 agonist and sensitized cutaneous responses to mechanical stimulation. C-Fos expression in response to touch was increased in trigeminal nucleus caudalis in animals exposed to acrolein compared with room air. Spontaneous activity in an open-field and scent preference behavior was different in acrolein-exposed compared with room air-exposed animals. Sumatriptan, an acute migraine treatment blocked acute blood flow changes in response to TRPA1 or transient receptor potential vanilloid receptor-1 agonists. Pretreatment with valproic acid, a prophylactic migraine treatment, attenuated the enhanced blood flow responses observed after acrolein inhalation exposures. Environmental irritant exposure yields an animal model of chronic migraine in which to study mechanisms for enhanced headache susceptibility after chemical exposure

The therapeutic armamentarium in migraine is quite elderly.

Global Burden of Disease 2010 study considers migraine as one of the most important noncommunicable diseases in the world, classifying it third in terms of global prevalence (14.70%): it sums up the 54.19% of all the years of life lived with disabilities caused by the rest of all neurological disorders. This Editorial provides an historical excursus of old and new-entry molecules in migraine therapeutic area. Drugs for acute treatment such as triptans date back to the early 1990s with the appearance of sumatriptan and the following six triptans in the years immediately after (zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, frovatriptan). Prophylaxis drugs, dedicated to patients with medium/high frequency of crises, show as last entries topiramate and botulinum toxin type A. The use of this preventative group, with its intrinsic limits, is mandatory to reduce the risk of migraine chronification, a highly harmful clinical phenomenon that produces as its natural consequence the medication overuse headache. The development of new acute and preventative compounds, such as 5HT (serotonin) 1F receptor (5-HT1F) agonist lasmiditan, calcitonin gene related peptide (CGRP) peptide receptor antagonists, anti-CGRP monoclonal antibodies (LY2951742, ALD403, LBR101) and anti-CGRP-r monoclonal antibody (AMG334), is warranted and might be soon completed in order to offer new opportunities to migraine patients