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To explore the role of a special butterbur root extract for migraine prevention in children and adolescents with severe migraines.
Two randomized and placebo-controlled trials with a total of 289 migraine patients have demonstrated the efficacy and safety of a special butterbur root extract in the reduction of migraine attacks in adults. We studied whether butterbur had the potential as an efficient and well-tolerated migraine preventive in children and adolescents.
108 children and adolescents between the ages of 6 and 17 were included in a multicenter prospective open-label study. Participants suffered from migraines diagnosed according to IHS classifications for at least 1 year. Patients were treated with 50 to 150 mg of the butterbur root extract depending on age for a period of 4 months. Treatment progression was recorded in migraine journals especially designed for children and adolescents.
77% of all patients reported a reduction in the frequency of migraine attacks of at least 50%. Attack frequency was reduced by 63%. 91% of patients felt substantially or at least slightly improved after 4 months of treatment. About 90% of each, doctors and patients, reported well-being or even improved well-being. Undesired effects (7.4%) included mostly eructation. No serious adverse events occurred and no adverse event caused a premature termination.
The results and low rate of adverse events in this open prospective migraine prevention study in children and adolescents are similar to the results of two multicenter placebo-controlled butterbur studies in adults. Butterbur root extract shows a potential as an effective and well-tolerated migraine prophylaxis also for children and teenagers.
... Its clinical efficacy in migraine therapy was evidenced in placebo-controlled double-blinded clinical investigations. A significant reduction in the frequency of migraine attacks was reported [3,4] particularly after four months of treatment [5,6]. In 2012, the American Academy of Neurology concluded butterbur to be effective for migraine prevention . ...
... Patients provided informed consent prior to the study entry and details of the clinical trials are given in . The HILI cases were evaluated according to the WHO-UMC system by an expert panel consisting of specialists in internal medicine/neurology, board certified pathologist and clinical pharmacologist and toxicologist. ...
... Unlike many HDS, it was extensively evaluated for safety and efficacy. In clinical studies, the spasmolytic properties and effectiveness in the prevention of migraine attacks was proven [5,6,21]. Therefore, butterbur extracts were recommended for migraine prevention ; however, reports of severe HILI cases (8 in Germany, 1 in UK and 1 in Austria) prompted concern regarding its safe use. ...
Petadolex®, a defined butterbur extract has clinically proven efficacy against migraine attacks. However, spontaneous reports indicate cases of herbal induced liver injury (HILI). While most HILI patients presented mild serum biochemistry changes (<3 ULN, dose range 50 to 225 mg/day; treatment duration 4–730 days) nine developed severe HILI (average time-to-onset 103 days, ALT-range 3–153; AST 2–104-fold ULN). HILI cases resolved after medication withdrawal though two patients required liver transplantation. Liver biopsies revealed an inconsistent injury pattern, i.e. necrosis, macrovesicular steatosis, inflammation, cholestasis, and bile duct proliferation. Causality assessment rated 3 cases likely, 13 possible, 8 unlikely and 24 as unclassifiable/unclassified. Note, 22 patients reported hepatotoxic co-medications especially during periods of pain. A no-observable-adverse-effect-level at 15-fold of the maximal clinical dose (3 mg/kg/day MCD) was established for rats. At >45 and 90-fold MCD bile duct hyperplasia was observed but could not be confirmed in an explorative minipig study at 218-fold MCD. Human hepatocyte studies at 49-fold Cmax serum petasins (=active ingredient) and therapeutic Ibuprofen, Paracetamol and Naratriptan concentrations evidenced liver transaminase and CYP-monooxygenase changes. Collectively, Petadolex® HILI cases are rare, idiosyncratic and frequently confounded by co-medications. A physician-supervised self-medication plan with herbs and pain relief medication is needed to minimize risk for HILI.
... This special extract is mainly available in the United States and Canada and is the only butterbur extract in the market with a proven published clinical efficacy in placebo-controlled randomized clinical trials of migraine prevention.  There is only one more well-characterized butterbur extract with published preclinical and clinical data available among the plethora of commercial butterbur products. However, this extract (ZE399) is used for seaso- nal rhinitis and is made from leaves of P. hybridus. ...
... Attack frequency reduced by 63% from baseline. 3 ...
... Liver enzymes were not analyzed in this noninterventional study. 3 Between 1972 and November 2015, a total number of 233 suspected adverse drug reactions have been reported outside of clinical trials 14 ; 198 of these spontaneous reports came from German patients/doctors, 20 reports from Swit- zerland, five reports from the United Kingdom, one report from Austria, and nine from the United States. ...
Butterbur supplements are available in the USA and Canada and are commonly used for treating migraines. Petadolex, a special butterbur extract from Petasites hybridus, is a natural herbal product and the only butterbur extract with proven clinical efficacy in migraine prevention. The Complimentary Migraine Guidelines of the AAN mention butterbur as level A recommendation for the prevention of chronic episodic migraine. However, these guidelines have been retired.
... In its purified form, Petasites has antispasmodic and anti-inflammatory properties, and is believed to be the reason it has been effective in the treatment of migraine in adults [ Grossman and Schmidramsel, 2001;Lipton et al. 2004]. There have been two studies published on use of Petasites in children and adolescents [ Pottman and Danesch, 2005;Oelkers-Ax et al. 2008]. A small pediatric randomized controlled study showed that Petasites improved migraine frequency, although there was no difference at 6-month follow up [Pottman and Danesch, 2005]. ...
... There have been two studies published on use of Petasites in children and adolescents [ Pottman and Danesch, 2005;Oelkers-Ax et al. 2008]. A small pediatric randomized controlled study showed that Petasites improved migraine frequency, although there was no difference at 6-month follow up [Pottman and Danesch, 2005]. In a larger uncontrolled study in children with episodic migraine, Petasites was given at doses ranging from 50 mg to 150 mg for 4 months [Oelkers-Ax et al. 2008]. ...
The recognition of the diagnosis of migraine in children is increasing. Early and aggressive treatment of migraine in this population with the use of over-the-counter medications has proven effective. The off-label use of many migraine-specific medications is often accepted in the absence of sufficient evidenced-based trials. Mild to severe cases of migraine should be treated with nonsteroidal anti-inflammatory drugs, with triptans used in moderate to severe headaches unresponsive to over-the-counter therapy. Rescue medication including dihydroergotamine [DHE] should be used for status migrainosus, preferably in the hospital setting. Antiemetics that have antidopaminergic properties can be helpful in patients with associated symptoms of nausea and vomiting through their action on central migraine generation. Furthermore, patients and families should be educated on nonpharmacologic management such as lifestyle modification and avoidance of triggers that can prevent episodic migraine.
... However, the Petadolux formulation had undetectable levels of the pyrrolizidine alkaloids which were not the case for several other formulations . An open-label trial of Petadolux 50 mg to 150 mg daily in 108 children and adolescents with migraine demonstrated 77% of patients had at least a 50% reduction in attack frequency . ...
Only in recent years has there been a mandate, if you would, to study newer pharmaceutical agents in children and adolescents. As such, there is a paucity of well controlled clinical trials, let alone drugs that have been through registration trials in these age groups. Migraine, while less common especially in children than adults however still requires treatment. This has led healthcare providers to utilize treatments from the ?adult? world in these younger patients. Even in the adult population there are relatively few agents that are approved by the Food and Drug Administration (FDA) or other regulatory bodies compared to the many treatments that are given for the treatment of migraine. These treatments have varying levels of evidence for efficacy and tolerability. Multiple guidelines and recommendations have been published in recent years examining the evidence based medicine of migraine treatment offering guidance oriented towards primary care clinicians and neurologists whose primary focus is not headache medicine.
... Herbal medicines have been used for centuries for alleviating pain and headaches. showed a beneficial action in migraine prevention ( Grossmann and Schmidramsl 2000;Lipton et al. 2004;Pothmann and Danesch 2005). These studies led to the indication by the American Headache Society guidelines with a level A recommen- dation of butterbur for migraine prophylaxis (Holland et al. 2012). ...
The benefit reported in a variety of clinical trials by a series of small molecule antagonists for the calcitonin gene-related peptide (CGRP) receptor, or four monoclonal antibodies against the neuropeptide or its receptor, has underscored the release of CGRP from terminals of primary sensory neurons, including trigeminal neurons, as one of the major mechanisms of migraine headaches. A large variety of excitatory ion channels and receptors have been reported to elicit CGRP release, thus proposing these agonists as migraine-provoking agents. On the other side, activators of inhibitory channels and receptors may be regarded as potential antimigraine agents. The knowledge of the intracellular pathways underlying the exocytotic process that results in CGRP secretion or its inhibition is, therefore, of importance for understanding how migraine pain originates and how to treat the disease.
... Im Einzelfall kann eine sinnvolle Indikation bestehen. Kriterien für eine Migräneprophylaxe sind: Migränepatienten im Alter von 6–17 Jahren belegt . In Einzelfällen sind aber schwer wiegende Leberfunktionsstörungen beschrieben worden, und Pestwurz sollte nicht kritiklos unter der Vorgabe " Phytotherapie gleich nebenwirkungsfrei " empfohlen werden. ...
Update Leitthema Kopfschmerzen bei Kindern nehmen in ihrer Häufigkeit zu. Sie werden im Vorschulalter bereits von bis zu 20%, nach der Grundschule von 80% der Kinder angegeben. Somit gewinnen deren Diagnostik, Klassifikation und Therapie im Kindesalter immer mehr an Bedeutung. Die am häufigsten be-richtete Kopfschmerzart ist Span-nungskopfschmerz, aber auch Mi-gräne spielt eine immer größere Rol-le. Ihre Therapie erfolgt stufenweise, abhängig vom Schweregrad.
... The pharmacological effects are due to the components petasin and isopetasin, which likely have anti-inflammatory and vasoconstrictor activity. A large prospective multicenter openlabel study conducted on young migraineurs found a reduction of 50% of attacks . ...
... Otherwise, if trading of crude drugs is abandoned and laborious methods are applied for producing a standardized medicine, then pre-extraction and elimination of dehydroPAs, e.g., by supercritical fluid extraction with carbon dioxide (EPO, 1992), might be a way to take advantage of the pharmacologically beneficial metabolites in asmachilca. For example, such an approach has been developed with Common Butterbur (Petasites hybridus), used to treat migraine symptoms, to develop medicinal products containing the presumed bioactive sesquiterpene petasins, but without the potentially toxic dehydroPAs (Pothmann and Danesch, 2005). ...
The literature on complementary and alternative medicine (CAM) is expanding. One of the most common conditions for which CAM is studied in the pediatric population is migraine. Nutraceuticals are a form of CAM that is being used for pediatric migraine prophylaxis.
A literature search was carried out in order to identify both observational studies and randomized controlled trials on the use of nutraceuticals for the prophylaxis of pediatric migraine. Adult studies on included nutraceuticals were also reviewed.
Thirty studies were reviewed on six different nutraceuticals: butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10 and polyunsaturated fatty acids.
Overall, the quality of the evidence for the use of nutraceuticals in pediatric migraine prophylaxis is poor. Further research needs to be done in order to study the efficacy of nutraceuticals for the prophylaxis of pediatric migraine.
Herbal (botanical) therapy has been used as treatment for headache disorders for millennia. Botanical therapy can be divided into 3 categories: oral, topical, and "aromatherapy." In this article, the options in these categories and the evidence supporting their use are discussed. Unfortunately, evidence is sparse for most herbal treatments, in large part due to a paucity of funding for the type of studies needed to assess their efficacy. Butterbur and feverfew are the 2 herbal oral preparations best studied, and they seem to have real potential to help many patients with migraine and perhaps other headache types. Patients most appropriate for trials of herbal therapy include those who have been refractory to pharmaceutical and other modes of therapy, patients who have had intolerable side effects from pharmaceutical medications, and patients willing to participate in controlled comparative studies. As for mechanisms behind botanical treatments, the lack of funding for studying these agents will continue to retard progress in this area as well, but hopefully the future will bring more concentrated efforts in this field.
Although many patients with migraine get positive benefits from conventional pharmacological treatments, many others do not benefit sufficiently or experience adverse effects from these treatments. For that reason, these patients usually seek complementary and/or alternative medical (CAM) treatments all over the world. In general, although CAM therapies are not recommended by neurologist in Turkey, most of migraine patients, who do not respond conventional medicine treatments, seek alternative therapy. Acupuncture, botulinum toxin, mind-body interventions, and nutraceutical options are the most popular treatments. In this review, the available evidence for all these treatments will be discussed.
The use of herbal therapies is ancient and increasing worldwide. There is a growing body of evidence supporting the efficacy of various "complementary" and alternative medicine approaches in the management of headache disorders. Promising tools to treat migraine patients are herbal products. In particular constituents of Petasites hybridus, Tanacetum Parthenium and Ginkgo Biloba have shown antimigraine action in clinical studies. A miscellaneous of recreational drugs and other herbal remedies have been supposed to have a role in headache treatment but quality of clinical studies in this field is low and inconclusive. Further research is warranted in this area.
Migraine in children is a common disorder that may present, at least initially, with a range of symptoms atypical from those of the adult form. The diagnostic procedure needs to recognise this, as well as the more typical headache and non-headache symptoms, if it is to be successful. However, a better driver of treatment need than diagnostic label is the impact the headache has on the patient's daily life. Treatment options are more limited than those available for adults, but most children can be provided with an effective acute medication by the GP. Paracetamol and ibuprofen can be recommended as initial therapies, with sumatriptan nasal spray reserved for rescue. Prophylactic medications are more problematic, due to an inadequate evidence base for efficacy, and are probably best left to the specialist. Long-term follow-up is essential to monitor the progress of this chronic illness to resolution, or to the development of adult-type symptoms. For management to be successful, healthcare professionals need to liaise with the patient, their parents or carers and peers, and with teaching professionals. Using these principles, the GP can provide effective management for the majority of children with migraine. Management of children with chronic headaches offers more challenges to the GP, and patients are probably best referred to a specialist physician. The GP should consider substance abuse as a possible cause of these headaches.
While headaches in children are quite common, the study and characterization of headache disorders in the pediatric age group has historically been limited. In the absence of controlled studies on prophylactic treatment of the primary headache disorders in this age group, the diagnosis of childhood migraine rests on criteria similar to those in adults. Data from adult studies are often extrapolated and applied to children as well. Although it appears that many preventive agents are safe in children, none are currently FDA-approved for this age group. As a result, despite experiencing significant disability, the vast majority of children who present to their physician with migraine headache do not receive prophylactic therapy. Furthermore, controlled clinical trials investigating the use of both abortive and preventive medications in children have suffered from high placebo response rates. The shorter duration of headaches and other characteristic features seen in children are such that designing randomized controlled trials in this age group is more problematic and limiting. As such, treatment practices vary widely, even among specialists, due to the absence of evidence-based guidelines from clinical trials.
Migraine has a heavy socioeconomic impact in terms of lost productivity and burden on the health care system. The efficacy of current drug regimens in migraine prophylaxis is limited, and therapeutic alternatives are needed. These include a range of herbal medicines based on butterbur, feverfew, St John's wort, and Ginkgo. Of these, Petadolex®, an extract of the butterbur root, is the most promising. Petadolex® has been investigated in four studies, including one good quality clinical trial involving 202 patients, two randomized controlled trials with smaller cohorts including adults and children, and a large observational, open-label study. However, post-marketing surveillance only supports its safety at lower doses and over treatment durations shorter than those used in the clinical trials. Moreover, the long-term safety of the product has been called into question, leading to withdrawal in some European countries. This review draws an overall picture of this complex set of data. The safety and efficacy of Petadolex® remains a matter of debate by a number of clinical, regulatory, and professional bodies.
The incidence of migraine headaches in childhood is increasing. Migraines are often difficult to diagnose in pediatrics and even more difficult to treat and prevent. In order to decrease the impact of the condition on the child and the family, prophylactic treatment is recommended if the child is experiencing disabling migraines. The medications currently prescribed for the prevention of pediatric migraines often have significant side effects and are of questionable therapeutic value. For those patients and parents who are interested in alternative therapies and natural remedies for preventive treatment of pediatric migraines, butterbur extract derived from the butterbur plant, Petasites hybridus, has emerged as a promising treatment. This paper discusses the impact of migraines among pediatric patients, the rationale for the preventative treatment of pediatric migraines, the current therapies and the relevance of butterbur extract as a prophylactic treatment for migraines in this patient population.
Preparations from rhizomes of Petasites hybridus (L.) Gaertn., B. Mey. & Scherb. (common
butterbur) have a long history of use in folk medicine in treatment of several diseases
as anti-inflammatory and spasmolytic drugs. Extracts from this species are of interest
to researchers in the field of phytopharmacology due to their biologically active compounds,
particularly two eremophilane sesquiterpenes (petasin and isopetasin), which
are contained not only in rhizomes and roots, but also in leaves. Moreover, P. hybridus
contains pyrrolizidine alkaloids, which showed hepatotoxic, carcinogenic and mutagenicproperties. Hence, special extracts devoid of alkaloids obtained by sub- and super-critic
carbon dioxide extraction were used in the preclinical, clinical studies and phytotherapy.
Our review aims to provide a literature survey of pharmacological as well as clinical trials
of P. hybridus, carried out in 2000–2013. Also several studies of other species used
in non-European countries have been included. Besides, the botanical description of
Petasites genus and phytochemical characteristic of P. hybridus and toxicological studies
of pyrrolizidine alkaloids as well as chemical profile of patented commercial extracts
from rhizomes, roots and leaves of this species used in European phytotherapy have
been performed. In this review, attention has also been paid to the promising and potential
application of special extracts of P. hybridus not only in the prevention of migraine,
treatment of allergic rhinitis symptoms, asthma and hypertension, but also in prevention
and slowing the progression of neurodegenerative diseases developing with the
inflammatory process in the CNS as a new therapeutic strategy. In fact, there is already
an evidence of promising properties of P. hybridus extracts and sesquiterpens – decrease
in the prostaglandins and leukotrienes release, inhibition of COX-1 and COX-2 activity,
as well as antagonism of L-type voltage-gated calcium channels. In order to explain the
new mechanisms of action of P. hybridus extracts in the CNS and their future application
in phytotherapy of diseases with neuroinflammatory process, further studies should be
To determine how common it is for parents to give natural health products (NHPs) to their children, which NHPs are being used, why they are being used, and parents' assessments of the benefits and side effects of NHPs.
Newfoundland and Labrador.
Parents waiting in their family doctors' offices.
Parent and child demographic characteristics; pediatric chronic medical conditions affecting the children; prescribed medications, over-the-counter medications, and NHPs used by the children; why the medications and NHPs were being used, the dose, and parents' assessments of the effectiveness and side effects; and where parents had heard about the NHPs, whether they had told their physicians that the children were taking the products, and where they had obtained the products.
A total of 202 (53.4%) of the 378 eligible adults who were approached completed the survey. This represented 333 children. Mean (SD) age of the children was 5.1 (3.3) years. Overall, 28.7% of parents reported using nonvitamin NHPs for their children. A total of 137 children (41.1%) had taken NHPs (including vitamins); 61.1% of the NHPs being used were vitamins. The remainder fell under teas (primarily chamomile and green teas), echinacea, fish or omega-3 oils, and a large category of "other" products. These NHPs were most commonly used to improve general health, improve immunity, and prevent colds and infections. Approximately half of the parents (51.7%) believed their children had benefited from taking NHPs, and 4.4% believed their children had experienced adverse side effects. Slightly less than half of the parents (45.0%) had informed their physicians that their children were taking NHPs.
Overall, 45.5% of parents attending physicians' offices reported using NHPs in their children. If vitamins are not included in the definition of NHPs, this rate drops to 28.7%. Parents most commonly use NHPs to maintain the general health of their children, to prevent colds, and to boost children's immune systems. About half of the parents believed the NHPs helped, very few had noticed any side effects, and approximately half had informed their physicians that they were giving their children NHPs.
Complementary and alternative medicine (CAM) is widely used by both physicians and patients with primary headache syndromes. Despite a considerable number of articles addressing CAM in primary headache syndromes, the overall evidence for CAM is still poor. The aim of this review was to give an overview of the current evidence of the main alternative therapies used in the treatment of primary headache syndromes of childhood. MEDLINE and Cochrane Library were systematically searched for articles dealing with complementary and alternative treatment or prophylaxis of headache and migraine published within the past 20 years.
Purpose of review:
This review covers recent advances in our understanding of migraine and childhood periodic syndromes in children and adolescents, as well as the treatment of these disorders.
The childhood periodic syndromes include benign paroxysmal torticollis, benign paroxysmal vertigo, abdominal migraine, and cyclic vomiting syndrome. Recent research suggests infant colic may also fit into this category. Migraine headache is common in children and adolescents, and chronic migraine effects 0.8-1.8% of adolescents and 0.6% of children. Two triptans are now FDA-approved for the acute treatment of migraine in pediatric patients. For preventive therapy, a number of medications have been studied and a major national trial is ongoing.
Childhood periodic syndromes are thought to be early life expressions of those genes that later in life are expressed as migraine headache. Future research into mechanisms of identifying children with these disorders prior to extensive and often invasive testing would be of benefit to these families and children. Migraine-specific therapies are now approved for the acute treatment of migraine in pediatric patients. Preventive migraine therapy is indicated in appropriate patients, although which medications are most effective in children is an area of active research.
Die herausragendsten Publikationen und Erkenntnisse zu Epidemiologie, Pathophysiologie und Therapie von Kopfschmerzen aus der zweiten Hälfte 2004 und der ersten Hälfte 2005 werden zusammengefasst. Die Diskussion über ein potenzielles Schlaganfallrisiko bei Patienten mit Migräne wird lange kontrovers geführt. Die CAMERA-Studie wies bei Patienten, die häufig Migräne mit Aura haben, subklinische Infarkte im Kleinhirn nach. In Folgestudien wurden sogar kognitive Defizite bei Patienten mit Migräne mit Aura postuliert. Widerlegt wurde die Hypothese durch eine dänische Zwillingsstudie an 1393 Zwillingen von denen 536 an Migräne litten und die in kognitiven Tests keine Unterschiede aufwiesen. Die Women Health Study (n = 39 754) belegt, dass Frauen mit Migräne mit Aura ein 1,53fach erhöhtes Schlaganfallrisiko haben. In einer holländischen Arbeit konnte gezeigt werden, dass vaskuläre Risikofaktoren inkl. Nikotin bei Patienten mit Migräne mit Aura signifikant häufiger auftreten, dies erklärt das erhöhte Schlaganfallrisiko in der Gruppe. Über die bekannten Genloki (Chromosom 19, neuronaler Kalziumkanal und Chromosom 1 Natrium-Kalium-Pumpe) konnte nun ein weiterer Genlokus auf Chromosom 2q24 dargestellt werden, der einen neuronalen, spannungsabhängigen Natriumkanal kodiert. Die Schwere des Kopfschmerzes ist ein valider Prädiktor für die Wirksamkeit eines Triptans. Die Therapieempfehlung lautet bei Patienten, die Migräne von Spannungskopfschmerzen unterscheiden können, bereits leichte Kopfschmerzen zu behandeln. Mittlerweile sind mehrere Publikationen erschienen, die die Wirksamkeit verschiedener Formulierungen (nasal, geringere Dosen für s. c. Gabe) belegen und auch die Sinnhaftigkeit eines Triptanwechsels bei Nonrespondern für ein Triptan bestätigen. Die Auswertung der bestehenden Schwangerschaftsregister zeigt keinen Hinweis auf Teratogenität der Triptane. Bei triptannaiven Patienten ist die lösliche Form einer neuen Galenik von Azetylsalizylsäure genauso gut wirksam wie Sumatriptan. Aufgrund des hohen Placeboeffektes bei Kindern und Jugendlichen sind bisher nur die Wirksamkeit von Ibuprofen und Sumatriptan nasal belegt worden, was sich in Therapieempfehlungen widerspiegelt. Neue Studien zur Migräneprophylaxe belegen die Wirksamkeit von Venlafaxin, Coenzym Q und Pestzwurz sowie Topiramat, membranstabilisierende Substanzen wie Lamotrigin scheinen insbesondere bei der Prophylaxe der Aura sinnvoll. Zwischen der Wirksamkeit von Akupunktur und Scheinakupunktur besteht in der bisher veröffentlichten Studie kein Unterschied. Clusterkopfschmerz: singuläre Gaben von Methylprednison in höherer Dosierung sind nicht prophylaktisch sinnlos, möglicherweise aber die Gabe von langwirksamen Triptanen als abendliche Einmalgabe. Die ventroposteriore Stimulation mit tiefen Hirnelektroden im Hypothalamus bleibt experimentell und suizidalen, therapierefraktären Patienten vorbehalten. Die Gammaknifetherapie kann derzeit nicht propagiert werden. Botulinumtoxin ist in der Behandlung des chronischen Spannungskopfschmerz nicht signifikant besser als Plazebo jedoch stehen weitere Studien aus, um abschließend über die Wirksamkeit zu entscheiden.
Objective: Complementary and alternative medicine (CAM) is widely used in patients with primary headache syndromes. The aim of this review is to give an overview of the current evidence concerning CAM use in children with headache. Methods: Medline and Cochrane library were systematically searched for articles dealing with CAM in children with headache taking into account articles published within the past 20 years. Results: Despite increasing CAM use in the multidisciplinary treatment of headache in children and adolescents, only very few clinical trials of higher quality exist. Only in acupuncture a certain level of evidence concerning efficacy for headache prophylaxis in children exists. Conclusion: There is still limited evidence concerning efficacy of CAM methods in children with headache. Randomised controlled trials with adequate numbers of cases are highly warranted.
Headache is one of the most common problems in children and particularly in adolescents in both the inpatient and outpatient settings. Unique challenges to making a diagnosis include the fact that young children may have difficulty describing and recalling their headache and associated symptoms. Therefore, headache in children is often unrecognized, under diagnosed and under treated. Familiarity with common headache syndromes in children combined with careful history taking from parents, and a thorough examination is crucial to exclude secondary etiologies and making the appropriate diagnosis. Knowledge of the variety of acute, prophylactic, and nonpharmacologic treatments of primary headache disorders is crucial to the success of managing headache in the pediatric age group.
Purpose of review:
Nutraceuticals are a form of complementary and alternative medicine that is commonly used by children and adolescents with migraine. In this review, observational studies, randomized controlled trials, systematic reviews, and meta-analyses on the efficacy and safety of single compound nutraceuticals for the management of migraine in children and adolescents were identified through a literature search of MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials.
Twenty-one studies were reviewed, of which 11 were observational studies, 7 were randomized controlled trials, and 3 were systematic reviews. Six different nutraceuticals were included in the review: vitamin D, riboflavin, coenzyme Q10, magnesium, butterbur, and polyunsaturated fatty acids. All but three of the studies assessed the role of nutraceuticals in migraine prevention, while three studies evaluated the role of intravenous magnesium for acute migraine management. Overall, the quality and size of the studies were limited. Due to low quality evidence and limited studies, no definite conclusions can be drawn on the efficacy of nutraceuticals for the treatment of pediatric migraine. Future studies are warranted in order to establish evidence upon which to define the role of nutraceuticals in this patient population.
Chronic migraine is a common cause of daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. Promising tools to treat migraine patients are herbal products. In particular constituents of Petasites hybridus, Pyrethrum parthenium and Ginkgo biloba have shown antimigraine action in clinical studies. Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Petasites hybridus is among the agents that appear to be effective in the treatment of chronic migraine.
The term “headache” encompasses primary conditions and those secondary to other illnesses. This chapter describes the pharmacotherapy of primary headaches in children affected by additional diseases. As in the adult population, the most common primary headaches in children are migraine and tension-type headaches. Overall, the international prevalence of migraine among children and adolescents is in the range of 7.7–9.1%. Migraines are more prevalent in girls than boys when the age is 12 years or older, and migraine with aura is less common than migraine without aura [1–3]. Chronic migraine in US adolescents aged 12–17 years was 0.79, and 2% when including medication overuse . Using a dedicated questionnaire, a population of children from 6 to 17 years of age exhibited the following 1-year prevalence: headache 89.3%; migraine 39.3%; and tension-type headache (TTH) 37.9%. Headache prevalence ≥15 days/month was 4.5% . Cluster headache (CH) is a rare condition in adults and even rarer in children, with prevalence in the pediatric population estimated as 0.03–0.09% [6, 7]. In particular, attention is paid to pharmacotherapy of comorbidity of migraine with other diseases. Comorbidities affect treatment strategy and follow-up, especially when pharmacologic treatment is needed. In this chapter, we summarize pharmacologic options for migraine and tension-type headache treatment with specific attention to comorbidities.
Purpose of Review
The aim of this paper is to familiarize readers with the breadth of nutraceutical options available to patients that may empower autonomous headache management and lessen headache burden with a low potential for adverse effects.
Over recent years, the demand and evidence for complementary and alternative medicine (CAM) options in the form of nutraceuticals has grown. Recent data also suggests the benefits of placebo may be equivalent when compared to first-line headache preventive medications in children.
While medications are often the mainstay of treatment for headache management, the evidence to support medication use in children continues to be weakened by high placebo rates. Patients are increasingly using nutraceuticals with or without physician input. The mechanisms of these therapies are often unclear, but placebo responses are likely involved. Given the high tolerability and low side effect profile reported in nutraceutical trials, these treatments may represent an opportunity to elicit the placebo response in this population, serving as an alternative or complement to medications. Future trials designed to compare nutraceuticals and first-line headache preventive medications would assist in clarifying relative efficacy and safety.
Several studies have supported the efficacy of complementary and alternative medicine approaches (physical, behavioral and nutraceutical therapies) in the treatment of headache disorders. Nutraceutical treatment consists of taking vitamins, supplements (magnesium, riboflavin, coenzyme Q10, and alpha lipoic acid) and herbal preparations (feverfew and butterbur), and its usage is frequently determined by dissatisfaction with conventional medical therapies. There is a growing body of research on nutraceutical use for migraine prophylaxis. This brief overview provides information about the potential efficacy and side effects of various nutraceutical products summarizing randomized controlled trials of some of the most commonly used non-pharmacological treatments for the prophylaxis and treatment of migraine, including magnesium, coenzyme Q10, riboflavin (vitamin B2), petasites, and feverfew.
Background and purpose:
The mechanism of the antimigraine action of butterbur [Petasites hybridus (L.) Gaertn.] is unknown. Here, we investigated the ability of isopetasin, a major butterbur constituent, to specifically target the transient receptor ankyrin 1 (TRPA1) channel and to affect functional responses relevant to migraine.
Single cell calcium imaging and patch-clamp recordings in human and rodent TRPA1-expressing cells, neurogenic motor responses in isolated rat/mouse urinary bladder, release of calcitonin gene-related peptide (CGRP) from mouse spinal cord in vitro, and facial rubbing in mice and meningeal blood flow in rat were examined.
Isopetasin produced (i) calcium responses and currents in rat/mouse trigeminal ganglion (TG) neurons and in cells expressing the human TRPA1, (ii) substance P-mediated contractions of isolated rat urinary bladders and (iii) CGRP release from mouse dorsal spinal cord, responses that were selectively abolished by TRPA1 genetic deletion/pharmacological antagonism. Pre-exposure to isopetasin produced marked desensitisation of allyl isothiocyanate (AITC, TRPA1 agonist)- or capsaicin (TRPV1 agonist)-evoked currents in rat TG neurons, contractions of rat or mouse urinary bladder and CGRP release from mouse central terminals of primary sensory neurons. Repeated intragastric administration of isopetasin attenuated mouse facial rubbing, evoked by local AITC or capsaicin, and dilation of rat meningeal arteries by acrolein or ethanol (TRPA1 and TRPV1 agonists, respectively).
Conclusion and implications:
TRPA1 agonism by isopetasin results in excitation of neuropeptide-containing nociceptors that is followed by remarkable heterologous neuronal desensitisation. Such attenuation in pain and neurogenic inflammation may account for the antimigraine action of butterbur.
Chronic migraine is a common cause of daily headache, which is often refractory to standard treatment. New research has increased our understanding of this disorder and its treatment. Promising tools to treat migraine patients are herbal products. In particular constituents of Petasites hybridus, Pyrethrum parthenium and Ginkgo biloba have shown antimigraine action in clinical studies. Migraine research has traditionally focused on the more common episodic form of the disorder, but recent clinical trials have started to focus on chronic migraine or chronic daily headache. Petasites hybridus is among the agents that appear to be effective in the treatment of chronic migraine.
This section focuses on the current evidence of integrative pediatric modalities for common pediatric conditions such as allergic rhinitis, asthma, attention deficit/hyperactivity disorder, migraine headaches, otalgia and otitis media, upper respiratory tract infections, and weight loss.
Introduction: Migraine is a common pediatric disorder, which results in chronic pain. Because of the limited effectiveness of conventional drug regimens, an increased number of pediatric patients look for an alternative medication regimen to prevent and treat migraines. Method: Search terms “pediatric, headache, migraine, treatment, alternative treatment” were used. Butterbur and riboflavin are suggested as alternative remedies for migraine prophylaxis, and a combination of feverfew and ginger for acute treatment. In addition to previous search terms, “butterbur, riboflavin, feverfew, ginger” were used to review their effectiveness. Result: Butterbur or riboflavin may be an appropriate alternative regimen to prevent migraine, and a combination of feverfew and ginger may be an option for acute episode. Conclusion: Study results are promising, but not yet conclusive. Study samples are relatively small. These alternative regimens may benefit pediatric migraine sufferers, but they should be carefully...
The actual evidence based guideline about self medication in migraine and tension type headache of the German, Austrian and Swiss headache societies and the German Society of Neurology is addressed to physicians engaged in the primary care as well as pharmacists and also patients. The guideline takes especially concern about the description of the used methodology of the selection process of the used literature and on which evidence the recommendations are based. The following recommendations about self medication in migraine attacks can be made: The effectiveness of the fixed combination of acetaminophen, acetylsalicylate and caffein and the monotherapy with ibuprofen or naratriptane or acetaminophen or phenacon are scientifically proven; none of the substance used in the self medication in migraine prophylaxis can be seen as proven effective. Concerning the self medication in tension type headache the following option can be recommended: the fixed combination of acetaminophen, acetylsalicylic acid and caffein as well as the fixed combination of acetaminophen and caffein as well as the monotherapy with ibuprofen or acetylsalicylic acid or diclofenac.
People who suffer from headaches often prefer nutraceutical treatment over traditional pharmacological approaches, due to fear of possible side effects, drug dependence, or addiction. Since treatment with nutraceuticals does not require a doctor's prescription, many patients rely on their own judgment as to when and which one to take, often without consultation or guidance from their physician. Some physicians could provide information about potential efficacy and side effects of various products, but many are not familiar with the nutraceuticals. Widespread skepticism persists among doctors about the effectiveness of these treatments. This is largely due to the lack of rigorous clinical studies. However, even when incontrovertible scientific evidence exists, many physicians remain distrustful of the evidence. The following review summarizes randomized controlled trials of some of the most commonly used non-pharmacological treatments, including magnesium, coenzyme Q10, riboflavin (vitamin B2), petasites, and feverfew (Table 1).
The effect of using omega-3 to prevent migraine attacks has been raised in recent studies. The majority of these studies have been conducted in adults. Conversely, other studies have yet to confirm the effect of omega-3. The main purpose of this study was to assess the effects of omega-3 in the prevention of migraine attacks in children.
Materials & methods:
In this study, children aged 5-15 years with a diagnosis of migraine were randomly assigned to case and control groups. The case group was treated with sodium valproate and 1 g of omega-3; the control group was treated with sodium valproate and a placebo for 2 months. The severity of attacks was evaluated before and after the treatment using PedMIDAS and parental satisfaction (CGI) using a 7-point Likert scale.
In this study, 12 cases and 13 controls were enrolled. The average number of headache attacks per month decreased significantly in both groups after starting the treatment but there was no significant difference between the two groups. The severity of attacks decreased significantly in both groups after starting the treatment but it was not significant between them. Examination of the CGI average showed the average was 6.08 (SD = 0.52) in the case group and 6.07 (SD = 0.65) in the control group.
The present study indicated that omega-3 with a dose of 1 mg per day has no effect in reducing the severity and frequency of migraine attacks in children. Sodium valproate was effective in reducing the frequency and severity of attacks.
Migraine as a highly disabling pain condition influences the daily activities of those affected, including children and adolescents. The pathomechanism of migraine is not fully understood, and the different types of prophylactic antimigraine drugs that are applied are not specific for migraine. There is a need for preventive treatment in the event of frequent migraine attacks, an impairment of the quality of life, severe accompanying or aura symptoms, and the failure of acute drug treatment. The following pharmacological classes are recommended: antidepressants, antiepileptics, antihistamines, beta-adrenergic receptor blockers, and calcium ion channel antagonists, besides onabotulinum toxin A and nutraceuticals (butterbur). The most urgent goal as concerns pharmaceutical innovation is the development of pathomechanism-based antimigraine drugs and personalized therapy tailored to the children and adolescents.
Petasites has been used in the history of medicine since antiquity in different indications. In the past years, even some biochemical mechanisms of the therapeutic efficacy of petasites have been detected. In particular, migraine prophylaxis as an indication for petasites has been investigated in evidence-based trials. Two placebo controlled trials have shown consistently an efficacy of petasites in migraine prophylaxis. The significant difference to placebo was between 19 and 30% with respect to responder rate. The most frequent side effects of petasites are gastrointestinal complaints. Elevation of liver enzymes caused by petasites have been discussed controversy. In the placebo controlled trials, the rate of reversible elevation of liver enzymes was lower than 10%. In the register of all reported adverse events,six 6 cases of a liver disease with a possible or probable causal relationship to the intake of petasites have been documented.
Chronic daily headache (CDH) is one of the top 10 causes of adult disability and one of the 5 most common causes of female disability. To treat patients with CDH is one of the most difficult tasks in neurological practice. Difficulties in managing patients with CHD are associated with the high prevalence of comorbid mental disorders, analgesic abuse, pain syndromes at another site, and misconceptions of a patient about his/her disease. A combination of drug and non-drug therapies is the mainstay of the current approach to treating patients with CDH. Standard, alternative, and auxiliary therapies are identified. The paper describes different types of current auxiliary and alternative therapy used in the world’s leading headache centers and clinics. It describes experience with cerebrolysin used as auxiliary and alternative pharmacotherapies for CDH.
Migraine is a common condition that for many begins in childhood and may progress over the course of one's life. The transition from adolescence to adulthood is a critical time for those who suffer from migraine and can be marked by a variety of important considerations for the patient and practitioner. Medication choices may be a challenge during adolescent years as Food and Drug Administration (FDA) approved options are few and many more studies are needed to understand the benefits and risks of use of these agents in adolescents. However, as patients transition to adulthood, FDA approved options and the level of evidence improve significantly. Late adolescents may also struggle with a variety of psychiatric comorbidities that may simultaneously create challenges in determining treatment but also open opportunities to manage multiple comorbidities and address underlying depression, anxiety, and behavioral issues. For late adolescent girls, the beginning of sexual activity, onset of gynecologic conditions, or presence of irregular or painful menses may raise questions regarding the use of oral contraceptives (OCs). Given data on the risks of these medications in women with migraine, especially those with aura or those who smoke, important conversations between physicians and their migraine patients can help risk stratify and determine the risk/benefit profile for the potential use of these agents. Much more data are needed to fully understand the transition from adolescence to adulthood for those suffering with migraine and this article seeks to shed light on the limited understanding currently available in established literature.
According to the principles of evidencebased medicine, the controlled studies on the treatment of idiopathic headache in childhood have been analysed. For the acute treatment of migraine attacks or tensiontype headache, ibuprofen (10 mg per kg body weight) is recommended with highest evidence. Drugs of second choice are acetaminophen (15 mg per kg body weight) for all ages and, for migraine attacks only, intranasal sumatriptan (10 mg) or intranasal zolmitriptan (5 mg) for the age of 12 and older, in single cases also in the age below 12. If the acute drugs of first or second choice are not efficacious, alternative drugs are oral triptans. For the prophylaxis of mi-graine, flunarizine and topiramate show the highest evidence of efficacy but also several side effects. Magnesium and betablockers are recommended as well. Flunarizine is the drug of first choice in the treatment of migraine-related disorders. No controlled studies are available for the treatment of further headache types.
In the European Union, the use of traditional herbal medicinal products has recently been regulated in Directive 2004/24/EC. According to this regulation, clinical studies and pre-clinical tests are not obligatory, but quality needs to be demonstrated in any individual case. Echinacea and butterbur (Petasites) will be used as examples for demonstrating the progress in medicinal plant research. Alkamides, the major lipophilic constituents of Echinacea, have recently been found to be rapidly absorbed after oral application. Using LC-MS their pharmacokinetics have been studied and ex-vivo effects have been measured. Alkamides have also been shown to bind to cannabinoid receptors (CB2) which may represent a molecular mechanism of action of Echinacea. Extracts of the rhizomes of Petasites hybridus have been shown to inhibit 5-lipoxygenase and cyclooxygenase-2 and COX-2 expression. They are useful for the prevention of migraine and for the treatment of asthma and seasonal allergic rhinitis.
Objective.—To compare gabapentin with placebo for use as a prophylactic agent in patients with migraine (with or without aura).
Study Design and Treatment.—After screening, a 4-week, single-blind, placebo baseline period was followed by a 12-week, double-blind, treatment period. The 12-week treatment period consisted of a 4-week titration phase and an 8-week stable-dosing phase. During the 4-week titration phase, patients were started on one 300-mg capsule of gabapentin or matching placebo. Patients were titrated weekly from 900 mg/day (end of week 1) to 2400 mg/day (end of week 4) and had to be receiving a stable dose of study medication by the end of the titration period. Study medication was to be given on a three-times-a-day dosing regimen.
Methods.—The study hypothesis was defined a priori as a lower 4-week migraine rate during the second stabilization period for the gabapentin-treated patients as compared with the placebo-treated patients. The analyses were performed with the 4-week migraine rate at baseline as a covariate and center as a blocking factor.
Results.—At seven participating centers, 143 patients with migraine were randomized in a 2:1 ratio and received either gabapentin (n = 98) or matching placebo (n = 45). Thirty-three patients (24.1%) discontinued prematurely from the study, including 24 (24.5%) of 98 gabapentin-treated patients and 9 (20.0%) of 45 placebo-treated patients; the majority of patients discontinued due to adverse events (16 [16.3%] of 98 gabapentin-treated patients; 4 [8.9%] of 45 placebo-treated patients). Patients included in the analysis were evenly balanced for age, sex, race, weight, and height. The majority of these patients were white (80 [92.0%] of 87) and women (72 [82.8%] of 87), with a mean age of approximately 39.4 years and a history of migraine episodes for a mean of about 21 years. At the end of the 12-week treatment phase, the median 4-week migraine rate was 2.7 for the gabapentin-treated patients maintained on a stable dose of 2400 mg/day and 3.5 for the placebo-treated patients (P = .006), compared with 4.2 and 4.1, respectively, during the baseline period. Additionally, 26 (46.4%) of 56 patients receiving a stable dose of 2400 mg/day gabapentin and 5 (16.1%) of 31 patients receiving placebo showed at least a 50% reduction in the 4-week migraine rate (P = .008). The average number of days per 4 weeks with migraine was also statistically significant and favored gabapentin (P = .006) during stabilization period 2. The median change in 4-week headache rate was statistically significant as well (P = .013). The most frequently reported adverse events for both treatment groups were asthenia, dizziness, somnolence, and infection. Adverse events determined by the investigator to be associated with study drug resulted in patient withdrawal in 13 (13.3%) of 98 gabapentin-treated patients and 3 (6.7%) of 45 placebo-treated patients. Somnolence and dizziness accounted for many of the premature withdrawals among those taking gabapentin.
Conclusion.—Gabapentin is an effective prophylactic agent for patients with migraine. In addition, gabapentin appears generally well tolerated with mild to moderate somnolence and dizziness.
In Petasites officinalis Moench kommt ein antispastisches Prinzip vor, das qualitativ ähnlich wie Papaverin wirkt. Es dürfte
quantitativ bedeutend wirksamer sein als Papaverin und eine günstigere therapeutische Breite haben. Seine chemische Natur
ist zur Zelt noch unbekannt.
The 3rd Petasites gathering took place in Romanshorn, Switzerland on March 29, 1996 and gave 16 European scientists the opportunity to transmit their latest considerable discoveries to interested researchers working in different scientific disciplines such as pharmacognosy, botany, chemistry, pharmacology, medicine or clinical pharmacy. The newest findings on Petasites hybridus as a significant plant drug showed very promising aspects of therapeutic utility. Great progress has been made in chemical analytical methods and the determination of pharmacological activities. Substantial advances have also occurred in the production of bioassay procedures and plant materials, particularly utilizing cell- and tissue-culture techniques.
Successful migraine prophylaxis with flunarizine has been reported in adults by several authors. We used flunarizine in a double-blind, placebo controlled, randomized trial in childhood migraine. Twenty-four children with classical or common migraine were followed by a 12-week flunarizine treatment period. Each patient took 5 mg/day of the drug before going to sleep. Twenty-four children with similar clinical characteristics were assigned to placebo treatment. Efficacy of flunarizine versus placebo was assessed on the basis of the reduction of headache frequency and duration. A statistical comparison was performed between values reported in the treatment period and those in the three months before. Children treated with flunarizine experienced a statistically significant reduction in headache (66%) and duration (51%). These results were statistically superior to those observed in the placebo group. Sixteen patients on flunarizine therapy experienced an improvement of more than 50% of both parameters. We found flunarizine is an effective agent in children's migraine prophylaxis. Moreover it is suitable for the low incidence of mild side effects.
An 8-month, double-blind, placebo-controlled, crossover trial of flunarizine in the prophylaxis of migraine has been performed in 70 children. After 4 weeks of medication-free base-line observation, 35 children (group A) received flunarizine (5 mg/day) and 35 (group B) received placebo over a 12-week period. After a 4-week washout they crossed treatments for another 12 weeks. Sixty-three patients completed the trial. In both groups flunarizine significantly reduced the frequency and average duration of headache attacks. In group A efficacy was maintained after placebo crossover for the last 4 months of the study. Five subjects in group B stopped placebo because of ineffectiveness; two children in group A discontinued flunarizine treatment, one because of excessive daytime sedation and the other because therapy was ineffective. The main side effects were daytime sedation and weight gain. It is concluded that flunarizine is an effective drug for the treatment of childhood migraine. In a study of this length no serious side effects were discovered.
Flunarizine was tested for prophylactic efficacy and for side effects in 10- to 13-year-old patients with severe migraine (greater than 2 attacks per month). The 13 preadolescents received a single 5-mg dose at night for 2 months. The attack frequency decreased significantly, and the effect was maintained over time. The endocrine status, investigated before and after treatment, showed no significant interference with pituitary, beta-pancreatic, or gonadal function.
Forty-seven children with migraine have been included in a double-blind cross-over study with pizotifen and placebo. The children received either pizotifen for 3 months followed by placebo or vice versa. Thirty-nine children completed the trial and there was no significant difference between active and placebo treatment as regards reduction of number of attacks, total and mean duration of attacks and duration of longest attacks. Pizotifen was well tolerated by the children.
In a prospective study we compared propranolol, placebo, and self-hypnosis in the treatment of juvenile classic migraine. Children aged 6 to 12 years with classic migraine who had no previous specific treatment were randomized into propranolol (at 3 mg/kg/d) or placebo groups for a 3-month period and then crossed over for 3 months. After this 6-month period, each child was taught self-hypnosis and used it for 3 months. Twenty-eight patients completed the entire study. The mean number of headaches per child for 3 months during the placebo period was 13.3 compared with 14.9 during the propranolol period and 5.8 during the self-hypnosis period. Statistical analysis showed a significant association between decrease in headache frequency and self-hypnosis training (P = .045). There was no significant change in subjective or objective measures of headache severity with either therapy.
Ergebnisse einer Praxisstudie am Beispiel eines Phytotherapeutikums [Biological treatment of pain. Results of a doctor's practice study with a phytopharmaceutical]
Gruia FS. Zur biologischen Schmerzbe ampfung. Ergebnisse einer Praxisstudie am Beispiel eines Phytotherapeutikums [Biological treatment of pain. Results of a doctor's practice study with a phytopharmaceutical]. Erfahrungsheilkunde. 1986;35:396-401.
About 4 per cent of schoolchildren suffer from migraine. In some cases the attacks can be frequent and severe. Often symptomatic and prophylactic treatments are either ineffective or cause pronounced side effects. There have been reports on studies in which a prophylactic effect on migraine by propranolol has been noted. This beta-receptor blocking agent has been tested in a double-blind single crossover study in 32 children aged 7–16 with migraine. Propranolol had an excellent prophylactic effect on migraine attacks. Since propranolol does not cause serious side effects provided certain patients are excluded, it seems justifiable to recommend this preparation where prophylactic therapy is indicated in cases of severe and frequent migraine.]
In a double-blind crossover study of 39 children with established migraine, there was no difference between treatment with propanolol and placebo as regards frequency, severity or average duration of migraine attacks. There was some evidence that propanolol increased the average length of headaches.
Propanolol (‘Inderal’) duns le traitement der migraines de l'enfance: étude en double aveugle
Dans une étude en double aveugle portant sur 39 enfants atteints de migraines fréquentes. il n'a pas été observé de différences entre un traitement par propanolol et un placebo en ce qui concerne la fréquence, l'intensité et la durée moyenne des crises de migraine. Il y a quelques indications que le propanolol pourrait accroitre la durée moyenne des maux de tête.
Propanolol (‘InderaI’) zur Behandlung der Migräne im Kindesalter: eine Doppelblinoktudie
In einer Doppelblind-Kreurstudie bei 39 Kindern mit gesicherter Migräne konnte kein Unterschied zwischen der Behandlung mit Propanolol oder Placebo hinsichtlich Häufigkeit, Schweregrad oder durchschnittlicher Dauer der Migräneanfälle gefunden werden. Es ergaben sich sogar Hinweise dafür, daß Propanolol die durchschnittliche Dauer der Kopfschmerzen verlängerte.
Propanolol en el tratamiento de la migraña infantil: estudio doble ciego
En un estudio cruzado doble ciego de 39 niños con diagnóstico de migraña, no hubo diferencia entre el tratamiento con propanolol y un placebo, por lo pue respecta a la frecuencia, gravedad y promedio de duración de los ataques de migraña. Hubo ciérta evidencia de que el propanolol aumentaba el promedio de duración de los ataques.
To compare the effectiveness and safety of divalproex sodium (Depakote) and placebo in the prophylaxis of migraine headache.
Multicenter, double-blind, randomized, placebo-controlled investigation, having a 4-week, single-blind placebo baseline phase and a 12-week treatment phase (4-week dose adjustment, 8-week maintenance).
Eight headache/neurology clinics throughout the United States.
One hundred seven patients randomized to divalproex or placebo (2:1 ratio): 70 receiving divalproex and 37 receiving placebo.
Divalproex and placebo dosages titrated in blinded fashion during dose adjustment period to achieve actual/sham trough valproate sodium concentrations of approximately 70 to 120 mg/L.
During the treatment phase, the mean migraine headache frequency per 4 weeks was 3.5 in the divalproex group and 5.7 in the placebo group (p < or = .001), compared with 6.0 and 6.4, respectively, during the baseline phase. Forty-eight percent of divalproex-treated patients and 14% of placebo-treated patients showed a 50% or greater reduction in migraine headache frequency from the baseline phase (P < .001). Among those with migraine headaches, divalproex-treated patients reported significantly less functional restriction than placebo-treated patients and used significantly less symptomatic medication per episode. No significant treatment group differences were observed in average peak severity or duration of individual migraine headaches. Treatment was stopped in 13% of divalproex-treated patients and 5% of placebo-treated patients because of intolerance (P, not significant).
Divalproex is an effective prophylactic drug for patients with migraine headaches and is generally well tolerated.
Extracts from Petasites hybridus are in therapeutic use for more than 2000 years. They have been claimed to improve gastrointestinal pain, lung-diseases such as asthma and cough, as well as spasms of the urogenital-tract. We have investigated these claims in animal models of gastro-intestinal ulcers and confirmed that alcoholic extracts of Petasites hybridus block the ethanol-induced gastric damage and reduce small intestinal ulcerations induced in rats by indomethacin. Searching for a possible mode of action, we found that ethanolic extracts of Petasites hybridus inhibit the peptido-leukotriene biosynthesis in mouse peritoneal macrophages but leave prostaglandin biosynthesis unimpaired. We conclude that the active principle could be useful in the treatment of gastro-intestinal human diseases and that Petasites hybridus may contribute to the inhibition of calcium-dependent processes such as leukotriene biosynthesis.
Objective.–Clinical observation of a decrease in migraine frequency in patients with comorbid asthma taking montelukast, a specific D4 leukotriene receptor antagonist, or zafirlukast, another leukotriene receptor antagonist, prompted us to explore a possible role for leukotriene modifiers in the treatment of migraine. (A further prompt was a pharmacist colleague's observation that a number of patients on these agents reported a decreased sensitivity to perfume triggers and improvement in migraine.)
Migraine according to the criteria of the International Headache Society, occurs in about 3 to 7% of all children. Despite this high incidence, and unlike the situation with adult migraine, only a very few controlled trials have investigated the acute and prophylactic treatment of migraine in children. In the acute migraine attack, ibuprofen 10 mg/kg and paracetamol (acetaminophen) 15 mg/kg have been shown to be effective, with only a few adverse effects. In severe migraine attacks, dihydroergotamine mesylate (dihydroergotamine) administered orally (20 to 40 microg/kg) or intravenously (maximum 1 mg/day) may be helpful, but there have been no large placebo-controlled trials of this treatment. Oral sumatriptan has not been effective in several double-blind and placebo-controlled trials; administered subcutaneously, this drug might be helpful but the only data for this application come from open trials. For migraine prophylaxis, only flunarizine 5 mg/day has been shown to be effective in more than 1 double-blind, placebo-controlled trial. Some evidence also exists that propranolol >60 mg/day and pizotifen 0.5 to 1.5 mg/day are effective; however, the results from different trials are contradictory. For all other drugs studied in migraine prophylaxis, the results remain vague (e.g. amitriptyline, nimodipine, trazodone) or suggest inefficacy (e.g. timolol, clonidine, tryptophan). In migraine-related disorders, pizotifen 0.5 to 0.75 mg/day for abdominal migraine and flunarizine 10 to 25 mg/day for alternating hemiplegia have been shown to be effective. Most of the drugs used in the treatment of migraine in children are well tolerated and without relevant adverse effects. In migraine prophylaxis, the most common adverse effects are drowsiness and bodyweight gain.
In vivo and in vitro studies were carried out to examine the putative hypotensive actions of S-petasin, a sesquiterpene extracted from the medicinal plant Petasites formosanus. Intravenous S-petasin (0.1-1.5 mg/kg) in anesthetized rats produced a dose-dependent hypotensive effect. In isolated aortic ring, isometric contraction elicited by KCl or the L-type Ca2+ channel agonist Bay K 8644 was reduced by S-petasin (0.1-100 microM), an action not affected by the cyclooxygenase inhibitor indomethacin, nitric-oxide synthase inhibitor N(omega)-nitro-L-arginine, guanylyl cyclase inhibitor methylene blue, or removal of vascular endothelium. Pretreatment with S-petasin for 10 min shifted the concentration-response curve for KCl (15-90 mM)-induced contraction to the right and reduced the maximal response. In Ca2+-depleted and high K+-depolarized aortic rings preincubation with S-petasin attenuated the Ca2+-induced contraction in a concentration-dependent manner, suggesting that S-petasin reduced Ca2+ influx into vascular smooth muscle cells (VSMCs). Moreover, in cultured VSMCs, whole-cell patch-clamp recording indicated that S-petasin (1-50 microM) inhibited the L-type voltage-dependent Ca2+ channel (VDCC) activities. Intracellular Ca2+ concentration ([Ca2+[(i)) estimation using the fluorescent probe 1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran-5-oxy]-2-(2'-amino-5'-methylphenoxy)-ethane-N,N,N,N-tetraacetic acid pentaacetoxymethyl ester indicated that S-petasin (10, 100 microM) suppressed the KCl-stimulated increase in ([Ca2+[(i)). Taken together, the results suggested that a direct Ca2+ antagonism of L-type VDCC in vascular smooth muscle may account, at least in part, for the hypotensive action of S-petasin.
A large production of leukotrienes (LTs) can be induced in human eosinophils or neutrophils by priming with granulocyte-macrophage colony-stimulating factor and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a. Here, we investigated the effects of a plant extract of petasites hybridus (Ze339) and its isolated active sesquiterpene ester petasin in these two in vitro cell models. Zileuton, a 5-lipoxygenase inhibitor, was used as a positive control. All compounds inhibited both cysteinyl-LT synthesis in eosinophils and LTB(4) synthesis in neutrophils. In contrast, only Ze339 and petasin, but not zileuton, abrogated PAF- and C5a-induced increases in intracellular calcium concentrations. These data suggest that Ze339 and petasin may block, compared to zileuton, earlier signalling events initiated by G protein-coupled receptors in granulocytes, perhaps at the level of or proximal to phospholipase C(beta). Taken together, petasin appears to be one major active compound of petasites hybridus extract, since it demonstrates the same inhibitory activities on calcium fluxes and subsequent LT generation in both eosinophils and neutrophils as Ze339 does.
We investigated the mechanisms of action of S-petasin and S-isopetasin, from Petasites formosanus Kitamura which is used as a folk medicine for treating hypertension, tumors, and asthma in Taiwan. The tension changes of tracheal segments were isometrically recorded on a polygraph. S-Petasin and S-isopetasin non-competitively inhibited cumulative histamine-, and carbachol-induced contractions with an exception that S-isopetasin produced a parallel, rightward shift of the concentration-response curve of carbachol in a competitive manner. S-Petasin also non-competitively inhibited cumulative Ca²⁺-induced contractions in depolarized (K⁺, 60 mM; histamine, 100 μM; or carbachol, 10 μM) guinea-pig tracheas. S-Isopetasin did in depolarized (K⁺, 60 mM) trachea too. The nifedipine (10 μM)-remaining tension of carbachol (0.2 μM)-induced precontraction was further relaxed by S-petasin or S-isopetasin, suggesting that no matter whether either blocked VDCCs or not, S-petasin or S-isopetasin may have other mechanisms of relaxant action. The relaxant effect of S-petasin or S-isopetasin was unaffected by the presence of propranolol (1 μM), 2′,5′-dideoxyadenosine (10 μM), methylene blue (25 μM), glibenclamide (10 μM), N ω-nitro-L-arginine (20 μM), or α-chymotrypsin (1 U/ml). However, S-petasin (100 - 300 μM), but not S-isopetasin, significantly inhibited cAMP-, but not cGMP-dependent PDE activity of the trachealis. The above results reveal that the mechanisms of relaxant action of S-petasin and S-isopetasin may be primarily due to its non-specific antispasmodic and antimuscarinic effects, respectively.
ROCCs:receptor-operated calcium channels
VDCCs:voltage dependent calcium channels
cAMP:adenosine 3′,5′-cyclic monophosphate
cGMP:guanosine 3′,5′-cyclic monophosphate
Priming of eosinophils with granulocyte-macrophage colony-stimulating factor (GM-CSF) and subsequent stimulation with platelet-activating factor (PAF) or the anaphylatoxin C5a is associated with a rapid production of leukotrienes (LTs) and release of eosinophil cationic protein (ECP).
This study was designed to determine the effects of the sesquiterpene esters petasin, isopetasin and neopetasin on LT generation and ECP release in eosinophils in vitro.
The model of eosinophil activation described above was used to induce LT production and ECP release. Cells were incubated with petasins and control inhibitors prior to priming and stimulation. To analyse intracellular steps of eosinophil activation and determine potential drug targets, some key signalling events were studied. Activity of cytosolic phospholipase A2 (cPLA(2)) was measured by analysing the generation of arachidonic acid (AA). Translocation of 5-lipoxygenase (5-LO) was observed using immunofluorescence microscopy. Intracellular calcium concentrations [Ca2+]i were measured by a bulk spectrofluorometric assay.
Whereas all three compounds inhibited LT synthesis, ECP release from eosinophils was blocked by petasin only, but not isopetasin or neopetasin. Similarly, PAF- or C5a-induced increases in [Ca2+]i were completely abrogated by petasin only, whereas isopetasin and neopetasin had significant lower blocking efficacy. Moreover, only petasin, but not isopetasin or neopetasin, prevented increases in cPLA(2) activity and 5-LO translocation from the cytosolic compartment to the nucleus envelope in calcium ionophore-stimulated eosinophils.
These data suggest that different petasins may at least partially block different intracellular signalling molecules. To reduce LT synthesis, isopetasin and neopetasin may act at the level of or distal to 5-LO. In contrast, petasin may inhibit inflammatory effector functions in human eosinophils by disrupting signalling events at the level of or proximal to phospholipase Cbeta (PLCbeta), besides its potential inhibitory activity within mitogen-activated protein kinase (MAPK) and LT pathways.
To evaluate the efficacy of topiramate in the preventative treatment of episodic migraine.
Topiramate is a broad-spectrum antiepileptic drug effective for treatment of multiple seizure types in adults and children. Antiepileptic agents have demonstrated efficacy in migraine prevention, and open-label experience from our clinic has suggested that topiramate might be effective for this use. We consequently conducted a single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate for the preventative treatment of migraine.
Forty patients, aged 19 to 62 years (mean, 38.2 years), were randomly assigned in a 1:1 ratio to receive topiramate (n = 19; all women) or placebo (n = 21; 20 women, 1 man). Following a prospective baseline phase of 4 weeks, the study drug dose was titrated weekly in 25-mg increments over 8 weeks to 200 mg per day or to the maximum tolerated dose. The titration phase was followed by an 8-week maintenance phase.
During the entire double-blind phase, topiramate-treated patients experienced a significantly lower 28-day migraine frequency (3.31 +/- 1.7 versus 3.83 +/- 2.1; P =.002) compared to placebo, irrespective of use of concomitant migraine prevention medications. The mean 28-day migraine frequency was reduced by 36% in patients receiving topiramate as compared with 14% in patients receiving placebo (P =.004). Twenty-six percent of the patients on topiramate and 9.5% of the patients on placebo achieved a 50% reduction in migraine frequency (P >.05). The mean dose of topiramate was 125 mg per day (range, 25 to 200 mg per day). Topiramate was well tolerated; 2 of 19 topiramate-treated patients discontinued treatment due to adverse events. Adverse effects that occurred more frequently in topiramate-treated patients included paresthesia, weight loss, altered taste, anorexia, and memory impairment.
Preventative therapy with topiramate significantly reduced migraine frequency. Larger multicenter clinical studies may further delineate the role of topiramate in migraine prevention.
Headaches are very common during childhood and become increasingly frequent during adolescence. The diagnosis of primary headache disorders (e.g., migraine and tension-type headache) rests principally on clinical criteria as set forth by the International Headache Society. Treatment options include acute or episodic measures, prophylactic agents and non-pharmacological or behavioural interventions. From review of available evidence, the most efficacious acute treatments of paediatric migraine include the non-steroidal anti-inflammatory agent ibuprofen at 7.5 - 10 mg/kg/dose or nasal sumatriptan at doses of 5 or 20 mg. For those patients with headaches that occur with sufficient frequency and severity to warrant daily prophylaxis, controlled data are limited. Agents which are likely to be beneficial include amitriptyline, flunarizine (not available in the US) and cyproheptadine. Clinical experience with the anti-epileptic agents topiramate and valproate suggests an expanding role for the prevention of paediatric migraine in the future.
This review considers the epidemiology, clinical manifestations and functional consequences of migraine in children and adolescents and surveys the studies establishing the efficacy and tolerability of sumatriptan nasal spray in this patient population. Although therapeutic advances in paediatric and adolescent migraine have lagged behind those in adult migraine, the first systematic studies of migraine medications in young patients have brought about progress in the past five years. These studies show that therapeutic approaches suitable for adult patients are not always applicable to paediatric and adolescent patients. Because of the unique characteristics of paediatric and adolescent migraine, it has been difficult to demonstrate in young patients the efficacy of oral sumatriptan and other triptan tablets, which are the medications of choice for adult migraine. With sumatriptan, this finding has proven to be a consequence of the form in which the drug was administered rather than the inherent properties of the drug. The availability of sumatriptan nasal spray allows the benefits of migraine-specific therapy to be extended to children and adolescents. In both well-controlled, single-episode studies and long-term, multiple-episode studies, sumatriptan nasal spray has been effective and well tolerated for the acute treatment of migraine in children and adolescents. Except for unpleasant taste, which is not significantly distressing to patients, sumatriptan nasal spray has a tolerability profile similar to thatof placebo in young patients.
This systematic review evaluated studies of drug treatments for preventing migraine headaches in children. Twenty randomised controlled trials were included. Two studies showed a beneficial effect on the primary outcome measure, headache frequency. These were trials of the drugs propranolol and flunarizine. Nimodipine, timolol, papaverine, pizotifen, trazodone, L-5-hydroxytryptophan (L-5HTP), clonidine, metoclopramide, and domperidone showed no efficacy in reduction of frequency of attacks. Available studies on other commonly used drugs failed to meet our inclusion criteria. The quality of evidence available for the use of drug prophylaxis in paediatric migraine is poor. Studies have generally been small, with no planning of sample size, so that for many drugs, despite the negative findings of this review, we do not have conclusive evidence of 'no effect'. More research is needed on this important topic.
This is an independent reanalysis of a randomised, placebo-controlled parallel-group study on the efficacy and tolerability of a special butterbur root extract (Petadolex) for the prophylaxis of migraine. The original protocol and analysis had a number of major shortcomings. In order to follow regulatory requirements, an independent reanalysis of the original data was performed. Following a 4-week baseline phase, 33 patients were randomised to treatment with two capsules 25 mg butterbur twice a day and 27 to placebo. The mean attack frequency per month decreased from 3.4 at baseline to 1.8 after 3 months (p = 0.0024) in the verum group and from 2.9 to 2.6 in the placebo group (n.s.). The responder rate (improvement of migraine frequency > or =50%) was 45% in the verum group and 15% in the placebo group. Butterbur was well tolerated. This small trial indicates that butterbur may be effective in the prophylaxis of migraine.
To evaluate the efficacy and tolerability of montelukast 20 mg in the prophylactic treatment of migraine.
A previous small open-label study in migraine patients suggested prophylactic efficacy for montelukast, an antagonist of the cysteinyl leukotriene receptor that is used in the treatment of asthma. We sought to confirm these findings in a randomized controlled trial.
This multicenter, randomized, double-blind, placebo-controlled, parallel-groups study enrolled adult migraine outpatients who experienced > or =3 and < or =8 migraine attacks per month for the last 6 months. Patients were entered into a 2-month, single-blind, placebo run-in phase. Only patients who experienced > or =3 migraine attacks in the second month were eligible to enter the subsequent 3-month, double-blind treatment phase of the study. The primary efficacy endpoint was the percentage of patients reporting at least a 50% decrease in migraine attack frequency per month during the double-blind treatment period (months 3-5) compared to baseline (run-in month 2).
A total of 93 patients were randomized to montelukast 20 mg and 84 patients to placebo at the end of the placebo run-in month 2; 76 patients on montelukast and 72 patients on placebo completed the double-blind treatment period. Over 3 months of treatment, there was no significant difference between the two groups in the percentage of patients who reported at least a 50% decrease in migraine attack frequency per month: 15.4% for montelukast versus 10.3% for placebo (P= .304). In addition, montelukast 20 mg was not significantly superior to placebo on any of the secondary endpoints. There were no differences between treatment groups for adverse events.
Montelukast 20 mg was well tolerated in migraine patients but was not an effective prophylactic for prevention of migraine.