European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention

BACKGROUND AND AIM: Monoclonal antibodies acting on the calcitonin gene-related peptide or on its receptor are new drugs to prevent migraine. Four monoclonal antibodies have been developed: one targeting the calcitonin gene-related peptide receptor (erenumab) and three targeting the calcitonin gene-related peptide (eptinezumab, fremanezumab, and galcanezumab). The aim of this document by the European Headache Federation (EHF) is to provide an evidence-based and expert-based guideline on the use of the monoclonal antibodies acting on the calcitonin gene-related peptide for migraine prevention. METHODS: The guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed systematic review and analysis of the literature, assessed the quality of available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided. RESULTS: We found low to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in patients with episodic migraine and medium to high quality of evidence to recommend erenumab, fremanezumab, and galcanezumab in patients with chronic migraine. For several clinical questions, there was not enough evidence to provide recommendations using the GRADE approach and recommendations relied on experts' opinion. CONCLUSION: Monoclonal antibodies acting on the calcitonin gene-related peptide are new drugs which can be recommended for migraine prevention. Real life data will be useful to improve the use of those drugs in clinical practice

Headache and pregnancy: a systematic review.

This systematic review summarizes the existing data on headache and pregnancy with a scope on clinical headache phenotypes, treatment of headaches in pregnancy and effects of headache medications on the child during pregnancy and breastfeeding, headache related complications, and diagnostics of headache in pregnancy. Headache during pregnancy can be both primary and secondary, and in the last case can be a symptom of a life-threatening condition. The most common secondary headaches are stroke, cerebral venous thrombosis, subarachnoid hemorrhage, pituitary tumor, choriocarcinoma, eclampsia, preeclampsia, idiopathic intracranial hypertension, and reversible cerebral vasoconstriction syndrome. Migraine is a risk factor for pregnancy complications, particularly vascular events. Data regarding other primary headache conditions are still scarce. Early diagnostics of the disease manifested by headache is important for mother and fetus life. It is especially important to identify "red flag symptoms" suggesting that headache is a symptom of a serious disease. In order to exclude a secondary headache additional studies can be necessary: electroencephalography, ultrasound of the vessels of the head and neck, brain MRI and MR angiography with contrast ophthalmoscopy and lumbar puncture. During pregnancy and breastfeeding the preferred therapeutic strategy for the treatment of primary headaches should always be a non-pharmacological one. Treatment should not be postponed as an undermanaged headache can lead to stress, sleep deprivation, depression and poor nutritional intake that in turn can have negative consequences for both mother and baby. Therefore, if non-pharmacological interventions seem inadequate, a well-considered choice should be made concerning the use of medication, taking into account all the benefits and possible risks.

Prevalence of low back pain in adolescent athletes - an epidemiological investigation.

Low back pain (LBP) is a common symptom in the populations of western countries, and adolescent athletes seem to be prone to LBP. The main objective of this study was to analyze the point (LBP within the last 48 h), 1-year (LBP within the last 12 months) and lifetime (LBP within the entire life) prevalence rates of LBP in adolescent athletes participating in various sports. We also assessed the characteristics of LBP and its association with potential risk factors. To this end, 272 competitive adolescent athletes involved in 31 different sports (158 males, 113 females, 15.4 ± 2.0 years, body mass index [BMI] 20.3 ± 2.4 kg/m(2)) were enrolled in a 10-month prospective clinical trial that included a questionnaire and physical examination. We found a point prevalence of 14%, a 1-year prevalence of 57%, and a lifetime prevalence of 66% for LBP. The mean age of first appearance of LBP was 13.1 ± 2.0 years. The lifetime prevalence was significantly higher in volleyball than in biathletes (74.3 vs. 45.7%, p = 0.015). Our findings confirm that LBP is a common symptom in adolescent athletes; LBP prevalence correlates with sports participation and individual competitive level. Adolescent athletes with LBP should receive a thorough diagnostic work-up and adapt training and technique correspondingly when indicated.

Peripheral endothelial function and arterial stiffness in women with migraine with aura: a case-control study.

BACKGROUND: Vascular dysfunction may be involved in migraine pathophysiology and contribute to the increased risk of ischemic stroke in migraine, particularly in women with migraine with aura (MA). However, data on endothelial function in MA are controversial. Here, we investigated whether systemic endothelial function and arterial stiffness are altered in women with MA, using a novel peripheral arterial tonometry device for the first time. METHODS: Twenty-nine female MA patients without comorbidities and 30 healthy women were included, and carotid intima-media thickness was assessed by a standardized procedure. Endothelial function was assessed using peripheral arterial tonometry. Reactive hyperaemic response of digital pulse amplitude was measured following 5 minutes of forearm occlusion of the brachial artery. Arterial stiffness was assessed by fingertip tonometry derived and heart-rate-adjusted augmentation index. RESULTS: No differences were found in peripheral arterial tonometry ratio (2.3 ± 0.6 vs 2.2 ± 0.8; p = 0.58) and left carotid intima-media thickness (in µm: 484 ± 119 vs 508 ± 60; p = 0.37). Women with MA had higher heart-rate-averaged augmentation index [median (interquartile range, IQR) of 5 (IQR 0.5 to 18) vs -5 (IQR -16.8 to 8.3), p = 0.005] and heart-rate-adjusted augmentation index [1 (IQR -6 to 12.5) vs -8 (IQR -20.3 to 2.5), p = 0.008] than healthy controls. CONCLUSION: Peripheral endothelial function is not impaired in women with MA, but they have greater arterial stiffness. This may contribute to the increased stroke risk in women with MA.

Migraines with and without aura and their response to preventive therapy with topiramate.

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

Intracisternal injection of inflammatory soup activates the trigeminal nerve system.

The release of calcitonin gene-related peptide (CGRP) and sensitization of the trigeminal nerve system are important elements in migraine pathophysiology. Sensitization can be induced by topical meningeal administration of inflammatory soup (IS). CGRP release is a marker of trigeminal nerve activation. We examined the effect of intracisternal IS administration on CGRP release in rat jugular vein blood at baseline, 2 and 15 min after the beginning of IS infusion. IS administration caused a significant increase of CGRP levels after 2 and 15 min compared with baseline. Daily oral treatment with topiramate for 4 and 8 weeks led to a dose- and time-dependent reduction of IS-induced CGRP release. Sumatriptan also attenuated stimulated neuropeptide release. These results indicate that intracisternal IS administration leads to activation of the trigeminal system. The inhibition of CGRP release by topiramate offers a possible mechanism that may in part account for the preventative antimigraine activity of this drug.

Health-related quality of life measures and psychiatric comorbidity in patients with migraine.

BACKGROUND AND PURPOSE: The identification of factors associated to health-related quality of life (HRQoL) measures in patients with migraine has major implications in terms of prognosis and treatment. This study aimed at investigating associations between HRQoL and comorbid mood and anxiety disorders. METHODS: Consecutive adult outpatients with a diagnosis of migraine with or without aura were assessed using the Mini International Neuropsychiatric Interview (M.I.N.I.) Plus version 5.0.0 and the Migraine-Specific Quality-of-Life Questionnaire (MSQ). RESULTS: Data of 112 patients (82 females), 69 without aura, mean age 41.2 +/- 13.3 years were analyzed. According to the M.I.N.I., 50% patients had a lifetime or current DSM-IV diagnosis of mood or anxiety disorder. There was no between-groups difference in MSQ total and subscale scores in relation to the presence/absence of psychiatric comorbidity, independently whether that was current or lifetime. In the group of subjects with psychiatric disorders, age at onset of migraine correlated with MSQ-total (rho = -0.407 P = 0.002), and subscale scores (Role Function-Restrictive, rho = -0.397, P = 0.002; Emotional Function, rho = -0.487, P < 0.001). CONCLUSIONS: Our findings suggest that current and/or lifetime psychiatric comorbidities are not associated with HRQoL measures in patients with migraine. However, patients with migraine and psychiatric comorbidities may represent a specific subgroup deserving particular attention for targeted interventions.

[Treatment of migraine]. / Aktuelle Therapie der Migräne.

Migraine attacks are characterized as unilateral and pulsating headache with autonomic features. In about 15 % of Migraine patients the attacks are accompanied by, mostly visual, transient focal neurologic disturbances, the migraine aura. Migraine attacks of mild or moderate intensity should initially be treated with non-steroidal anti-inflammatory drugs (NSAID). A combination with prokinetic and antiemetic drugs like metoclopramide or domperidone has proved to relieve nausea and increase efficacy of the analgesic drugs. In case of severe attacks or lack of treatment efficacy the migraine attacks should be treated with 5-HT (1B/1D) receptor agonists (triptans). Patients that suffer under very frequent and/or very severe migraine attacks should receive a prophylactic treatment. Prophylactic drugs of first choice are Betablockers (Propranolol and Metoprolol), Topiramate and Flunarizine. Prophylactic treatment should be administered over a period of at least 6 - 12 months.

Nitric oxide in migraine.

The potent vasodilatator and messenger molecule nitric oxide (NO) is believed to play a key role in migraine pathogenesis. NO donors such as glyceryl trinitrate (GTN) can cause headache. Infusion of GTN leads to a migraine attack in migraineurs with a latency of 4 to 6 hours. In this review we focus in the role of nitric oxide and the transcription factor nuclear factor-kappaB (NF-kappaB) in migraine pathophysiology in humans and animal models. NO is involved in pain transmission, hyperalgesia, chronic pain, inflammation and central sensitization mostly in a cyclic guanosinemono-phosphate (cGMP) dependent way. We aim to illustrate how NO is implicated in the induction of a migraine attack in migraineurs and how experimental animal models may help to elucidate the mechanisms of the human GTN response. Because of the role of NO in migraine we try to assess if and how the action of preventative migraine drugs involves the NO pathways. More knowledge about the involvement of NO in the genesis of migraine headache may also provide possible future therapeutic targets for acute migraine therapy.

The use of gabapentin in chronic cluster headache patients refractory to first-line therapy.

Chronic cluster headache (CCH) is a rare but challenging condition. About 20% of CCH patients get refractory to treatment. Gabapentin has recently been reported to be efficacious in the treatment of CCH. To test the potential of gabapentin as second-line drug, we prospectively studied the efficacy of gabapentin as add-on drug in eight patients suffering from CCH refractory to first-line treatment. Six of eight CCH patients responded to treatment. After the end of the study phase, the patients' clinical course was further followed up until January 2006. The longest period of being continuously pain-free under gabapentin treatment was 18 months. In some individuals, increasing doses were needed with time. We conclude that gabapentin may be offered as treatment trial in patients refractory to first-line treatment. However, patients may fail to respond to treatment and drug tolerance may occur with time.

Efficacy of lisinopril in migraine prophylaxis--an open label study.

The ACE-inhibitor lisinopril has previously been shown to be effective in migraine prophylaxis at a daily dose of 20 mg. To test the effect of a low dose of lisinopril (5 mg daily) in migraine prevention, we performed an open label study in 21 migraineurs. The primary outcome measure was frequency of migraine attacks. Secondary efficacy measures were migraine hours, intake of acute migraine drugs, pain intensity and responder rate. Compared with baseline conditions, the attack frequency of migraine attacks was significantly reduced (P < 0.0005). The number of acute migraine drugs dropped significantly (P = 0.002). Three patients dropped out because of intolerable cough. Our study suggests that even low doses of lisinopril may be effective in migraine treatment. However, its use may be limited by intolerable side-effects.

[Development of a screening tool for migraine prophylaxis]. / Entwicklung eines Migräneprophylaxe-Screeninginstruments (MPS).

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

Animal models of migraine: looking at the component parts of a complex disorder.

Animal models of human disease have been extremely helpful both in advancing the understanding of brain disorders and in developing new therapeutic approaches. Models for studying headache mechanisms, particularly those directed at migraine, have been developed and exploited efficiently in the last decade, leading to better understanding of the potential mechanisms of the disorder and of the action for antimigraine treatments. Model systems employed have focused on the pain-producing cranial structures, the large vessels and dura mater, in order to provide reproducible physiological measures that could be subject to pharmacological exploration. A wide range of methods using both in vivo and in vitro approaches are now employed; these range from manipulation of the mouse genome in order to produce animals with human disease-producing mutations, through sensitive immunohistochemical methods to vascular, neurovascular and electrophysiological studies. No one model system in experimental animals can explain all the features of migraine; however, the systems available have begun to offer ways to dissect migraine's component parts to allow a better understanding of the problem and the development of new treatment strategies.

Vertebral artery dissections after chiropractic neck manipulation in Germany over three years.

Vertebral artery dissection (VAD) has been observed in association with chirotherapy of the neck. However, most publications describe only single case reports or a small number of cases. We analyzed data from neurological departments at university hospitals in Germany over a three year period of time of subjects with vertebral artery dissections associated with chiropractic neck manipulation. We conducted a country-wide survey at neurological departments of all medical schools to identify patients with VAD after chirotherapy followed by a standardized questionnaire for each patient. 36 patients (mean age 40 + 11 years) with VAD were identified in 13 neurological departments. Clinical symptoms consistent with VAD started in 55% of patients within 12 hours after neck manipulation. Diagnosis of VAD was established in most cases using digital subtraction angiography (DSA), magnetic resonance angiography (MRA) or duplex sonography. 90% of patients admitted to hospital showed focal neurological deficits and among these 11 % had a reduced level of consciousness. 50% of subjects were discharged after 20 +/- 14 hospital days with focal neurological deficits, 1 patient died and 1 was in a persistent vegetative state. Risk factors associated with artery dissections (e. g. fibromuscular dysplasia) were present in only 25% of subjects. In summary, we describe the clinical pattern of 36 patients with vertebral artery dissections and prior chiropractic neck manipulation.

CGRP release and c-fos expression within trigeminal nucleus caudalis of the rat following glyceryltrinitrate infusion.

Neuropeptide release and the expression of c-fos like immunoreactivity (c-fos LI) within trigeminal nucleus caudalis neurons (TNC) are activation markers of the trigeminal nerve system. Glyceryltrinitrate (GTN) is believed to stimulate the trigeminal nerve system, thereby causing headache. We examined the effects of a 30 min NO-donor infusion on CGRP release in jugular vein blood and c-fos LI within TNC of the rat. GTN (2 and 50 microg/kg/min) or NONOate infusion (25 nmol/kg/min) did not cause any CGRP release during and shortly after infusion, whereas administration of capsaicin resulted in strongly increased CGRP levels. GTN infusion (2 microg/kg/min for 30 min) did not lead to enhanced c-fos LI after 2 h and 4 h, whereas capsaicin infusion caused a time- and dose-dependent expression of c-fos LI within laminae I and II of the TNC. Surprisingly, GTN attenuated capsaicin-induced c-fos expression by 64%. The nitric oxide synthase (NOS) inhibitor L-NAME (5 and 50 mg/kg) reduced capsaicin-induced c-fos LI dose dependently (reduction by 13% and 59%). We conclude that GTN may lead to headaches by mechanisms independent of CGRP release from trigeminal nerve fibres. GTN doses comparable to those used in humans did not activate or sensitize the trigeminal nerve system. Both GTN and L-NAME reduced capsaicin-induced c-fos LI. This is most likely due to a feedback inhibition of nitric oxide synthases, which indicates that the c-fos response to capsaicin within TNC is mediated by NO dependent mechanisms.

High-dose riboflavin treatment is efficacious in migraine prophylaxis: an open study in a tertiary care centre.

The aim of this study was to investigate the efficacy of riboflavin for the prevention of migraine. An open label study was performed in a specialized outpatient clinic. Patients received 400 mg riboflavin capsules per day. Headache frequency, duration, intensity and the use of abortive drugs were recorded at baseline and 3 and 6 months after treatment. Headache frequency was significantly reduced from 4 days/month at baseline to 2 days/month after 3 and 6 months (P < 0.05). The use of abortive drugs decreased from 7 units/month to 4.5 units/month after 3 and 6 months of treatment (P < 0.05). In contrast, headache hours and headache intensity did not change significantly. We could demonstrate a significant reduction of headache frequency following riboflavin treatment. In addition, the number of abortive anti-migraine tablets was reduced. In line with previous studies our findings show that riboflavin is a safe and well-tolerated alternative in migraine prophylaxis.

[What is needed to develop a headache? Anatomical and pathophysiological implications]. / Voraussetzungen für das Symptom Kopfschmerz. Aspekte zur Pathogenese.

The shared anatomical and physiological substrate for headache syndromes is the neural innervation of the cranial circulation. Evidence suggests, that the observed dilatation of vessels in trigeminal pain is not inherent to a specific headache syndrome but rather a feature of the physiology of the trigeminal neural innervation of the cranial circulation. Moreover, the impact of vascular changes for the generation of headaches remains elusive. The trigeminal nerve innervates blood vessels within ipsilateral meninges. Upon activation neuropeptides such as CGRP are released. Blockade of both the trigeminal nerve system and neuropeptides are crucial targets for headache alleviating drugs. While these mechanisms are well known the events within and outside the CNS which initiate headaches are poorly understood. This article will review the anatomy and physiology of the trigeminovascular system which demand renewed consideration of the neural influences in many primary headaches.

Effects of chronic sumatriptan and zolmitriptan treatment on 5-HT receptor expression and function in rats.

Triptans are commonly used anti-migraine drugs and show agonist action mainly at serotonin 5-HT(1B/1D/1F) receptors. It is not known whether frequent or long-term treatment with these drugs would alter 5-HT receptor function. We investigated the effects of protracted (14-18 days) sumatriptan and zolmitriptan treatment in rats on 5-HT(1) receptor mRNA expression and function in tissues related to migraine pathophysiology. RT-PCR analysis revealed that 5-HT(1B/1D/1F) receptor mRNA was reduced in the trigeminal ganglion after treatment with either triptan (reduction by: sumatriptan 39% and zolmitriptan 61% for 5-HT(1B); 60%vs 41% for 5-HT(1D); 32%vs 68% for 5-HT(1F)). Sumatriptan attenuated 5-HT(1D) receptor mRNA by 49% in the basilar artery, whereas zolmitriptan reduced 5-HT(1B) mRNA in this tissue by 70%. No change in 5-HT(1) receptor mRNA expression was observed in coronary artery and dura mater. Chronic triptan treatment had no effect in two functional assays [sumatriptan mediated inhibition (50 mg/kg, i.p.) of electrically induced plasma protein extravasation in dura mater and 5-nonyloxytryptamine-stimulated [(35)S]guanosine-5'-O-(3-thio)triphosphate binding in substantia nigra]. Furthermore, vasoconstriction to 5-HT in isolated basilar artery was not affected by chronic triptan treatment, while it was slightly reduced in coronary artery. We conclude that, although our treatment protocol altered mRNA receptor expression in several tissues relevant to migraine pathophysiology, it did not attenuate 5-HT(1) receptor-dependent functions in rats.