Tolerability and safety of perampanel: two randomized dose-escalation studies.

OBJECTIVES: To evaluate, for the first time in patients with epilepsy, the tolerability and safety of escalating doses of oral perampanel, a novel, selective, non-competitive AMPA antagonist, as adjunctive therapy for refractory partial-onset seizures. MATERIALS AND METHODS: Two consecutive, randomized, double-blind, dose-escalation studies recruited adults (18-70 years) with uncontrolled partial-onset seizures receiving one to three concomitant antiepileptic drugs. In study 206, patients were treated for 12 weeks (8-week dose-titration, 4-week dose-maintenance) with placebo or perampanel (up to 4 mg/day, dosed once- or twice-daily). In study 208, patients received placebo or perampanel once-daily (up to 12 mg) for 16 weeks (12-week titration, 4-week maintenance). RESULTS: Overall, 153 patients were randomized into study 206 (perampanel twice-daily, n = 51; perampanel once-daily, n = 51; placebo, n = 51). Study 208 included 48 patients (perampanel once-daily, n = 38; placebo, n = 10). The highest dose in study 206 - 4 mg/day - was well tolerated, with similar proportions of patients tolerating once-daily (82.4%) and twice-daily (82.4%) perampanel and placebo (82.4%) treatments. In study 208 most patients tolerated doses of ≥ 6 mg perampanel once-daily in a Kaplan-Meier analysis. In both studies, the most common adverse events were CNS-related; most were of mild/moderate severity. CONCLUSIONS: Perampanel was well tolerated across doses of 4-12 mg/day. The studies showed preliminary evidence of efficacy and identified doses to be evaluated in larger clinical studies.

Perampanel Study 207: long-term open-label evaluation in patients with epilepsy.

OBJECTIVES: Evaluate interim long-term tolerability, safety and efficacy of adjunctive perampanel, a novel α-amino-3-hydroxy-5-methyl-5-isoxazolepropionic acid (AMPA)-receptor antagonist, in patients with refractory partial-onset seizures. MATERIALS AND METHODS: Study 207, an open-label extension (OLE) study (ClinicalTrials.gov identifier: NCT00368472), enrolled patients (18-70 years) who completed one of two randomized, placebo-controlled, dose-escalation Phase II studies. The OLE Treatment Phase comprised a 12-week Titration Period (2 mg increments of perampanel every 2 weeks to 12 mg/day, maximum) and a Maintenance Period, during which patients continued treatment up to a planned maximum of 424 weeks (~8 years). Interim analysis data cut-off date was 1 December, 2010. RESULTS: Of 180 patients completing the Phase II studies, 138 enrolled in study 207. At the time of interim analyses (approximately 4 years after study start), over a third (n = 53, 38.4%) remained on perampanel; 41.3% (n = 57) of patients had >3 years of exposure; and 13.0% (n = 18) had at least 4 years' exposure. Mean ± standard deviation (SD) duration of exposure was 116 ± 75 weeks and mean ± SD dose during the OLE Maintenance Period was 7.3 ± 3.3 mg. No new safety signals emerged with long-term treatment. Consistent with previous studies, the most common treatment-emergent adverse events were as follows: dizziness, headache and somnolence. Overall median (range) per cent change from baseline in seizure frequency per 28 days during open-label treatment was -31.5% (-99.2 to 512.2). CONCLUSIONS: Long-term - up to 4 years - adjunctive perampanel had a favourable tolerability profile in patients with refractory partial-onset seizures. Improvements in seizure control were maintained with long-term treatment.

Tonabersat, a gap-junction modulator: efficacy and safety in two randomized, placebo-controlled, dose-ranging studies of acute migraine.

Tonabersat is a novel benzopyran derivative that blocks the cortical spreading depression proposed to be associated with migraine attacks. The ability of single oral doses of 15, 25, 40 and 80 mg of tonabersat to relieve the symptoms of moderate to severe migraine was evaluated in 859 migraineurs enrolled in two dose-ranging, double-blind, randomized, placebo-controlled, parallel-group trials, one international and the other North American. In the international study, significantly more patients given tonabersat than given placebo experienced relief of headache pain at 2 h (15 mg, 36.8%; 40 mg, 40.7%), the principal efficacy variable, and at 4 h (40 mg, 63.0%) and complete abolition of headache at 4 h (40 mg, 34.3%). None of the primary or secondary efficacy variables indicated significant differences between tonabersat and placebo in the North American study. Tonabersat was generally well tolerated, with dizziness and nausea the most common side-effects. Serious adverse events were uncommon, and no patient withdrew from either study because of adverse events. These results suggest a possible interplay between tonabersat pharmacokinetics (the relatively long time required to reach maximum plasma concentrations) and patient characteristics (previous triptan exposure) in the management of acute migraine attacks. Based on the pharmacokinetics and actions on cortical spreading depression, tonabersat may have potential value in migraine prophylaxis.

Recurrent brainstem encephalitis associated with herpes simplex virus type 1 DNA in cerebrospinal fluid.

A 47-year-old man had recurrent signs and symptoms of brainstem encephalitis over a 4-year period. Although CSF viral cultures were repeatedly negative, herpes simplex virus type 1 (HSV-1) DNA was detected in CSF by polymerase chain reaction (PCR). HSV-1-specific antibodies were absent at the time of the first positive PCR test, but CSF seroconversion to high HSV-1-specific antibody titer subsequently occurred. CSF antibody to cytomegalovirus (CMV) and varicella-zoster virus (VZV) was not detectable, nor could CMV, VZV, or Epstein-Barr virus nucleic acid be detected by CSF by PCR. This is the first report of the use of CSF PCR for the rapid antemortem diagnosis of herpetic brainstem encephalitis.

Clinical efficacy and tolerability of 2.5 mg zolmitriptan for the acute treatment of migraine. The 042 Clinical Trial Study Group.

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for > or = 1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitriptan compared with 36% for placebo (p < 0.001); at 4 hours, headache response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

Standards of care for treating headache in primary care practice. National Headache Foundation.

The following is a summary of guidelines created under the auspices of the National Headache Foundation, in an effort to improve the care of headache patients in primary care practice. The guidelines represent the consensus of an advisory panel of practitioners chosen by the NHF for their expertise in four specialty areas. A complete set of guidelines can be obtained by calling the National Headache Foundation at 1-800-843-2256 or by writing to them at 428 W. St. James Pl., 2nd Floor, Chicago, IL 60614-2750; the cost is $10.

Denial of hospitalization by insurers for inpatient treatment of medication rebound headaches.

Inpatient treatment with intravenous dihydroergotamine has been remarkably successful in managing chronic daily headaches due to excessive use of analgesics or ergotamine tartrate. Recently we have been denied authorization in appropriate patients for this procedure by third party payers on the grounds that it was "not medically necessary," "based on anecdotal information," or is "an outpatient procedure." Three cases are described in which the insurer's decision was either contested as an issue of substandard care, or the patient elected to pay for the procedure. The outcome in two cases was dramatically favorable, at least from the patient's and the physician's point of view. The third case is currently being appealed. Time and energy spent on combating the position of the third party payer on issues of standards of specialist care should be unnecessary. Publication of standards of care by specialists, and a requirement that these care standards must be provided by third party payers are needed in order that quality medical care can continue in this society.

Toward a standard drug formulary for the treatment of headache.

The recent publication of drug formularies by third-party payers has serious implications for the practice of medicine. These formularies list the medications for which the consumer can be reimbursed by the third-party payer. The most restrictive of the five formularies I have received lists only two agents for the treatment of migraine headaches: Cafergot (at an incorrect dose of 1/100 mg) and Ergotrate which is no longer available. The most liberal of the formularies lists analgesics, Cafergot, Midrin, and Imitrex for the treatment of acute attacks, and as prophylactic agents, Inderal, Sansert, and analgesics (known to cause rebound headaches when used in this fashion in migraine patients). Abortive agents of proven value, such as DHE-45 and NSAIDs, and preventative medications, such as calcium channel blockers, tricyclic antidepressants, serotonin reuptake inhibitors, methylergonovine, and divalproex sodium, are not available. No one could quarrel with a goal of developing a cost-effective formulary. However, the authors of these formularies have clearly demonstrated their inability to provide even a current, accurate, and adequate formulary by existent standards of care in the treatment of migraine headache. While it is easy to criticize these formularies, it is more difficult to develop a comprehensive list that would satisfy the practitioners' need to provide relief for their patients with a minimum of side effects, and the needs of third-party payers (presumed) to provide quality care at the most economical level.

Rizatriptan wafer--sublingual vs. placebo at the onset of acute migraine.

Rizatriptan wafer is a 5HT1B/1D agonist for use in the acute treatment of migraine. It is a freeze-fried formulation, approved for oral administration, which dissolves on the tongue and is swallowed with saliva. In this study the efficacy of sublingually administered rizatriptan 10-mg wafer was evaluated in a randomized, double-blind, placebo-controlled, out-patient study involving 39 migraineurs. Patients were instructed to treat a migraine at the onset of pain in order to evaluate time of onset of pain relief and pain relief at 1 h. The average time to onset of relief was 25 min for patients treated with rizatriptan wafer and 27 min for patients treated with placebo. At 1 h, 50% of the patients receiving rizatriptan wafer and 50% of the patients receiving placebo experienced significant relief. Implications and potential reasons for a high placebo response are discussed.

Ketorolac versus DHE and metoclopramide in the treatment of migraine headaches.

Ketorolac IM was compared to DHE and metoclopramide IV in migraine patients whose regular abortive medication had failed and who presented to a headache clinic for acute treatment. Pain scale ratings and ratings of ability to function were recorded before and after injection. Ketorolac provided moderate relief in headache in six of nine patients compared to eight of nine given DHE and metoclopramide. The average improvement in patients receiving DHE and metoclopramide was greater in pain (p = .031) and disability scores (p = .057), than in those patients given ketorolac.

Current emergency treatment of severe migraine headaches.

OBJECTIVE: To compare the efficacy of the combination of meperidine and hydroxyzine IM, versus dihydroergotamine and metoclopramide IV in the treatment of severe migraine headaches. DESIGN: This was a randomized double-blind, double-dummy study. SETTING: Established patients, whose headache had failed to respond to their usual abortive agent, were invited to an out-patient headache clinic for the study. PATIENTS: Twenty-eight patients, diagnosed as suffering from either migraine headache or chronic daily headache, were screened on arrival to exclude life-threatening causes. INTERVENTION: Group A (14 patients) received dihydroergotamine 1mg and metoclopramide 10mg IV and a placebo injection IM, and Group B (14 patients) received meperidine 75mg and hydroxyzine 75mg IM and a placebo injection IV. MAIN OUTCOME MEASURES: Patients rated their headaches on a scale of 0-3 prior to treatment and again at 30 and 60 minutes. RESULTS: Both groups experienced improvement in headache severity. (Group A P = 0.001 and Group B P = 0.003). Improvement in pain scale score was greater for Group A than Group B. (P = 0.006). The number of patients having a mild or no headache in Group A (13/14) was significantly greater than Group B (3/14). (P < 0.001) CONCLUSIONS: The combination of dihydroergotamine and metoclopramide IV should replace the standard IM narcotic and anti-emetic as the parenteral treatment of choice for severe migraine headache.

Clinical experience with patient administered subcutaneous dihydroergotamine mesylate in refractory headaches.

This study examines the practicality and efficacy of dihydroergotamine mesylate (DHE) when self-administered subcutaneously in a population of refractory headache patients. Forty-three patients with chronic daily headache or migraine headache without aura, who had been taught self-injection of DHE either through the Raskin Protocol or in an outpatient headache clinic, were contacted by telephone and administered a questionnaire regarding usage and results from DHE injection. Ninety-two percent of patients could successfully administer DHE. Forty-six percent of patients experienced 90% or greater relief of pain and the majority of patients (77%) had greater than 50% relief. Emergency room use was decreased in 83% and 80% preferred DHE to their previous therapy. While side effects were common (79%), only four patients (9%) stopped DHE for this reason. No convincing evidence for the development of rebound headaches due to DHE was found in this sample.

The misdiagnosis of cluster headache: a nonclinic, population-based, Internet survey.

OBJECTIVE: We conducted the first nonclinic, Internet-based survey of cluster headache to investigate this population with regard to diagnostic problems encountered, effective and ineffective medications, problems obtaining medications through third-party payers, and symptoms as they relate to International Headache Society criteria. BACKGROUND: Previous cluster headache surveys have been at specialty centers. These patients might be different from cluster headache sufferers in the general population. An Internet-based population of cluster headache sufferers who connected to a Web site responded to the questionnaire, and e-mailed it back to our site to be analyzed. We analyzed a total of 789 respondents, 76% men and 28% women. RESULTS: Eighty-seven percent of respondents qualified as having cluster headache according to International Headache Society criteria. However, diagnosis was delayed an average of 6.6 years from the onset of symptoms. The average number of physicians seen before the correct diagnosis was made was 4.3, and the average number of incorrect diagnoses was 3.9. Seventy-one percent of respondents had undergone unnecessary magnetic resonance or computed tomography scans, and 4% had unnecessary sinus or deviated septum surgery. We found that many inappropriate medications such as propranolol, amitriptyline, and antibiotics were prescribed and that successful medications for clusters such as sumatriptan and oxygen were often denied due to a failure to understand the nature of this disorder. Seventy-seven percent of respondents were smokers. Seventy-four percent stopped smoking in an attempt to improve their condition; however, only 3% experienced relief. CONCLUSIONS: The most alarming finding was the delay in diagnosing cluster headache in this population--an average of 6.6 years. The selection of medications demonstrated to be successful in the treatment of clusters proved effective for the majority of this population. Many respondents reported being denied some of these effective medications by their physicians or third-party payers. Using International Headache Society criteria for cluster headache, 87% of the respondents should have been correctly diagnosed by the first physician seen.

Demographics of attendees at public education seminars.

PURPOSE: The demographics of patients who attend public awareness seminars relating to headache have not been studied. In order to improve the presentations at these meetings, it was felt that the meeting planners should know as much as possible about the audience. METHODS: Attendees at a public awareness seminar entitled Help for Headaches were asked to respond to a series of questions using an audience response system. RESULTS: The majority of the 212 responders were women (90%) and were over the age of 50 (53%). Most felt that they had more than one type of headache (64%), were treated by a family practitioner or internist (58%), and had been denied important diagnostic or therapeutic modalities (42%). The majority were dissatisfied with current treatment (87%) and attended the meeting to find out more about new treatments (64%). Fifty-eight percent felt their physicians did not know enough about headaches. Forty-nine percent felt they had rebound headaches. CONCLUSIONS: Public awareness seminars for headache should be designed with the realization that most attendees will be women who have more than one type of headache. The majority will be interested in new and alternative therapies, and approximately half will have rebound headaches.

Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the treatment of migraine.

OBJECTIVE: To compare the safety and efficacy of isometheptene mucate, dichloralphenazone with acetaminophen to sumatriptan succinate for the treatment of mild-to-moderate migraine, with or without aura, when taken at the first sign of an attack. BACKGROUND: The Food and Drug Administration approved sumatriptan succinate and the combination of isometheptene mucate, dichloralphenazone with acetaminophen for the treatment of migraine. As part of the stratified treatment of migraine, those patients whose headaches are mild or moderate may benefit from nontriptan medications. Additionally, early treatment of acute migraine before the headache has become moderate or severe may improve response to treatment. METHODS: This was a multicenter, double-blind, randomized, parallel-group study to assess the safety and efficacy of the combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the early stages of a single migraine attack. Patients diagnosed with migraine, with or without aura, as defined by the International Headache Society diagnostic criteria were enrolled. RESULTS: One hundred thirty-seven patients were enrolled in the study. Data for efficacy were available for 126 patients; safety data were available for 128 patients. No statistically significant difference between the two active agents in the patient's response to treatment was demonstrated. Headache recurrence was not significantly different over the 24-hour evaluation period for those patients responding in the first 4 hours. In those with headache recurrence, it was statistically significantly more severe in those patients treated with sumatriptan succinate. Improvement in functional disability was, in general, better among those treated with isometheptene mucate, dichloralphenazone with acetaminophen. Global analysis of efficacy was similar in the two active groups. Patients treated with sumatriptan succinate were somewhat more likely to have adverse effects than the isometheptene mucate, dichloralphenazone with acetaminophen group. CONCLUSIONS: Both isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate are safe and effective when used early in the treatment of an acute migraine. Several parameters suggest that isometheptene mucate, dichloralphenazone with acetaminophen may have a slight advantage compared with sumatriptan succinate in the early treatment of mild-to-moderate migraine.

Safety and efficacy of PNU-142633, a selective 5-HT1D agonist, in patients with acute migraine.

In this randomized, double-blind, placebo-controlled, parallel-group study, patients received a single 50-mg oral dose of a 5-HT(1D) agonist, PNU-142633 (n = 34), or matching placebo (n = 35) during an acute migraine attack. No statistically significant treatment effects were observed at 1 and 2 h after dosing, even after stratifying by baseline headache intensity. At 1 and 2 h post-dose, 8.8% and 29.4% of the PNU-142633 group, respectively, and 8.6% and 40.0% of the placebo group, respectively, experienced headache relief; 2.9% and 8.8% of the PNU-142633 group and 0% and 5.7% of the placebo group were free of headache pain. Adverse events associated with PNU-142633 treatment included chest pain (two patients) and QTc prolongation (three patients). Results from this study suggest that anti-migraine efficacy is not mediated solely through the 5-HT(1D) receptor subtype, although this receptor may contribute, at least in part, to the adverse cardiovascular effects observed with 5-HT agonist medications.