"Mixing triptans": patient satisfaction

(Headache 2011;51:135‐140) Background.— Although some patients may prefer using an oral triptan other than sumatriptan and injectable sumatriptan to treat an attack of persistent migraine, administration of 2 different triptans within a 24‐hour period currently is contradicted. Objective.— We sought to determine patient satisfaction with an acute migraine treatment regimen wherein patients were permitted to administer an oral triptan other than sumatriptan and injectable sumatriptan within 24 hours of one another Methods.— We evaluated a consecutive series of migraine patients who either had tried and failed oral sumatriptan or were using another oral triptan and were satisfied with it. We advised subjects that they could administer their oral triptan and injectable sumatriptan within a single 24‐hour period (but not within 2 hours of one another); we termed such treatment “mixing triptans.” We asked all subjects to keep detailed written headache diaries for the 6‐month treatment period, and at the 6‐month end‐of‐study visit we asked subjects who had treated at least 3 migraine attacks by mixing triptans to rate their satisfaction with that treatment according to a 5‐point Likert scale. Results.— Of the 200 subjects enrolled, 132 (66%) used an oral triptan other than sumatriptan and injectable sumatriptan within a 24‐hour period on at least 3 occasions. At their final follow‐up visits, 117 (89%) of the 132 reported themselves “very satisfied” or “satisfied” with this specific treatment regimen. No serious adverse events were recorded. Conclusion.— The option of sequentially using an oral triptan other than sumatriptan and injectable sumatriptan to treat a given attack of migraine appears to correlate with a high rate of patient satisfaction. While in our subject population this treatment regimen was well tolerated, our study results do not suffice to establish the safety of “mixing triptans.”     

Sumatriptan plus metoclopramide in triptan-nonresponsive migraineurs

OBJECTIVES: We evaluated the effectiveness of combination treatment using sumatriptan plus metoclopramide versus sumatriptan alone for the treatment of acute migraine. The patients who were treated had failed to respond to triptans in the past despite adequate doses on at least 2 separate trials of the same triptan or 2 trials involving different triptans. BACKGROUND: There is limited evidence that dopaminergic antagonists may benefit the migraineur by relieving migraine pain and associated symptoms. The exact mechanism of action in migraine is unknown. The postulated action is the inhibition of dopaminergic overactivity. A dopaminergic antagonist, metoclopramide, may improve the efficacy of a 5-HT1B/1D agonist, sumatriptan. METHODS: In this double-blind, randomized, crossover study, 16 adult migraineurs fulfilling International Headache Society (IHS) criteria for migraine with or without aura who had failed to receive adequate relief from triptans treated one migraine with each treatment: sumatriptan 50 mg plus metoclopramide 10 mg or sumatriptan 50 mg plus placebo to match metoclopramide. Patients treated their migraines when they were moderate or severe in intensity and recorded pain severity and symptoms prior to treatment and 30, 60, 90, and 120 minutes and 24 hours after treatment. RESULTS: Thirteen women and 3 men (mean age, 40 years) completed the study; ie, treated 2 migraines (a total of 32 migraines), one attack with each treatment. Meaningful relief was attained in 10 (63%) of 16 migraines treated with the combination of sumatriptan 50 mg plus metoclopramide 10 mg compared with 5 (31%) of 16 migraines treated with sumatriptan 50 mg plus placebo. Headache response (moderate or severe to mild or no pain at 2 hours) was achieved in 7 (44%) of 16 migraines with the combination of sumatriptan 50 mg plus metoclopramide 10 mg compared with 5 (31%) of 16 migraines treated with sumatriptan 50 mg plus placebo. There did not appear to be a difference between treatment groups with respect to associated symptoms. The combination of sumatriptan 50 mg plus metoclopramide 10 mg was well tolerated. CONCLUSIONS: Combining sumatriptan with metoclopramide provided relief in some migraineurs who failed to achieve adequate relief with a triptan alone. It remains unknown whether initiating therapy when pain was mild or using a higher dose of sumatriptan (ie, 100 mg) would have provided additional benefit. Further studies are indicated.     

Marketed oral triptans in the acute treatment of migraine: a systematic review on efficacy and tolerability

BACKGROUND: In the current literature, there is neither a reported systematic review comparing the efficacy of triptans at 30 minutes and 1 hour after the migraine treatment, nor data related to efficacy of new marketed triptans. OBJECTIVE: The main objective of this analysis was to compare the efficacy and tolerability of currently marketed oral, non-reencapsulated triptan formulations vs placebo in the treatment of moderate-to-severe migraine attacks. METHODS: A systematic review of double-blind, randomized clinical trials reporting data after a single migraine attack was conducted. Efficacy results are shown using relative risk ratios with 95% confidence intervals. A sensitivity analysis was also conducted. RESULTS: After reviewing 221 publications, 38 studies were included. All marketed triptans provided significant relief and/or absence of pain at 2 hours, and relief at 1 hour when compared with placebo. After 30 minutes, fast-dissolving sumatriptan 50 and 100 mg, sumatriptan 50 mg, and rizatriptan 10 mg showed significant relief when compared to placebo, whereas the fast-dissolving formulation of sumatriptan 100 mg was the only oral triptan that was superior to placebo in meeting the pain-free endpoint. On the other hand, fast-dissolving sumatriptan 50 and 100 mg and eletriptan 40 mg showed a lower rate of recurrence than placebo, whereas rizatriptan 10 mg was the only triptan with a recurrence rate greater than that of placebo. Adverse events associated with treatment with tablet formulations of sumatriptan and zolmitriptan were significantly more frequent than those of the placebo group. The inclusion of trials with reencapsulated triptans in the analysis introduced minor specific changes in these results. CONCLUSION: This analysis updates the comparative data available for the 7 currently marketed oral triptans and clearly demonstrates their efficacy when compared to placebo, even with stricter endpoints, such as efficacy at 30 minutes. No triptan exhibited better tolerability than placebo. Results are diverse, depending on the triptan, which probably is a reflection of heterogeneous pharmacokinetics.     

Theory-based analysis of clinical efficacy of triptans using receptor occupancy

Background

Triptans, serotonin 5-HT_1B/1D receptor agonists, exert their action by targeting serotonin 5-HT_1B/1D receptors, are used for treatment of migraine attack. Presently, 5 different triptans, namely sumatriptan, zolmitriptan, eletriptan, rizatriptan, and naratriptan, are marketed in Japan. In the present study, we retrospectively analyzed the relationships of clinical efficacy (headache relief) in Japanese and 5-HT_1B/1D receptor occupancy (Φ_1B and Φ_1D). Receptor occupancies were calculated from both the pharmacokinetic and pharmacodynamic data of triptans.

Methods

To evaluate the total amount of exposure to drug, we calculated the area under the plasma concentration-time curve (AUC_cp) and the areas under the time curves for Ф_1B and Ф_1D (AUC_Ф^1B and AUC_Ф^1D). Moreover, parameters expressing drug transfer and binding rates (A _cp , A _Ф ^1B , A _Ф ^1D ) were calculated.

Results

Our calculations showed that Ф_max^1B and Ф_max^1D were relatively high at 32.0-89.4% and 68.4-96.2%, respectively, suggesting that it is likely that a high occupancy is necessary to attain the clinical effect. In addition, the relationships between therapeutic effect and AUC_cp, AUC_Φ^1B, AUC_Φ^1D, and A _cp  · AUC_cp differed with each drug and administered form, whereas a significant relationship was found between the therapeutic effect and A _Φ ^1B  · AUC_Φ^1B or A _Φ ^1D  · AUC_Φ^1D that was not affected by the drug and the form of administration.

Conclusions

These results suggest that receptor occupancy can be used as a parameter for a common index to evaluate the therapeutic effect. We considered that the present findings provide useful information to support the proper use of triptans.     

Sumatriptan 6 mg subcutaneous as an effective migraine treatment in patients with cutaneous allodynia who historically fail to respond to oral triptans

The objective of the study was to assess the efficacy of 6 mg subcutaneous (SC) sumatriptan to treat migraine and the relationship between response of migraine and cutaneous allodynia in a population of migraine patients who historically failed to respond to oral triptan medications. This was an openlabel study consisting of patients with migraines who historically failed to respond to oral triptan medications. Forty-three patients were asked to treat three migraine attacks with 6 mg SC sumatriptan. The primary efficacy endpoint was the percentage of patients achieving relief of headache at 2 h. Ninetyone percent of the patients responded to a single dose of SC sumatriptan 6 mg. Fifty percent of all patients were pain-free by 2 h and over 30% had a 24-h sustained pain-free response. When administered within 90 min from the onset of migraine (i.e., during the developing phase of cutaneous allodynia), SC 6 mg sumatriptan proved to be effective despite the occurrence of allodynia in a group of patients, who historically had failed to respond to oral triptan medications. These findings suggest that the window of opportunity to treat allodynic patients with injectable triptans may be longer (up to 2 h) than with oral triptans (up to 1 h).     

Triptans in clinical practice: the basic scientist’s point of view

Since the observation that sumatriptan, the first triptan to be synthetized as a specific antimigraine compound, was able to block neurogenic inflammation (NI) in intra– and extracranial rat tissues, the experimental model for NI development has been used to predict the efficacy in aborting migraine pain of other compounds with activity on 5-HT1B/1D receptors. Most of the drugs active on 5–HT1 receptors that have been tried in the NI model effectively inhibited or decreased this response, although some of them lack of clinical efficacy on migraine pain, suggesting that pain relief does not correlate with NI blockade. A central pathophysiological mechanism has been advocated since migraine attack is considered to be a discharge from a central “generator”, probably located in the brainstem. The hypothesis is supported by experimental data showing that triptans inhibit excitability of neurons in the trigeminal nucleus caudalis when locally applied. This experimental model does not rule out the involvement of peripheral blockade during migraine attack. Probably, neurophysiological studies in humans provide better information than do experimental animal models about central mechanisms of action of triptans. Receptor pharmacology is also important for understanding beneficial or undesidered side effects other than pain relief. Biochemical studies are therefore needed to better understand how triptans work and to design new abortive or preventive drugs.     

Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium

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

Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT receptor expression and function in rats

Triptans are commonly used anti-migraine drugs and show agonist action mainly at serotonin 5-HT(1B/1D/1F) receptors. It is not known whether frequent or long-term treatment with these drugs would alter 5-HT receptor function. We investigated the effects of protracted (14-18 days) sumatriptan and zolmitriptan treatment in rats on 5-HT(1) receptor mRNA expression and function in tissues related to migraine pathophysiology. RT-PCR analysis revealed that 5-HT(1B/1D/1F) receptor mRNA was reduced in the trigeminal ganglion after treatment with either triptan (reduction by: sumatriptan 39% and zolmitriptan 61% for 5-HT(1B); 60%vs 41% for 5-HT(1D); 32%vs 68% for 5-HT(1F)). Sumatriptan attenuated 5-HT(1D) receptor mRNA by 49% in the basilar artery, whereas zolmitriptan reduced 5-HT(1B) mRNA in this tissue by 70%. No change in 5-HT(1) receptor mRNA expression was observed in coronary artery and dura mater. Chronic triptan treatment had no effect in two functional assays [sumatriptan mediated inhibition (50 mg/kg, i.p.) of electrically induced plasma protein extravasation in dura mater and 5-nonyloxytryptamine-stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding in substantia nigra]. Furthermore, vasoconstriction to 5-HT in isolated basilar artery was not affected by chronic triptan treatment, while it was slightly reduced in coronary artery. We conclude that, although our treatment protocol altered mRNA receptor expression in several tissues relevant to migraine pathophysiology, it did not attenuate 5-HT(1) receptor-dependent functions in rats.     

Sumatriptan (5-HT1B/1D-agonist) causes a transient allodynia

Unpleasant sensory symptoms are commonly reported in association with the use of 5-HT1B/1D-agonists, i.e. triptans. In particular, pain/pressure symptoms from the chest and neck have restricted the use of triptans in the acute treatment of migraine. The cause of these triptan induced side-effects is still unidentified. We have now tested the hypothesis that sumatriptan influences the perception of tactile and thermal stimuli in humans in a randomized, double-blind, placebo-controlled cross-over study. Two groups were tested; one consisted of 12 (mean age 41.2 years, 10 women) subjects with migraine and a history of cutaneous allodynia in association with sumatriptan treatment. Twelve healthy subjects (mean age 38.7 years, 10 women) without migraine served as control group. During pain- and medication-free intervals tactile directional sensibility, perception of dynamic touch (brush) and thermal sensory and pain thresholds were studied on the dorsal side of the left hand. Measurements were performed before, 20, and 40 min after injection of 6 mg sumatriptan or saline. Twenty minutes after injection, sumatriptan caused a significant placebo-subtracted increase in brush-evoked feeling of unpleasantness in both groups (P < 0.01), an increase in brush-evoked pain in migraineurs only (P = 0.021), a reduction of heat pain threshold in all participants pooled (P = 0.031), and a reduction of cold pain threshold in controls only (P = 0.013). At 40 min after injection, no differences remained significant. There were no changes in ratings of brush intensity, tactile directional sensibility or cold or warm sensation thresholds. Thus, sumatriptan may cause a short-lasting allodynia in response to light dynamic touch and a reduction of heat and cold pain thresholds. This could explain at least some of the temporary sensory side-effects of triptans and warrants consideration in the interpretation of studies on migraine-induced allodynia.     

Infrequent or non-response to oral sumatriptan does not predict response to other triptans--review of four trials

A migraineur can claim to be an infrequent responder ('non-responder') to an oral triptan independent of which triptan he or she is presently using. Four trials of an alternative triptan (zolmitriptan/rizatriptan; eletriptan; naratriptan; almotriptan) in patients with a history of infrequent response to oral sumatriptan were compared and contrasted in terms of study design, patient characteristics, and efficacy and tolerability of the triptan under investigation. Unfortunately, none of the reported studies used an appropriate parallel design, which would have had the non-responding triptan (oral sumatriptan) in one arm and without encapsulation. While the four trials differed in terms of study design (open-label vs. placebo-controlled), definition of sumatriptan 'non-responder' (retrospective vs. prospective) and pain intensity at baseline (30% severe to 70% severe), all four demonstrated that lack of response to sumatriptan did not predict lack of response to an alternative triptan. Changing triptans resulted in 2-h pain-relief rates of 25-81% in patients with a history of poor response to sumatriptan. It can be concluded that migraine patients who respond infrequently to sumatriptan should be switched to a different triptan, as lack of response to one triptan does not predict likelihood of responsiveness to another. A review of the available evidence suggests that almotriptan may be one of the most appropriate choices for an alternative triptan.     

Switching patients with migraine from sumatriptan to other triptans increases primary care costs

Treatment of migraine with triptans is highly effective, although cost considerations may prompt a change in therapy. This retrospective database analysis of 3196 patients with migraine, established on sumatriptan therapy, found that 54% of the 292 experiencing a triptan switch returned to sumatriptan within 15 months, suggesting that the alternative was less acceptable. Excluding patients with unusually high use of triptans (> or = 208 tablets/year), switching therapy resulted in a significant increase of pounds sterling 53/patient in total costs, compared with patients continuing on sumatriptan (p = 0.014). Cost savings (pounds sterling 17/patient over 15 months) were observed only among the 41% of patients in whom the initial switch was successful and did not result in a further switch or return to sumatriptan. Among patients who were relatively low cost initially, switching resulted in increased costs, irrespective of the outcome. This study suggests that there is no economic justification for switching from sumatriptan to another triptan.     

Symptomatic pharmacotherapy of migraine.

This review summarizes data on the effectiveness of various symptomatic migraine pharmacotherapies and makes recommendations for treatment. A wide variety of agents are available for the symptomatic treatment of migraine headache, including over-the-counter analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), combination products, opiates, ergot alkaloids, corticosteroids, dopamine antagonists, and triptans. In the stepped-care approach, simple analgesics and NSAIDs are the recommended first step for the treatment of mild-to-moderate migraine headaches. Patients who do not respond to first-step treatments may be given ergots, combination products, dopamine antagonists, or triptans as the second step. Corticosteroids or opiates may be used as rescue treatment in patients who do not respond to second-step treatment. A stratified approach to care individualizes treatment based on the severity of the headache and other patient-specific factors. In a stratified approach, dihydroergotamine or triptans may be the first-step treatment for patients who present with a history of severe migraines that have responded poorly to previous treatments. Sumatriptan was the first triptan approved for the symptomatic treatment of migraine headache; newer triptans include zolmitriptan, naratriptan, and rizatriptan. Since sumatriptan is rapidly absorbed by the subcutaneous route, its time to onset of effect is shortest. Among triptan drugs that are administered orally, the relative time to onset may be shorter with rizatriptan than sumatriptan. Naratriptan has a longer time to onset but is associated with a lower rate of migraine recurrence than other triptans. graine headache, ergot alkaloids, triptans,     

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.     

The role of triptans and analgesics for primary headache treatment

Primary headache especially migraine is very common disorder. The mainstay in the acute treatment of migraine is triptans (sumatriptan, zolmitriptan, eletriptan, naratriptan) and analgesics or NSAIDs. However, it is still unclear the appropriate usage of triptans and analgesics or NSAIDs for migraine treatment. Mild attacks may be managed with analgesics or NSAIDs while severe disabling ones usually respond better to specific antimigraine drugs, triptans. Analgesics or NSAIDs administration is always plagued with the potential of subsequent drug induced headache phenomenon. Therefore usage of analgesics or NSAIDs should be restricted only for young and typical type patients with migraine. As triptan medication method corresponding to various life style, in addition to tablet formulation, there are subcutaneous injector and nasal spray formulation in sumatriptan, rapid melt tablet formulation in zolmitriptan (rapimelt) and naratriptan (rapidisk). These different type of formulation are valuable for patient's needs.     

Difference in triptan effect in patients with migraine and early allodynia

The aim of this study was to determine whether in migraine patients with and without aura early treatment with various triptans leads to differences in pain reduction after 1 h and in modulating cutaneous allodynia. Thirty-six patients with early manifestation of a clinically recognizable allodynia of the face and non-responders to earlier treatment with sumatriptan 100 mg were included. Patients were randomized to six triptan treatment groups. Significant pain reduction was seen only in the group receiving zolmitriptan nasal spray 5 mg with a mean visual analogue scale (VAS) score of 3.8 (s.d. 1.2) at baseline and 2.4 (s.d. 1.3; P = 0.015) at 1 h after using the triptan and was thus a predictor of a VAS score 3 within 1 h. The study results indicate that migraine headache intensity can be reduced within 1 h by using zolmitriptan 5 mg nasal spray in spite of the presence of early cutaneous allodynia.     

Patients’ preference for triptans and other medications as a tool for assessing the efficacy of acute treatments for migraine

Oral triptans are effective and well tolerated acute treatments for migraine, but clinical differences between them are small and difficult to measure in conventional clinical trials. Patient preference assesses a global measure of efficacy and tolerability, and may be a more sensitive means of distinguishing between these drugs. In a series of studies, patients consistently expressed a clear preference for triptans over their usual non–triptan acute medications, e.g., analgesics and ergotamine. Direct comparator studies of patient preference with oral triptans showed that patients could distinguish between different triptans, and between different formulations of the same triptan. Patients could even distinguish between the three oral doses of sumatriptan. The most frequently provided reasons for preference were speed of response and overall effectiveness. Patient preference is a sensitive clinical trial endpoint and physicians should consider using it when reviewing the efficacy of acute migraine medications.     

Pharmacological synergy: the next frontier on therapeutic advancement for migraine

The burden of migraine significantly impacts the individual sufferer, their families, the workplace, and society. The World Health Organization has identified migraine as an urgent public health priority and has initiated a global initiative to reduce the burden of migraine. Underlying the World Health Organization initiative is the need to discover means of optimizing migraine treatments and make them accessible to the broader portion of the world population. Development of acute migraine medications over the past several decades has largely centered on engineering highly specific receptor molecules that alter migraine pathophysiological mechanisms to abort or reverse the acute attack of migraine. The first product of this line of discovery was sumatriptan and heralded as a landmark therapeutic breakthrough. Sumatriptan is a 5-HT-1B/D receptor agonist considered to activate receptors involved in the pathophysiology specific to migraine. Large-scale regulatory/clinical studies demonstrated statistical superiority for sumatriptan over placebo in reduction or elimination of headache, nausea, photophobia, and phonophobia. Since the introduction of sumatriptan, 6 other triptan products have been released in the United States as acute treatments for migraine, all having the same mechanism of action and similar efficacy. Despite their utility as migraine abortive medications, the triptans do not successfully treat all attacks of migraine or necessarily treat all migraine associated symptoms. In fact, in less than 25% of attacks do subjects obtain and maintain a migraine-free response to treatment for at least beyond 24 hours. A wide range of non-triptan medications also have demonstrated efficacy in acute migraine. These include non-steroidal anti-inflammatory drugs (NSAIDs), opioids, phenothiazines, and valproic acid to name a few. Given the distinctly different mechanisms of actions of these various medications, it is likely that several unique pathophysiological mechanisms are involved in terminating acute episodes of migraine. Clinicians now capitalize on this observation and use migraine medication in combination with another to improve patient outcomes, for example, using an antiemetic with an opioid or a triptan and NSAIDs. More recently, the Food and Drug Adminstration has approved a combination product containing 85mg of sumatriptan plus 500mg of naproxen sodium for acute treatment of migraine. Clinical trials conducted prior to approval demonstrated that the combination of sumatriptan and naproxen was more effective as a migraine abortive than either of its components but that each component and the combination were more effective than placebo. Exactly how sumatriptan and naproxen interact to create therapeutic synergism is unknown though its mere occurrence suggests that models assisting medical understanding and prediction of pharmacological synergism may improve clinical outcome over products acting through a single receptor mechanism. Migraine is a syndrome, meaning it is defined by observed symptoms rather than known pathophysiology. Multiple pathogenic mechanisms are likely involved in generating this diverse array of symptoms understood as the migraine symptom complex. Sumatriptan and naproxen have independent mechanisms of action and target distinct aspects of the vascular and inflammatory processes hypothesized to underlie migraine. Sumatriptan acts on the 5-HT(1B) and 5-HT(1D) receptors, whereas naproxen inhibits the COX-1 and COX-2 enzymes. Sumatriptan has vasoconstricting effects as well as effects on neurogenic inflammation by decreasing the release of substance P and calcitonin gene-related peptide. In contrast, naproxen affects prostaglandins and other inflammatory mediators. Because sumatriptan and naproxen both relieve migraine yet interact with different cellular targets within the migraine pathway, it is reasonable to assume there is a unique synergy between these medications that improves treatment outcomes. Clinical trials supported this contention by demonstrating the combination of sumatriptan/naproxen alleviated migraine pain quickly (primarily based on the sumatriptan mechanism of action), and sustained the response longer (primarily based on the naproxen mechanism of action) than is possible when either drug is given alone. The working hypothesis is that when sumatriptan and naproxen are given at the same time, they affect different mechanisms of the migraine pathway and produce an enhanced therapeutic effect. The purpose of this article is to apply statistical analyses to data from phase II and phase III studies of the combination of sumatriptan and naproxen to determine if this enhanced therapeutic effect is synergistic. This methodology of accessing synergy can be used in the development of future combination migraine treatments to improve treatment outcomes.     

The Efficacy of Triptans in Childhood and Adolescence Migraine

Studies on the acute treatment of migraine in children and adolescents are rare and difficult to design. In particular, the high placebo response in some trials makes it difficult to prove efficacy of a verum drug. All available placebo-controlled trials on the acute migraine treatment in children and adolescents with a triptan were analyzed with respect to different end points (rate of pain free and pain relief at 2 hours; rate of adverse events). We identified 6 crossover and 11 parallel group trials. Although the trials were heterogenous with respect to the triptans and the dosage, pooled data were calculated. The pooled responder rate of triptans for 2 hours pain free was 36.0 % in crossover trials (significant difference to placebo with 17.7 %) and 32.5 % in parallel group trials (significant difference to placebo with 26.3 %). Triptans also showed a significantly higher pain relief rate at 2 hours than placebo both in crossover and parallel group trials. The rate of adverse events was significantly higher after triptans than after placebo. However, triptans were well tolerated in all trials. At least 1 trial with significant efficacy was found for sumatriptan (10–20 mg nasal spray), zolmitriptan (2.5–5 mg tablet), rizatriptan (5–10 mg tablet), and almotriptan (12.5–25 mg tablet). Placebo rates for efficacy were considerably lower in crossover trials than in parallel group trials. This analysis suggests that parallel group trials on the acute treatment of migraine in children and adolescents with a triptan show a very low therapeutic gain because of a high placebo rate. The verum response rates, however, are very similar to those seen in adulthood trials. However, there is sufficient evidence that at least some triptans are efficacious even in childhood and adolescence.     

Naratriptan: an alternative for migraine.

OBJECTIVE: To critically evaluate the literature regarding naratriptan's clinical pharmacology, efficacy, safety, and indications. DATA SOURCE: A MEDLINE search was conducted for the period from January 1990 to June 1998. Key words used included naratriptan, triptan, serotonin agonists, migraine, and migraine therapy. In addition, pertinent references cited in articles obtained from MEDLINE and product information for triptans were reviewed. STUDY SELECTION AND DATA EXTRACTION: All original and review articles and abstracts pertaining to naratriptan were reviewed, as were product information extracts. Clinical trials of naratriptan were critically reviewed and compared with pertinent clinical trials of other oral triptans. DATA SYNTHESIS: The treatment of migraine has been dramatically improved with the use of sumatriptan, other triptans, and serotonin-receptor subtype 1B and 1D agonists. Drawbacks to these medications, however, have included poorly tolerated adverse effects and the recurrence of the migraine. Naratriptan has been recently approved for acute oral migraine therapy. In two Phase III trials of naratriptan compared with placebo, relief at four hours was obtained in 60% and 68% of patients using the 2.5-mg dose, with recurrence of headache in 24 hours in 27% and 28% of patients. The data on migraine recurrence were similar to those of other oral triptans; the efficacy of naratriptan at two hours was not specifically analyzed. Adverse effects of naratriptan were similar to placebo, and its tolerability seemed superior compared with studies of other oral triptans. CONCLUSIONS: Naratriptan is a promising new oral therapy for acute migraine; it may successfully treat patients who poorly tolerate other triptan therapies or have longer duration migraine headaches.