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Background and Purpose: OnabotulinumtoxinA was effective and well tolerated for prophylaxis of headache in patients with chronic migraine (CM) in two randomized, double-blind, placebo-controlled, phase 3 trials. To further assess the safety and tolerability of onabotulinumtoxinA in CM prophylaxis in adults, the pooled safety data from four double-blind, placebo-controlled trials were analyzed., Methods: The pooled analysis included two phase 2 and two phase 3 double-blind, placebo-controlled trials. The safety population was 2436 patients, 1997 of whom received ≥1 dose of onabotulinumtoxinA. The studies shared similar dosing intervals (approximately 12 weeks) with doses between 75 and 260 U. Safety assessments included adverse events (AEs), physical examination and clinical laboratory tests., Results: OnabotulinumtoxinA was safe and well tolerated, with a low discontinuation rate (3.4%) due to AEs. The majority of patients in this pooled analysis received doses between 150 and 200 U, with an average of 163 U per treatment cycle. Of the 1997 patients who received any onabotulinumtoxinA injections, 1455 patients (72.9%) reported at least one AE. Neck pain (12.6%) was the most common onabotulinumtoxinA-associated AE, followed by muscle weakness (8.0%), musculoskeletal stiffness (6.1%) and eyelid ptosis (4.6%). Serious AEs were infrequent, occurring in 5.4% of patients who received any onabotulinumtoxinA treatment and 3.0% of patients receiving placebo. AEs were consistent with the known tolerability profile of onabotulinumtoxinA., Conclusions: Multiple treatments with onabotulinumtoxinA at doses of 75-260 U administered every 12 weeks, and up to five treatment cycles, were well tolerated for the prophylaxis of headache in adults with CM., (© The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of EAN.)

Objective: Chronic migraine (CM) is a prevalent and disabling neurological disorder. Phase III REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program assessed efficacy and safety of onabotulinumtoxinA (BOTOX(®)) for prophylaxis of headaches in adults with CM. This secondary analysis assessed patients who received all five treatment cycles and completed the study., Materials and Methods: PREEMPT (two phase III studies: 24-week double-blind, placebo-controlled [DBPC], parallel-group phase, followed by 32-week open-label [OL] phase) evaluated the efficacy and safety of onabotulinumtoxinA in CM (≥15 days/month with headache lasting ≥4 h a day). Patients were randomized (1:1) to onabotulinumtoxinA or placebo every 12 weeks for two cycles, followed by onabotulinumtoxinA for three cycles. Multiple headache symptom measures were evaluated. Results for the completer (five cycles) subgroup of patients are reported., Results: Of 1384 total PREEMPT patients, 1005 received all five treatment cycles (513 received onabotulinumtoxinA only [onabotulinumtoxinA/onabotulinumtoxinA (O/O)] and 492 received two cycles of placebo then three cycles of onabotulinumtoxinA [placebo/onabotulinumtoxinA (P/O)]). Demographics were similar between treatment groups. At Week 56, after all patients were treated with onabotulinumtoxinA, there continued to be significant between-group differences favoring the O/O vs P/O group for the following headache symptom measures: LS mean change from baseline in frequencies of headache days (-12.0 O/O, -11.1 P/O; P = 0.035), migraine days (-11.6 O/O, -10.7 P/O; P = 0.038), and moderate/severe headache days (-11.0 O/O, -10.1 P/O; P = 0.042). For other measures (cumulative hours of headache on headache days, frequency of headache episodes, and percentage with severe Headache Impact Test (HIT)-6 score, and total HIT-6 and Migraine-Specific Quality of Life Questionnaire scores), there were also large mean improvements from baseline. The percent of patients with a ≥50% reduction from baseline in frequency of headache days was significantly greater for the onabotulinumtoxinA-only group at Week 56 (69.6% O/O, 62.8% P/O; P = 0.023). The treatment-related adverse event rate was 28.5% for onabotulinumtoxinA vs 12.4% for placebo in the DBPC phase and 34.8% for patients treated with onabotulinumtoxinA for all five cycles throughout the 56-week trials., Conclusions: This subgroup analysis demonstrated improvements with onabotulinumtoxinA treatment (five cycles) vs placebo (two cycles)/onabotulinumtoxinA (three cycles) for multiple headache symptom measures and suggests that at Week 56, patients treated earlier with onabotulinumtoxinA had better outcomes. These findings demonstrate the continued need and cumulative benefit over time with continued prophylaxis, an important and clinically pragmatic observation for clinicians and patients., (© 2013 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The classification of the International Headache Society (IHS) generally differentiates episodic from chronic headache. Chronic migraine is defined as headache on 15 and more days a month over more than 3 months and headache on 8 days or more fulfils the criteria for migraine or were triptan/ergot-responsive when thought to be migrainous in early stages of the attack. The prevalence of chronic migraine is estimated at 2-4 %. The quality of life is highly compromised in this condition and comorbidities are much more frequent compared to episodic migraine. Data from prospective randomized studies are scarce as most patients with chronic migraine were excluded from previous trials and only few studies were conducted for this condition. The efficacy for prophylactic treatment compared with placebo is proven for topiramate and onabotulinum toxin A.

Tension-type headache and migraine are the most frequent primary headaches. Diagnosis is based on the patient's history and a normal neurological examination. Most patients with these two headache entities treat headache episodes with over-the-counter analgesics or non-steroidal anti-inflammatory drugs (NSAIDs). There is good scientific evidence from randomised, placebo-controlled trials indicating that aspirin, ibuprofen, ketoprofen, diclofenac and naproxen are effective in tension-type and migraine headache. Paracetamol seems to be less effective. In patients with migraine who do not respond to analgesics or NSAIDs, triptans should be prescribed. Frequent primary headaches should not be treated with frequent intake of analgesics or triptans. In these cases, preventive therapy needs to be implemented., (© 2012 Blackwell Publishing Ltd.)

Chronic migraine (CM) was first defined in the second edition of the International Headache Society (IHS) classification in 2004. The definition currently used (IHS 2006) requires the patient to have headache on more than 15 days/month for longer than 3 months and a migraine headache on at least 8 of these monthly headache days and that there is no medication overuse. In daily practice the majority of the patients with CM also report medication overuse but it is difficult to determine whether the use is the cause or the consequence of CM. Most the patients also have other comorbidities, such as depression, anxiety and chronic pain at other locations. Therapy has to take this complexity into consideration and is generally multimodal with behavioral therapy, aerobic training and pharmacotherapy. The use of analgesics should be limited to fewer than 15 days per month and use of triptans to fewer than 10 days per month. Drug treatment should be started with topiramate, the drug with the best scientific evidence. If there is no benefit, onabotulinum toxin A (155-195 Units) should be used. There is also some limited evidence that valproic acid and amitriptyline might be beneficial. Neuromodulation by stimulation of the greater occipital nerve or vagal nerve is being tested in studies and is so far an experimental procedure only.

Introduction: Data on clinical differences between episodic (eCH) and chronic cluster headache (cCH) and accompanying migraine features are limited., Methods: History and clinical features of 209 consecutive cluster headache patients (144 eCH, 65 cCH; male:female ratio 3.4 : 1) were obtained in a tertiary headache centre by face-to-face interviews. Relationship between occurrence of accompanying symptoms, pain intensity, comorbid migraine, and circannual and circadian rhythmicity was analysed., Results: 99.5% of patients reported a minimum of one ipsilateral cranial autonomic symptom (CAS); 80% showed at least three CAS. A seasonal rhythmicity was observed in both eCH and cCH. A comorbid headache disorder occurred in 25%. No significant difference was detected between patients with comorbid migraine and without regarding occurrence of phonophobia, photophobia or nausea during cluster attacks. Patients with comorbid migraine reported allodynia significantly (p = 0.022) more often during cluster attacks than patients without comorbid migraine., Conclusion: Occurrence of CAS and attack frequency, as well as periodic patterns of attacks, are relatively uniform in eCH and cCH. Multiple CAS are not related to pain intensity. Allodynia during cluster attacks is a frequent symptom. The unexpectedly high rate of accompanying migrainous features during cluster attacks cannot be explained by comorbid migraine.

The objective of this study is to assess effects of beta-blocker migraine prophylaxis on cortical excitability determined by transcranial magnetic stimulation (TMS). Phosphene and motor thresholds (PT, MT) were investigated in 29 patients with migraine, in 15 of them prior to and following preventive medication with metoprolol and in 14 patients without prophylaxis. Following prophylaxis headache frequency significantly decreased (p = 0.005) and mean PT were significantly increased (51.5 ± 7.5 vs. 63.6 ± 8.4%) compared to patients without preventive treatment (53.7 ± 5.3 vs. 52.3 ± 6.3%; p = 0.040). Mean MT did not significantly differ either between groups or due to treatment. In the group of all patients, a significant inverse correlation between headache frequency and the level of PT was found (R = -0.629; p < 0.01). There was, however, no significant correlation in the subgroups of patients. We conclude that (a) clinical efficacy of beta-blocker treatment in migraine could be (at least partly) linked to its ability to modulate the excitability of the visual cortex and (b) the PT determined by TMS appears suitable to assess the effects of prophylaxis on cortical excitability in the individual patient. This may be useful in clinical trials investigating migraine preventive drugs.

Objective: To assess the effects of treatment with onabotulinumtoxinA (Botox, Allergan, Inc., Irvine, CA) on health-related quality of life (HRQoL) and headache impact in adults with chronic migraine (CM)., Methods: The Phase III Research Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical program (PREEMPT 1 and 2) included a 24-week, double-blind phase (2 12-week cycles) followed by a 32-week, open-label phase (3 cycles). Thirty-one injections of 5U each (155 U of onabotulinumtoxinA or placebo) were administered to fixed sites. An additional 40 U could be administered "following the pain." Prespecified analysis of headache impact (Headache Impact Test [HIT]-6) and HRQoL (Migraine-Specific Quality of Life Questionnaire v2.1 [MSQ]) assessments were performed. Because the studies were similar in design and did not notably differ in outcome, pooled results are presented here., Results: A total of 1,384 subjects were included in the pooled analyses (onabotulinumtoxinA, n = 688; placebo, n = 696). Baseline mean total HIT-6 and MSQ v2.1 scores were comparable between groups; 93.1% were severely impacted based on HIT-6 scores ≥60. At 24 weeks, in comparison with placebo, onabotulinumtoxinA treatment significantly reduced HIT-6 scores and the proportion of patients with HIT-6 scores in the severe range at all timepoints including week 24 (p < 0.001). OnabotulinumtoxinA treatment significantly improved all domains of the MSQ v2.1 at 24 weeks (p < 0.001)., Conclusions: Treatment of CM with onabotulinumtoxinA is associated with significant and clinically meaningful reductions in headache impact and improvements in HRQoL., Classification of Evidence: This study provides Class 1A evidence that onabotulinumtoxinA treatment reduces headache impact and improves HRQoL.

Background: We investigated efficacy and tolerability of two tablets of the fixed combination of 250 mg acetylsalicylic acid (ASA) + 200 mg paracetamol + 50 mg caffeine (Thomapyrin) in comparison to two tablets of placebo in a post-hoc analysis of a subgroup of patients with severe headache., Methods: Patients where included if they were used to treating their episodic tension-type headache or migraine attacks with non-prescription analgesics and reported a history of headache attacks characterized by at least severe pain and greatly impaired usual daily activities and treated headaches with pain intensity of at least 48 mm assessed on a 100-mm visual analogue scale and associated with greatly impaired usual daily activities., Results: For the primary endpoint 'time to 50% pain relief' in this intention-to-treat subset (n = 179 patients), the fixed combination of ASA, paracetamol, and caffeine was statistically significantly superior to placebo (p = 0.0008). The superior efficacy of the triple combination could also be shown for all secondary endpoints such as time until reduction of pain intensity to 10 mm, weighted sum of pain intensity difference (%SPIDweighted), extent of impairment of daily activities, and global assessment of efficacy. Both treatments were well tolerated. The incidence of adverse events observed was low. The results for this subgroup analysis are consistent with respect to all endpoints and to the patients with non-severe headache and the overall patient population. As with all post-hoc subgroup analyses, the findings are hypothesis generating only and must be interpreted with caution., Discussion: The results of this subgroup analysis confirm that the fixed combination of ASA (250 mg), paracetamol (200 mg), and caffeine (50 mg) is effective and well tolerated in a broad spectrum from mild to severe migraine and tension-type headache severity independently of the headache diagnosis.

Objective: The objective of our study was to field test different chronic migraine (CM) criteria and compare CM epidemiological profiles, which include demographic, personal, and lifestyle characteristics, with high-frequency episodic migraine (HFEM) and low-frequency episodic migraine (LFEM)., Methods: Questionnaires were mailed to a random sample of 18,000 18-65-year-olds in demographically diverse regions of Germany. The epidemiological data for the three classifications of CM, LFEM and HFEM were assessed using descriptive statistics, Pearson Chi-square, and analysis of variance tests., Results: Among 9350 respondents, CM&#95;I was the most restrictive (N = 37, 0.4%), followed by CM&#95;II (N = 45, 0.5%) and CM&#95;III (N = 185, 2.0%). CM groups did not differ in distribution by age, gender, body mass index, education or smoking and alcohol consumption. Compared to those with LFEM and HFEM, those with CM (CM&#95;III) had significantly different epidemiological profiles., Conclusions: CM prevalence varies by case definition. The epidemiological profiles of the three CM groups are similar but differ significantly from those of HFEM and LFEM. Optimal definitions for clinical practice and epidemiological research require additional field testing.

Objectives: This is the first of a pair of studies designed to assess efficacy, safety and tolerability of onabotulinumtoxinA (BOTOX) as headache prophylaxis in adults with chronic migraine., Methods: The Phase III REsearch Evaluating Migraine Prophylaxis Therapy 1 (PREEMPT 1) is a phase 3 study, with a 24-week, double-blind, parallel-group, placebo-controlled phase followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections every 12 weeks of onabotulinumtoxinA (155 U-195 U; n = 341) or placebo (n = 338) (two cycles). The primary endpoint was mean change from baseline in headache episode frequency at week 24., Results: No significant between-group difference for onabotulinumtoxinA versus placebo was observed for the primary endpoint, headache episodes (-5.2 vs. -5.3; p = 0.344). Large within-group decreases from baseline were observed for all efficacy variables. Significant between-group differences for onabotulinumtoxinA were observed for the secondary endpoints, headache days (p = .006) and migraine days (p = 0.002). OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events., Conclusions: There was no between-group difference for the primary endpoint, headache episodes. However, significant reductions from baseline were observed for onabotulinumtoxinA for headache and migraine days, cumulative hours of headache on headache days and frequency of moderate/severe headache days, which in turn reduced the burden of illness in adults with disabling chronic migraine.

Objectives: This is the second of a pair of studies designed to evaluate the efficacy and safety of onabotulinumtoxinA (BOTOX) for prophylaxis of headaches in adults with chronic migraine., Methods: PREEMPT 2 was a phase 3 study, with a 24-week, double-blind, placebo-controlled phase, followed by a 32-week, open-label phase. Subjects were randomized (1:1) to injections of onabotulinumtoxinA (155U-195U; n = 347) or placebo (n = 358) every 12 weeks for two cycles. The primary efficacy endpoint was mean change in headache days per 28 days from baseline to weeks 21-24 post-treatment., Results: OnabotulinumtoxinA was statistically significantly superior to placebo for the primary endpoint, frequency of headache days per 28 days relative to baseline (-9.0 onabotulinumtoxinA/-6.7 placebo, p < .001). OnabotulinumtoxinA was significantly favoured in all secondary endpoint comparisons. OnabotulinumtoxinA was safe and well tolerated, with few treatment-related adverse events. Few patients (3.5% onabotulinumtoxinA/1.4% placebo) discontinued due to adverse events., Conclusions: The results of PREEMPT 2 demonstrate that onabotulinumtoxinA is effective for prophylaxis of headache in adults with chronic migraine. Repeated onabotulinumtoxinA treatments were safe and well tolerated.

Data from the Prolonged Migraine Prevention (PROMPT) with Topiramate trial were evaluated post hoc to determine whether topiramate could prevent migraine auras, and whether its efficacy in preventing migraine headaches was similar in patients with (MA; n = 269) and without (MoA; n = 542) aura. Migraines and auras were recorded during prospective baseline, 6-month open-label (OL) topiramate and 6-month double-blind (DB), placebo-controlled phases. In the last 28 OL days, migraines without aura and migraine auras decreased by 43.1% and 54.1%, respectively, in MA patients. MoA patients experienced a 44.3% reduction in migraines. In the DB phase, increases in migraines with placebo vs. topiramate were similar to the full study, but were generally not statistically significant, probably due to lack of power in the subgroup analysis. Similarly, there were no statistically significant changes in number of auras between groups. Thus, topiramate appears to reduce migraine auras in parallel with headache reductions, which are similar in patients with and without aura.

Often without sufficient scientific evidence, unconventional methods for migraine treatment are being put forward. Recently a trial using "migraine surgery" has been published. Its design is based on a concept of migraine pathogenesis without any scientific background and includes several severe methodological flaws. In spite of the above, the study is frequently cited in the lay press. The surgical procedure as well as the study are critically discussed.

A growing number of clinical trials are testing Chinese acupuncture in the management of headache disorders. Little is known, however, about the relationship between International Headache Society diagnostic criteria and traditional Chinese medicine (TCM) diagnosis in primary headache disorders. We conducted a secondary analysis of the data of the prospective, controlled, blinded German acupuncture trials for migraine and tension-type headache. Data were collected from 1042 headache patients, of whom 633 were diagnosed with migraine and 409 with tension-type headache. We found that the diagnoses of migraine and tension-type headache were mirrored by different patterns of TCM diagnoses, with the patterns Liver Yang Rising, Liver Fire Rising, and Phlegm appearing to be best suited to differentiating between migraine and tension-type headache. Although not unexpected, given that the diagnosis of primary headache disorders in both diagnostic systems is based largely on the nature and quality of patient-reported symptoms, this finding suggests that migraine and tension-type headache are associated with different patterns of TCM diagnosis.

Unilateral head pain focused on frontal, orbital or parietal regions is a leading symptom of migraine attacks. Rarely, head pain in migraine can extend involving the maxillary or mandibular region of the face, sometimes isolated facial pain is the only and atypical presentation of migraine. The prevalence of these unusual symptoms in migraine is unknown. We aimed to estimate the true prevalence of facial pain in migraine in a population-based sample of 517 migraine patients in Germany. In 46 (8.9%) cases migraine pain involved the head and the lower half of the face. Patients with facial pain suffer more trigemino-autonomic symptoms than migraine patients (47.8% vs. 7.9%; alpha(2) = 66.23, P < 0.001). In one case isolated facial pain without headache was the leading symptom of migraine. Our results demonstrate that facial pain is not unusual in migraine, whereas isolated facial migraine is extremely rare.

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.

Chronic migraine has been linked to the excessive use of acute headache medications. Medication overuse (MO) is commonly considered the most significant risk factor for the progression of migraine from an episodic to a chronic condition. Managing MO is a challenge. Discontinuation of the acute medication can result in withdrawal headache, nausea, vomiting and sleep disturbances. This review summarizes the results from two similarly designed, randomized, placebo-controlled, multicentre studies of chronic migraine conducted in the USA and European Union. Both studies demonstrate the efficacy and safety of the migraine preventive medication, topiramate, for the treatment of chronic migraine in patient populations both with and without MO. These studies may have important implications for the future of chronic migraine management, suggesting that detoxification prior to initiating prophylactic therapy may not be required in all patients if MO is present.

Background: The neuropeptide calcitonin gene-related peptide (CGRP) plays a key role in migraine pathophysiology. In this large phase 3 clinical trial, we sought to confirm the efficacy of telcagepant, the first orally bioavailable CGRP receptor antagonist., Methods: Adults with migraine with or without aura (International Headache Society criteria) treated a moderate or severe attack with oral telcagepant 50 mg (n = 177), 150 mg (n = 381), 300 mg (n = 371), or placebo (n = 365) in a randomized, double-blind trial. The 5 co-primary endpoints were pain freedom, pain relief, and absence of photophobia, absence of phonophobia, and absence of nausea, all at 2 hours postdose. The key secondary endpoint was 2-24 hour sustained pain freedom. The prespecified primary efficacy analyses evaluated the 150 mg and 300 mg groups; the 50-mg group was included on an exploratory basis to further characterize the dose response but was not prespecified for analysis. Tolerability was assessed by adverse experience reports., Results: Telcagepant 300 mg was more effective (p

We evaluated telmisartan 80 mg for migraine prophylaxis. Migraine patients (n = 95) with three to seven migraine attacks in 3 months were randomized, double-blind to telmisartan or placebo. The primary end-point was the reduction in the number of migraine days (i.e. a day with > or = 1 h of symptoms) between the 4-week baseline period and the last 4 weeks of the 12-week treatment period. A responder was recorded when there was a symptom reduction of > or = 50% in these 4-week baseline and treatment periods. The reduction in migraine days was 1.65 with telmisartan and 1.14 with placebo (P > 0.05). Post hoc analyses adjusting for baseline and centre showed a 38% reduction in migraine days with telmisartan vs. 15% with placebo (P = 0.03), and a borderline significant difference in responders (40% vs. 25%, P = 0.07). The incidence of adverse events was similar between treatments. This study indicates that telmisartan might be effective in migraine prophylaxis.

Background: The prevalence of anxiety and depression and the influence of headache severity on these illnesses were examined in patients who were part of the managed care of headache in Bavaria., Patients and Methods: A total of 181 patients with headache were screened for anxiety and depression with the German version of the Hospital Anxiety and Depression Scale (HADS-D). Headache severity was evaluated using the Migraine Disability Assessment Questionnaire (MIDAS). Apart from purely descriptive evaluations, Spearman's coefficients of correlation were calculated., Results: Of the patients 22.7% and 44.7% obtained results at or above the limit of the normal range of depression and anxiety, respectively and 19.3% had results at or above the limit of the normal range for both illnesses. There were significant coefficients of correlation between the severity of headache and both anxiety and depression., Conclusion: The results confirm the necessity for an interdisciplinary procedure in treating headache patients in order to achieve a successful therapy. Such a treatment can be realised with the concept of managed care.

We investigated the consistency between the headache diagnosis based on medical history and three treated headache episodes diagnosed based on a diary. In a randomized double-blind study including individuals with either migraine or tension-type headache (TTH) we showed significant superiority of the fixed combination of acetylsalicylic acid + paracetamol + caffeine over the combination without caffeine, the single preparations, and placebo in the treatment of headache. A neurologist performed a classification of the usual headache episodes and each of the three treated ones in a blinded fashion based on a structured questionnaire. This was done for the 1734 patients included in the efficacy analysis who usually treated their episodic TTH or migraine attacks with non-prescription analgesics. The overall percentage of patients with migraine and TTH remained relatively stable. The treated headache episodes were between 75 and 77% migraine, 18-20% were TTH and 5-7% could not be classified. We observed some shift in headache type within patients from prior history and in treated attacks. In 60% of patients all three treated episodes were of the type initially diagnosed by the neurologist by history (56% migraine and 4% episodic TTH). Of those with an initial diagnosis of migraine, 24% had at least one attack meeting criteria for TTH. Of patients with an initial diagnosis of TTH, 54% had at least one attack meeting the diagnostic criteria for migraine. Our results demonstrate that an initial headache diagnosis does not accurately predict the headache type treated in a randomized trial. Symptom features of treated headaches should be captured to ensure that the attack is of the type targeted by the clinical trial. The International Headache Society Guidelines for controlled clinical trials should be updated accordingly.

Background: Prevalence rates of headache in multiple sclerosis (MS) patients varied widely in recent studies. This study aimed to investigate the 1 year prevalence of headache in MS compared with the general population., Methods: Population-based case-control study in Germany., Results: We included 491 patients with definite MS (68% female, mean age 45.3 years, 63.7% relapsing remitting MS, mean Expanded Disability Status Scale (EDSS) 3.2, 106 treated with interferon-beta, 53 with glatiramer acetate, 271 untreated) and 447 age and gender matched controls. Headache was diagnosed with a validated questionnaire according to the International Headache Society Criteria. Headache prevalence was 56.2% (tension type headache 37.2%, migraine 24.6%). Headache prevalence rates did not differ from controls. Headache was not associated with disability or treatment. Trigeminal neuralgia was found in 6.3% of MS cases., Conclusion: Results suggest that headache in MS patients reflects comorbidity in most conditions.

Allodynia--perception of pain from non-noxious stimuli--is a common clinical feature in various pain syndromes. The significance for migraine has increasingly been recognized and the pathophysiology has been investigated in detail. Allodynia is a marker for sensitization of central trigeminal neurons. Intensity and persistence of allodynic symptoms are a function of duration of migraine attacks, frequency of attacks, and migraine history. It has been hypothesized that treatment success with triptans may be severely impaired in the presence of allodynia. However, randomized controlled trials did not confirm that. Treatment with cyclooxygenase inhibitors and dihydroergotamine does not seem to be limited by allodynia; these medications may be able to reverse allodynia. Data on the new class of calcitonin-gene related-peptide antagonists are not yet available. Additional and more refined randomized controlled trials, focusing on methodological issues pertaining to the determination of allodynia, are warranted to resolve the true relationship between allodynia and treatment response. Regardless--based on available randomized controlled trials--the recommendation prevails to initiate abortive treatment as soon as possible after attack onset when pain is still mild.

The best way to appreciate the efficacy of drug and behavioural therapy in the acute and prophylactic treatment of headache is to perform placebo-controlled randomized trials. In order to plan and conduct these studies in the most appropriate way, it is desirable to know which factors influence the placebo response. This paper reviews factors which influence the placebo response in clinical trials, such as expectation, blinding, route of application of drugs and age, gender and geographical distribution. Response rates of placebo in the treatment of acute headache episodes are higher than in headache prophylaxis. Invasive procedures such as injections have a higher placebo response compared with oral drugs. Variables known to influence the placebo response have to be taken into consideration to calculate properly the power of planned randomized trials.

Migraine pathophysiology is determined by genetic and environmental factors. Based on altered cerebral habituation and low serotonin levels, certain triggers can elicit a migraine attack. Following initial unspecific prodromi, an aura follows in many patients which most often consists of visual symptoms. Cortical spreading depression is the electrophysiological correlate of the aura and can activate the trigemino-vascular system. This is one potential mechanism initiating the pain process. The characteristic unilateral pulsating headache is caused by a neurogenic inflammation in the meninges. Neck pain as reported by some patients is a migraine-specific feature, the anatomical basis being the trigemino-cervical complex. Functional changes in the pain processing system maintain the headache. Among these are sensitization of trigeminal nucleus caudalis neurons and an altered antinociception descending from the periaquaductal grey. Triptans have a peripheral and central mode of action, but they are no longer effective once central sensitization has occurred.

This review reports important co-morbid conditions of migraine and resulting consequences for the choice of acute and preventive treatments of migraine. Comorbidity in this context means the occurrence of two diseases in an individual beyond chance. The basis of comorbidity can be genetic and/or based on common environmental factors. In some cases, the temporal relationship is unclear and one disease can cause another disease. In order to prove a real comorbidity, large-scale and well-performed epidemiological studies are required.

Headaches are one of the most common disorders and symptoms in daily medical practice. The prevalence of migraine is 8% in men and 12-15% in women. Dramatic progress in the areas of epidemiology, pathophysiology, and acute and preventive therapy of migraine has been made over the past 100 years, with triptans being the breakthrough for treating acute migraine attacks. Beta blockers, calcium antagonists, and neuromodulators are available for preventive migraine therapy. Nonpharmacologic treatment also plays an important role in migraine prevention. New medical care structures such as integrated headache care provide better support for patients with migraine, particularly those with chronic migraine.

Headaches are one of the most common disorders and symptoms in daily medical practice. The prevalence of migraine is 8% in men and 12-15% in women. Dramatic progress in the areas of epidemiology, pathophysiology, and acute and preventive therapy of migraine has been made over the past 100 years, with triptans being the breakthrough for treating acute migraine attacks. Beta blockers, calcium antagonists, and neuromodulators are available for preventive migraine therapy. Nonpharmacologic treatment also plays an important role in migraine prevention. New medical care structures such as integrated headache care provide better support for patients with migraine, particularly those with chronic migraine.

The aim of the present study was to develop a screening tool to aid non-headache specialists, like general practitioners, in deciding whether migraine prophylaxis in the individual migraine patient is useful or not. The first step was the development of a questionnaire, consisting of 10 items, which was filled in by 132 migraineurs who called on neurologists or headache experts. Independently, the physicians filled in another questionnaire to answer the question of whether they decided to prescribe migraine prophylaxis and if they had, to give their reasons for doing so. Using logistic regression analysis, we identified the three questions which had the most influence on the decision regarding prophylaxis in the data set. As results, we identified the following three questions: 1. Do you suffer from migraine on more than 3 days/month? 2. Do you have to rest in bed while experiencing a migraine attack? 3. Do you have to take medication against migraine on more than 5 days/month? Validation of this reduced questionnaire is currently ongoing and involves 150 migraine patients of general practitioners.

Headaches are one of the most common disorders and symptoms in daily medical practice. There has been dramatic progress of knowledge in the fields of epidemiology, pathophysiology, acute treatment, and preventive therapy over the past 100 years. Triptans have been the breakthrough in the treatment of acute migraine attacks. Beta blockers, calcium antagonists, and neuromodulators are available for preventive migraine therapy. Treatment for chronic tension headache is still unsatisfying. Cluster headache is part of the group of trigemino-autonomic headaches. Headache from medication overuse plays an increasingly important role. New medical care structures such as integrated headache care provide better support for patients with chronic headache disorders.

The aim of this study was to evaluate the efficacy and tolerability of topiramate for the prevention of chronic migraine in a randomized, double-blind, placebo-controlled trial. Chronic migraine is a common form of disabling headache presenting in headache subspecialty practice. Preventive treatments are essential for chronic migraine management, although there are few or no controlled empirical trial data on their use in this patient population. Topiramate is approved for the prophylaxis of migraine headache in adults. Patients (18-65 years) who experienced chronic migraine (defined as > or =15 monthly migraine days) for > or =3 months prior to trial entry and had > or =12 migraine days during the 4-week (28-day) baseline phase were randomized to topiramate or placebo for a 16-week, double-blind trial. Topiramate was titrated (25 mg weekly) to a target dose of 100 mg/day, allowing dosing flexibility from 50 to 200 mg/day, according to patient need. Existing migraine preventive treatments, except for antiepileptic drugs, were continued throughout the trial. The primary efficacy measure was the change in number of migraine days from the 28-day baseline phase to the last 28 days of the double-blind phase in the intent-to-treat population, which consisted of all patients who received at least one dose of study medication and had one outcome assessment during the double-blind phase. Health-related quality of life was evaluated with the Migraine Specific Quality of Life Questionnaire (MSQ, Version 2.1), the Headache Impact Test (HIT-6) and the Migraine Disability Assessment (MIDAS) questionnaires, and tolerability was assessed by adverse event (AE) reports and early trial discontinuations. Eighty-two patients were screened. Thirty-two patients in the intent-to-treat population (mean age 46 years; 75% female) received topiramate (mean modal dose +/- SD = 100 +/- 17 mg/day) and 27 patients received placebo. Mean (+/-SD) baseline number of migraine days per 4 weeks was 15.5 +/- 4.6 in the topiramate group and 16.4 +/- 4.4 in the placebo group. Most patients (78%) met the definition for acute medication overuse at baseline. The mean duration of treatment was 100 and 92 days for topiramate- and placebo-treated patients, respectively. Study completion rates for topiramate- and placebo-treated patients were 75% and 52%, respectively. Topiramate significantly reduced the mean number of monthly migraine days (+/-SD) by 3.5 +/- 6.3, compared with placebo (-0.2 +/- 4.7, P < 0.05). No significant intergroup differences were found for MSQ and HIT-6. MIDAS showed improvement with the topiramate treatment group (P = 0.042 vs. placebo). Treatment emergent adverse events were reported by 75% of topiramate-treated patients (37%, placebo). The most common AEs, paraesthesia, nausea, dizziness, dyspepsia, fatigue, anorexia and disturbance in attention, were reported by 53%, 9%, 6%, 6%, 6%, 6% and 6% of topiramate-treated patients, respectively, vs. 7%, 0%, 0%, 0%, 0%, 4% and 4% of placebo-treated patients. This randomized, double-blind, placebo-controlled trial demonstrates that topiramate is effective and reasonably well tolerated when used for the preventive treatment of chronic migraine, even in the presence of medication overuse.

Epidemiological data on trigeminal unilateral autonomic symptoms in patients with migraine are scarce. The authors wanted to provide a population-based evaluation of the prevalence of unilateral autonomic features in migraine patients and an assessment of the expression of unilaterality of autonomic symptoms and head pain in patients with UAs compared to other migraine patients. A population based sample of 6000 inhabitants of the city of Essen in Germany was screened using a previously validated standard questionnaire. Three thousand three hundred and sixty subjects (56% of a total 6000) responded. 841 subjects had migraine, out of which 226 reported accompanying unilatral auetonomic symptoms (26.9%, CI 95% [23.9-30%]). Unilateral autonomic symptoms in patients with migraine are common and have been widely underestimated in the past. One out of four migraine patients regularly experiences one or more unilateral autonomic symptoms during their attack. Migraine patients with accompanying autonomic symptoms seem to experience their pain more unilateral and more severe than non-UA patients.

Migraine is often associated with health consequences including impaired quality of life, and the cost of treating migraine headaches places a significant financial burden on patients who suffer from migraines. Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans are commonly used for the treatment of acute migraine attacks. Aspirin is widely accepted as a treatment option for migraine pain relief and could provide an alternative not only for treatment of moderate migraine attacks, but also for severe migraine attacks. The efficacy and safety of 1,000 mg effervescent aspirin (eASA) was evaluated in comparison to 50 mg sumatriptan and placebo in an individual patient data meta-analysis of three randomized, placebo-controlled, single- dose migraine trials. Pain-relief at 2 h, pain-free at 2 h and sustained pain-free up to 24 h were calculated. For eASA, the response rates were 51.5 % (95 % CI: 46.6-56.5 %), 27.1 % (95 % CI: 22.6-31.4 %), and 23.5 % (95 % CI: 19.3-27.7 %). For sumatriptan, the response rates were 46.6 % (95% CI: 40.0-53.2 %), 29% (95 % CI: 23.0-34.9 %), and 22.2 % (95 % CI: 16.7-27.6 %). The corresponding rates for placebo were 33.9 % (95% CI: 29.1-38.6 %), 15.1 % (95 % CI: 11.5-18.7 %), and 14.6 % (95 % CI: 11.0-18.1 %). The treatment effect of eASA and sumatriptan were significantly different from placebo (p < 0.001), but differences between eASA and sumatriptan were not significant. The remission of accompanying symptoms and the subgroup analyses of patients with moderate or severe migraine pain at baseline revealed no significant differences between eASA and sumatriptan. Safety was evaluated based on the frequency of reported adverse events, and treatment with eASA was associated with lower incidence of adverse events than was with sumatriptan. This individual patient data meta-analysis provided evidence that eASA 1,000 mg is as effective as sumatriptan 50mg for the treatment of acute migraine attacks and has a better side effect profile. This is also true for patients with moderate as well as severe headache at baseline. Patients therefore should be advised to use eASA first for migraine attacks and use a triptan in case of no response.

In routine clinical practice, the question whether instrumental examinations of patients with headaches should be carried out, is not always easy. If secondary headaches are suspected, with atypical presentation and focal neurological signs or symptoms, magnetic resonance imaging (MRI) may be indicated. In primary headaches, such as migraine, tension headache or trigemino-autonomic headaches, no further diagnostic procedures are warranted, as long as the clinical presentation is typical (i.e. corresponds to the International Headache Society guidelines) and neurological examination is normal. This article reviews the evidence from the literature and recommendations of European and American task forces regarding the use of instrumental examinations in case of non-acute primary headache.

Objective: To compare almotriptan and zolmitriptan in the treatment of acute migraine., Methods: This multicentre, double-blind trial randomized adult migraineurs to almotriptan 12.5 mg (n = 532) or zolmitriptan 2.5 mg (n = 530) for the treatment of a single migraine attack. The primary end point was sustained pain free plus no adverse events (SNAE); other end points included pain relief and pain free at several time points, sustained pain free, headache recurrence, use of rescue medication, functional impairment, time lost because of migraine, treatment acceptability, and overall treatment satisfaction., Results: No significant difference was seen in SNAE (almotriptan 29.2% vs zolmitriptan 31.8%) or the other efficacy end points measured. The incidence of triptan-associated AEs and triptan-associated central nervous system AEs was significantly lower for patients receiving almotriptan compared to zolmitriptan., Conclusions: Almotriptan and zolmitriptan were associated with similar efficacy and overall tolerability in the treatment of acute migraine. Almotriptan was associated with a significantly lower rate of triptan-associated AEs.

After the introduction of chronic migraine and medication overuse headache as diagnostic entities in The International Classification of Headache Disorders, Second Edition, ICHD-2, it has been shown that very few patients fit into the diagnostic criteria for chronic migraine (CM). The system of being able to use CM and the medication overuse headache (MOH) diagnosis only after discontinuation of overuse has proven highly unpractical and new data have suggested a much more liberal use of these diagnoses. The International Headache Classification Committee has, therefore, worked out the more inclusive criteria for CM and MOH presented in this paper. These criteria are included in the appendix of ICHD-2 and are meant primarily for further scientific evaluation but may be used already now for inclusion into drug trials, etc. It is now recommended that the MOH diagnosis should no longer request improvement after discontinuation of medication overuse but should be given to patients if they have a primary headache plus ongoing medication overuse. The latter is defined as previously, i.e. 10 days or more of intake of triptans, ergot alkaloids mixed analgesics or opioids and 15 days or more of analgesics/NSAIDs or the combined use of more than one substance. If these new criteria for CM and MOH prove useful in future testing, the plan is to include them in a future revised version of ICHD-2.

Patients with functional gastrointestinal disorders frequently report migraine. We aimed to determine the prevalence of idiopathic upper abdominal symptoms in patients with migraine and compare it with a control population of healthy blood donors. We assessed abdominal symptoms using the Bowel Disease Questionnaire in a series of 488 consecutive blood donors without migraine and 99 patients with migraine. Upper abdominal symptoms were reported by 38%[95% confidence interval (CI) 32, 44] of blood donors compared with 81% (67, 91, P<0.001) of migraine patients. Of the blood donors, 23% (18, 28) reported frequent dyspepsia compared with 60% (44, 74, P<0.001) of the migraine patients. Migraine was associated with frequent upper abdominal symptoms (odds ratio 2.7, 95% CI 1.2, 6.1) after adjusting for age, gender, smoking and consumption of analgesics and alcohol. Upper abdominal symptoms are significantly more frequent in patients with migraine compared with healthy controls. The association between migraine and idiopathic upper abdominal symptoms may suggest common pathophysiological mechanisms.

A randomized, controlled, cross-over trial compared single doses of 50 mg diclofenac potassium sachets and tablets with placebo in 328 patients with migraine pain, treating 888 attacks. For the primary endpoint 24.7% of the patients were pain free at 2 h postdose with sachets, 18.5% for tablets and 11.7% for placebo. Treatment differences were significant for sachets vs. placebo (P<0.0001), tablets vs. placebo (P=0.0040) and for sachets vs. tablets (P=0.0035). The numbers needed to treat compared with placebo to achieve pain free at 2 h were 7.75 [95% confidence interval (CI) 5.46, 13.35] for sachets and 15.83 (95% CI 8.63, 96.20) for tablets. Sachets were also statistically superior to tablets for sustained headache response, sustained pain free and reduction in headache intensity within the first 2 h postdose measured on a visual analogue scale (P<0.05). Onset of analgesic effect was 15 min for sachets and 60 min for tablets. Fewer patients needed rescue medication, and there were marked improvements in accompanying symptoms and working ability with both sachets and tablets vs. placebo. No safety issues were identified. This study demonstrates that sachets offer patients suffering from migraine pain a more effective treatment with a faster onset of analgesia when compared with tablets.

The prevalence of migraine in Germany is up to 14% in the female and up to 8% in the male population and peaks between the age of 35 and 45. Few studies have investigated the productivity loss and resulting costs attributable to migraine in Germany or addressed the question whether these costs can be reduced by optimal treatment. In recent years, 5-HT(1B/D) agonists (so-called triptans), a generation of drugs highly specific for migraine treatment, have been introduced. Seven 5-HT(1B/D) agonists have been approved in Germany with more than 20 dosage forms. We present a model that enables employers to estimate the annual cost of migraine and the annual cost that could be saved by treatment of migraine with rizatriptan compared with the use of non-specific antimigraine medication. A representative German company with 10,000 employees is used for the reference case analysis. This company is predicted to have 580 female and 284 male employees with migraine. These employees are estimated to lose 6992 workdays or 31.8 person years of productive effort annually due to migraine, valued approximately 1,431,719 euros. The value of work loss that could be avoided by treating migraine with rizatriptan is estimated at 619,094 euros annually. These data indicate that costs arising from lost productivity can be reduced by treating migraine headaches with a triptan.