Headache research in 2015: Progress in migraine treatment

TY - JOUR

T1 - Headache research in 2015

T2 - Progress in migraine treatment

AU - Diener, Hans Christoph

AU - Dodick, David W.

N1 - Funding Information: Hans-Christoph Diener a hans.diener@uk-essen.de David W Dodick b a Department of Neurology and Headache Center, University Hospital Essen, 45122 Essen, Germany Department of Neurology and Headache Center University Hospital Essen Essen 45122 Germany b Department of Neurology, Mayo Clinic, Phoenix, AZ, USA Department of Neurology Mayo Clinic Phoenix AZ USA Migraine is the third most prevalent and sixth most disabling medical disorder in the world. Unsurprisingly, advances in our understanding of disease biology, treatment mechanisms, and new treatments have been achieved primarily for migraine. Treatment with triptans was a major step forward in the treatment of acute migraine attacks as compared with ergotamines and analgesics, which were not as effective or consistent in their effects. The mode of action of triptans was initially thought to be vasoconstriction of dilated cerebral and meningeal blood vessels and inhibition of neurogenic inflammation. Later, triptans were also found to reduce the release of calcitonin-gene-related peptide (CGRP) during migraine attacks by binding serotonin receptors on trigeminal nerve terminals. Triptans also affect photophobia and phonophobia, which suggests that they act via a CNS-dependent mechanism. Kröger and May 1 used functional MRI to elucidate the possible central mode of action of triptans compared with acetylsalicylic acid and placebo in the treatment of acute migraine attacks. Using painful trigemino-nociceptive stimulation, the investigators measured blood oxygen level-dependent signal intensity in the trigeminal nuclei, the thalamus, and trigemino-cortical pathways. They noted an increase in the blood oxygen level-dependent signal in the trigeminal nuclei and the thalamus after treatment with sumatriptan, which was not recorded after acetylsalicylic acid treatment. These results identify another potential site of action of triptans, and the changes in trigemino-cortical pathways caused by sumatriptan could explain why sumatriptan is effective in migraine, but not in other head or facial pains (except for cluster headache). Alice S/BSIP/Science Photo Library Many drugs are used for migraine prevention. For most of these drugs, the positive effect on migraine frequency was detected by chance when these drugs were given for their original indication (eg, β-blockers for hypertension). A network effectiveness meta-analysis included 132 placebo-controlled trials with α-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, anticonvulsants, β-blockers, calcium channel blockers, flunarizine, serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, serotonin agonists, and tricyclic antidepressants. 2 Drugs that were more effective than placebo for episodic migraine in at least three trials include amitriptyline, flunarizine, fluoxetine, metoprolol, pizotifen, propranolol, topiramate, and valproate. The most remarkable result was that the effect size was similar between drugs, with a monthly reduction of migraine days between 0·5 and 1·7 headache days per month. This finding suggests that these drugs are almost equally effective in all patients, but that their efficacy could be improved in future. All of the available data suggest that there seems to be a ceiling effect for preventive migraine drugs. Compliance is poor because of the high frequency of adverse events. Therefore, more effective and better tolerated drugs for migraine prevention are still needed. Humanised antibodies against CGRP or the CGRP receptor are the new treatments that are being tested in clinical trials for migraine prevention. Results from proof-of-concept and dose-finding studies for ALD403 3 and LY2951742 4 for the prevention of episodic migraine were published, and results for AMG334 reported, in 2014. These biologics were reported to be superior to placebo and have an excellent short-term tolerability profile. Data for TEV-48125 were published in 2015 for high-frequency episodic migraine 5 and chronic migraine. 6 In the high-frequency episodic migraine study, 5 patients who had 8–14 migraine attacks per month were randomly assigned to receive placebo (n=104, 225 mg TEV-48125 (n=95), or 675 mg TEV-48125 (n=96). The least square mean change in number of migraine-days from baseline to weeks 9–12 was −3·46 days in the placebo group, −6·27 days in the 225 mg dose group, and −6·09 days in the 675 mg dose group. Numbers of adverse events were similar in placebo and active treatment. In the chronic migraine study, 6 participants were randomly assigned to receive placebo (n=89), 675 mg in the first cycle and 225 mg TEV-48125 in the following cycles (n=88), or 900 mg TEV-48125 (n=87). The mean change from baseline in number of headache-hours in weeks 9–12 was −59·84 in the 675 mg (first cycle), 225 mg (following cycles) group, −67·51 in the 900 mg group, and −37·10 in the placebo group. Taken together, all of the new monoclonal CGRP antibodies have preliminary shown effectiveness in migraine prevention and have a favourable tolerability profile. An advantage of these drugs is that they need to be injected; therefore, compliance is not an issue. Additionally, these antibodies only need to be injected once per month because of their long half-lives. Long-term efficacy and safety data are not yet available. Another well tolerated approach to migraine prevention is the combination of simvastatin and vitamin D3. In a trial 7 with 57 patients with episodic migraine, participants given twice daily simvastatin (20 mg per dose) and vitamin D3 (1000 IU per dose) reported a reduction in the number of migraine days from the baseline period to intervention weeks 1–12; a change of −8·0 days in the treatment group versus +1·0 days in the placebo group. Eight patients (25%) in the active treatment group had a 50% reduction in the number of migraine days at 12 weeks after randomisation, which increased to nine patients (29%) at 24 weeks. In comparison, only one patient (3%) in the placebo group had a significant reduction in number of migraine days (p=0·03). Adverse events were similar in both treatment and placebo groups. Chronic migraine is defined as a patient having more than 15 headache days per month, eight of which need to fulfil the criteria for migraine. At present the diagnosis depends on patient history and headache diaries. MRI could be used as a new way to classify these patients in the context of clinical trials. Schwedt and colleagues 8 used MRI to determine cortical thickness, surface area, and volume in patients with episodic and chronic migraine and healthy controls. Statistically significant differences were found in pain-modulating brain areas between patients with episodic versus chronic migraine. These observations suggested that a threshold of 15 headache days per month is supported by MRI data. H-CD has received honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Addex Therapeutics, Alder BioPharmaceuticals, Allergan, Almirall, Amgen, Autonomic Technologies, AstraZeneca, Bayer Vital, Berlin Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Chordate, Coherex Medical, CoLucid Pharmaceuticals, Electrocore, GlaxoSmithKline, Grünenthal, Janssen-Cilag, Labrys Biologics, Lilly, Roche, 3M Medica, Medtronic, Menarini, Minster, MSD, NeuroScore, Novartis, Johnson & Johnson, Pierre Fabre, Pfizer, Schaper and Brümmer, Sanofi, St Jude Medical, Teva, and Weber & Weber. Financial support for research projects was provided by Allergan, Almirall, AstraZeneca, Bayer, Electrocore, GlaxoSmithKline, Janssen-Cilag, MSD, and Pfizer. Headache research at the Department of Neurology in Essen is supported by the German Research Council, the German Ministry of Education and Research and the European Union. H-CD has no ownership interest and does not own stocks of any pharmaceutical company. DWD, within the past 3 years, has served on advisory boards or has consulted for Allergan, Amgen, Alder, Alcobra, Arteaus Therapeutics, Pfizer, CoLucid Pharmaceuticals, Merck, eNeura, NuPathe, Lilly, Autonomic Technologies, Ethicon, Zogenix, Supernus, Labrys Biologics, Boston Scientific, MAP, Novartis, Tonix Pharmaceuticals, Teva, and Trigemina. DWD has received funding for travel, speaking, editorial activities, or royalty payments from IntraMed, SAGE Publishing, Sun Pharma, Allergan, Oxford University Press, Healthlogix, Universal Meeting Management, WebMD, UptoDate, Starr Clinical, Decision Resources, and Synergy.

PY - 2016/1/1

Y1 - 2016/1/1

UR - http://www.scopus.com/inward/record.url?scp=84965190035&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84965190035&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(15)00341-5

DO - 10.1016/S1474-4422(15)00341-5

M3 - Comment/debate

C2 - 26700894

AN - SCOPUS:84965190035

SN - 1474-4422

VL - 15

SP - 4

EP - 5

JO - The Lancet Neurology

JF - The Lancet Neurology

IS - 1

ER -