Migraine Disorders: Limmroth V

Silberstein S, Tfelt-Hansen P, Dodick DW, Limmroth V, Lipton RB, Pascual J, Wang SJ, Anonymous00408. · Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA. [corrected] · Cephalalgia. · Pubmed #18294250 No free full text.

Abstract: In 1991 the Clinical Trials Subcommittee of the International Headache Society (IHS) developed and published its first edition of the Guidelines on controlled trials of drugs in episodic migraine because only quality trials can form the basis for international collaboration on drug therapy, and these Guidelines would 'improve the quality of controlled clinical trials in migraine'. With the current trend for large multinational trials, there is a need for increased awareness of methodological issues in clinical trials of drugs and other treatments for chronic migraine. These Guidelines are intended to assist in the design of well-controlled clinical trials of chronic migraine in adults, and do not apply to studies in children or adolescents.

Diener HC, Katsarava Z, Limmroth V. · Universitätsklinik für Neurologie und Westdeutsches Kopfschmerzzentrum, Universitätsklinikum Essen, Hufelandstrasse 55, 45147, Essen, Germany. · Schmerz. · Pubmed #18219499 No free full text.

Abstract: 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.

Puppe A, Limmroth V. · Department of Neurology, Cologne City Hospitals, University of Cologne, Germany. · CNS Neurol Disord Drug Targets. · Pubmed #17691980 No free full text.

Abstract: Within the last decades significant progress has been made in the understanding of the underlying pathophysiological mechanisms of migraine. There is a general agreement now that migraine is not only a vascular phenomenon but also a genetically determined heterogenic ion-channelopathy resulting in cortical-spreading-depression-like events, the temporary impairment of antinociceptive structures of the brainstem and the activation of the trigeminal-vascular system. The development and use of drugs targeting ion-channels and subsequently reducing cortical excitability appears as a promising avenue for both the acute treatment of migraine and migraine prevention. This review summarizes the current knowledge and evidence for GABAergic drugs in the treatment of migraine.

Diener HC, Limmroth V. · Universitätsklinik für Neurologie, Essen. · Internist (Berl). · Pubmed #15995849 No free full text.

Abstract: With more than 8 million sufferers in Germany alone, migraine is one of the most frequent medical disorders. Recent discoveries in the pathophysiology and genetics of headaches, as well as specific developments in pharmacology, have paved the way for a significant improvement in both acute migraine treatment and migraine prevention. Within the group of 5-HT(1B/D)-agonists (triptans), seven substances with 23 dosages and formulations have been approved in Germany that allow the customized treatment of migraine attacks. In addition, several new drugs such as valproic acid or topiramate are now available as drugs of first choice for migraine prevention, as well as the well established beta blockers, thus enabling the physician to tailor the preventative treatment according to the individual needs of the patient.

Dowson AJ, Dodick DW, Limmroth V. · King's Headache Service, King's College Hospital, London, UK. · CNS Drugs. · Pubmed #15962999 No free full text.

Abstract: Medication overuse headache (MOH) is a common medical condition that is associated with considerable long-term morbidity and disability. Patients experiencing MOH have primary headache disorders (migraine, tension-type headache [TTH] or the combination of migraine and TTH) that change to a pattern of daily or near-daily headaches over a period of years or decades following the overuse of symptomatic headache medications. Overused drugs include analgesics, ergot alkaloids, serotonin 5-HT(1B/1D) receptor agonists ('triptans') and medications containing barbiturates, codeine, caffeine, tranquillisers and mixed analgesics. Affected patients usually have a long history of primary headache, overuse of medications and MOH before they consult a physician for care. Patients with MOH are usually managed in specialist centres by withdrawal of the overused drugs and treatment of withdrawal symptoms (on an inpatient or outpatient basis), headache prophylaxis and limited use of symptomatic acute medications. Most patients respond to this therapy, although the prognosis is not always good and >or=50% may lapse over an initial 5-year follow-up period. The best practical strategy at present is to prevent the overuse of drugs in the first place by patient education and formal management approaches conducted in primary care to treat the primary headache before it changes to MOH. The quality of the clinical evidence on MOH is suboptimal and further biological and clinical research is urgently required to help facilitate the management of these patients more effectively in the future.

Yoon MS, Savidou I, Diener HC, Limmroth V. · University Hospital Essen, Department of Neurology, Hufelandstrasse 55, 45122 Essen, Germany. · Expert Rev Neurother. · Pubmed #15938666 No free full text.

Abstract: Migraine headache is a chronic, painful, disabling and potentially progressive, condition primarily occurring in early and middle adulthood. For many patients, daily activities are impaired by the sudden and unpredictable occurrence of migraine attacks. In recent years, significant progress has been made in the field of migraine treatment. For the acute treatment of migraine attacks, 5-hydroxytryptophan(1B/D) agonists (so called triptans), were the most innovative development, successfully aborting attacks in less than 1 h. The search for innovative drugs usable for migraine prevention, however, was less successful, mainly due to the lack of reliable and predictive animal models. Recently, neuromodulators such as valproic acid and topiramate, initially developed as anticonvulsants, have been shown in large clinical trials to be effective in the prevention of migraine. As for the acute treatment of migraine attacks more than 10 years ago, large clinical trial programs are now setting new standards for evidence-based medicine in migraine prevention. This review summarizes the current options in migraine prevention with special emphasis on clinical trial design and new developments such as topiramate.

Kavuk I, Katsarava Z, Selekler M, Sayar K, Agelink MW, Limmroth V, Diener HC. · Department of Neurology, University of Diusburg-Essen, Essen, Germany. · Eur J Med Res. · Pubmed #15689304 No free full text.

Abstract: Inappropriate use of headache medication (>15 times/month) for the treatment of headache episodes may contribute to the development of chronic headache which is refractory to most treatments. Physicians experienced in the treatment of migraine and other headaches are well aware that the daily intake of antipyretic or antiinflammatory analgesics, opioids, ergot alkaloids and "triptans" may result in chronic daily headache. Conversely, if a patient complains of chronic headache and takes pain medication every day, this headache is most likely to be caused and sustained by the medication and will vanish or improve with abstinence. Treatment includes drug withdrawal followed by structured acute therapy and initiation of migraine prophylactic treatment.

Limmroth V, Hubrecht L, Diener HC. · Neurologische Klinik, Universitätsklinikum Essen. · Schmerz. · Pubmed #15322886 No free full text.

Abstract: In the past months significant new data have been published in the field of headache and migraine. With the publication of the second and revised version of the classification of headache disorders, new entities such as chronic migraine have been introduced. Moreover, the repertoire of drugs available for the treatment of migraine has changed as well. Whereas ergot derivatives have been almost completely taken off the market, seven triptans in 23 different preparations are now available and allow the physician to customize the treatment of acute attacks. CGRP antagonists, a completely new generation of anti-migraine compounds for the treatment of acute attacks, have now been tested successfully in clinical trials. For the prophylaxis of migraine, several agents that had been well established for decades have recently been taken off the market too, but new agents such as topiramate, which possesses different modes of action, have been tested successfully and are now available for the prophylaxis of migraine. The following review will summarize the newest developments in acute therapy and prophylactic treatment of migraine.

Diener HC, Limmroth V. · Department of Neurology, University Hospital Essen, Germany. · Lancet Neurol. · Pubmed #15261608 No free full text.

Abstract: Medication overuse and subsequent medication-overuse headache (MOH) is a growing problem worldwide. Epidemiological data suggest that up to 4% of the population overuse analgesics and other drugs for the treatment of pain conditions such as migraine and that about 1% of the general population in Europe, North America, and Asia have MOH. Recent clinical studies gave further insights in clinical and pharmacological features, such as critical monthly doses and frequencies. These features seem to vary significantly and depend on the primary headache disorder and the type of drug that is overused. Along with these findings the new international classification of headache disorders has now incorporated additional criteria and new headache entities that will facilitate the diagnosis of MOH. Withdrawal therapy is the only treatment for this disorder and clear restriction of monthly doses is the central requirement for successful prevention.

Limmroth V, Katsarava Z. · Department of Neurology, University Hospital Essen, Essen, Germany. · Curr Opin Neurol. · Pubmed #15167065 No free full text.

Abstract: PURPOSE OF REVIEW: The current literature on medication overuse headache will be reviewed with regard to clinical presentation, pathophysiology, therapy and prognosis in the light of the new headache classification. RECENT FINDINGS: Medication overuse headache is a widely unrecognized medical condition, which according to recent epidemiological studies has evolved to the third most frequent form of headache after tension-type headache and migraine. The first classification of headache disorders from 1988 defined medication overuse headache (formerly called 'drug-induced headache') on the bases of drugs that were available in the 1980s. For the most important anti-headache drugs, including triptans, new data on specific clinical features and more important mean critical monthly dosages and mean critical monthly intake frequencies are now available. Furthermore, recent prospectively conducted studies have revealed rates and predictors of relapse after successful withdrawal. SUMMARY: The newly available data on medication overuse headache may provide the basis for future consensus guidelines for the management of this condition.

Linde M, May A, Limmroth V, Dahlöf C, Anonymous00332. · Gothenburg Migraine Clinic and Institute of Clinical Neuroscience, Sahlgrenska University Hospital, Göteborg, Sweden. · Cephalalgia. · Pubmed #12950373 No free full text.

Abstract: Randomized placebo-controlled clinical trials have been the 'golden standard' during the last decades in the development of new drug therapies. This scientifically valid approach has recently been questioned in the fifth revised version of the Declaration of Helsinki, which states that the use of placebo-controlled clinical trials is only acceptable when no proven treatment exists for the studied disease. The World Medical Association further claims that no national ethical, legal or regulatory requirements should be allowed to reduce or eliminate any of the statements in the declaration. In spite of this, the document is not generally accepted as the world ethical standard, as demonstrated by its lack of adoption by many professional associations. In the evaluation process for a drug to be approved in many countries today, clinical investigators at the hospitals and researchers at the pharmaceutical companies are obliged to use study protocols that would be rejected if the new declaration were to be fully adopted. Adherence to the clinical trial guidelines of the International Headache Society could also mean violation of the new Helsinki declaration of ethics. Some ethics committees have already adopted the new declaration, which has caused concern among clinical investigators, who find this document to be vastly out of the line with common practice. At the moment, the situation is unclear and debated with increasing polarity concerning the scientific and ethical issues regarding the use of placebo in clinical trials.

Diener HC, Limmroth V. · Department of Neurology, University of Essen, Germany. · Curr Med Res Opin. · Pubmed #12463271 No free full text.

Abstract: Analgesics such as acetaminophen (paracetamol), acetylsalicyclic acid and non-steroidal anti-inflammatory drugs are effective in the treatment of migraine attacks. Comparative studies indicate that their efficacy is similar or slightly inferior to sumattriptan, a specific antimigraine drug. Few data on the efficacy of opioid drugs in the treatment of migraine are available. They seem to be effective but carry the risk of dependency and may cause drug-induced headache.

Limmroth V. · Neurologische Universitätsklinik Essen Hufelandstr. 55 45122 Essen. · Pharm Unserer Zeit. · Pubmed #12369163 No free full text.

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Diener HC, Limmroth V. · Department of Neurology, University Essen, Hufelandstr. 55, 45122 Essen, Germany. · Expert Opin Investig Drugs. · Pubmed #11772289 No free full text.

Abstract: Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. This review summarises new treatment options both for the therapy of the acute attack as well as for migraine prophylaxis. Analgesics like aspirin or non-steroidal anti-inflammatory drugs (NSAIDs) are effective in treating migraine attacks. Few controlled trials were performed for the use of ergotamine or dihydroergotamine. These trials indicate inferior efficacy compared with serotonin (5-HT(1B/D)) agonists (triptans). The triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan), are highly effective. They improve headache as well as nausea, photo- and phonophobia. The different triptans show only minor differences in efficacy, headache recurrence and adverse effects. The knowledge of their different pharmacological profile allows a more specific treatment of the individual migraine characteristics. Migraine prophylaxis is recommended, when more than three attacks occur per month, if attacks do not respond to acute treatment or if side effects of acute treatment are severe. Substances with proven efficacy include the beta-blockers metoprolol and propranolol, the calcium channel blocker flunarizine, several 5-HT antagonists and amitriptyline. Recently anti-epileptic drugs (valproic acid, gabapentin, topiramate) were evaluated for the prophylaxis of migraine. The use of botulinum toxin is under investigation.

Limmroth V, Michel MC. · Department of Neurology, University of Essen, Germany. · Br J Clin Pharmacol. · Pubmed #11560555 links to  free full text

Abstract: Migraine is one of the most frequent neurological disorders affecting up to 15% of the general population. Many patients require not only management of individual migraine episodes but also prophylactic treatment. beta-adrenoceptor blockers, flunarizine and valproic acid have been established as first-line agents for the prophylaxis of migraine attacks. Among the beta-adrenoceptor blockers propranolol and metoprolol are best documented and hence deserve preferential use. On the other hand, it appears that other beta-adrenoceptor blockers, perhaps with the exception of those with intrinsic sympathomimetic activity, can be equally effective. Uncertainties regarding the relative merits of various treatment modalities are largely caused by lack of adherence to specific requirements for clinical trials on migraine prophylaxis. Therefore, this article reviews internationally recommended conditions for reliable studies on migraine prophylaxis and appraises individual agents in the light of these criteria.

Diener HC, Kaube H, Limmroth V. · Klinik und Poliklinik für Neurologie, Essen. · Internist (Berl). · Pubmed #10798191 No free full text.

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Diener HC, Kaube H, Limmroth V. · Klinik und Poliklinik für Neurologie, Universität Essen. · Anaesthesist. · Pubmed #10631450 No free full text.

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Diener HC, Limmroth V. · Department of Neurology, University of Essen, Germany. · Curr Opin Neurol. · Pubmed #10499171 No free full text.

Abstract: Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia and phonophobia, and malaise. This review summarizes new treatment options for the therapy of acute attacks. Sumatriptan was the first specific serotonin-1B/D agonist for the treatment of acute migraine attacks. Apart from the oral and subcutaneous formulation, it is also available as nasal spray and suppository. The other new migraine drugs zolmitriptan, naratriptan, rizatriptan and eletriptan differ in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence and side-effects. Importantly, in clinical practice individual patients may show a preference for one treatment over another. New drugs in migraine treatment include substance-P antagonists, nitric oxide synthetase inhibitors and calcitonin gene-related peptide antagonists.

Diener HC, Kaube H, Limmroth V. · Department of Neurology, University of Essen, Germany. · J Neurol. · Pubmed #10463349 No free full text.

Abstract: Migraine is a paroxysmal disorder characterized by attacks of headache, nausea, vomiting, photophobia, phonophobia, and malaise. This review summarizes new treatment options for therapy of the acute attack. Mild or moderate migraine attacks are treated with antiemetics followed by analgesics such as aspirin, paracetamol, nonsteroidal anti-inflammatory drugs, or antiemetics combined with ergotamine or dihydroergotamine. Sumatriptan, a specific serotonin (5-HT)1B/D agonist is used when attacks do not respond to ergotamine, or when intolerable side effects occur. The new migraine drugs zolmitriptan, naratriptan, rizatriptan, and eletriptan differ slightly in their pharmacological profiles, which translates into minor differences in efficacy, headache recurrence, and side effects. New drugs in migraine prophylaxis include cyclandelate, valproic acid and magnesium.

Limmroth V, Katsarava Z, Diener HC. · Department of Neurology, University Hospital Essen, Germany. · Cephalalgia. · Pubmed #10448540 No free full text.

Abstract: Acetylsalicylic acid (ASA) is used to treat a broad range of symptoms and disorders. Since its discovery in 1897, it has been used to treat fever and rheumatic pain, to inhibit the formation of thrombocytes, to prevent myocardial ischemia and strokes, and as preventive medication against neoplasms. ASA is best known, however, as a headache medication. For this function alone, ASA underwent an evolution: from powder to tablet to effervescent and chewable tablets. In addition to these oral formulations, an injectable form was developed in the 1970s for intravenous and intramuscular application. Furthermore, coated (slow-releasing) tablets are now used in the prophylactic treatment of migraine. The various forms of ASA used to treat headache are discussed and the controlled studies conducted to evaluate ASA's efficacy in headache treatment are summarized.

Lampl C, Katsarava Z, Diener HC, Limmroth V. · Department of Neurology and Psychiatry, Pain and Headache Centre, Linz General Hospital, 4020 Linz, Austria. · J Neurol Neurosurg Psychiatry. · Pubmed #16291905 links to  free full text

Abstract: This study examined the efficacy of lamotrigine in the prevention of migraine aura. Fifty nine patients suffering from migraine with aura received lamotrigine in a controlled three year prospective open study. Treatment response was defined as a reduction of aura frequency each month by at least 50%. Primary endpoint was reached by three quarters of the patients. Lamotrigine significantly reduced both frequency of migraine aura (mean, 1.5 (SD, 0.6) each month before v 0.4 (0.7) after treatment; p < 0.001) and aura duration (mean, 27 (SD, 11) minutes before v 8 (14) after treatment; p < 0.001). Furthermore, more than three quarters of those patients with a reduction of aura symptoms experienced a significant reduction of frequency of migraine attacks (mean, 2.1 (SD, 1.0) each month before v 1.2 (1.1) after treatment; p < 0.001). Lamotrigine was highly effective in reducing migraine aura and migraine attacks. The strong correlation between reduction of aura symptoms and migraine attacks stresses the potential role of aura-like events and possibly cortical spreading depression as a trigger for trigeminal vascular activation, and subsequently the development of migraine headaches.

Leniger T, Pageler L, Stude P, Diener HC, Limmroth V. · Department of Neurology, University of Essen, Hufelandstr.55, 45122 Essen, Germany. · Headache. · Pubmed #15663612 No free full text.

Abstract: OBJECTIVE: The study compared efficacy and tolerability of intravenous valproate (iVPA) with intravenous lysine-acetylsalicylic acid (iLAS) in acute migraine attacks. Background.-iLAS has been proven to be a highly effective treatment in acute migraine attacks, but it is not available in many countries and contraindicated in patients with asthma or peptic ulcers. Current data suggest that iVPA may be effective in the treatment of acute migraine attacks. DESIGN/METHODS: In this randomized, double-blind, parallel-group phase-II study, 40 patients with acute migraine attacks (onset <5 hours, severe or moderate headache on a four-point IHS scale) alternately received iVPA 800 mg or iLAS 1000 mg. Primary outcome criteria were the percentage of patients reporting pain relief after 1 hour and patients who remained sustained pain free for 24 hours following drug administration. Secondary outcome criteria were relief of pain and associated migrainous symptoms (nausea, photophobia, and phonophobia) at 1, 2, 24, and 48 hours following drug administration. RESULTS: There were no significant differences in demographic and clinical features between both treatment groups. Percentage of pain relief after 1 hour in the iVPA and iLAS groups were 25% and 30%, respectively, and of sustained pain free for 24 hours were 20% and 30%, respectively, without significant differences (P = 1 and P= .72, respectively). Both drugs improved associated migrainous symptoms without significant differences at the different time points, but again with a trend in favor of iLAS. No adverse events were observed. CONCLUSION: Both drugs were effective in acute migraine attacks with a trend in favor of iLAS. As both drugs were well tolerated, further studies with higher doses of iVPA for the treatment of acute migraine attacks are recommended.

Katsarava Z, Limmroth V, Baykal O, Akguen D, Diener HC, Kaube H. · Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, UK. · Cephalalgia. · Pubmed #15265054 No free full text.

Abstract: The aim of this study was to investigate central anti-nociceptive mechanisms of i.v. acetylsalicylic acid (ASA) and oral zolmitriptan (ZOL) in migraine patients and healthy subjects using the 'nociceptive' blink reflex (nBR). Twenty-eight migraine patients received ASA (n = 14, 1000 mg i.v) or ZOL (n = 14, 5 mg p.o) during the acute migraine attack and interictally. Thirty healthy subjects received either ASA or ZOL vs. placebo using a double blind cross over design. nBR was recorded in all patients and subjects before, 60 and 90 min after treatment. ASA and ZOL did not inhibit nBR responses in healthy subjects. Both ASA and ZOL suppressed nBR responses (ASA by 68%, ZOL by 78%) only during the acute attack but not interictally. The data suggest, that the anti-nociceptive effects of migraine drugs on the trigeminal nociceptive processing are different during and outside an acute migraine attack.

Limmroth V, May A, Diener H. · Neurologische Universitätsklinik Essen, Germany. · Eur Neurol. · Pubmed #10023111 No free full text.

Abstract: Vasoconstrictive agents have been widely used in the treatment of migraine. These types of drugs have various side effects and are not suitable for many patients. Due to nausea or vomiting, nonoral treatment is often required, but only a few nonvasoconstrictive drugs exist in a parenteral form and are suitable for the treatment of acute migraine in the emergency setting. In a randomized, double-blind, crossover trial we evaluated the efficacy of 1,000 mg lysine-acetylsalicylic acid i.v. (LAS) compared to 0.5 mg ergotamine s.c. in 56 patients (112 attacks) with acute migraine. To gain further insight into the possible role of vasoconstriction, blood flow velocities (BFV) were measured in intra- and extracranial arteries using duplex sonography and transcranial Doppler sonography. Both agents were equally potent in relieving headache. Intravenous LAS resulted in a significantly faster relief and had fewer side effects. LAS had no effect on BFV. Ergotamine increased BFV in the middle cerebral artery only. No correlation was found between changes in BFV and the relief of headache. This is the first trial to compare the intravenous formulation of LAS in the treatment of migraine with another antimigraine medication and suggests that it is an effective and safe drug for the parenteral treatment of acute migraine attacks.

Putzki N, Pfriem A, Limmroth V, Yaldizli O, Tettenborn B, Diener HC, Katsarava Z. · Department of Neurology, University Hospital Essen, Essen, Germany. · Eur J Neurol. · Pubmed #19138330 No free full text.

Abstract: 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.