Individual triptan selection in migraine attack therapy.

About 6% of men and 18% of women suffer migraine attacks. Migraine can induce a great impact in the quality of life of the patient and the costs of medical care and lost productivity can be also high. There are two therapeutic approaches in the treatment of migraine: preventive therapy and acute treatment of migraine attack. Immediate treatment with selective serotonin [5-HT1B/1T] receptor agonists (so-called triptans) is the first-line option in the acute treatment of moderate-severe migraine attacks. The introduction in early nineties of triptans was a revolution in migraine therapy and evidences about their efficacy are at present irrefutable. At the moment, there are seven marketed molecules: sumatriptan, rizatriptan, zolmitriptan, eletriptan, naratriptan, almotriptan and frovatriptan. Obviously, every molecule has different pharmacokinetic and pharmacodinamic properties and, moreover, some triptans have several formulations: tablets, dissolvable tablets, nasal and injections. The prescription of one of these seven triptans for a specified patient is based in the drug profile: efficacy, safety, pharmacokinetics and pharmacodynamics. Despite there are a lot of published studies using triptans, no clinical trial has analyzed all the molecules at the same time. Other data to take account in the final prescription are clinical characteristics of the migraine attack and patient characteristics: labour aspects, style of life and the patient medical history. We present a state-of-the-art of the triptan selection in treatment of moderate-severe migraine attacks.

Pathways to the best fit of triptans for migraine patients.

Variability in drug response is a major barrier to the successful treatment of migraine, and most treatments are only optimal in a subset of patients. Although triptans provide the best therapeutic option for the treatment of acute migraine, it has not previously been possible to predict how well patients will respond to a specific triptan or whether they will experience unpleasant adverse events. Hence, it has been difficult for physicians to match individual patients with the most suitable agent to treat their migraine pain. Intrapatient variability has been associated with polymorphisms in genes encoding drug-metabolizing enzymes, drug transporters and drug targets. Pharmacogenetics provides the possibility of tailoring the therapeutic approach to individual patients, in order to maximize treatment efficacy while minimizing the potential for unwanted side-effects. This review demonstrates how almotriptan may overcome genetically determined responses by utilizing diverse metabolic pathways to provide therapeutic benefit to many migraineurs.

Acute migraine therapy: recent evidence from randomized comparative trials.

(1) A wide array of data regarding acute migraine treatment are available, but few trials strictly adhere to International Headache Society guidelines for patient inclusion criteria.(2) Triptans appear to have similar efficacy profiles, but among newer triptans, almotriptan offers improved tolerability over sumatriptan.(3) Combination indomethacin/caffeine/prochlorperazine most likely has similar therapeutic efficacy to triptan therapy, with further research needed to complete understanding of any potential differences between these treatments.(4) Multi-targeted combination therapy with a triptan plus a non-steroidal anti-inflammatory (NSAID), such as sumatriptan/naproxen sodium, is more effective in acute migraine treatment than monotherapy with either agent alone.(5) It is unclear whether triptans offer clinically relevant benefits over aspirin or NSAIDs in migraine patients. Thus NSAIDs, particularly effervescent aspirin, should be considered the first-line treatment of migraine attacks.

Which triptan for which patient?

The triptans were developed for the acute treatment of a migraine attack and have revolutionised the treatment of this disorder since their introduction in the early 1990s. Although their mechanisms of actions are similar and based on the stimulation of specific serotonin (5-hydroxytryptamine) receptors including peripheral 1B and central and peripheral 1D subtypes, each triptan has its own distinctive pK properties that result in different profiles of efficacy and tolerability. Triptans work by decreasing neurogenic inflammation peripherally in the meninges, vasoconstriction of meningeal vessels and by modulating secondary-order neurons in the brain stem. Studies of patient attitudes towards their acute care regimens reveal that they are often unhappy with some aspect of their treatment-usually the speed of action, degree of efficacy, presence of adverse events and the need for additional doses due to frequent and/or rapid recurrence. The majority of patients, when asked in a clinical trial performed at tertiary care headache centres, are willing to try another triptan. The aim of this article is to review the pK and clinical characteristics of these acute care, migraine-specific triptan medications and discuss how their individual characteristics lead to their preferred choice in various clinical scenarios. The pK and clinical efficacy data presented are taken from older published studies in which triptans were compared to placebo or each other, but the patients were asked to wait till the headache reached moderate or severe intensity prior to taking study medication. New studies have looked at early treatment paradigms and result in better efficacy data, but are difficult to compare due to different endpoints.

An economic evaluation of triptan products for migraine.

OBJECTIVE: A composite outcome measure in migraine treatment assessment is useful to clinical decision-makers and payers as it can provide a more accurate reflection of effectiveness and allows for more complete modeling of economic value. The objective of this study was to compare the total triptan cost to treat 100 migraine patient attacks and the cost per successfully treated patient (CPSTP) for six marketed triptans using a composite measure of effectiveness, the "successfully treated" migraine (defined as requiring only one triptan dose to treat one migraine attack during a 24-h period). METHODS: This analysis was conducted from the perspective of the payer. Clinical data were abstracted from a rigorous, published meta-analysis. Two-hour response and pain-free response were used in conjunction with the recurrence rate reported in the meta-analysis to calculate the number of doses used by treatment successes and failures. The average wholesale price per dose was then used to calculate total triptan cost. RESULTS: Of the nine oral triptan doses compared, eletriptan 40 mg was associated with both the lowest total triptan cost for treating 100 migraine attacks ($1560) and with the lowest CPSTP ($56.39). CONCLUSIONS: The relative CPSTP rankings for migraine therapies are dependent on the definition of treatment success and relative pricing. The results of this study support the use of eletriptan for the treatment of acute migraine based on the model assumptions. This study can be used to assist in formulary considerations and offers a model that can be adapted by health-care decision-makers.

Patterns of use of triptans and reasons for switching them in a tertiary care migraine population.

OBJECTIVE: To assess the reasons for switching triptans within migraine patients presenting to a specialty clinic. DESIGN AND METHODS: We reviewed data of migraineurs who (1) were currently using a triptan as acute treatment medication for migraine, and (2) had previously used at least one other triptan, or a different triptan formulation. All subjects were followed for at least 1 year. For every triptan/formulation used, the reasons for discontinuation were obtained. RESULTS: Our sample consisted of 386 patients, 339 of whom (87.8%) were females. Sumatriptan was first used by 349 (90.4%); zolmitriptan, by 238 (61.5%); rizatriptan, by 195 (50.5%); naratriptan, by 137 (35.4%); and almotriptan, by 31 (8.0%). Almotriptan was excluded from this analysis because of our small sample. We found significant differences among those who wanted to try another triptan to see if it would be better in those who first used sumatriptan 25 mg, compared to those first using sumatriptan 50 mg (P = .01), sumatriptan 100 mg (P < .001), sumatriptan nasal spray (NS) (P < .001), sumatriptan subcutaneous (SC) (P < .001), zolmitriptan 5 mg (P < .001), rizatriptan 10 mg (P < .001), and naratriptan (P = .001). Patients using rizatriptan, sumatriptan NS, and sumatriptan SC had significantly lower rates of reporting this answer. Subjects first using naratriptan were less likely to report recurrence than those using sumatriptan 25 mg (P = .004), sumatriptan 50 mg (P = .0005), sumatriptan 100 mg (P = .003), zolmitriptan (P = .02), and rizatriptan (P = .006). Incomplete relief was more frequently reported by those first using sumatriptan 25 mg and naratriptan. Inconsistency was a reason for switching in those initially using sumatriptan NS, sumatriptan 25 mg, and naratriptan and less frequently reported in those using zolmitriptan and sumatriptan SC. Side effects were major factors for those first using sumatriptan 100 mg, NS, and SC, and less for those using naratriptan and sumatriptan 25 mg. From those subjects that initially used sumatriptan SC and were switched to a different triptan or formulation, 19.5% returned to sumatriptan SC; for the other triptans/formulations, the percentages were: sumatriptan 25 mg, 7.8%; sumatriptan 50 mg or 100 mg, 42.3%; sumatriptan NS, 17.7%; zolmitriptan, 17.6%; rizatriptan, 16.5%; naratriptan, 9.4%. For those who used more than three triptans/formulations, the last triptan used was: sumatriptan, 29.5%; zolmitriptan, 31.8%; rizatriptan, 25.0%; naratriptan, 12.5%. CONCLUSIONS: A variety of treatment attributes are important in determining the reasons involved in switching a triptan. To assess this attributes can provide additional information to supplement the traditional tests of efficacy provided by randomized clinical trials.

G-protein coupled receptors: SAR analyses of neurotransmitters and antagonists.

BACKGROUND: From the deductive point of view, neurotransmitter receptors can be divided into categories such as cholinergic (muscarinic, nicotinic), adrenergic (alpha- and beta-), dopaminergic, serotoninergic (5-HT1 approximately 5-HT5), and histaminergic (H1 and H2). Selective agonists and antagonists of each receptor subtype can have specific useful therapeutic applications. For understanding the molecular mechanisms of action, an inductive method of analysis is useful. OBJECTIVE: The aim of the present study is to examine the structure-activity relationships of agents acting on G-protein coupled receptors. METHOD: Representative sets of G-PCR agonists and antagonists were identified from the literature and Medline [P.M. Walsh (2003) Physicians' Desk Reference; M.J. O'Neil (2001) The Merck Index]. The molecular weight (MW), calculated logarithm of octanol/water partition coefficient (C log P) and molar refraction (CMR), dipole moment (DM), E(lumo) (the energy of the lowest unoccupied molecular orbital, a measure of the electron affinity of a molecule and its reactivity as an electrophile), E(homo) (the energy of the highest occupied molecular orbital, related to the ionization potential of a molecule, and its reactivity as a nucleophile), and the total number of hydrogen bonds (H(b)) (donors and receptors), were chosen as molecular descriptors for SAR analyses. RESULTS: The data suggest that not only do neurotransmitters share common structural features but their receptors belong to the same ensemble of G-protein coupled receptor with seven to eight transmembrane domains with their resultant dipoles in an antiparallel configuration. Moreover, the analysis indicates that the receptor exists in a dynamic equilibrium between the closed state and the open state. The energy needed to open the closed state is provided by the hydrolysis of GTP. A composite 3-D parameter frame setting of all the neurotransmitter agonists and antagonists are presented using MW, Hb and mu as independent variables. CONCLUSION: It appears that all neurotransmitters examined in this study operate by a similar mechanism with the G-protein coupled receptors.

Neural substrates underlying impulsivity.

Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder whose three main symptoms are impulsiveness, inattention, and hyperactivity. Although ADHD is an early developmental disorder, it may persist into adulthood, resulting in deficits associated with poor academic performance, frequent job changes, poor and unstable marriages, and increases in motor vehicle accidents. Of the three primary symptoms of ADHD, deficits in impulse control are the most challenging to the social network and the judicial system. While the etiology of ADHD remains unknown, recent work suggests that the central deficits in ADHD may be due to poor response inhibition that is linked to monoamine and prefrontal lobe deficiencies. In the past, preclinical studies designed to understand the lack of impulse control have generally been relegated to studies linked to aggression and drug abuse. With the use of innovative noninvasive techniques, like anatomical and functional magnetic resonance imaging, selective neurochemical and behavioral paradigms have converged with preclinical reports and lend support to the premise that monoaminergic neurotransmitter systems and the cortico-striatal circuitry are essential to impulse control. Furthermore, new emerging data on neural substrates underlying impulsivity have incorporated brain regions involved in reinforcement, reward, and decision making such as the nucleus accumbens, cerebellum, and amygdala. As noninvasive brain imaging, neurochemical, and behavioral approaches are combined, our knowledge of the neural networks underlying impulsivity will hopefully give rise to therapeutic approaches aimed at alleviating this disorder.

Tripstar: a comprehensive patient-based approach to compare triptans.

Several second-generation triptans have been introduced that differ in their pharmacologic profiles relative to each other and to sumatriptan. As therapeutic options multiply, clinicians must be able to distinguish among these compounds. Recently, a meta-analysis was conducted on data from 53 double-blind, randomized, placebo- or active-controlled trials involving over 24,000 patients receiving oral triptans. Results indicated that almotriptan 12.5 mg, rizatriptan 10 mg, and eletriptan 80 mg are generally superior to sumatriptan 100 mg based on individual treatment attributes, such as pain relief, sustained pain freedom, consistency of response, and tolerability. Meta-analyses are limited, however, as the analysis can only be performed for individual end points, whereas patients and prescribers balance a variety of treatment attributes when assessing drug acceptability. A flexible overall scoring system ("Tripstar") is proposed that compares triptans to a hypothetical "ideal" using meta-analysis data combined with ratings of the relative importance of clinically relevant treatment criteria. An informal test of the Tripstar model indicated that sumatriptan is most similar to a hypothetical ideal for both mild and severe migraine, primarily due to its high worldwide clinical exposure. However, after exclusion of worldwide exposure as a contributing factor, almotriptan 12.5 mg is most similar to the ideal, principally because of its good tolerability. Further tests of the Tripstar model are planned that will gauge the relative importance of a broader range of attributes.

Migraine: diagnosis, management, and new treatment options.

OBJECTIVE: The safety and tolerability of medications used to treat acute migraine attacks are summarized, the classification of headaches and the causes of and diagnostic criteria for migraine are reviewed, and the clinical tolerability profiles and therapeutic benefits of second-generation triptans are presented. BACKGROUND: Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, and phonophobia. Drugs used to prevent migraine and those that effectively treat acute migraine attacks are readily available. METHODS: Mild or moderate migraines are often treated with aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs, antiemetic drugs, or isometheptene. Triptans (5-HT1 receptor agonists) are used to treat moderate or severe migraine and when nonspecific medications have been ineffective. Because sumatriptan, the first triptan used, is effective but can induce adverse events, second-generation triptans (zolmitriptan, naratriptan, rizatriptan, and almotriptan) were developed to increase the benefit-to-risk ratio in migraine management. RESULTS: Important pharmacologic, pharmacokinetic, and clinical differences exist among those drugs, but the tolerability profile of the newer triptans is very good, and they provide rapid relief from headache and sustained duration of effect. CONCLUSION: Primary care physicians must manage migraine patients with treatments that demonstrate a balance between efficacy and tolerability.

Frovatriptan: a selective type 1B/1D serotonin receptor agonist for the treatment of migraine headache.

Frovatriptan belongs to an innovative family of compounds aimed at breaking through the long-standing barrier of migraine headache understanding and treatment. While a typology of headaches has been recognized for some time, and a number of therapies have been introduced for reduction of headache pain and duration, the causes of migraine remain a subject of debate. Those prone to attacks continue to endure them and suffer the related symptoms such as nausea and disorientation. Frovatriptan, like all the triptans, acts by inducing vasoconstriction of the meningeal arteries. It has been shown in pharmacological tests to act selectively as a potent agonist of serotonin 5-HT1B/1D receptors. Frovatriptan has been well tolerated in humans and efficacious in reducing headache pain and duration in clinical trials, which have also indicated that dose adjustments for age or gender are not necessary for the drug. Patients have found the use of frovatriptan acceptable over the long-term, and overall a low-incidence of adverse effects has been reported. Though not a prophylactic, frovatriptan has demonstrated the potential to significantly improve the therapeutic approaches to the treatment of migraine.

Drug therapy options for patients with irritable bowel syndrome.

Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation.

Differentiating the efficacy of 5-HT(1B/1D) agonists.

OBJECTIVE: To examine, for a set of published clinical trials of serotonin (5-HT(1B/1D)) agonists as acute treatments for migraine, whether transformation of efficacy data into therapeutic gain (TG) or number needed to treat (NNT) is useful. BACKGROUND: Pivotal clinical trials of 5-HT(1B/1D) agonists in migraine use a primary end point of change in pain score from 3 or 2 to 1 or 0. Placebo response rates among such studies are variable. Meta-analytic comparisons of 5-HT(1B/1D) agonists often employ TG and NNT as efficacy measures. METHODS: Data from US product labeling or published sources were converted into TG (TG = active response rate [%] - placebo response rate [%]) and NNT (NNT = 1/TG). Pivotal clinical trial data were compared before and after transformation. RESULTS: Therapeutic gain ranged from 17.5% to 51%. The transformation of TG into NNT yielded no clinically significant difference in efficacy estimate for the range of 17.5% to 47% (N = 29 clinical trials). However, NNT and TG had a nonlinear relationship for some secondary end points. When the relationship between the standard primary and secondary end points was compared, the correlation of TG with clinical disability (Pearson coefficient R = 0.93) was stronger than for NNT. Placebo response rates correlated more strongly with NNT (R = 0.66) than active response rates (R = 0.42; N = 29 clinical trials), although both TG and NNT were sensitive to placebo response rate. CONCLUSIONS: Transforming efficacy rates into TG or NNT adds no new information to placebo-controlled trials. The variables, TG and NNT, should not be used to compare members of this class of drugs. Migraine therapies can only be compared using well-designed head-to-head studies and not by meta-analysis. Broader measures of efficacy should be used to describe and compare 5-HT(1B/1D) efficacy.

Profiles of 5-HT 1B/1D agonists in acute migraine with special reference to second generation agents.

The efficacy of 5-hydroxytryptamine 1B/1D (5-HT 1B/1D) agonists is related to their inhibitory effects on neurogenic inflammation, mediated through serotoninergic control mechanisms. Recently, a series of oral second generation 5-HT 1B/1D agonists (eletriptan, naratriptan, rizatriptan and zolmitriptan) have been developed and are reviewed in this paper. Their in vitro and in vivo pharmacological properties, clinical efficacy, drug interactions, and adverse effects are evaluated and compared to the gold standard in the treatment of acute migraine, sumatriptan.

[New prospects in the treatment of migraine]. / Nuevas perspectivas en el tratamiento de la migraña.

The options for migraine treatment have increased in the recent years and will expand in the near future. In this work both recent and future options for migraine treatment are critically reviewed. Firstly the late advances in the symptomatic treatment of migraine, including the new 5-HT1B/D agonists "triptans" appeared after sumatriptan, are reviewed. Possible alternative, such as selective 5-HT1D and 5-HT1F agonists, are also discussed. In the second part of this manuscript the new, possible options for the preventive treatment of migraine comprising "antiepileptics", such as valproic acid, gabapentin and topiramate, calcium-antagonists, such as cyclandelate and dotarizin, and a miscellany, including riboflavin, are analysed. Finally, possible compounds for the future, such as the selective inhibitors of neurokinin receptors or drugs acting upon neuronal calcium channels, are commented. From this review we conclude that while there have been relevant advances in the symptomatic treatment of migraine, there is a need for the development of better preventive compounds.

Role of 5-HT1B, 5-HT2A and 5-HT2C receptors in the generalization of 5-HT receptor agonists to the ethanol cue in the rat.

Although accumulating evidence suggests that serotonergic drugs are able to substitute for the ethanol (EtOH) cue in rats, it is still unclear which 5-HT receptor subtypes are responsible for this phenomenon, and whether these receptors are critically involved in the EtOH cue. In the present study, rats were trained to discriminate EtOH (1000 mg/kg, i.p., t-15 min) from saline in a two-lever food-reinforced procedure, and it was investigated to which extent serotonergic compounds with a certain level of specificity for either 5-HT1B, 5-HT2A or 5-HT2C receptors generalized to the EtOH cue. Subsequently, the involvement of these receptor subtypes was ascertained by the use of selected 5-HT receptor antagonists. The 5-HT1B receptor agonist CP 94,253 (0.3-5 mg/kg, i.p.) and the mixed 5-HT(2C/1B) receptor agonist mCPP (0.1-1 mg/kg, i.p.), but not the preferential 5-HT2A receptor agonist DOI (0.3-1 mg/kg, i.p.), completely generalized to the EtOH cue. Complete generalization of the former two compounds coincided with a decrease in response rate. In antagonism studies, it was shown that the 5-HT1B receptor antagonist GR 127935 (10 mg/kg, i.p.) completely blocked generalization of CP 94,253 to the EtOH cue, suggesting that stimulation of 5-HT1B receptors produces discriminative stimulus effects which are similar to those of EtOH. GR 127935 (10 mg/kg, i.p.), as well as the mixed 5-HT(1B/2C) receptor antagonist metergoline (1 mg/kg, i.p.), and the 5-HT2C receptor antagonist SB 206,553 (1 mg/kg, i.p.) completely blocked generalization of mCPP to the EtOH cue. This suggests that 5-HT1B and 5-HT2C receptors are required for the generalization of mCPP to the EtOH cue. The present findings indicate that activation of 5-HT1B and 5-HT2C, but not of 5-HT2A receptors, mimics the EtOH cue. However, the finding that neither metergoline, nor the 5-HT2A receptor antagonist MDL 100,907 blocked the EtOH cue, suggests that these receptors play only a minor role in the discriminative stimulus effects of a moderately low dose of EtOH.

Serotonin receptors and therapeutics.

Since its discovery, serotonin (5-hydroxytryptamine = 5-HT) has become a major player on the neurotransmitter "stage". Multiple receptor subtypes for 5-HT have been identified and classified, and a vast pharmacology of 5-HT has emerged. In particular, 5-HT has been shown to exert marked effects on the cardiovascular system, central nervous system (CNS) and gastrointestinal (GI) tract, and important ligands have been developed that mimic or block its action selectively. Furthermore, drugs that release 5-HT, and others that prevent its uptake, have been developed. This brief review focuses on the pharmacology of 5-HT agonists and antagonists that exhibit, at least partly, clinical relevance.