Efficacy and safety of MAP0004, orally inhaled DHE in treating migraines with and without allodynia.

BACKGROUND: Central sensitization develops once migraine attacks become established and can be clinically detected by the development of cutaneous allodynia. The efficacy of triptans for migraine resolution has been shown to be markedly reduced when administered in patients with established cutaneous allodynia. OBJECTIVE: The study aimed to evaluate the efficacy and safety of MAP0004, a novel, orally inhaled, form of dihydroergotamine, in patients with and without cutaneous allodynia at the time of treatment. METHODS: This evaluation was a post hoc subanalysis of a randomized, double-blind, placebo-controlled, 2-arm, phase 3, multicenter study. The presence or absence of baseline cutaneous allodynia at the time of drug administration was based on the response to a standard questionnaire. Treatment efficacy at 2 hours posttreatment was compared in patients with and without baseline allodynia. RESULTS: At the time of treatment, allodynia was present in 216 patients treated with MAP0004 and 202 patients treated with placebo. MAP0004 treatment efficacy was superior to placebo, as measured by 2-hour pain relief for patients with and without allodynia (P < .0001) and as measured by 2-hour pain freedom for patients with (P < .0001) and without (P < .0002) allodynia. No significant within-treatment differences after treatment with MAP0004 in patients with and without allodynia at baseline were observed. Patients were more likely to be allodynia-free after treatment with MAP0004 compared with placebo (73% vs 66%, P = .0013). Furthermore, treatment with MAP0004 prevented the development of allodynia in patients not experiencing allodynia at baseline (P = .0057). MAP0004 was generally well tolerated. CONCLUSIONS: This post hoc subanalysis shows that MAP0004 was similarly effective in patients whether or not allodynia was present at treatment baseline. Patients were also more likely to be allodynia-free following treatment of a migraine with MAP0004.

Randomized, controlled study of telcagepant in patients with migraine and coronary artery disease.

OBJECTIVE: To evaluate the efficacy of telcagepant in patients with migraine and coronary artery disease. BACKGROUND: Calcitonin gene-related peptide receptor antagonists, such as telcagepant, may be useful for acute migraine treatment in patients with cardiovascular disease, a population for whom triptans are contraindicated. METHODS: Randomized, double-blind, two-period (6 weeks per period) crossover study in patients with stable coronary artery disease and migraine. Patients were randomized 1:1 to either: (1) Period 1: telcagepant (280-mg tablet/300-mg capsule), Period 2: acetaminophen (1000-mg); or (2) Period 1: placebo for attack 1 then acetaminophen for subsequent attacks, Period 2: telcagepant. Patients could treat up to 12 migraine attacks per period to assess the tolerability of telcagepant. The primary efficacy analysis evaluated telcagepant vs placebo on 2-hour pain freedom during the first attack of Period 1. RESULTS: One hundred and sixty-five of the planned 400 patients were enrolled, and 114 took at least one dose of treatment. Telcagepant was not statistically different from placebo for 2-hour pain freedom (25.0% vs 18.9%, odds ratio = 1.62 [95% confidence interval: 0.62, 4.25]). The median number of attacks treated per period was 3. No cardiovascular thrombotic adverse events occurred within 14 days of dosing. CONCLUSION: The study was underpowered due to enrollment difficulties and did not demonstrate a significant efficacy difference between telcagepant and placebo for the treatment of a migraine attack in patients with stable coronary artery disease. Telcagepant was generally well tolerated for acute intermittent migraine treatment in these patients.

Topiramate intervention to prevent transformation of episodic migraine: the topiramate INTREPID study.

OBJECTIVE: The study sought to evaluate whether topiramate prevents development of chronic daily headache (CDH, ≥15 headache days per month) in adult subjects with high-frequency episodic migraine (HFEM, 9-14 migraine headache days/month). A secondary objective was to assess the efficacy of topiramate as preventive migraine treatment in this population. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study comparing topiramate 100 mg/day and placebo for 26 weeks. The primary efficacy variable was new-onset CDH at month 6. Secondary efficacy measures included migraine and headache days. Adverse events (AEs) were evaluated. RESULTS: A total of 159 topiramate subjects and 171 placebo subjects were efficacy-evaluable. At month 6, 1.4% of topiramate subjects versus 2.3% of placebo subjects had CDH (p = .589). Compared with placebo, topiramate treatment was associated with statistically significant reductions in mean number of migraine days (6.6 vs. 5.3/28 days; p = .001) and headache days (6.6 vs 5.3/28 days; p = .001). Most commonly reported AEs in the topiramate versus placebo group included paresthesia (32.4% vs. 7.0%), fatigue (14.8% vs. 8.6%), dizziness (11.4% vs. 7.6%) and nausea (10.8% vs. 9.2%). CONCLUSION: Topiramate 100 mg/day did not prevent the development of CDH at six months in subjects with HFEM. Topiramate was effective in reducing headache days and migraine headache days and generally well tolerated.

Pathophysiology of chronic migraine and mode of action of preventive medications.

Evidence has accumulated in recent years indicating structural, physiologic, and biochemical alterations in the brain of patients with chronic migraine (CM). Altered pharmacologic responses to opioids and other analgesics have also been reported. Structural or morphologic changes include reduced cortical gray matter of the pain processing areas of the brain and iron accumulation in the periaqueductal gray matter (PAG), red nucleus, and basal ganglia structures. These changes correlate with the duration of migraine disorder and, therefore, are more marked in CM compared to episodic migraine (EM). A dysmodulation of trigeminovascular nociception resulting from changes in PAG may be an important factor in the pathophysiology of CM. Even though the pathophysiology and significance of subcortical white matter lesions and infarct like cerebellar lesions are not fully understood, their occurrence in patients with frequent migraine is further evidence of structural alterations in the brain in CM. Physiologic changes in CM are altered brain metabolism, excitability, and central sensitization of nociceptive pathways. CM is associated with alterations in the brain metabolism confirmed by positron emission tomography (PET) studies. Of special interest is the reversible hypometabolism in the insula, thalamus, anterior cingulate, and parietal lobe and sustained hypometabolism in the orbitofrontal cortex in medication overuse headache. Cortical excitability is increased in CM compared to EM, as confirmed by magnetic suppression of visual accuracy. Cutaneous allodynia, which is more often seen in CM, is a marker of central sensitization. Central sensitization generates free radicals that damage PAG. Cutaneous allodynia is correlated with frequency of migraine attacks and duration of migraine illness. Chronically sensitized central nociceptive neurons may account for CM and its resistance to treatment. Alterations in central glutamate neurotransmission have been reported in the anterior cingulate and insula using magnetic resonance spectroscopy. Medications affecting central glutamatergic neurotransmission may have a potential therapeutic role in CM. Frequent use of opioids and analgesics in EM leads to CM. Opioid-induced hyperalgesia, recognized in recent years, can lead to intractability of migraine. Better understanding of the pathophysiology of CM should lead to better ways to treat these patients. The various effective preventive agents used in migraine prophylaxis, such as topiramate, valproate, ß-blockers, and tricyclic antidepressants, appear to have a common effect of suppressing cortical excitability (cortical spreading depression). Suppression of cortical spreading depression by these agents is correlated with the dosages and the duration of treatment. The beneficial effect of botulinum toxin in CM may be due to its antinociceptive effect. Changes in the glutamate and calcitonin gene-related peptide at the peripheral nerve endings reduce peripheral sensitization, which eventually leads to reduced central sensitization.

Quantifying the return of headache in triptan-treated migraineurs: an observational study.

To improve understanding of secondary treatment failure in migraine patients, we evaluated 'headache return' as a novel endpoint to assess returning headaches according to their severity, expanding on current standard assessments of overall recurrence or relapse rates, in a six-month observational study of triptan-treated migraineurs. A total of 359 patients (91% female; mean age, 42.5 years) recorded data for 2168 headaches in electronic diaries. Two-thirds of headaches responded to triptan treatment (improved-to-mild or no pain two hours post-dose); 34% of headaches had a pain-free response. By 48 hours post-dose, 19% of all responding headaches returned; 24% of headaches achieving a pain-free response returned, predominantly to mild pain. More severe baseline headache, short duration since diagnosis of migraine, and female gender were associated with increased likelihood of headache return. Treatment satisfaction declined with increasing severity of headache return, demonstrating the value of assessing headache return by severity to fully evaluate its impact.

A practice guide for continuous opioid therapy for refractory daily headache: patient selection, physician requirements, and treatment monitoring.

OBJECTIVES: To provide a guide to the use and limitations of continuous opioid therapy (COT, or daily scheduled opioids) for refractory daily headache, based on the best available evidence and expert clinical experience. BACKGROUND: There has been a dramatic increase in opioid administration over the past 25 years, with limited evidence of efficacy for either pain reduction or increased function, and increasing evidence of adverse effects, including headache chronification. To date, there has been no consensus on headache-specific guidelines for selecting patients for COT, physician requirements, and treatment monitoring. METHODS: A multidisciplinary committee of physicians and allied health professionals with extensive experience and expertise in the administration of opioids to headache patients, undertook a review of the available evidence from the research and clinical literature (using the PubMed database for articles through December 2009) to develop headache-specific treatment recommendations. This guide reflects the opinions of its authors and is not an official document of the American Headache Society. RESULTS: The guide identifies factors that would qualify or disqualify the use of COT, including, determination of intractability prior to initiating COT, requisite experience of the prescriber, and requirements for a formal monitoring system to assess appropriate use, safety, efficacy, and functional impact. An appendix reviews the available evidence for efficacy of COT in chronic headache and noncancer pain, paradoxical effects (opioid-induced hyperalgesia, medication overuse headache, opioid-related reduction in triptan and nonsteroidal anti-inflammatory drug efficacy), other adverse effects (nausea and constipation, insomnia and sleep apnea, respiratory depression and sudden cardiac death, reductions in sex hormones, issues during pregnancy, neurocognitive functioning), and issues related to comorbid psychiatric disorders. CONCLUSIONS: Only a select and very limited group (estimate of 10-20%) of refractory headache patients who meet criteria for COT respond with convincing headache reduction and functional improvement over the long-term. Conservative and empirically based guidelines will help identify those patients for whom a COT trial may be appropriate, while protecting their welfare and safety.

A double-blind comparison of onabotulinumtoxina (BOTOX) and topiramate (TOPAMAX) for the prophylactic treatment of chronic migraine: a pilot study.

BACKGROUND: There is a need for effective prophylactic therapy for chronic migraine (CM) that has minimal side effects. OBJECTIVE: To compare the efficacy and safety of onabotulinumtoxinA (BOTOX), Allergan, Inc., Irvine, CA) and topiramate (TOPAMAX), Ortho-McNeil, Titusville, NJ) prophylactic treatment in patients with CM. METHODS: In this single-center, double-blind trial, patients with CM received either onabotulinumtoxinA, maximum 200 units (U) at baseline and month 3 (100 U fixed-site and 100 U follow-the-pain), plus an oral placebo, or topiramate, 4-week titration to 100 mg/day with option for additional 4-week titration to 200 mg/day, plus placebo saline injections. OnabotulinumtoxinA or placebo saline injection was administered at baseline and month 3 only, while topiramate oral treatment or oral placebo was continued through the end of the study. The primary endpoint was treatment responder rate assessed using Physician Global Assessment 9-point scale (+4 = clearance of signs and symptoms and -4 = very marked worsening [about 100% worse]). Secondary endpoints included the change from baseline in the number of headache (HA)/migraine days per month (HA diary), and HA disability measured using Headache Impact Test (HIT-6), HA diary, Migraine Disability Assessment (MIDAS) questionnaire, and Migraine Impact Questionnaire (MIQ). The overall study duration was approximately 10.5 months, which included a 4-week screening period and a 2-week optional final safety visit. Follow-up visits for assessments occurred at months 1, 3, 6, and 9. Adverse events (AEs) were documented. RESULTS: Of 60 patients randomized to treatment (mean age, 36.8 +/- 10.3 years; 90% female), 36 completed the study at the end of the 9 months of active treatment (onabotulinumtoxinA, 19/30 [63.3%]; topiramate, 17/30 [56.7%]). In the topiramate group, 7/29 (24.1%) discontinued study because of treatment-related AEs vs 2/26 (7.7%) in the onabotulinumtoxinA group. Between 68% and 83% of patients for both onabotulinumtoxinA and topiramate groups reported at least a slight (25%) improvement in migraine; response to treatment was assessed using Physician Global Assessment at months 1, 3, 6, and 9. Most patients in both groups reported moderate to marked improvements at all time points. No significant between-group differences were observed, except for marked improvement at month 9 (onabotulinumtoxinA, 27.3% vs topiramate, 60.9%, P = .0234, chi-square). In both groups, HA/migraine days decreased and MIDAS and HIT-6 scores improved. Patient-reported quality of life measures assessed using MIQ after treatment with onabotulinumtoxinA paralleled those seen after treatment with topiramate in most respects. At month 9, 40.9% and 42.9% of patients in the onabotulinumtoxinA and topiramate groups, respectively, reported > or =50% reduction in HA/migraine days. Forty-one treatment-related AEs were reported in 18 onabotulinumtoxinA-treated patients vs 87 in 25 topiramate-treated patients, and 2.7% of patients in the onabotulinumtoxinA group and 24.1% of patients in the topiramate group reported AEs that required permanent discontinuation of study treatment. CONCLUSIONS: OnabotulinumtoxinA and topiramate demonstrated similar efficacy in the prophylactic treatment of CM. Patients receiving onabotulinumtoxinA had fewer AEs and discontinuations.

Evaluation of carisbamate for the treatment of migraine in a randomized, double-blind trial.

OBJECTIVE: This study explored the dose-response relationship of carisbamate administered at doses of 100 mg per day, 300 mg per day, or 600 mg per day, in the prevention of migraine. BACKGROUND: Carisbamate ([S]-2-O-carbamoyl-1-o-chlorophenyl-ethanol; RWJ 333369) is a new chemical entity being studied for efficacy as adjunctive therapy in partial onset epilepsy. Because some antiepileptic drugs are also efficacious in migraine, for example, topiramate and valproate sodium, we tested carisbamate in migraine prophylaxis. DESIGN/METHODS: This was a double-blind, placebo-controlled trial, approximately 22-week duration. The primary efficacy variable was the percent reduction from baseline through the double-blind phase in average monthly migraine frequency using a 48-hour rule. Patients were randomized 1 : 1 : 1 : 1 to treatment with carisbamate 100, 300, or 600 mg per day, or placebo. Migraine attacks were counted during a prospective 4-week baseline period, which was followed by a 2-week titration period, a 12-week maintenance period, a 1-week medication reduction period, and a 3-week observation period. Patients had an established history of migraine, with or without aura, for at least 1 year and a 3-month history of 3-12 migraine attacks per month. RESULTS: Patients (n = 323) were predominantly women (85%) and white (89%); mean age was 41 years. There were no statistically significant differences between any of the carisbamate groups and placebo (P > or = .6) for the median (range) percentage reduction from baseline to end point in average monthly migraine frequency (P value vs placebo): 37% (-250%, 100%) for placebo; 33% (-210%, 100%; P = .7) CRS 100 mg/day; 27% (-100%, 100%; P = .8) CRS 300 mg/day; and 35% (-87%, 100%; P = .6) CRS 600 mg/day. Results for secondary efficacy measures (responder rate, percent reduction in average monthly migraine frequency using the 24-hour rule, and percent reduction in average monthly migraine days) were consistent (P > or = .075). The proportion of patients discontinuing because of adverse events was similar for placebo and carisbamate-treated patients (13% each). The most common (occurring in > or =5% of patients) treatment-emergent adverse events in patients treated with carisbamate were fatigue (17%) and nasopharyngitis (13%). Fatigue appeared to be dose related. CONCLUSIONS: Carisbamate was not more efficacious in migraine prophylaxis than placebo in this well-controlled study that included a suitable population. However, carisbamate monotherapy was well tolerated at doses up to 600 mg per day.

Fixed-dose sumatriptan and naproxen in poor responders to triptans with a short half-life.

OBJECTIVE: To evaluate efficacy and tolerability of a single, fixed-dose tablet of sumatriptan 85 mg/naproxen sodium 500 mg (sumatriptan/naproxen sodium) vs placebo in migraineurs who had discontinued treatment with a short-acting triptan because of poor response or intolerance. BACKGROUND: Triptan monotherapy is ineffective or poorly tolerated in 1 of 3 migraineurs and in 2 of 5 migraine attacks. In April, 2008, the Food and Drug Administration approved the combination therapy sumatriptan/naproxen sodium, developed specifically to target multiple migraine mechanisms. This combination product offers an alternative migraine therapy for patients who have reported poor response or intolerance to short-acting triptans. METHODS: Two replicate, randomized, multicenter, double-blind, placebo-controlled, 2-attack crossover trials evaluated migraineurs who had discontinued a short-acting triptan in the past year because of poor response or intolerance. Patients were instructed to treat within 1 hour and while pain was mild. RESULTS: Patients (n = 144 study 1; n = 139 study 2) had discontinued an average of 3.3 triptans before study entry. Sumatriptan/naproxen sodium was superior (P < .001) to placebo for 2- through 24-hour sustained pain-free response (primary end point) (study 1, 26% vs 8%; study 2, 31% vs 8%) and pain-free response 2 hours post dose (key secondary end point) (study 1, 40% vs 17%; study 2, 44% vs 14%). A similar pattern of results was observed for other end points that evaluated acute (2- or 4-hour), intermediate (8-hour), or 2- through 24-hour sustained response for migraine (ie, pain and associated symptoms), photophobia, phonophobia, or nausea (with the exception of nausea 2 and 4 hours post dose). The percentage of patients with at least 1 adverse event (regardless of causality) was 11% with sumatriptan/naproxen sodium compared with 4% with placebo in study 1 and 9% with sumatriptan/naproxen sodium compared with 5% with placebo in study 2. Only 1 adverse event in 1 study was reported in > or =2% of patients after treatment with sumatriptan/naproxen sodium and reported more frequently with sumatriptan/naproxen than placebo: chest discomfort was reported in 2% of subjects in study 1, and no events met this threshold in study 2. No serious adverse events attributed to study medication were reported in either study. CONCLUSION: In migraineurs who reported poor response to a short-acting triptan, sumatriptan/naproxen sodium was generally well tolerated and significantly more effective than placebo in conferring initial, intermediate, and sustained efficacy for pain and migraine-associated symptoms of photophobia and phonophobia.

Topiramate treatment of chronic migraine: a randomized, placebo-controlled trial of quality of life and other efficacy measures.

OBJECTIVE: To define yet more clearly the utility of topiramate in the treatment of chronic migraine, we evaluated prespecified secondary endpoints from a recent randomized, double-blind, placebo-controlled, multicenter clinical trial. BACKGROUND: We previously reported that topiramate 100 mg per day produced a statistically significant reduction in mean monthly migraine/migrainous and migraine headache days compared with placebo treatment and that it was safe and generally well tolerated. METHODS: Variables analyzed included between-treatment group differences in percent responders, change in the mean monthly rate of total headache days and headache-free days, change in average and worst daily headache severity, change in the mean monthly use of acute headache medications, and absolute change and percent change in a headache index. Additional analyses included evaluation of changes in: the associated symptoms of photophobia, phonophobia, and nausea; Migraine-Specific Quality of Life Questionnaire scores; Migraine Disability Assessment Scale scores; and Physician's and Subjects Global Impression of Change. RESULTS: The intent-to-treat population consisted of 306 patients (topiramate, n = 153; placebo, n = 153). Categorical responder rates of reductions in mean monthly migraine/migrainous days for topiramate- vs placebo-treated subjects were as follows: for > or =25% reduction: 68.6% vs 51.6% (P = .005); > or =50%: 37.3% vs 28.8% (P = .093); and > or =75%: 15.0% vs 9.2% (P = .061). The decrease in mean monthly total headache days and headache-free days for topiramate vs placebo treatment was 5.8 vs 4.7 days (P = .067). Compared with placebo, topiramate treatment resulted in statistically significant mean improvements in the Role Restrictive (P = .028) and Emotional Function (P = .036) domains of the Migraine-Specific Quality of Life Questionnaire, in the worst daily severity of migraine (P = .016), severity of photophobia (P = .032), frequency of vomiting (P = .018), photophobia (P = .038), phonophobia (P = .010), unilateral pain (P = .015), pulsatile pain (P = .023), and pain worsened because of physical activity (P = .047). In addition, there were trends observed (favoring topiramate) in average daily severity of migraine (P = .077), acute headache medication use (P = .127), severity of nausea (P = .098), frequency of nausea (P = .166), the Role Preventive domain of the Migraine-Specific Quality of Life Questionnaire (P = .061), and severity of phonophobia (P = .062). CONCLUSIONS: In addition to significantly reducing mean monthly migraine/migrainous and migraine headache days, treatment of chronic migraine with topiramate was effective with regard to several traditionally important and clinically relevant secondary outcomes in migraine prevention trials. Treatment with topiramate was well tolerated and not associated with serious adverse events.

Allodynia-associated symptoms, pain intensity and time to treatment: predicting treatment response in acute migraine intervention.

OBJECTIVE: To evaluate the relationship between treatment outcomes and allodynia-associated symptoms (AAS) at the time of treatment with almotriptan. METHODS: Analyses were performed with data collected prospectively from patients in 2 recently completed early intervention trials, AXERT Early miGraine Intervention Study (AEGIS) and AXERT 12.5 mg time vs Intensity Migraine Study (AIMS): 2-hour pain free, 2-hour pain relief (AEGIS only), sustained pain free (SPF), use of rescue medication, and median headache duration (AIMS only), in the presence and absence of pretreatment AAS, which was determined by responses to a questionnaire. Analyses were conducted to evaluate possible prognostic variables. RESULTS: The presence of pretreatment AAS did not have a significant effect on 2-hour pain-free, 2-hour pain-relief or SPF rates, use of rescue medication, or headache duration. Significant factors for most favorable outcomes (greater 2-hour pain-free, 2-hour pain-relief and SPF rates, less use of rescue medication, and shorter headache duration) included treatment with almotriptan 12.5 mg, treatment of mild or moderate headache pain, and treatment within 1 hour of headache onset. CONCLUSION: Almotriptan 12.5 mg was efficacious in providing 2-hour pain free, 2-hour pain relief, SPF, and reducing rescue medication use irrespective of the presence of AAS at the time of treatment. The most optimal efficacy outcomes occurred when patients treated migraine attacks early and before the onset of severe pain. The presence of AAS, which may indicate an early phase of allodynia, did not influence the efficacy of almotriptan therapy.

American headache through the decades: 1950 to 2008.

As the American Headache Society approaches its 50th anniversary, it seems worthwhile to step back and survey the many changes in the headache field since the 1950s. Many, perhaps most, of the trends, ideas, and changes we review in this article cannot easily be assigned to a particular decade but we have nonetheless chosen a by-the-decade format because it is a familiar and useful way of understanding history. Our focus is on events in the United States and the American Headache Society; space and the need to limit the scope of the article preclude a full description of the many parallel and influential trends, personalities, and ideas in other parts of the world or in other professional organizations. The authors hope you will find this summary of American Headache Medicine in the last half of the 20th and the beginning of the 21st centuries entertaining and educational.

Rational combination therapy in refractory migraine.

Refractory migraine (RM) headaches pose important treatment challenges to the patients who live with them and the clinicians who try to treat them. Defined based on the lack of response to acute, preventive, and nonpharmacologic treatment, RM is often treated with a combination of treatments. Although combination therapy for RM has not been systematically studied in randomized trials, clinical experience suggests that a rational approach to RM treatment, utilizing a combination of treatments, may be effective where monotherapy has failed. In this article we briefly identify patient populations appropriate for more aggressive migraine prevention with combination therapy. We then discuss modifiable risk factors and comorbidities in migraine and then focus on the use of rational combination therapy, as well as the duration migraine preventatives should be considered for use. Future research is needed to evaluate the full potential of rational combination treatment as a strategy for treating and ultimately preventing RM.

Efficacy and tolerability of almotriptan in adolescents: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To assess the efficacy and safety of almotriptan 6.25 mg, 12.5 mg, and 25 mg vs placebo for acute migraine treatment in adolescents. PATIENTS AND METHODS: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 866 patients aged 12 to 17 years with a >1 year history of migraine (per International Headache Society criteria) were randomized to treat one migraine headache with almotriptan 6.25 mg, 12.5 mg, 25 mg, or placebo. The primary efficacy endpoint was headache pain relief 2 hours after dosing, adjusted for baseline severity, with absence of nausea, photophobia, and phonophobia 2 hours after dosing as coprimary endpoints. RESULTS: The 2-hour pain-relief rate was significantly higher with almotriptan 25 mg compared with placebo (66.7% vs 55.3%; P = .022). The incidence of nausea, photophobia, and phonophobia at 2 hours (adjusted for baseline pain intensity) for the almotriptan 25 mg and placebo groups was not significantly different. The 2-hour pain-relief rates (unadjusted) were significantly higher with almotriptan 6.25 mg (71.8%), 12.5 mg (72.9%), and 25 mg (66.7%) than with placebo (55.3%; P = .001, P < .001, and P = .028, respectively). Rates for sustained pain relief also were significantly greater with almotriptan 6.25 mg (67.2%), 12.5 mg (66.9%), and 25 mg (64.5%) than with placebo group (52.4%), P < .01 for the 6.25- and 12.5-mg doses and P < .05 for the 25-mg dose. Age group subanalysis demonstrated significantly greater 2-hour pain-relief rates with all 3 doses of almotriptan compared with placebo for patients aged 15 to 17 years, a significantly lower incidence of photophobia and phonophobia at 2 hours with almotriptan 12.5 mg compared with placebo for patients aged 15 to 17 years, and a significantly lower incidence of photophobia with almotriptan 12.5 mg compared with placebo for those aged 12 to 14 years. Almotriptan treatment was well tolerated, with the most common adverse events (>2%) of nausea, dizziness, and somnolence. CONCLUSIONS: Oral almotriptan was efficacious for relieving migraine headache pain in adolescents, with the 12.5-mg dose associated with the most favorable efficacy profile with respect to relieving headache pain and associated symptoms of migraine (photophobia and phonophobia). Almotriptan treatment was well tolerated in this adolescent population.

Evaluating the triptans.

The debilitating effect of migraine has fueled the search for more specific agents to treat its characteristic and associated symptoms. Second-generation oral triptans have shown an improved efficacy profile in comparison with the pioneer sumatriptan and with the over-the-counter medications and prescription analgesics that have been staples of migraine treatment. Although all triptans exert effects through the 5-hydroxytryptamine 1B/1D receptors, each triptan has distinctive pharmacokinetic properties that determine its efficacy and tolerability profile. Empirical findings based on clinical trials have led to associations between triptan pharmacology and efficacy. With the expanded treatment choices, the onus is on healthcare providers (especially primary care physicians, who see the majority of patients with migraine) to determine which treatment has an efficacy profile that best suits the individual patient's needs. Patients prefer pharmacotherapy with a rapid onset of action that facilitates complete pain relief and no recurrence. Data from published comparator trials, based on commonly used efficacy end points and pharmacokinetic properties underlying patient-preferred outcomes, are reviewed in this article.

Speed of onset, efficacy and tolerability of zolmitriptan nasal spray in the acute treatment of migraine: a randomised, double-blind, placebo-controlled study.

INTRODUCTION: Migraine is a common, disabling condition that has a significant impact on patients and relatives, and is a considerable economic burden on society. Migraine patients want fast-acting treatments with high efficacy. Previous studies have demonstrated that orally administered formulations of zolmitriptan are rapidly and highly effective in the acute treatment of migraine. The objective of this study was to assess the efficacy, speed of onset and tolerability of the nasal spray formulation of zolmitriptan in migraine treatment. METHODS: This multicentre, randomised, double-blind study recruited 2122 patients (aged 18-65 years) who had an established diagnosis of migraine (according to International Headache Society criteria), with or without aura. Patients were randomised to receive zolmitriptan 5mg nasal spray or placebo to treat up to two migraine attacks within 15 minutes of headache pain becoming moderate or severe. The primary endpoint was headache response (reduction in migraine pain from severe/moderate to mild/none) at 2 hours, 1 hour, 30 minutes and 15 minutes post-dose (analysed using a step-down approach). Secondary endpoints included headache response at 4 hours, pain-free rates at 30 minutes and 1, 2 and 4 hours, and sustained headache response and pain-free status at 24 hours post-dose. RESULTS: The headache response rate at 2 hours post-dose was 66.2% for the zolmitriptan group, compared with 35.0% for the placebo group (p < 0.001). Zolmitriptan nasal spray also produced significantly higher headache response rates than placebo at all earlier timepoints assessed, starting as early as 15 minutes post-dose (p < 0.001). Similar results were obtained for the analysis of the first attack. Significantly higher pain-free rates were obtained with zolmitriptan nasal spray, compared with placebo, from 15 minutes post-dose onward (p < 0.005). Zolmitriptan nasal spray was also significantly superior to placebo for headache response at 4 hours, sustained headache response at 24 hours and sustained pain-free rate at 24 hours. Zolmitriptan nasal spray was well tolerated, with most adverse events being of short duration and mild or moderate intensity. CONCLUSIONS: Zolmitriptan nasal spray is highly effective in the acute treatment of migraine and has a very fast onset of action, producing significant headache response and pain-free rates as early as 15 minutes post-dose (the earliest assessment in this study). In addition to the very fast onset of action, zolmitriptan nasal spray produced significantly higher sustained headache response and pain-free rates at 24 hours post-dose compared with placebo. These desirable efficacy outcomes were combined with good tolerability.

Sarcomatous Carcinoma of the Orbit: A Case Report and Review of the Literature.

Sarcomatous carcinomas (SCs) are rare tumours that contain malignant cells with epithelial and mesenchymal characteristics. SC rarely presents in the head and neck, and occurs even less often in the orbit. Only 8 cases of SCs located in the orbit or affecting the globe function have been described in the English literature. Here, we report a case of SC affecting the right orbit. SC is associated with a poor prognosis and advanced disease at presentation. Diagnosis is difficult, as histology often fails to definitively identify SC, necessitating a wide panel of molecular/immunological markers. Treatment options are generally aggressive but risky, and frequently yield poor results. Due to the rarity of SC, there has been little focus on the development of improved treatment options.

Intranasal civamide for the treatment of episodic cluster headaches.

OBJECTIVE: To evaluate the safety and efficacy of intranasal civamide solution for preventive treatment during an episodic cluster headache period. SUBJECTS AND METHODS: This was a multicenter, double-blind, randomized, vehicle-controlled study with a 7-day treatment period and a 20-day posttreatment period performed at 14 headache/neurology centers in the United States. Twenty-eight subjects were randomized to receive civamide or its vehicle in a 2:1 ratio; 18 received civamide and 10 received the vehicle. Subjects received 100 microL of 0.025% civamide (25 microg) or 100 microL of the vehicle to each nostril via dropper once daily for 7 days. The total daily dose of civamide was 50 microg. MAIN OUTCOME MEASURES: The number of cluster headaches per week during the treatment and posttreatment periods, pain intensity, presence of associated symptoms, and the incidence of adverse events were assessed. RESULTS: Subjects in the civamide group had a significantly greater percent decrease in the number of headaches from baseline to posttreatment during days 1 through 7 (-55.5% vs -25.9%; P =.03) and a trend toward significance during days 8 through 14 (-66.9% vs -32.3%; P =.07) and days 15 through 20 (-70.6% vs -34.9%; P =.07), as well as a near-significant decrease during the entire posttreatment period (days 1 through 20 [P =.054]) compared with the vehicle group. There were larger decreases in the number of headaches per week during the posttreatment period in the civamide-treated group, with trends toward significance during posttreatment days 8 through 14 (-8.6 vs -3.6; P =.09) and days 15 through 20 (-8.9 vs -3.6; P =.07). There were no significant differences between groups in cluster headache pain intensity, number of severe headaches, or associated symptoms. The most common adverse events included nasal burning (14 of 18 civamide-treated subjects, 1 of 10 vehicle-treated subjects; P =.001) and lacrimation (9 of 18 civamide-treated subjects, 0 of 10 vehicle-treated subjects; P =.01). CONCLUSION: Intranasal civamide solution at a dose of 50 microg may be modestly effective in the preventive treatment of episodic cluster headache.

Use of rescue medication in trials of almotriptan versus placebo in the treatment of acute migraine.

BACKGROUND: Almotriptan malate is a recently marketed triptan for the treatment of acute migraine. Results from controlled clinical trials demonstrate efficacy superior to placebo and an adverse event rate comparable to that with placebo. OBJECTIVE: The goal of this study was to assess the effect of oral almotriptan on the use of rescue medication in the treatment of acute migraine attacks. METHODS: Three Phase II and III, placebo-controlled, randomized, double-blind studies of almotriptan used as the basis for regulatory approval of the drug were included in the analysis. Two studies (1 single dose, 1 multiple dose) assessed almotriptan 6.25 mg and 12.5 mg and a third compared almotriptan 12.5 mg and sumatriptan 100 mg. Primary results from all 3 trials were previously published. Rescue medication was permitted if migraine pain had not decreased to mild severity or to no pain at 2 hours after study medication. The primary end point of this analysis was use of rescue medication. RESULTS: A total of 1777 patients were included in the analysis. Mean patient age ranged from 39.4 to 44.0 years; approximately 87% were women, and >98% were white. Patients were well matched for demographic characteristics. Overall, use of rescue medication was significantly lower with almotriptan 6.25 mg and 12.5 mg compared with placebo (P < or = 0.05 for each group). No significant difference was noted between the almotriptan 12.5-mg and sumatriptan 100-mg groups. In 2 of the studies, patients with moderate or severe baseline pain used significantly less rescue medication in the almotriptan groups compared with placebo. CONCLUSIONS: Oral almotriptan 6.25 mg or 12.5 mg significantly reduced use of rescue medication compared with placebo among patients with acute migraine. Use of rescue medication was comparable with almotriptan 12.5 mg and sumatriptan 100 mg.

Almotriptan increases pain-free status in patients with acute migraine treated in placebo-controlled clinical trials.

OBJECTIVES: Evaluate the efficacy of a single oral dose of almotriptan in achieving pain-free status during treatment of acute migraine attacks. METHODS: This pooled analysis (N=1321) used data from two randomized, placebo-controlled, phase III trials (studies A and B) to determine the proportion of patients with migraine achieving pain-free status 2 hours after a single oral dose of study medication (almotriptan or placebo). Pain was assessed using a 4-point integer scale (0=no headache, 3=severe headache), and recorded in a patient self-assessment booklet. RESULTS: The proportion of patients pain-free at 2 hours after study medication was significantly greater with almotriptan 6.25 mg (both studies P