Migraine Disorders: Göbel H

Anonymous00401, Olesen J, Bousser MG, Diener HC, Dodick D, First M, Goadsby PJ, Göbel H, Lainez MJ, Lance JW, Lipton RB, Nappi G, Sakai F, Schoenen J, Silberstein SD, Steiner TJ. · Department of Neurology, University of Copenhagen, Glostrup Hospital, Demark. · Cephalalgia. · Pubmed #16686915 No free full text.

Abstract: 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.

Göbel H. · Kiel Neurological Pain Centre, Kiel, Germany. · Rev Neurol (Paris). · Pubmed #16141959 No free full text.

Abstract: The target of non-drug treatment of migraine is to reduce attack frequency and intensity. To reach this goal, the general relationship between the patient and the physician, i.e. the drug consumer and prescriber, has to be changed fundamentally. To understand migraine attacks the patient must learn to distinguish between the cause of migraine, a special readiness of the brain to react, and the triggers of a headache attack. Today, we have access to effective methods that prevent inherited migraine from coming to an effect, or to effectively arrest an attack if it has nevertheless broken out. There are three available strategies: prevention by avoiding trigger factors, prevention via reduction of attack readiness and treatment of the acute effects of the migraine attack.

Göbel H. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Heikendorfer Weg 9-27, 24149 Kiel, Germany. · J Neurol. · Pubmed #14991336 No free full text.

Abstract: Migraine is a chronic headache disorder manifesting in attacks lasting 4-72 hours. Characteristics of headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea, photophobia and phonophobia. The migraine aura is a complex of neurological symptoms, which occurs just before or at the onset of migraine headache. Botulinum toxin A represents a completely new option for patients with chronic pain conditions. Numerous retrospective open-label chart reviews and 4 double-blind, placebo-controlled studies have demonstrated that botulinum toxin type A is significantly effective in migraine prophylaxis and reduces the frequency, severity, and disability associated with migraine headaches. Studies have generally reported a good and consistent efficacy. The differential therapeutic use of botulinum toxin appears to be worth attempting in migraine patients with the following characteristic features: (1) Muscular stress as migraine trigger, e. g., in craniocervical dystonia, pericranial painful muscular trigger points or tender points, oromandibular dysfunction, (2) concurrent chronic tension-type headache with the aggravating factors of muscular stress or oromandibular dysfunction, (3) chronic migraine with frequent migraine attacks on more than 15 days per month for longer than 3 months and if other therapeutic options have been either ineffective or have not been tolerated. The use of the agent does not cause CNS side effects. Migraine patients in particular, often suffer greatly, as a result of the adverse effects of the drugs used, from fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair loss and changes in libido. These side effects are not known in association with botulinum toxin A. To date, neither organic damage nor allergic complications have been reported. Thus, both the tolerability and the safety of this therapeutic measure are high. The mode of action by which botulinum toxin is effective in migraine prophylaxis is not fully understood and is under investigation. Currently, a number of other randomized, placebo-controlled, clinical trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A in the prophylaxis of migraine and other headache entities.

Göbel H. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Universität Kiel, Heikendorfer Weg 9-27, D-24149 Kiel. · MMW Fortschr Med. · Pubmed #14579489 No free full text.

Abstract: Medical treatment of migraine has the twofold task of cutting short an acute attack and preventing further episodes. Mild attacks are treated with analgesics and antiemetics. Fixed combination preparations are associated with the risk of analgesic-induced headaches and nephropathy and should not be employed. Severe attacks are treated with triptanes, depending on a number of features of the attack. A "migraine status" requires a special approach. When migraine occurs on more than seven days a month, prophylactic measures are indicated with the aim of preventing drug-induced headache. The objective is a 50% reduction in the number of attacks.

Göbel H, Heinze A. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Germany. · Schmerz. · Pubmed #11845342 No free full text.

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Göbel H, Heinze A, Heinze-Kuhn K, Jost WH. · Kiel Pain Clinic, Heikendorfer Weg 9-27 D-24149 Kiel, Germany. · J Neurol. · Pubmed #11357239 No free full text.

Abstract: The therapeutic effect of botulinum toxin in headache was observed coincidentally. The rationale for this new indication initially met with a great deal of scepticism, because the toxin's mechanism of action, cholinergic chemodenervation, does not fit the pathophysiological concept of migraine and other forms of headache. Meanwhile a fair number of studies have been published which indicate efficacy for botulinum toxin and recommend its use for the treatment of tension headache and migraine. According to the evidence-based medicine criteria, grade I evidence has been demonstrated. In addition the use of botulinum toxin for cluster-headache and secondary headache is discussed. Further large scale studies will be regarded to demonstrate the long-term efficacy.

Göbel H, Heinze A, Heinze-Kuhn K, Austermann K. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel in Kooperation mit der Universität Kiel, Heikendorfer Weg 9-27, 24149 Kiel. · Nervenarzt. · Pubmed #11320861 No free full text.

Abstract: For 20 years botulinum toxin A has been used for the treatment of a variety of disorders characterised by pathologically increased muscle contraction. Recently, treatment of tension headache, migraine, cluster headache, and myofascial pain syndromes of neck, shoulder girdle, and back with botulinum toxin A has become a rapidly expanding new field of research. Several modes of action are discussed for these indications. The blockade of cholinergic innervation reduces muscular hyperactivity for 3 to 6 months. Degenerative changes in the musculoskeletal system of the head and neck are prevented. Nociceptive afferences and blood vessels of the pericranial muscles are decompressed and muscular trigger points and tender points are resolved. The normalisation of muscle spindle activity leads to a normalisation of muscle tone and central control mechanisms of muscle activity. Oromandibular dysfunction is eliminated and muscular stress removed. However, the effect of botulinum toxin A cannot be explained by muscular actions only. Its retrograde uptake into the central nervous system modulates the expression of substance P and enkephalins in the spinal cord and nucleus raphe. Recent findings suggest an inhibition of sterile inflammation which may lead to a blockade of the neurogenic inflammation believed to be the pathophysiological substrate of primary headache disorders. The efficacy of botulinum toxin A in the treatment of pain disorders is being investigated in several studies at the moment. The results and experiences obtained so far present new alternatives in the treatment of chronic pain disorders. The practical use of botulinum toxin A is demonstrated.

Göbel H, Heinze A, Heinze-Kuhn K. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel in Kooperation mit dem Klinikum der Universität Kiel. · Dtsch Med Wochenschr. · Pubmed #10587715 No free full text.

This publication has no abstract.

Lipton RB, Göbel H, Einhäupl KM, Wilks K, Mauskop A. · Department of Neurology, Albert Einstein College of Medicine, 1165 Morris Park Ave., Rousso Bldg., Rm. 332, Bronx, NY 10461, USA. · Neurology. · Pubmed #15623680 No free full text.

Abstract: OBJECTIVE: To evaluate the clinical efficacy of a standardized special root extract from the plant Petasites hybridus as a preventive therapy for migraine. METHODS: This is a three-arm, parallel-group, randomized trial comparing Petasites extract 75 mg bid, Petasites extract 50 mg bid, or placebo bid in 245 patients with migraine. Eligible patients met International Headache Society criteria for migraine, were ages 18 to 65, and had at least two to six attacks per month over the preceding 3 months. The main outcome measure was the decrease in migraine attack frequency per month calculated as percentage change from baseline over a 4-month treatment period. RESULTS: Over 4 months of treatment, in the per-protocol analysis, migraine attack frequency was reduced by 48% for Petasites extract 75 mg bid (p = 0.0012 vs placebo), 36% for Petasites extract 50 mg bid (p = 0.127 vs placebo), and 26% for the placebo group. The proportion of patients with a > or =50% reduction in attack frequency after 4 months was 68% for patients in the Petasites extract 75-mg arm and 49% for the placebo arm (p < 0.05). Results were also significant in favor of Petasites 75 mg at 1, 2, and 3 months based on this endpoint. The most frequently reported adverse reactions considered possibly related to treatment were mild gastrointestinal events, predominantly burping. CONCLUSIONS: Petasites extract 75 mg bid is more effective than placebo and is well tolerated as a preventive therapy for migraine. Petasites 50 mg PO bid was not significantly more effective than placebo on the primary study endpoints.

Diener HC, Bussone G, de Liano H, Eikermann A, Englert R, Floeter T, Gallai V, Göbel H, Hartung E, Jimenez MD, Lange R, Manzoni GC, Mueller-Schwefe G, Nappi G, Pinessi L, Prat J, Puca FM, Titus F, Voelker M, Anonymous00008. · Department of Neurology, University Essen, Germany. · Cephalalgia. · Pubmed #15482357 No free full text.

Abstract: Acetylsalicylic acid (ASA) in combination with metoclopramide has been frequently used in clinical trials in the acute treatment of migraine attacks. Recently the efficacy of a new high buffered formulation of 1000 mg effervescent ASA without metoclopramide compared to placebo has been shown. To further confirm the efficacy of this new formulation in comparison with a triptan and a nonsteroidal anti-inflammatory drug (ibuprofen) a three-fold crossover, double-blind, randomized trial with 312 patients was conducted in Germany, Italy and Spain. Effervescent ASA (1000 mg) was compared to encapsulated sumatriptan (50 mg), ibuprofen (400 mg) and placebo. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (primary endpoint) was 52.5% for ASA, 60.2% for ibuprofen, 55.8% for sumatriptan and 30.6% for placebo. All active treatments were superior to placebo (P < 0.0001), whereas active treatments were not statistically different. The number of patients who were pain-free at 2 h was 27.1%, 33.2%, 37.1% and 12.6% for those treated with ASA, ibuprofen, sumatriptan or placebo, respectively. The difference between ASA and sumatriptan was statistically significant (P = 0.025). With respect to other secondary efficacy criteria and accompanying symptoms no statistically significant differences between ASA and ibuprofen or sumatriptan were found. Drug-related adverse events were reported in 4.1%, 5.7%, 6.6% and 4.5% of patients treated with ASA, ibuprofen sumatriptan or placebo. This study showed that 1000 mg effervescent ASA is as effective as 50 mg sumatriptan and 400 mg ibuprofen in the treatment of migraine attacks regarding headache relief from moderate/severe to mild/no pain at 2 h. Regarding pain-free at 2 h sumatriptan was most effective.

Göbel H, Heinze A, Niederberger U, Witt T, Zumbroich V. · Kiel Pain Clinic, Germany. · Cephalalgia. · Pubmed #15377321 No free full text.

Abstract: In this study we compared the efficacy of 1000 mg phenazone with that of placebo in the treatment of acute migraine attacks in a randomized double-blind, placebo-controlled study of 208 patients. The main target criterion was the number of patients with a pain reduction from severe or moderate to slight or no pain 2 h after taking the pain medication. The percentage of patients satisfying the main target criterion was 48.6% for phenazone and 27.2% (P < 0.05) for placebo. Freedom from pain after 2 h was reported by 27.6% with phenazone treatment and 13.6% (P < 0.05) with placebo. Compared with placebo, the phenazone treatment also resulted in a significant improvement in the associated migraine symptoms of nausea, phonophobia and photophobia. Of patients treated with phenazone 11.4%, and 5.8% of those treated with placebo reported adverse events. There was no significant difference between the groups with regard to numbers of patients with adverse events. No serious adverse events occurred. The results show that phenazone at a dosage of 1000 mg is effective and well tolerated in the treatment of acute migraine attacks.

Diener HC, Eikermann A, Gessner U, Göbel H, Haag G, Lange R, May A, Müller-Schwefe G, Voelker M. · Department of Neurology, University of Essen, Hufelandstrasse 55, DE-45147 Essen, Germany. · Eur Neurol. · Pubmed #15240983 No free full text.

Abstract: Recently a new effervescent acetylsalicylic acid (ASA) tablet with high buffering capacity has been developed. In this double-blind, 3-arm, multicenter, parallel-group study, 433 patients were treated either with 1,000 mg effervescent ASA or 50 mg encapsulated sumatriptan or placebo. The primary endpoint was the percentage of patients with complete remission of the 3 accompanying symptoms nausea, photophobia and phonophobia within 2 h after intake of the study drug. 43.8% of patients treated with ASA, 43.7% of patients treated with sumatriptan and 30.9% of patients treated with placebo showed complete remission of all 3 accompanying symptoms (p < 0.05 for ASA and sumatriptan vs. placebo). Both active treatments were superior to placebo regarding the individual symptoms photophobia and phonophobia, but not for nausea. The percentage of patients with reduction in headache severity from moderate or severe to mild or no pain (secondary objective) was 49.3% for ASA, 48.8% for sumatriptan and 32.9% for placebo. All active treatments were superior to placebo (p < 0.05). 25.3, 24.4 and 14.5% of patients treated with ASA, sumatriptan or placebo were pain free at 2 h. Drug-related adverse events were reported in 3.9, 4.7 and 6.7% of patients treated with placebo, ASA or sumatriptan. The study showed that administration of effervescent ASA leads to remission of the migraine symptoms nausea, photophobia and phonophobia, reduces migraine headache and is comparable to sumatriptan.

Christie S, Göbel H, Mateos V, Allen C, Vrijens F, Shivaprakash M, Anonymous00006. · Ottawa Headache Centre, Ottawa, Canada. · Eur Neurol. · Pubmed #12464714 No free full text.

Abstract: Rizatriptan is a selective 5-HT(1B/1D) receptor agonist with rapid oral absorption and early onset of action in the acute treatment of migraine. This randomized double- blind crossover outpatient study assessed the preference for 1 rizatriptan 10 mg tablet to 2 ergotamine 1 mg/caffeine 100 mg tablets in 439 patients treating a single migraine attack with each therapy. Of patients expressing a preference (89.1%), more than twice as many preferred rizatriptan to ergotamine/caffeine (69.9 vs. 30.1%, p < or = 0.001). Faster relief of headache was the most important reason for preference, cited by 67.3% of patients preferring rizatriptan and 54.2% of patients who preferred ergotamine/caffeine. The co-primary endpoint of being pain free at 2 h was also in favor of rizatriptan. Forty-nine percent of patients were pain free 2 h after rizatriptan, compared with 24.3% treated with ergotamine/caffeine (p < or = 0.001), rizatriptan being superior within 1 h of treatment. Headache relief at 2 h was 75.9% for rizatriptan and 47.3% for ergotamine/caffeine (p < or = 0.001), with rizatriptan being superior to ergotamine/caffeine within 30 min of dosing. Almost 36% of patients taking rizatriptan were pain free at 2 h and had no recurrence or need for additional medication within 24 h, compared to 20% of patients on ergotamine/caffeine (p < or = 0.001). Rizatriptan was also superior to ergotamine/caffeine in the proportions of patients with no nausea, vomiting, phonophobia or photophobia and for patients with normal function 2 h after drug intake (p < or = 0.001). More patients were (completely, very or somewhat) satisfied 2 h after treatment with rizatriptan (69.8%) than at 2 h after treatment with ergotamine/caffeine (38.6%, p < or = 0.001). Recurrence rates were 31.4% with rizatriptan and 15.3% with ergotamine/caffeine. Both active treatments were well tolerated. The most common adverse events (incidence > or = 5% in one group) after rizatriptan and ergotamine/caffeine, respectively, were dizziness (6.7 and 5.3%), nausea (4.2 and 8.5%) and somnolence (5.5 and 2.3%).

Göbel H, Heinze A, Heinze-Kuhn K, Lindner V. · Kiel Pain Clinic, Germany; Department of Neurology, University of Kiel, Germany. · Headache. · Pubmed #11264686 No free full text.

Abstract: As patients who suffer from migraine need long-term treatment, the safety and consistent efficacy of such therapy is very important. Concurrent illness and additional medication can interfere with the treatment chosen for the attacks of migraine. The objective of this open-label study was to investigate the efficacy and tolerability of rizatriptan, in the treatment of up to three attacks of migraine, in the clinical setting. From October 1998 to July 1999, 6 174 doctors enrolled 33 147 patients into the study (26 644 women, 650 men). The mean age was 42.7 years. We were able to examine standardized migraine diaries relating to 25 501 patients and 70 537 migrainous episodes. Rizatriptan scored consistently high on efficacy and showed a consistently rapid onset. There was no evidence of tolerance to repeated use. An effect was reported within 1 hour of ingestion in 79% of attacks treated. In 27.8% of attacks, remission of headache was complete at 1 hour. Two hours after ingestion, 74% of attacks had subsided completely. Repeated administration of rizatriptan was well tolerated, and few adverse effects were seen. The most common unwanted effects were dizziness, weakness, fatigue, and nausea. No cardiovascular disturbance was seen. In the clinical setting, rizatriptan, 10 mg, is an effective and well-tolerated agent for the treatment of migraine attacks. Particularly noteworthy is the rapid onset of effect, with swift disappearance of headache. Rizatriptan has a favorable side effect profile, and, provided contraindications are observed, severe adverse cardiovascular complications are extremely unlikely.

Göbel H, Winter P, Boswell D, Crisp A, Becker W, Hauge T, Mihout B, Niewold J, Tørring J. · Klinik fur Neurologie der University Kiel, Germany. · Clin Ther. · Pubmed #10972634 No free full text.

Abstract: OBJECTIVE: This randomized, double-blind, crossover study was undertaken to compare the incidence of headache recurrence after treatment with naratriptan or sumatriptan in migraine patients with a history of frequent headache recurrence (recurrence in > or =50% of successfully treated attacks). BACKGROUND: Although the selective 5-hydroxytryptamine, (5-HT1) agonist sumatriptan is effective and well tolerated for acute treatment of migraine in most patients, headache recurrence within 24 hours of initial successful treatment with sumatriptan and other medications has been reported in approximately 35% of patients. The novel 5-HT1 agonist naratriptan possesses pharmacologic and pharmacokinetic characteristics that may address the issue of headache recurrence. METHODS: Men and women aged 18 to 65 years with a > or =1-year history of migraine with or without aura were randomly assigned to treat 1 moderate or severe migraine attack in a nonclinical setting with one 2.5-mg naratriptan tablet and 1 attack with one 100-mg sumatriptan tablet. A pain-free interval of > or =24 hours was required between attacks. At 4 hours, patients not using rescue medication and experiencing headache recurrence could take a second, identical dose of study medication to treat recurrence. No more than 2 tablets of study medication were permitted in any 24-hour period. RESULTS: A total of 253 patients treated > or =1 migrane attack and were included in the safety analysis; the 225 patients who treated both attacks were included in the efficacy analysis. Of the 164 naratriptan-treated and 181 sumatriptan-treated patients experiencing headache relief after > or =1 attack, headache recurrence 4 to 24 hours after treatment was reported by 74 naratriptan-treated patients (45%) and 101 sumatriptan-treated patients (57%; not statistically significant). (One naratriptan- and 3 sumatriptan-treated patients who experienced headache relief did not record recurrence status and were not included in the denominator for the percentage calculation.) In a subset of patients experiencing headache relief after 2 attacks, headache recurrence 4 to 24 hours after initial dosing was reported by 55 naratriptan- and 77 sumatriptan-treated patients (41% and 57%, respectively; P = 0.005). The overall incidence of adverse events was 22% after treatment with naratriptan and 33% after treatment with sumatriptan. This incidence did not increase after use of a second dose of naratriptan (20%) or sumatriptan (31%). CONCLUSION: These data suggest that naratriptan is a long-acting and well-tolerated addition to currently available medications for the treatment of acute migraine.

Bertin L, Brion N, Färkkilä M, Göbel H, Wessely P. · Glaxo-Wellcome, Greenford, Middlesex, France. · Int J Clin Pract. · Pubmed #10692752 No free full text.

Abstract: In this dose-ranging, randomised, multinational, multicentre, double-blind, placebo-controlled, parallel group study, 431 patients treated a single migraine attack with study medication: sumatriptan suppository 6 mg, 12.5 mg, 25 mg, 50 mg, 100 mg, or placebo. Patients were treated in the clinic with a single dose in suppository form. All doses of sumatriptan, except 6 mg, were significantly better than placebo (p < 0.004) and achieved similar rates of headache relief within two hours of dosing. The highest response rate was in the 25 mg group (72%) compared with placebo (37%) (p < 0.001). Fewer patients required rescue medication in the active groups (1% 100 mg to 13% 6 mg) compared with placebo (17%), and more patients were able to work and function normally two hours after dosing (41%, 100 mg; 20%, placebo). The overall incidence of adverse events was similar in the placebo, 6 mg and 12.5 mg groups (14-17%) but higher in the 25 mg, 50 mg and 100 mg groups (25%, 32% and 29% respectively). Analysis of plasma sumatriptan levels indicated rapid rectal absorption for all doses (median tmax = 1.0 hr). It is concluded that sumatriptan, in doses above 6 mg, is an effective and well tolerated treatment for acute migraine. From this study doses of 12.5 mg and 25 mg sumatriptan were identified as having the best efficacy/safety profile and were evaluated further.

Todt U, Netzer C, Toliat M, Heinze A, Goebel I, Nürnberg P, Göbel H, Freudenberg J, Kubisch C. · Institute of Human Genetics, University of Cologne, Germany. · Hum Genet. · Pubmed #19152006 No free full text.

Abstract: In order to systematically test the hypothesis that genetic variation in the dopamine system contributes to the susceptibility to migraine with aura (MA), we performed a comprehensive genetic association study of altogether ten genes from the dopaminergic system in a large German migraine with aura case-control sample. Based on the genotyping results of 53 variants across the ten genes in 270 MA cases and 272 controls, three genes-DBH, DRD2 and SLC6A3-were chosen to proceed to additional genotyping of 380 MA cases and 378 controls. Four of the 26 genotyped polymorphisms in these three genes displayed nominally significant allelic P-values in the sample of 650 MA patients and 650 controls. Three of these SNPs [rs2097629 in DBH (uncorrected allelic P value = 0.0012, OR = 0.77), rs7131056 in DRD2 (uncorrected allelic P value = 0.0018, OR = 1.28) and rs40184 in SLC6A3 (uncorrected allelic P value = 0.0082, OR = 0.81)] remained significant after gene-wide correction for multiple testing by permutation analysis. Further consideration of imputed genotype data from 2,937 British control individuals did not affirm the association with DRD2, but supported the associations with DBH and SLC6A3. Our data provide new evidence for an involvement of components of the dopaminergic system-in particular the dopamine-beta hydroxylase and dopamine transporter genes-to the pathogenesis of migraine with aura.

Nyholt DR, LaForge KS, Kallela M, Alakurtti K, Anttila V, Färkkilä M, Hämaläinen E, Kaprio J, Kaunisto MA, Heath AC, Montgomery GW, Göbel H, Todt U, Ferrari MD, Launer LJ, Frants RR, Terwindt GM, de Vries B, Verschuren WM, Brand J, Freilinger T, Pfaffenrath V, Straube A, Ballinger DG, Zhan Y, Daly MJ, Cox DR, Dichgans M, van den Maagdenberg AM, Kubisch C, Martin NG, Wessman M, Peltonen L, Palotie A. · Genetic Epidemiology Laboratory, Queensland Institute of Medical Research, PO Royal Brisbane Hospital, Brisbane4029, Queensland, Australia. · Hum Mol Genet. · Pubmed #18676988 links to  free full text

Abstract: The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

Netzer C, Freudenberg J, Heinze A, Heinze-Kuhn K, Goebel I, McCarthy LC, Roses AD, Göbel H, Todt U, Kubisch C. · Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany. · Genomics. · Pubmed #18455362 No free full text.

Abstract: We performed the first replication study for the reported association of the insulin receptor gene (INSR) with migraine with aura (MA). Two of 35 SNPs (rs1052371 and rs2860174) reached borderline significance (best uncorrected allelic p value of 0.052 for rs2860174) in stage 1 of our study (270 MA patients, 280 controls). As rs2860174 was 1 of the 5 SNPs with prior evidence of association, we also genotyped this SNP in our stage 2 sample (679 MA patients, 368 controls), and it was nonsignificant (allelic p value 0.478). The combined analysis of our samples showed just a nonsignificant trend for rs2860174 (p=0.1). However, the joint analysis of our study and the initial study reporting an association-including 1278 Caucasian MA patients and 1337 Caucasian controls altogether-displayed a significant allelic p value of 0.005. In conclusion, further association studies for rs2860174 with even larger numbers of individuals are required to exclude or confirm definitely a small effect of this SNP on migraine susceptibility.

Göbel H, Heinze A. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Heikendorfer Weg 9-27, 24149 Kiel, Deutschland. · Schmerz. · Pubmed #17926068 No free full text.

Abstract: Whilst headache disorders belong to the most common health problems of the younger population, the occurrence diminishes with advancing age. However, in individual cases headaches may be especially severe in old age significantly reducing the quality of life. Typical causes of headache in the elderly are giant cell arteritis (arteritis temporalis), cranial neuralgia and hypnic headache. The incidence of intracranial mass lesions also increases with age. In addition to these secondary forms of headache, the typical primary headache disorders migraine, tension headache and cluster headache may also persist in the elderly. In drug treatment of headaches in the elderly, an impairment of renal and/or hepatic function has to be taken in account, as should be the potential multimorbidity of elderly patients.

Netzer C, Freudenberg J, Toliat MR, Heinze A, Heinze-Kuhn K, Thiele H, Goebel I, Nürnberg P, Ptácek LJ, Göbel H, Todt U, Kubisch C. · Institute of Human Genetics, University of Cologne, Cologne, Germany. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17680603 No free full text.

Abstract: Recently, a novel susceptibility locus for migraine with aura (MA) on chromosome 15q containing three GABA-A receptor subunits has been identified by linkage analysis in several large pedigrees. To further study the role of this locus in MA etiology we genotyped 56 SNPs capturing the known common haplotype variations of these three candidate genes in a sample comprising 270 MA patients and 273 matched controls. In a single marker analysis, four SNPs displayed nominally significant (P < 0.05) association with MA. However, after permutation-based correction for the number of tests performed, the P-values of these SNPs were non-significant. Furthermore, a replication study of two of these SNPs in a second independent sample of 379 MA patients and 379 controls did not result in a significant finding. We also compared haplotype estimates based on case-control genotypes. Again we could not demonstrate a significant association with the phenotype after correction for multiple testing. In summary, we found no convincing evidence for an involvement of common SNPs at the GABA-A receptor cluster on 15q11-q12 in the pathophysiology of MA.

Todt U, Freudenberg J, Goebel I, Heinze A, Heinze-Kuhn K, Rietschel M, Göbel H, Kubisch C. · Institute of Human Genetics, Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany. · Neurology. · Pubmed #17101915 No free full text.

Abstract: To replicate a reported association between migraine with aura (MA) and a promoter polymorphism in the serotonin transporter gene (SLC6A4), we performed a case-control study in a large German sample comprising 472 patients with MA and 506 controls. Neither this polymorphism nor a systematic analysis with single nucleotide polymorphisms capturing the main haplotype diversity of the SLC6A4 locus provided evidence for a contribution of SLC6A4 to the predisposition of complex inherited MA.

Göbel H, Heinze A, Heinze-Kuhn K. · Neurologisch-verhaltensmedizinische Schmerzklinik Kiel, Heikendorfer Weg 9-27, 24149 Kiel, Deutschland. · Schmerz. · Pubmed #17048020 No free full text.

Abstract: The treatment of migraine consists of the acute treatment of the migraine attack and prophylactic measures for either pharmacological or non-pharmacological management. Since the retreat of the ergotamines one can only choose between one of the well-established analgesics and one of seven triptans for the treatment of the migraine attack. Although neither a new triptan nor an innovative new application form has been introduced, the year 2006 will be remembered as the year when the first triptan (naratriptan) was released as a prescription-free over-the-counter drug and when the first sumatriptan generics were marketed in Germany. In addition to the beta-blockers metoprolol and propranolol and the calcium antagonist flunarizine two antiepileptic drugs, topiramate and valproic acid, have been rated as first-line prophylactic drugs in Germany. Due to an extensive and successful study program topiramate has been officially approved in Germany.

Göbel H, Gessner U, Petersen-Braun M, Weingärtner U. · Neurologisch-verhaltensmedizinische Schmerzklinik, Kiel, Deutschland. · Schmerz. · Pubmed #16955294 No free full text.

Abstract: BACKGROUND: The aim of the study was to investigate the efficacy and tolerability of acetylsalicylic acid in the treatment of acute migraine attacks by self-medication under daily life conditions when bought in a pharmacy and also the ability of patients to self-diagnose correctly. METHODS: A total of 296 patients were recruited from 156 pharmacies and recorded up to 3 migraine attacks. Following an advisory discussion the pharmacists gave a questionnaire to persons who had purchased acetylsalicylic acid (Aspirin Migraine) in the pharmacy to treat migraine. A total of 578 questionnaires containing 36 questions about demographic details, headache phenotype, medical history, efficacy over 2 h and tolerability of the preparation were analyzed. RESULTS: The IHS criteria (1988) for migraine were identified correctly by 92.7% of the patients. In 66.3% of the attacks, the intensity of the headache was reported as severe. In 60% of the documented attacks, a decrease from severe or moderate to mild or no headache was recorded after medication, and freedom from headache was achieved in 35.8%. The effect was reproducible over 3 migraine attacks. Nausea, photophobia and phonophobia were reduced by 71-86% compared to the baseline level. Side-effects were reported twice as often by the participants in response to closed questions than to open questions (16.6 vs. 8.3%). CONCLUSION: A high percentage of migraine patients are capable of diagnosing their condition themselves when they seek advice in a pharmacy. The data on efficacy confirm the results from controlled clinical studies. The same parameters as those used in controlled clinical studies can also be recorded in pharmacy-based observational studies, therefore, the safety and tolerability of the medication can be recorded under real conditions.

Todt U, Dichgans M, Jurkat-Rott K, Heinze A, Zifarelli G, Koenderink JB, Goebel I, Zumbroich V, Stiller A, Ramirez A, Friedrich T, Göbel H, Kubisch C. · Institut für Humangenetik, Universitätsklinikum Bonn, Bonn, Germany. · Hum Mutat. · Pubmed #16110494 No free full text.

Abstract: Migraine is a recurrent neurovascular disease. Its two most common forms-migraine without aura (MO) and migraine with aura (MA)-both show familial clustering and a complex pattern of inheritance. Familial hemiplegic migraine (FHM) is a rare monogenic subform caused by mutations in the calcium channel gene CACNA1A or the Na(+)/K(+)-ATPase gene ATP1A2. An involvement of FHM genes in the pathogenesis of common forms of migraine is not proven. We therefore systematically screened ATP1A2 in families with several members affected by MA and/or MO. We identified two novel missense alterations [c.520G>A (p.E174 K) and c.1544G>A (p.C515Y)] in two out of 45 families, which were not found in 520 control chromosomes. Functional studies of these variants in Xenopus oocytes by two-electrode voltage clamp measurements and radiochemical determination of ATPase activity showed that C515Y leads to a complete loss of function comparable with the effect of FHM-mutations whereas for E174 K no functional alteration could be found in the in vitro assays. In conclusion we propose that rare variants in ATP1A2 are involved in the susceptibility to common forms of migraine, because of 1) the absence of alterations in controls, 2) the particular pattern of segregation in both families, 3) the high conservation of mutated residues in Na(+)/K(+)-ATPases, 4) the functional effect of C515Y, and 5) the involvement of ATP1A2 in a monogenic form of migraine.