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12 Tran HT, Chung CH, Iba M, et al. Alpha-synuclein immunotherapy blocks uptake and templated propagation of misfolded alpha-synuclein and neurodegeneration. Cell Rep 2014; 7: 205465.

13 Holmes BB, Furman JL, Mahan TE, et al. Proteopathic tau seeding predicts tauopathy in vivo. Proc Natl Acad Sic USA 2014; 111: E437685.

14 Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell culture model of Alzheimers disease. Nature 2014; 515: 27478.

15 Villeda SA, Plambeck KE, Middeldorp J, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med 2014; 20: 65963.

16 Cruchaga C, Karch CM, Jin SC, et al. Rare coding variants in the phospholipase D3 gene confer risk for Alzheimers disease. Nature 2014; 505: 55054.

17 Cady J, Koval ED, Benitez BA, et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol 2014; 71: 44953.

Headache research in 2014: advancing migraine therapyAcute migraine attacks can be distressing and disabling. The problem is increased if pain killers, and even triptans, are ine ective or cant be given because of contraindications, as is the case for 1015% of patients. Headache researchers have been looking for new alternatives to the available treatments for decades. These alternatives should ideally not have vasoconstrictive properties, which are one of the main drawbacks of the triptans. For nearly three decades, calcitonin gene-related peptide (CGRP) has been known to play a crucial part in the pathophysiology of various primary headache disorders. Over the past 35 years, pharmacological targeting of structures involved in CGRP signalling has become a promising approach in pharmacological migraine therapy. In 2013, CGRP-receptor antagonists were shown to be e ective for prevention of migraines, but possibly unsafe because of hepatotoxicity concerns.1 In 2014, two large, randomised, controlled, double-blind phase 2 trials showed that two CGRP-antibodies, ALD4032 and LY2951742,3 signi cantly reduced the

number of migraine days per month compared with placebo (saline in both studies) treatment. In the ALD403 trial,2 174 patients with migraine were randomised and assigned to either ALD403 or placebo treatment. Migraine frequency, measured as migraine days per 28 day period, was reduced by 56 days in the ALD403 group compared with 46 days in the saline group (p=00306) in weeks 58. In the LY2951742 trial,3 217 patients randomly received either a single dose of LY2951742 or placebo. LY2951742 reduced the number of migraine headache days per 28 days by 42 (625%) days, compared with 30 (423%) days in the saline group (p=00030) after 12 weeks. In both trials, no safety concerns with respect to administration of CGRP-antibodies or severe drug-speci c adverse e ects were reported. About 16% of patients in both trials were completely headache-free after administration of medication, and this e ect lasted for several months for most patients. Since all these patients were refractory to most medications when they entered the study, these results are remarkable. The substantial placebo response in both studies is puzzling, however, and warrants further investigation. Nevertheless, these new antibodies represent a promising therapeutic approach for migraine prevention, and seem to be well tolerated and short of side e ects.4,5

Another pivotal study6 last year focused on the pituitary adenylate cyclase activating polypeptide-38 (PACAP) pathway. PACAP has been shown to induce migraine-like attacks in patients with migraine,7 whereas the structurally related vasoactive intestinal polypeptide (VIP) probably does not.8 Researchers from Copenhagen6 compared the attack-inducing properties of PACAP with those of VIP in patients with migraine and reported a signi cantly higher attack-inducing potential for PACAP. Since the a nity of PACAP for the pronociceptive PAC1 receptor is much greater than that of VIP,9 it seems that BSIP

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the PAC1 receptor might play an important part in the generation of migraine attacks and could be a promising target for future migraine treatments.

2014 brought new insights from preclinical work with botulinum neurotoxin type A (BoNT-A) into the mechanisms of action of treatments for chronic migraine. Why and how BoNT-A has a therapeutic e ect in chronic migraine, but not in episodic migraine or tension-type headaches, has remained unknown. Rami Burstein and colleagues10 now show that BoNT-A selectively inhibits meningeal nociceptors and prevents or reverses C- bre-mediated mechanical hypersensitivity, possibly through decreased tra cking of mechanosensitive ion channels to the cell surface. Notably, BoNT-A inhibited the mechanical sensitivity of the suture branches of intracranial meningeal nociceptors when administered extracranially. Clinically, migraine pain usually worsens with physical activities that momentarily increase intracranial pressure, such as bending over or sneezing. These ndings suggest that BoNT-A inhibits the high-threshold mechanosensitive ion channels linked preferentially to mechanical pain. The researchers therefore suggested that the prophylactic e ects of BoNT-A in migraine are caused by the reduction of the overall ow of sensory signals originating from mechano-nociceptors in the peripheral structures.10 Whether this a ects intracranial or extracranial structures needs to be established.

Another important advance in 2014 was the con-tribution to the e cacy of acute migraine medi cation. In a well designed and much discussed study,11 66 patients with migraine were asked to treat six consecutive migraine attacks with medication (rizatriptan)two attacks labelled as placebo, two labelled as Maxalt or placebo, and two labelled as maxaltin a randomised order. Each box contained the same two tablets: rizatriptan or placebo. Generally, the e ect of either placebo or drug increased progressively with the patients level of certainty that they were taking the actual drug, as suggested by the label. Pain decrease (measured with the numeric rating scale) after placebo administration was therefore greatest if placebo was labelled as rizatriptan, whereas the drug labelled as placebo was less potent than the drug labelled as rizatriptan.11 The e ect of rizatriptan mislabelled as placebo did not di er signi cantly from placebo mislabelled as rizatriptan. This nding is of great clinical relevance; although the information accompanying drug administration is known to be an

important factor in drug e cacy, the nding that even a placebo labelled as a placebo a ects treatment outcome signi cantly is new. A possible explanation could be that if a patient agrees to treatment, they will not believe that the doctors actionin this case, giving medicationwill be deliberately useless, even if the doctor says that it is. This argument could explain the ndings of another 2014 study,12 which showed that deliberately decreasing patients expectations of the e ects of acute migraine medication did not change the e cacy of the medication for more than 150 patients in emergency departments.

These new ndings o er fascinating insights and solid foundations for headache research in 2015. The future is looking a little brighter for patients with headache and their doctors.

Laura H Schulte, *Arne MayDepartment of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg D-22046, Germanya.may@uke.de

LHS declares no competing interests. AM is or has been consultant or speaker for P zer, Bayer Vital, GlaxoSmithKline, Allergan, Electrocore, ATI, MSD, and Desitin.

1 Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention. Neurology 2014; 83: 95866.

2 Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and e cacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol 2014; 13: 110007.

3 Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS. Safety and e cacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 88592.

4 Walter S, Alibhoy A, Escandon R, Bigal ME. Evaluation of cardiovascular parameters in cynomolgus monkeys following IV administration of LBR-101, a monoclonal antibody against calcitonin gene-related peptide. MAbs 2014; 6: 87178.

5 Bigal ME, Walter S, Bronson M, Alibhoy A, Escandon R. Cardiovascular and hemodynamic parameters in women following prolonged CGRP inhibition using LBR-101, a monoclonal antibody against CGRP. Cephalalgia 2014; 34: 96876.

6 Amin FM, Hougaard A, Schytz HW, et al. Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 2014; 137: 77994.

7 Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M. PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 2009; 132: 1625.

8 Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M. Vasoactive intestinal peptide causes marked cephalic vasodilation, but does not induce migraine. Cephalalgia 2008; 28: 22636.

9 Harmar AJ, Fahrenkrug J, Gozes I, et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol 2012; 166: 417.

10 Burstein R, Zhang X, Levy D, Aoki KR, Brin MF. Selective inhibition of meningeal nociceptors by botulinum neurotoxin type A: Therapeutic implications for migraine and other pains. Cephalalgia 2014; 34: 85369.

11 Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug labeling changes the outcome of episodic migraine attacks. Sci Transl Med 2014; 6: 218ra5.

12 Oktay C, Eken C, Goksu E, Dora B. Contribution of verbal suggestion to the therapeutic e cacy of an analgesic agent for acute primary headache. Cephalalgia 2014; published online Oct 10. DOI:10.1177/0333102414553821.

Headache research in 2014: advancing migraine therapyReferences