2014 Round-up

12

13
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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.
Holmes BB, Furman JL, Mahan TE, et al. Proteopathic tau seeding predicts
tauopathy in vivo. Proc Natl Acad Sic USA 2014; 111: E437685.
Choi SH, Kim YH, Hebisch M, et al. A three-dimensional human neural cell
culture model of Alzheimers disease. Nature 2014; 515: 27478.
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.

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Cruchaga C, Karch CM, Jin SC, et al. Rare coding variants in the
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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 therapy

BSIP, V&L/Science Photo Library

Acute migraine attacks can be distressing and disabling.

The problem is increased if pain killers, and even
triptans, are ineective 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 generelated 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 eective for prevention of migraines,
but possibly unsafe because of hepatotoxicity concerns.1
In 2014, two large, randomised, controlled, doubleblind phase 2 trials showed that two CGRP-antibodies,
ALD4032 and LY2951742,3 signicantly 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-specic
adverse eects were reported. About 16% of patients
in both trials were completely headache-free after
administration of medication, and this eect 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 eects.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
signicantly higher attack-inducing potential for PACAP.
Since the anity of PACAP for the pronociceptive PAC1
receptor is much greater than that of VIP,9 it seems that
www.thelancet.com/neurology Vol 14 January 2015

2014 Round-up

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 eect 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-bremediated mechanical hypersensitivity, possibly through
decreased tracking 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
eects 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 aects intracranial or extracranial structures
needs to be established.
Another important advance in 2014 was the contribution to the ecacy of acute migraine medication. 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 eect 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 eect of rizatriptan
mislabelled as placebo did not dier signicantly from
placebo mislabelled as rizatriptan. This nding is of
great clinical relevance; although the information
accompanying drug administration is known to be an
www.thelancet.com/neurology Vol 14 January 2015

important factor in drug ecacy, the nding that even a

placebo labelled as a placebo aects treatment outcome
signicantly 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 medication
will 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 eects of acute migraine
medication did not change the ecacy of the medication
for more than 150 patients in emergency departments.
These new ndings oer 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 May
Department of Systems Neuroscience, University Medical Center
Hamburg-Eppendorf, Hamburg D-22046, Germany
a.may@uke.de
LHS declares no competing interests. AM is or has been consultant or speaker for
Pzer, Bayer Vital, GlaxoSmithKline, Allergan, Electrocore, ATI, MSD, and Desitin.
1

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Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of the CGRP
receptor antagonist telcagepant for migraine prevention. Neurology 2014;
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Dodick DW, Goadsby PJ, Silberstein SD, et al. Safety and ecacy 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.
Dodick DW, Goadsby PJ, Spierings ELH, Scherer JC, Sweeney SP, Grayzel DS.
Safety and ecacy of LY2951742, a monoclonal antibody to calcitonin generelated peptide, for the prevention of migraine: a phase 2, randomised,
double-blind, placebo-controlled study. Lancet Neurol 2014; 13: 88592.
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.
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.
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.
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.
Rahmann A, Wienecke T, Hansen JM, Fahrenkrug J, Olesen J, Ashina M.
Vasoactive intestinal peptide causes marked cephalic vasodilation, but
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Kam-Hansen S, Jakubowski M, Kelley JM, et al. Altered placebo and drug
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Cephalalgia 2014; published online Oct 10. DOI:10.1177/0333102414553821.