Review
New therapeutic approaches for the prevention and
Lancet Neurol 2015; 14: 1010–22
Department of Neurology and
Headache Center, University of
Duisburg-Essen, Essen,
Germany (Prof H-C Diener MD,
D Holle MD); Department of
Neurology, David Geffen
School of Medicine at UCLA,
Los Angeles, CA, USA
(Prof A Charles MD); and
NIHR-Wellcome Trust King’s
Clinical Research Facility, King’s
College London, London, UK
(Prof P J Goadsby MD)
Correspondence to:
Prof Hans-Christoph Diener,
Department of Neurology and
Headache Center, University of
Duisburg-Essen, Essen 45147,
Germany
hans.diener@uk-essen.de
1010
treatment of migraine
Hans-Christoph Diener, Andrew Charles, Peter J Goadsby, Dagny Holle
The management of patients with migraine is often unsatisfactory because available acute and preventive therapies
are either ineffective or poorly tolerated. The acute treatment of migraine attacks has been limited to the use of
analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for
the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine,
5-HT1F) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate,
GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated
but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches
are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation
approaches also show promise as both acute and preventive therapies, although further studies are needed to define
appropriate candidates for these therapies and optimum protocols for their use.
Introduction including counselling, exercise, stress management,
Migraine is the most prevalent disabling neurological and relaxation techniques. If necessary, medicines for
disorder.1 Until 25 years ago, neurologists had few migraine prevention should be offered. Drugs classes
options to treat patients with acute migraine attacks. for migraine prevention include β-blockers, anti—
These options included analgesics such as acetylsalicylic epileptics (topiramate and valproic acid), calcium-
acid and acetaminophen (paracetamol); the combination channel blockers (flunarizine), angiotensin II receptor
of analgesics with caffeine; non-steroidal anti-inflam- antagonist inhibitors (candesartan), and antidepressants
matory drugs (NSAIDs) such as ibuprofen, naproxen, (amitriptyline and venlafaxine).7,8 These drugs, on
ketoprofen or diclofenac;2 and other medications with average, reduce migraine frequency by 50% in about
less clear mechanisms of action, such as metamizole. 40–45% of patients. Compliance and adherence is poor
Ergotamine preparations, which act on serotonin because of their many adverse events.9 As for acute
receptors but also on other receptors, have also been therapies, new treatments are needed that are more
used, with vasoconstriction presumed to be their effective, better tolerated, and without contraindications.
primary mechanism of action. The triptan sumatriptan Several new drugs are under development for the
was the first drug specifically developed as an acute prevention of migraine attacks, and these drugs will
migraine therapy, acting with higher specificity on also be covered in this Review.
serotonin (5-HT1B and 5-HT1D) receptors than In addition to drug therapies, several new neuro-
ergotamine. Triptans are generally effective only in the modulatory methods are being investigated for the
acute treatment of migraine3,4 and cluster headache;5 acute treatment and prevention of migraine. These
although they can be highly effective in many new treatment approaches are also discussed in this
individuals, triptans can also have substantial Review.
limitations, including recurrence of migraine symptoms
after initial efficacy. Additionally, despite having only New drugs for acute treatment
weak vasoconstrictor properties in humans, triptans are Depending on what measure is used, between 40% and
contraindicated in patients with severe vascular 70% of patients are non-responsive to a triptan at 2 h
conditions such as myocardial infarction, angina after treatment onset, or do not tolerate existing acute
pectoris, transient ischaemic attack or ischaemic stroke, treatment options, including triptans (40% when
and peripheral arterial disease, and in people with headache response is defined as a transition of
several untreated vascular risk factors.6 Therefore, new moderate or severe pain to mild or no pain, 2 h after
drugs are needed to treat migraine attacks in patients in intake of drug; 70% when pain free is defined as
whom triptans are not effective, are initially effective transition from severe, moderate, or mild headache
but symptoms recur, are poorly tolerated, or are pain to no pain, 2 h after intake of drugs).4 Additionally,
contraindicated. This Review provides an overview of headache recurrence after an initial positive response is
new drugs for the acute treatment of migraine attacks, an unsolved problem in about a third of responders.
covering studies regarding clinical evidence, side Triptans are more effective if taken when the pain is
effects, contraindications, and the different stages of mild or moderate. The efficacy of a triptan can be
clinical development. markedly attenuated if patients wait until the headache
Patients with frequent migraine attacks need is severe to take the drug.10 Several potential alternatives
migraine-preventive therapy. Prevention should be to triptans have been developed as acute migraine
primarily initiated with non-medical approaches, treatments (table 1).
www.thelancet.com/neurology Vol 14 October 2015
 Review

Status of clinical studies Efficacy of treatment (based on primary endpoint)

Calcitonin gene-related peptide receptor antagonist
Olcegepant (BIBN-4096BS)11 Development terminated because only intravenous Better than placebo (response 2 h after treatment: p=0·001)
administration was possible
Telcagepant (MK-0974) 12 Development terminated because of increased liver enzymes13 Better than placebo (reduction of migraine or probable migraine days: p<0·05)
MK-3207 14
Development terminated after emergence of delayed Better than placebo (pain freedom at 2 h after 200 mg dose: p=0·001)
asymptomatic liver test abnormalities
Rimegepant (BMS-927711) 15 No future development plans have been announced owing to Better than placebo (pain freedom at 2 h after 75 mg, 150 mg, 300 mg dose
commercial decision p=0·002, p<0·001, p=0·002)
BI 44370 TA16 Development terminated for unknown reasons Better than placebo (pain freedom at 2 h after 400mg dose: p=0·005)
MK-1602 Status unclear (NCT01613248) Unknown
Serotonin 5-HT1F receptor agonist
Lasmiditan (COL-144)17 Phase 2 proof of concept study Of participants treated in the 10 mg, 20 mg, 30 mg, and 45 mg lasmiditan dose
groups, 54–75% showed a 2 h headache response compared with 45% in the placebo
group (p=0·0126 for the linear association between response rates and dose levels)
Lasmiditan (COL-144)18 Phase 3 study started in 2015 (NCT02439320) Better than placebo in phase 2 (pain freedom at 2 h after 200 mg dose: p=0·032)
Combined serotonin (5-HT 1B/1D) receptor agonist and neuronal nitric oxide synthase (nNOS) inhibitor
NXN-18815 Phase 2 study completed Moderate effect compared with placebo (pain freedom at 2 h after dose: p=0·0801)
Transient receptor potential vanilloid (TRPV1) receptor modulators
SB-70549819 Phase 2 study completed (NCT00269022) Not better than placebo (pain freedom at 24 h: p value not stated)
Civamide20 Phase 2 study completed Moderate effect on pain freedom (pain freedom at
2 h after either 20 μg or 150 μg dose: no placebo control group)
Glutamatergic targets
Ketamine21 Phase 3 study completed 2012 Moderate effect in patients with aura- (reduction of aura severity: p=0·032)
Tezampanel (LY293558)22 Phase 2 study completed Better than placebo but less effective than sumatriptan (headache response rate at
2 h: LY29358 p=0·017; sumatriptan p<0·01)
BGG49223 Development terminated owing to absence of efficacy Not better than placebo (p=0·2)
LY46619524 Phase 2 study completed Moderate effect compared with placebo but less effective than sumatriptan
(p value not stated)
ADX1005925 Development terminated owing to increased liver enzymes Better than placebo (pain freedom at 2 h after dose p=0·039)
Propofol
Propofol26 Phase 2 study completed; phase 2/3 study in children started Effect comparable to sumatriptan (high risk of addiction, therefore not
2015 (NCT02485418) recommended for treatment; pain intensity measure on a 11 point VAS: p= 0·53)
Benzopyran derivative
Tonabersat27 Phase 2 studies completed, development terminated Study results inconsistent

VAS=visual analogue scale.

Table 1: New pharmacological treatments for acute migraine attacks

Calcitonin gene-related peptide (CGRP) receptor
antagonists
CGRP is produced in peripheral and central neurons,
and acts as a potent vasodilatator. CGRP is also
implicated in the transmission of pain signals in both
the peripheral nervous system and the CNS, and is
released during severe migraine attacks.28,29 CGRP
receptor antagonists have no effect on cerebral or
systemic haemodynamics,30 so they could be safe in
patients with triptan contraindications, such as previous
myocardial infarction, angina, or previous stroke.6 In a
proof-of-concept study,11 olcegepant (BIBN-4096BS), a
selective CGRP receptor antagonist,31 was effective in
126 patients with migraine. The drug could only be given
intravenously and was not further developed. Telcagepant
(MK-0974), another CGRP receptor antagonist,
underwent an extended development programme and
was found effective in the treatment of acute migraine
attacks.12 In a study13 in which telcagepant was planned to
be given daily for 3 months for migraine prevention, the
trial was terminated early when 13 patients showed a
three or more times increase of alanine transaminase or
aspartate transaminase. Interestingly, an analysis of the
effect on migraine or probable migraine days showed a
significant effect (telcagepant 140 mg = –2·7,
280 mg = –3·0, placebo = –1·6; p<0·05).13 The follow-up
compound MK-320714 displays roughly 400-times higher
affinity than telcagepant for the human and rhesus
monkey CGRP receptors compared with the rat receptor,
but also had its development pathway terminated, most
likely after emergence of asymptomatic liver test
abnormalities in pharmacological studies during the
phase 1 clinical trials.
Rimegepant (BMS-927711) is a potent, selective,
competitive human CGRP receptor antagonist without
vasoconstrictor effects.32 In a randomised, double-blind,

www.thelancet.com/neurology Vol 14 October 2015 1011

 Review
placebo-controlled, dose-ranging study,15 885 patients with
migraine were randomised with an adaptive dose-finding
design to sumatriptan 100 mg (active comparator) or
placebo. The drug was better than placebo in terms of the
primary endpoint of pain freedom at 2 h after dose
(rimegepant 75 mg 31% [p=0·002], 150 mg 33% [p<0·001],
300 mg 30% [p=0·002]; sumatriptan 100 mg 35%
[p<0·001]; placebo 15%).15 The company has not announced
future development plans for rimegepant.33
The CGRP receptor antagonist BI 44370 TA was
investigated in 341 adult participants randomly assigned
to one of three doses of the compound, eletriptan as an
active comparator, or placebo.34 Efficacy was shown in a
dose-dependent manner in the treatment of acute
migraine attacks (primary endpoint pain-free after 2 h:
BI 44370 TA 50 mg 7·8% odds ratio [OR] 0·89, 95 % CI
0·2–3·77; 200 mg 21·5% 2·8, 0·93–9·51; 400 mg 27·4%
4·56, 1·56–15·42, p<0·005; eletriptan 40 mg 34·8% 5·74,
2·06–18·84, p=0·005; placebo 8·6%).16 The development
of BI 44370 TA was discontinued for unknown reasons.
At present, no further CGRP-receptor antagonists are
being actively developed for the acute treatment of
migraine. The last publically disclosed compound was
MK-1602, a CGRP-receptor antagonist, for which a
phase 2 study has been reportedly completed without
further details being available (NCT01613248). Whether
the liver toxicity observed with some of the CGRP-
antagonists when taken on a daily basis is a class effect or
not and if any of the identified compounds will be further
developed remains unclear.
Serotonin-5-HT1F receptor agonist
Lasmiditan (COL-144) is a non-triptan 5-HT1F-receptor
agonist in the ditan drug class. Lasmiditan is selective for
the 5-HT1F receptor and, unlike triptans, does not
substantially activate 5-HT1B or 5-HT1D receptors.34 5-HT1F
receptors are not expressed in the vasculature, and
activation of this subtype of receptors has no vascular
effects.34 In preclinical studies, lasmiditan was reported
to inhibit plasma protein extravasation evoked by
stimulation of the trigeminal ganglion. Lasmiditan also
inhibited activation of cells in the trigeminal nucleus
caudalis evoked by trigeminal stimulation.35 This drug
has been studied as an acute treatment for migraine in
two randomised, placebo-controlled, double-blind trials.
The first trial (phase 2)17 compared outcomes of
88 patients treated with intravenous lasmiditan with
those of 42 patients receiving placebo. Of the
130 participants treated in the 10 mg, 20 mg, 30 mg, and
45 mg lasmiditan dose groups, a significantly higher
proportion had headache relief at 2 h, compared with
those taking placebo (lasmiditan dose groups 54–75%,
placebo group 45%; p=0·0126 for the linear association
between response rates and dose levels). Dizziness,
paraesthesias, and sensations of heaviness of the limbs
were more common in the lasmiditan groups than in the
placebo group.
1012
The second study18 investigated the efficacy and
tolerability of oral lasmiditan as an acute migraine
therapy in 305 patients receiving different doses of
lasmiditan (50 mg, 100 mg, 200 mg, or 400 mg) versus
81 patients receiving placebo. Each dose of lasmiditan
showed significant improvement for the endpoint of
headache relief at 2 h, and the response was dose-
dependent (lasmiditan 50 mg difference compared with
placebo 17·9%, p=0·022; 100 mg difference 38·2%,
p<0·0001; 200 mg difference 28·8%, p=0·0018; 400 mg
difference 38·7%, p<0·0001). A dose-dependent
increased incidence of adverse effects also occurred,
most commonly dizziness, vertigo, and fatigue. However,
several commonly reported adverse effects of triptans,
namely tightness or heaviness in the chest, neck, or jaw,
were not reported.
The results with lasmiditan suggest that selective
activation of 5-HT1F receptors can have therapeutic effects
for migraine, and that migraine can be treated with a
5-HT1F receptor agonist in the absence of any vascular
effects. The occurrence of side-effects attributable to the
CNS also suggests a central mechanism of action.
Whether or not activation of 5-HT1F receptors alone is as
effective on a population basis, or indeed in individuals,
as activation of 5-HT1B, 5-HT1D, and 5-HT1F receptors
together is yet to be seen. Regardless, the results to date
suggest that lasmiditan might represent an option for
acute migraine therapy for patients who have
cardiovascular contraindications to taking triptans. A
phase 3 programme started in 2015 (NCT02439320).
Neuronal nitric oxide synthase (nNOS) inhibitors
Nitric oxide and CGRP are key mediators in the
pathophysiology of migraine.36–38 In a randomised,
double-blind, placebo-controlled phase 2 trial,39 a single
dose of 600 mg NXN-188 was used for treatment of
moderate-to-severe acute migraine headache attacks in
86 patients and compared with placebo treatment
(88 patients). Unfortunately, findings have only been
presented in abstract form,39 but not published. The
primary endpoint of pain relief at 2 h was not met
(p=0·0801). Significant treatment response was reported
from 4 h to 24 h. Efficacy of NXN-188 was also shown for
the secondary endpoints of sustained pain freedom and
use of rescue drugs (p=0·0122). The drug was well
tolerated with no serious adverse events, especially no
triptan-like side-effects.
NXN-188 was also investigated when taken during a
migraine aura in a single-centre, randomised, double-
blind, placebo-controlled, two-way crossover trial.40
50 patients were included in the study, 18 of who
completed both treatments. 4 (22%) patients reported
freedom of headache at 2 h after NXN-188 intake and
2 (11%) patients reported freedom of headache after
placebo treatment, a difference that was not significant.
Based on the available data for NXN-188, this dual
effect molecule will need further study. A selective
www.thelancet.com/neurology Vol 14 October 2015

inducible NOS (iNOS) inhibitor GW27415041 did not
show efficacy either in an acute migraine study42 or as a
preventive drug43 at doses equivalent to those that clearly
inhibited pain responses in experimental animals and
had dural inflammatory effects.44 Another non-selective
NOS inhibitor (L-NG-methyl-arginine hydrochloride;
546C88) has showed promising results in migraine
treatment.45 Both of these compounds were not further
developed. However, owing to cardiovascular safety
concerns and an unfavourable pharmacokinetic profile,
the development of this drug was stopped. The possible
role on acute migraine treatment for a pure nNOS
inhibitor has yet to be assessed.
Transient receptor potential vanilloid (TRPV1) receptor
modulators
TRPV1 receptors are implicated in peripheral pain
perception and are present in the periaqueductal grey,
hypothalamus, thalamus, amygdala, cortex, trigeminal
nucleus caudalis, and several other regions of the brain
in humans, rats, and mice. TRPV1 receptor activation
leads to a release of CGRP, which is capable of triggering
trigeminal activation.46 Therefore, TRPV1 receptor was
chosen as a possible target for drug development despite
the fact that studies in models predictive of acute
antimigraine effects have failed to show any response to
TRPV1 receptor antagonists in rats.47 Preclinical models
of migraine are not predictive of efficacy of a particular
drug in human migraine attacks. TRPV1 receptor
antagonists were investigated in human migraine
because of the anatomical location of TRPV1 receptors
and their capability of triggering CGRP release.
SB-705498, a potent, selective, orally bioavailable
TRPV1 receptor antagonist48 has been studied in a
randomised placebo-controlled trial in patients with
acute migraine (NCT00269022). No differences were
reported between active treatment and placebo in terms
of pain-free outcomes up to 24 h. On some endpoints (ie,
pain relief at several timepoints and treatment of
phonophobia and photophobia) actively treated patients
did worse than those on placebo.19 Hence, in light of
these results, TRPV1 receptor antagonism does not seem
a promising avenue for acute migraine treatment.
Civamide is a TRPV1 receptor agonist.49 In a small
(n=34) double-blind, randomised study20 without a
control group, patients received 20 μg or 150 μg of
civamide to treat a single migraine attack. At 2 h 17% and
27% of patients, respectively, were pain free.20 Given that
the study was in effect unblinded, the beneficial effect
seems modest. In summary, the approach to treat
migraine attacks with drugs affecting the TRPV1 receptor
has shown little or no beneficial effect.
Drugs acting through glutamatergic targets
Ketamine is an antagonist of the NMDA-subtype of the
excitatory transmitter glutamate that also modulates the
activity of opioid receptors and monoamine transporters.
www.thelancet.com/neurology Vol 14 October 2015
Review
Ketamine is primarily used as a general anaesthetic and
has also been used as a therapy for complex regional pain
syndrome. In animal models, ketamine can inhibit
cortical-spreading depression.50 Based on this preclinical
evidence, ketamine has been studied as a treatment for
migraine aura. In one study,51 25 mg intranasal ketamine
was given to 11 patients with auras resulting from familial
hemiplegic migraine. In five of these patients, ketamine
reduced the severity and duration of the neurological
deficits associated with the migraine aura. In a second
study (table 1),21 with a double-blinded, randomised
parallel-group design, the effect of 25 mg intranasal
ketamine was examined on migraine with prolonged
aura in 30 patients; 2 mg intranasal midazolam was used
as an active control. In this study,21 ketamine reduced the
average severity but not the duration of migraine aura,
whereas midazolam had no effect. These studies suggest
that ketamine might have a specific role in the treatment
of migraine aura. In patients with severe and long-lasting
aura, ketamine might be a promising treatment option,
especially as no other treatments exists at the moment. A
ketamine nasal spray is not, however, approved for the
treatment of migraine aura and is not available
commercially.
Tezampanel (LY293558) is an antagonist of the AMPA
and kainate subtypes of ionotropic glutamate receptors.52
The efficacy of tezampanel as an acute migraine therapy
was investigated in a small (45 patients), triple-blind,
parallel group trial that compared 1·2 mg/kg of
tezampanel delivered intravenously, 6 mg of
subcutaneous sumatriptan, or placebo delivered when
migraine pain was moderate to severe.22 The primary
endpoint was headache response rate at 2 h, defined as
improvement from moderate-to-severe pain to mild or
no pain. Response rates were 69% for tezampanel
(p=0·017) and 86% for sumatriptan (p<0·01) versus 25%
for placebo. Tezampanel and sumatriptan were also
better than placebo on several other measures of
improvement in pain and migraine-associated symptoms
(pain-free after 2 h: tezampanel p=0·004, sumatriptan
p=0·001; sustained response: tezampanel and
sumatriptan both p<0·01; sustained pain free tezampanel
and sumatriptan both p<0·01; use of rescue medication
tezampanel p=0·00], sumatriptan p=0·001). An
additional clinical trial of tezampanel as an acute
migraine therapy has been completed, according to the
information provided by Clinicaltrials.gov, but the results
of this study have not been published (NCT00567086). A
novel AMPA receptor antagonist, BGG492, was not
effective for the treatment of acute migraine.23 This
randomised, double-blind, proof-of-concept study
assessed the efficacy of BGG492 (250 mg) versus placebo
and sumatriptan (100 mg) in 75 participants with acute
migraine attacks. Improvement from severe-to-moderate
to mild-to-no headache pain (primary response) was
reported in 58%, 58%, and 54% of BGG492-treated
patients at 2 h, 3 h, and 4 h post-dose (p=0·2, p=0·5, and,
1013
 Review
p=0·5 vs placebo), respectively, compared with 68%, 84%,
and 92% sumatriptan-treated patients, and 40%, 48%,
and 44% in the placebo group. Pain-free response at 2 h
was reported for 25%, 24%, and 16% of BGG492,
sumatriptan, and placebo participants, respectively.
LY466195 is a selective competitive antagonist of the
iGluR5 (kainate) subtype of the ionotropic glutamate
receptor.53 A randomised, blinded, parallel-group phase 2
trial24 compared LY466195 with sumatriptan 6 mg or
placebo for the treatment of acute migraine attacks. This
study,24 with endpoints similar to those described for
tezampanel, reported that response rates at the 2 h time-
point were 35% for LY466195 1 mg (n=23, no significant
difference from placebo), 50% for LY466195 3 mg (n=24,
no significant difference from placebo), 74% for
sumatriptan (n=23, p<0·05), and 39% for placebo. Pain-
free rates at 2 h were 4% for LY466195 1 mg (not
significant), 29% for LY466195 3 mg (p<0·05), 43% for
sumatriptan (p<0·05), and 0% for placebo. Visual side
effects (hazy vision) similar to those noted with tezampanel
were observed in a dose-dependent manner in 4% of
patients receiving the 1 mg dose and 21% receiving the
3 mg dose, compared with none in patients taking
sumatriptan.
These studies suggested that AMPA and kainate
receptors represent novel therapeutic targets for acute
migraine therapy. However, the efficacy of the
investigated drugs was less than that of sumatriptan, and
visual side effects were substantial. Further studies
would be needed to show efficacy in patients who do not
benefit from triptans or cannot take triptans.
ADX10059 is a negative allosteric modulator of the
mGluR5 subtype receptors of the excitatory transmitter
glutamate. mGluR5 receptors have been implicated in
several animal models of pain, and it has been
hypothesised that mGluR5 antagonists could have
efficacy in migraine. A small proof-of-concept study25
showed a significant effect of ADX10059 versus placebo
in the acute treatment of migraine. A trial of ADX10059
for prevention of migraine was initiated in 2008. The
trial was ended early because increase of liver enzymes
was observed in a substantial number of patients. It is
not clear whether the liver damage was due to ADX10059
specifically or whether it is a class effect. Although
investigation of this drug has not been continued,
mGluR5 is an interesting potential therapeutic target for
migraine.
Propofol
Propofol is considered to have several mechanisms of
action, through potentiation of GABAA receptor activity,
thereby slowing the channel-closing time, and also acting
as a sodium-channel blocker. The endocannabinoid
system might contribute substantially to the anaesthetic
action of propofol. In two small trials in the emergency
room setting, subanaesthetic doses of propofol were
compared with intravenous dexamethasone26 or
1014
subcutaneous sumatriptan.54 Propofol reduced the
intensity of acute headache attacks more than intravenous
dexamethasone by a 1 point VAS scale after 10 min,
20 min, and 30 min [mean of reported VAS p<0·05).26
Subcutaneous sumatriptan and propofol had a comparable
efficacy on headache (headache intensity was measured
on a 11-point visual analogue scale), whereas propofol was
associated with better control of nausea and vomiting
than sumatriptan. However, propofol can be addictive.54
Tonabersat
Tonabersat is a benzopyran derivative that can inhibit
cortical-spreading depression and cerebrovascular
responses to trigeminal nerve stimulation in animal
models.55–57 Tonabersat was purported to be a modulator
of cellular gap junctions by binding at a stereo-specific
binding site, although this mechanism of action is not
well supported by evidence. Based on its promise in
preclinical models, tonabersat was studied in clinical
trials of migraine with and without aura. Two
randomised, double-blind, parallel-group placebo-
controlled trials59 examined the efficacy of tonabersat
(15 mg, 25 mg, 40 mg, and 80 mg) as an acute therapy for
migraine. In an international study,58 tonabersat was
superior to placebo at 15 mg and 40 mg doses for the
primary endpoint of headache relief at 2 h (tonabersat
15 mg 37% (p=0·013), 40 mg 41% (p=0·002), placebo
21%). In a North American study,59 none of the primary
or secondary endpoints suggested significant differences
between tonabersat and placebo. Methodological
differences were discussed as the reason for these
different study results (eg, more sumatriptan-naive
patients in the international study), but ultimately why
these two studies had such different outcomes is unclear.
In summary, tonabersat showed promise in preclinical
models based on inhibition of cortical-spreading
depression. Unfortunately, tonabersat showed
inconsistent results in trials in patients with acute
migraine. Up to now, no further studies have been
planned to investigate the efficacy of tonabersat in acute
migraine treatment.
New drugs for preventive treatment of migraine
In a subgroup of patients, migraine attacks can be very
frequent. In some patients with migraine, the treatment
of acute migraine attacks is either not effective or not
tolerated and preventive pharmacological treatment is
warranted. Approved drugs for migraine prevention are
the β blockers propranolol and metoprolol, the
anticonvulsants valproic acid and topiramate, the tricyclic
antidepressant amitriptyline, and the calcium channel
modulator flunarizine (table 2).
Monoclonal antibodies that target the CGRP pathway
In view of the role of CGRP in migraine, four companies
have embarked on programmes to develop monoclonal
antibodies against CGRP.
www.thelancet.com/neurology Vol 14 October 2015
 Review

Status of clinical studies Efficacy of treatment (based on primary end point)

Monoclonal antibodies targeting the calcitonin gene-related peptide pathway
LY2951742 Phase 2 study completed,59 phase 2 recruiting at present (NCT02163993) Better than placebo (comparison of migraine headache days between a 1-month
baseline and weeks 9–12: p=0·0030)
ALD403 Phase 2 study completed,59 phase 2 recruiting at present (NCT02275117) Better than placebo (comparison baseline migraine days to weeks 5–8: p=0·0306)
AMG 334 Phase 2 completed, phase 2 study currently recruiting (NCT02066415) Better than placebo (reduction of mean monthly migraine days: p=0·021)
TEV-48125 (LBR-101) Phase 2 studies active, but not recruiting at present (NCT02025556, Well tolerated in healthy volunteers
NCT02021773)
Benzopyran derivative
Tonabersat27,60 Phase 2 studies completed, no further studies planned Study results inconsistent (primary endpoints were change in mean number of
migraine days between 3 months and the baseline period27 and reduction in aura
attacks with and without headache and a reduction in migraine headache days with
and without aura in the 12 week treatment periods60)
Dual-orexin receptor antagonist
Filorexant (MK-6096)61 Phase 2 studies completed, development terminated owing to lack of efficacy Not effective (results presented as confidence intervals)
Non-selective phosphodiesterase inhibitor
Ibudilast Phase 1, recruiting at present (NCT01389193) No data available
Angiotensin II receptor antagonist
Candesartan62 Phase 2 study completed Comparable to propranolol, better than placebo (migraine days per month: p=0·02)
Anticonvulsant drug
Carisbamate63 Phase 2 study completed, development terminated due to absence of efficacy Not effective (reduction in monthly migraine frequency: p=0·6)

Table 2: New pharmacological treatments for the prevention of migraine

LY2951742 is a humanised monoclonal antibody to
CGRP. In a phase 2 proof-of-concept study64 in patients
with episodic migraine, subcutaneous administration of
LY2951742 150 mg every 2 weeks was compared with
placebo. The primary efficacy endpoint was a comparison
of migraine headache days between a 1 month baseline
and weeks 9–12. The mean change in the number of
migraine headache days, at 4·2 days, was significantly
greater in the LY2951742 group than in the placebo
group, at –3·0 days (p=0·0030). There was a 15%
difference between placebo versus active drug in a post-
hoc analysis of complete responders defined as the
proportion of patients with a 100% reduction in the
number of migraine headache days in a 28-day period
during the 12-week treatment period. No serious adverse
events occurred on treatment.
ALD403 is another humanised monoclonal antibody to
CGRP that has been tested in a phase 2 proof-of-concept
trial65 in patients with episodic migraine that compared
frequency of migraine days at baseline to that at
weeks 5–8. ALD403 1 g administered intravenously
caused a mean change reduction of –5·6 days, compared
with −4·6 days in the placebo group (p=0·0306). Again,
looking at weeks 1– 12, the proportion of 100% responders
was 0 of 76 for placebo and 11 (16%) of 67 for ALD403.65
The treatment was also generally well tolerated. Notably,
presentation of the 6 month blinded data showed a
complete response in 11% of participants (100% response
means no more migraine attacks).66
AMG 334 is a human monoclonal antibody to the
CGRP receptor. The CGRP receptor is a multimeric
complex consisting of the seven-transmembrane
G-protein coupled receptor designated calcitonin
receptor-like receptor (CLR) and a single transmembrane
protein-designated receptor activity-modifying protein
(RAMP) 1 (CLR/RAMP1 complex) that shows more than
5000-times selectivity for its CGRP ligand than other
closely related receptors in this class.67 In a phase 2
study in patients with episodic migraine that compared
three doses (7 mg, 21 mg, and 70 mg) of AMG 334 and
placebo, the 70 mg dose was effective at the primary
endpoint, with a reduction in mean monthly migraine
days of –3·40 compared with placebo (–2·28; p=0·021).
No major safety events were reported.68 AMG 334 is also
being tested in a phase 2 trial in patients with chronic
migraine (NCT02066415).
TEV-48125 (formerly LBR-101) is a humanised
monoclonal antibody to CGRP that has been tested
extensively in phase 1 studies, and in non-human
primates. Single intravenous doses of LBR-101 ranging
from 0·2 mg to 2000 mg and several intravenous doses
up to 300 mg were well tolerated in healthy volunteers.69
Safety issues were not reported. TEV-48125 is now in
phase 2 development for patients with episodic or
chronic migraine (NCT02025556: monthly subcutaneous
administration for migraine prevention in high-
frequency episodic migraine; NCT02021773: monthly
subcutaneous administration for migraine prevention in
chronic migraine).
There seems little doubt that blockade of the CGRP
pathway is an effective preventive strategy of migraine,
and the results of ongoing studies are eagerly awaited.
However, there are also several caveats associated with
this therapeutic strategy:70 none of the new monoclonal
antibodies has been tested long enough to exclude
adverse events on long-term use. The frequency and

www.thelancet.com/neurology Vol 14 October 2015 1015

 Review
biological consequence of the generation of auto-
antibodies against these therapeutic antibodies are still
unknown. Additionally, high placebo response rates were
noted in these studies; this finding might be due to the
fact that these drugs are injected instead of given as oral
formulation, and to some extent due to excitement
around their development. We look forward to the release
of findings of the phase 3 studies that will elucidate
efficacy and associated adverse events.71
Tonabersat
One randomised, double-blind, parallel group, placebo-
controlled trial27 studied the efficacy of tonabersat as a
migraine-preventive therapy. This study, which included
68 patients in the placebo and 58 patients in the tonabersat
intention-to-treat groups, reported that tonabersat 40 mg
for 10 weeks was not superior to placebo for the primary
endpoint of change in mean number of migraine days in
the third month of therapy compared with baseline. There
were 10 secondary efficacy endpoints, of which two were
significant. In month 3 of treatment, the responder rate,
defined as a 50% reduction in migraine attacks, was 62%
for tonabersat and 45% for placebo (p<0·05), and the
rescue medication use was reduced in the tonabersat
group compared with placebo by 1·8 days (p=0·02).
Another study60 examined the efficacy of tonabersat on
episodes of migraine with aura versus episodes without
aura. This study was a double-blind, placebo-controlled
crossover trial with 31 patients with migraine with aura
included in the efficacy analysis. The study reported that
tonabersat 40 mg orally for 3 months resulted in a
significant reduction in the number of episodes of aura
with or without headache (median number of episodes of
aura over 12 weeks: tonabersat 1·0, placebo 3·2; p=0·01).
The median number of migraine headache days per
12 weeks was not changed during tonabersat treatment
(tonabersat 3 days, placebo 3 days).
In summary, study results about migraine preventive
properties of tonabersat are inconsistent. A small study60
suggested that tonabersat might be s useful specifically
for treatment of migraine aura, raising the possibility of
different mechanisms of action of migraine with aura
compared with migraine without aura. Thus far, no
further studies have been done to follow up on this
possibility.
Dual-orexin receptor antagonists
The orexinergic system comprises the neuropeptides
orexin A and B, which are exclusively produced in the
hypothalamus. These neuropeptides act via G-protein-
coupled OX1 and OX2 receptors through projections to the
prefrontal cortex, thalamus, and other subcortical areas to
promote arousal72 and exert modulating effects on
nociceptive neurotransmission, thermoregulation,
neuroendocrine, and autonomic functions.73–75 These
areas are known to modulate basal and dural-evoked
nociceptive activation in the trigeminocervical complex.76–78
1016
The premonitory phase of a migraine might include
symptoms such as yawning, food cravings, and changes
in wakefulness,79 which are thought to be regulated to a
substantial extent by the hypothalamus and its orexinergic
neurons. Neuroimaging data have further implicated this
region of the brain in the premonitory phase of migraine.80
Filorexant (MK-6069) is a dual (OX1 and OX2) receptor
antagonist that has been developed for insomnia;81
indeed, a related compound has now been approved for
treatment of insomnia.82 A placebo-controlled study61 has
been done with filorexant once daily dose (10 mg at night)
in the preventive treatment of migraine in a parallel
group study with 120 patients treated with filorexant and
115 treated with placebo. The primary endpoint was the
mean monthly migraine days during the 3 months of
treatment. No significant difference was reported
between placebo and fliorexant. A higher proportion of
patients on filorexant (13% vs 4%) reported somnolence.
Non-selective phosphodiesterase inhibitors
Ibudilast is a non-selective phosphodiesterase inhibitor
that has a variety of vascular and non-vascular effects
including vasodilation, inhibition of platelet aggregation,
reduction in airway hypersensitivity, and inhibition of
allergic and inflammatory reactions.83,84 Its mechanisms
of action include suppression of proinflammatory
cytokine production and inhibition of the activation of
brain glial cells that occurs under pathological conditions
in animal models.84
On the basis of its anti-inflammatory actions and its
ability to inhibit pathological glial cell activation, ibudilast
has been proposed as a potential therapy for migraine.
Ibudilast is being tested in a phase 1 trial as a preventive
therapy for patients with chronic migraine
(NCT01389193). No results are available thus far. The
status of a trial of ibudilast on medication overuse
headache is unknown (NCT01317992).
Angiotensin II receptor antagonists
Based on patient reports on the improvement of migraine
during treatment of hypertension with angiotensin II
receptor antagonists, a small randomised study85 was
done with candesartan and suggested a possible positive
effect. A more recent crossover study compared
candesartan (16 mg) with propranolol and placebo.62 Both
active drugs were equally effective and superior to
placebo (migraine days per month: candesartan 2·95
(p=0·02), propranolol 2·91 (p=0·02), placebo 3·53).
Overall, the number of patients treated in these trials is
small. Angiotensin II receptor agonists are not approved
for the prevention of migraine. However, to give these
substances a try in clinical practice seems reasonable in
patients in whom first-line preventive therapy has failed.
Anticonvulsant drugs
At present, only valproic acid and topiramate have been
shown to have proven efficacy for migraine prevention.86
www.thelancet.com/neurology Vol 14 October 2015

Carisbamate is a new anticonvulsant based on a modified
topiramate molecule which is devoid of some of the
adverse events of topiramate. In a dose-finding study63 with
323 migraine patients, carisbamate 100 mg, 300 mg, or
600 mg per day given for 22 weeks was not better than
placebo. The primary outcome was percent reduction from
baseline through the double-blind phase in average
monthly migraine frequency.
Neuromodulation approaches
For some patients with refractory chronic headache or
patients who do not tolerate or want prophylactic
medication or have contraindications, peripheral
neuromodulation might offer a new treatment option.
Invasive (ie, occipital nerve stimulation or stimulation of
the sphenopalatine ganglion) and non-invasive (ie, single
pulse transcranial magnetic stimulation, transcutaneous
vagal nerve stimulation, or transcutaneous supraorbital
nerve stimulation) neuromodulatory treatment
approaches are being developed (table 3). Some of these
approaches can be used for the acute treatment of
migraine, some for migraine prophylaxis, and some for
both treatment and prophylaxis.
Occipital nerve stimulation
Weiner and Reed91 first described occipital nerve
stimulation for the treatment of patients with occipital
neuralgia. Detailed phenotyping of some of these
patients revealed that they had chronic migraine.92
Neuromodulation using occipital nerve stimulation has
been applied across a range of primary headache
disorders. These patients have generally been medically
refractory93 and standardisation of the stimulation
parameters has been elusive.94 Three studies of occipital
nerve stimulation in patients with in migraine have been
reported.87,88,95
Occipital nerve stimulation for the treatment of
intractable chronic migraine headache (ONSTIM)87 was
done as a multicentre, double-blind randomised
Occipital nerve stimulation (invasive, preventive treatment)
Phase 3 study completed (NCT00615342)
Stimulation of the sphenopalatine ganglion (invasive, acute treatment)
Phase 2 study ongoing (NCT01540799)
Single pulse transcranial magnetic stimulation (non-invasive, acute treatment)
Open label post-market, observational study recruiting at present (NCT02357381)
Randomized double-blind sham controlled trial90
Transcutaneous vagal nerve stimulation (non-invasive, acute and preventive treatment)
Phase 3 studies in 2015 planned (NCT not yet available)
Transcutaneous supraorbital nerve stimulation (non-invasive, acute and preventive treatment)
Phase 2 study completed, pilot trial for chronic migraine recruiting at present (NCT02342743)
Table 3: Neuromodulation for treatment of migraine
www.thelancet.com/neurology Vol 14 October 2015
Review
investigation to examine feasibility for large studies in
preventive treatment of chronic migraine. 3 month 50%
responder rates were 39% for active stimulation, 6% for
preset stimulation (short burst daily), and 0% for medical
management. Lead migration occurred in 12 (24%) of
51 patients.
Precision Implantable Stimulator for Migraine
(PRISM)88 was a multicentre, double-blind randomised
parallel group sham-controlled active stimulation study
of patients with more than 6 days a month of migraine,
including chronic migraine patients. The patients should
have migraines that were not controlled by two preventive
and two acute treatments (inclusion criteria). Compared
with baseline, the sham group (−3·9 days) was not
different to the active group (−5·5 days), although a post-
hoc analysis showed an effect in the active group if
patients with medication overuse headache were
excluded.
The most recent study96 investigated 105 active
stimulation and 52 sham stimulation patients with a
modified diagnosis of chronic migraine, much like
ICHD-III-β proposals (diagnostic criteria: headaches on
15 or more days per month for >3 months; headaches
meet the International Headache Society [IHS] criteria
for migraine without aura (1·1), migraine with aura (1·2)
or probable migraine (1·6) on >50% of the headache
days).95 Patients were implanted if eligible (patients who
have tried at least two migraine-specific acute drugs,
such as triptan and ergotamine and migraine symptoms
were reported to be refractory; patients who have tried at
least two different classes of prophylactic drugs, such as
an anticonvulsant and a β blocker and migraine
symptoms were found to be refractory; patients with a
visual analogue scale score of 6 cm or greater on a 10 cm
line; and patients in whom headache pain is posterior
head pain or pain originating in the cervical region) and
had a trial of stimulation, which was defined as successful
in patients with a 50% reduction in pain. These patients
went into the remainder of the study. In the body of the
Efficacy of treatment (based on primary endpoint)
Diverse results, treatment cannot be recommended at the moment; ONSTIM87 (3 month 50%
responder rates, 39% for active stimulation, and 6% for preset stimulation); PRISM88 (comparison
headache days to baseline: p=0·29); NCT0061534289 (headache response: p=0·55)
Based on the insufficient study data, treatment cannot be recommended at the moment
Might be some effects in patients with migraine with aura (work not yet published)
Pain free rates at 2 h significantly higher with transcranial magnetic stimulation (therapeutic
gain 17%,p=0·179)
Some evidence for efficacy; at present, treatment should be applied within a clinical trial
Moderate efficacy
1017
 Review
study, in which patients are randomised, 105 patients
received active stimulation and 52 patients received
sham stimulation. The analysis of findings on the
primary endpoint, which was a difference in the
percentage of responders (defined as patients who
achieved a >50% reduction in mean daily visual analogue
scale scores) in each group at 12 weeks showed no
difference between active stimulation and controls.96 In
essence, for an unblinded responder study, the outcome
was certainly disappointing.
The limitation of unblinding plagues the field of
occipital nerve stimulation research as it does
neuromodulation research in general. As technologies
emerge that will overcome this limitation, much in this
research area needs careful re-examination with blinded,
controlled trials. In summary, occipital nerve stimulation
cannot be recommended for the prevention of migraine
at present.
Stimulation of the sphenopalatine ganglion
The sphenopalatine ganglion is a parasympathetic
ganglion that innervates structures supposed to be
involved in the autonomic symptoms of migraine, such
as the meninges, the conjunctiva, and the lacrimal
glands.97 A double-blind, placebo-controlled study89 of
repeated sphenopalatine ganglion blockade with 0·5%
bupivacaine in 38 patients (26 in the bupivacaine group
and 12 in the saline group) showed efficacy for the
treatment of acute migraine attacks (primary outcome
was to compare numerical rating scale scores at
pretreatment baseline vs 15 min, 30 min, and 24 h
postprocedure for all 12 treatments), suggesting that
the sphenopalatine ganglion might also be a potential
target for migraine prevention. A small open-label
study98 with 11 patients with intractable migraine
reported a possible effect of invasive electrical
stimulation of the sphenopalatine ganglion for the
treatment of acute migraine attacks. A randomised
study with an implantable stimulator for the treatment
of chronic migraine is underway (NCT01540799). Based
on the insufficient data and associated potentially
relevant side-effects, sphenopalatine ganglion
stimulation cannot be recommended for migraine
treatment at the moment. This approach should be
confined treatment of chronic therapy to refractory
migraineurs (migraine patients who do not respond to
or cannot tolerate approved migraine preventive
therapy) within clinical studies.
Single pulse transcranial magnetic stimulation
Transcranial magnetic stimulation is a non-invasive,
seemingly safe, and painless method of activating the
human motor cortex.99 Because of early suggestions of an
effect of single pulse transcranial magnetic stimulation
in migraine with aura,100 single pulse transcranial
magnetic stimulation was studied in cortical-spreading
depression in the laboratory,101 because cortical-spreading
1018
depression in rats is deemed to be comparable to the
human aura. Single pulse transcranial magnetic
stimulation can block cortical-spreading depression in
rats.
Single pulse transcranial magnetic stimulation has
been studied in a randomised double-blind, placebo-
controlled parallel group study with a sham control in
patients with migraine with aura. 164 Patients were
instructed to treat up to three migraine attacks after aura
symptoms had started. Pain free responses rates were
39% on active stimulation and 22% on sham stimulation,
which was significantly different (p=0·0179).90 The
treatment was well tolerated, as it is usually in clinical
practice.102 Moreover, transcranial magnetic stimulation
is broadly accepted to be safe,103 particularly in
pregnancy.104,105 Whether single pulse transcranial
magnetic stimulation is not only effective in treating
migraine pain but also useful in aura termination has
not been assessed yet.
Transcutaneous vagal nerve stimulation
Vagus nerve stimulation can be a treatment option for
some patients with intractable epilepsy or those with
depression. In the past, case series have shown that
implanted vagus nerve stimulation leads to an
improvement of migraine frequency in patients with
epilepsy or depression.106–109 The exact underlying
mechanism of vagal nerve stimulation is still enigmatic.
A novel device now offers a non-invasive method of vagal
nerve stimulation (gammaCore device, electroCore LLC,
Basking Ridge, NJ, USA). The amplitude generated by
the non-invasive vagal nerve stimulation is not high
enough to affect efferent vagus fibres.110 The safety and
efficacy of the device for preventative treatment was
tested in patients with primary headache.111 18 patients
were included in the study, 12 of them having a migraine
without aura (5 with medication overuse and 3 with
chronic headache). Transcutaneous vagal nerve
stimulation was applied 3 times per day for 90 s by
stimulating the cervical branch of the vagus nerve
transcutaneously. Findings were inconsistent. Adverse
effects included local discomfort, tonic muscle
contraction, fatigue, palpitations, and cervical muscle
spasm. The investigators of the study concluded that
transcutaneous vagal nerve stimulation might be
effective in some headache patients. A randomised
controlled trial on prophylactic treatment of
transcutaneous vagal nerve stimulation in chronic
migraine has been completed, but not yet published
(NCT01667250). A phase 3 programme with active versus
sham stimulation is planned for 2015 for the prevention
of frequent episodic migraine and chronic migraine.
To date, the shortage of evidence regarding efficacy and
side-effects of the device suggests that transcutaneous
vagal nerve stimulation should be used only in chronic
migraine patients and within a clinical trial.
Transcutaneous vagal nerve stimulation might be
www.thelancet.com/neurology Vol 14 October 2015

preferred to invasive vagal nerve stimulation, which is
not proven to be more effective than transcutaneous
vagal nerve stimulation, but is associated with more side-
effects. However, head-to-head studies comparing both
approaches have not been performed
Transcutaneous supraorbital nerve stimulation
Transcutaneous stimulation of the supraorbital nerves
using transcutaneous electric nerve stimulation
technology by the Cefaly device (STX-Med, Liège,
Belgium) is another new non-invasive peripheral
neuromodulation method that has shown some positive
results in migraine treatment. With reusable electrodes,
a steady current at 16 mA is delivered to the end branches
of the trigeminal nerve. A treatment session lasts 20 min
and should be applied once daily for prophylactic
treatment. An initial double-blind, randomised, sham-
controlled trial (PREMICE study)112 investigated the
efficacy of the Cefaly device in 67 patients with migraine
for the reduction of migraine days, migraine attacks,
headache days, and intake of acute medication. In the
treatment group, the 50% responder rate was 38%
compared with 12% in the sham device group. Adverse
events were not reported in the study. In a larger internet-
based open-label study, the Cefaly device was investigated
in 2313 patients with headache who rented the device for
a 40-day trial period.113 After a testing period of 58·2 days
on average, 46% of the 2313 renters were not satisfied
and returned the device, but the compliance check
showed that they used it only for 48·6% of the
recommended time. The remaining 54% of participants
were satisfied with the treatment. 99 (4·3%) participants
of the 2313 reported one or more adverse events, but
none of them was serious.
Up to now, based on the available study results, there is
only a limited degree of certainty about the efficacy of the
device in migraine prevention. Further studies are
urgently needed. A pilot study on the efficacy of the
Cefaly device in patients with chronic migraine is
ongoing (NCT02342743)
Conclusions and future directions
In summary, although there is a variety of interesting
new therapeutic targets and novel approaches for acute
and preventive migraine treatment, many of them have
not been able to achieve the expected and hoped for
efficacy. The development for drugs to treat acute
migraine attacks has been especially disappointing. In
preventive treatment, promising results from phase 2
studies with antibodies against CGRP suggest that these
antibodies might represent new treatment options for
the many patients for whom present therapies are either
ineffective or poorly tolerated. Efficacy in large phase 3
trials and safety in long-term studies have to be
demonstrated in the future. Many other promising
drugs did not show any or showed only little beneficial
effects in preventive migraine treatment. Randomised
www.thelancet.com/neurology Vol 14 October 2015
Review
Search strategy and selection criteria
We searched PubMed and Medline from Jan 2009, to
May 2015, with the search terms “Calcitonin gene-related
peptide receptor antagonist”, “BMS-927711”, “BI44370TA”,
“MI44370TA”, “MK-1602”, “Serotonin 5-HT1F receptor
agonist”, “COL-144”, “Transient receptor potential vanilloid
(TRPV1) receptor modulator”, “SB705498”, “Civamide”,
“NXN-188”, “Calcitonin gene-related peptide antibody”,
“ALD-403”, “LY-2951742”, “LBR-101”, “Calcitonin gene-
related peptide receptor antibody”, “AMG-334”, “Dual- orexin
receptor antagonist”, “MK-6096”, “Ketamine”, “Tonabersat”,
“LY293558”, “LY466195”, “ADX10059”, “Ibudilast”,
“Angiotension II receptor antagonist”, “Telmisartan”,
“Candesartan”, “Carisbamate”, “Single pulse transcranial
magnetic stimulator”, “stimulation sphenopalatine ganglion”,
“Transcutaneous vagal nerve stimulation”, and
“Transcutaneous supraorbital nerve stimulation”. We hand
searched bibliographies of relevant articles and identified
articles through searches of the authors’ own files. We
reviewed only animal, experimental, and observational
studies and randomised trials published in English. The final
reference list was generated on the basis of relevance to the
scope of this Review.
trials for neurostimulation had small numbers of
participants and were therefore underpowered, and did
not provide long-term outcome data. In our opinion,
invasive neuromodulatory therapeutic approaches
should be used only within clinical trials and, at the
moment, predominantly in chronic refractory
migraineurs. Non-invasive treatment approaches might
be considered in migraineurs when other therapeutic
options are either ineffective or poorly tolerated.
Although the development of new migraine treatments
has been frustratingly slow, there are some highly
promising new therapeutic approaches on the horizon.
Advances in the understanding of the basic mechanisms
of migraine are leading to the identification of new
therapeutic targets at a rapid rate. Despite some
substantial disappointments in clinical trials, the future
for new migraine treatment looks promising. Migraine
is an extraordinarily common and disabling disorder for
which definitive treatments are within reasonable reach.
It is important for us to continue pursuing these more
definitive treatments for the millions of individuals
worldwide who are disabled by migraine.
Contributors
All authors contributed equally to the text. HCD drafter the introduction
and the discussion. All authors edited the final manuscript.
Declaration of interests
H-CD reports personal fees from Addex Pharma and Adler, grants and
personal fees from Allergan, Almirall, AstraZeneca, Bayer, electroCore,
GlaxoSmithKline, Janssen-Cilag, MSD, and Pfizer, personal fees from
Amgen, Autonomic Technologies, Vital, Berlin Chemie, Boehringer
Ingelheim, Bristol-Myers Squibb, Chordate Medical, Coherex Medical,
CoLucid Pharmaceuticals, Grünenthal, Labrys Biologicals, Eli Lilly,
1019
 Review
La Roche, 3M Medica, Medtronic, Menarini, Minster Pharmaceuticals,
NeuroScore, Novartis, Johnson and Johnson, Pierre Fabre, Schaper and
Brümmer, St Jude Medical Foundation, and Weber and Weber, and
grants from Germ`an Science Council, German Secretary of Education,
the European Union, and Teva Pharmaceuticals. PJG reports grants and
personal fees from Allergan, eNeura, and Amgen, and personal fees
from Autonomic Technologies Inc, BristolMyerSquibb, AlderBio, Pfizer,
Zogenix, Nevrocorp, Impax, DrReddy, Zosano, Colucid, Eli-Lilly,
Medtronic, Avanir, Gore, Ethicon, Heptares, Nupathe, Ajinomoto, and
Teva outside the submitted work. AC is a consultant for Amgen and
eNeura and is on the Clinical Trial Steering Committee for St Jude
Medical. DH declares no competing interests.
References
1 Steiner TJ, Birbeck GL, Jensen R, Katsarava Z, Martelletti P,
Stovner LJ. The Global Campaign, World Health Organization and
Lifting The Burden: collaboration in action. J Headache Pain 2011;
12: 273–74.
2 Holland S, Silberstein SD, Freitag F, Dodick DW, Argoff C,
Ashman E, and the Quality Standards Subcommittee of the
American Academy of Neurology and the American Headache
Society. Evidence-based guideline update: NSAIDs and other
complementary treatments for episodic migraine prevention in
adults: report of the Quality Standards Subcommittee of the
American Academy of Neurology and the American Headache
Society. Neurology 2012; 78: 1346–53.
3 Thorlund K, Mills EJ, Wu P, et al. Comparative efficacy of triptans
for the abortive treatment of migraine: a multiple treatment
comparison meta-analysis. Cephalalgia 2014; 34: 258–67.
4 Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans
(serotonin 5-HT(1B/1D) agonists) in acute migraine treatment:
a meta-analysis of 53 trials. Lancet 2001; 358: 1668–75.
5 The Sumatriptan Cluster Headache Study Group. Treatment of acute
cluster headache with sumatriptan. N Engl J Med 1991; 325: 322–26.
6 Dodick D, Lipton RB, Martin V, et al, and the Triptan Cardiovascular
Safety Expert Panel. Consensus statement: cardiovascular safety
profile of triptans (5-HT agonists) in the acute treatment of
migraine. Headache 2004; 44: 414–25.
7 Worthington I, Pringsheim T, Gawel MJ, et al, and the Canadian
Headache Society Acute Migraine Treatment Guideline
Development Group. Canadian Headache Society Guideline: acute
drug therapy for migraine headache. Can J Neurol Sci 2013;
40 (suppl 3): S1–80.
8 Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C,
Ashman E, and the Quality Standards Subcommittee of the
American Academy of Neurology and the American Headache
Society. Evidence-based guideline update: pharmacologic treatment
for episodic migraine prevention in adults: report of the Quality
Standards Subcommittee of the American Academy of Neurology
and the American Headache Society. Neurology 2012; 78: 1337–45.
9 Evans RW, Linde M. Expert opinion: adherence to prophylactic
migraine medication. Headache 2009; 49: 1054–58.
10 Diener HC, Dodick DW, Goadsby PJ, Lipton RB, Almas M, Parsons B.
Identification of negative predictors of pain-free response to triptans:
analysis of the eletriptan database. Cephalalgia 2008; 28: 35–40.
11 Olesen J, Diener HC, Husstedt IW, et al, and the BIBN 4096 BS
Clinical Proof of Concept Study Group. Calcitonin gene-related
peptide receptor antagonist BIBN 4096 BS for the acute treatment
of migraine. N Engl J Med 2004; 350: 1104–10.
12 Ho TW, Ferrari MD, Dodick DW, et al. Efficacy and tolerability of
MK-0974 (telcagepant), a new oral antagonist of calcitonin
gene-related peptide receptor, compared with zolmitriptan for acute
migraine: a randomised, placebo-controlled, parallel-treatment trial.
Lancet 2008; 372: 2115–23.
13 Ho TW, Connor KM, Zhang Y, et al. Randomized controlled trial of
the CGRP receptor antagonist telcagepant for migraine prevention.
Neurology 2014; 83: 958–66.
14 Hewitt DJ, Aurora SK, Dodick DW, et al. Randomized controlled
trial of the CGRP receptor antagonist MK-3207 in the acute
treatment of migraine. Cephalalgia 2011; 31: 712–22.
15 Medve RA, Andrews JS. Effects of fixed dose combination of nNOS
inhibition and 5HT agonism on progression of migraine with and
without aura. Presented at the European Headache and Migraine
Trust International Congress 2008; London, Sept 4–7, 2008.
Abstract PC.23.
1020
16 Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J.
BI 44370 TA, an oral CGRP antagonist for the treatment of acute
migraine attacks: results from a phase II study. Cephalalgia 2011;
31: 573–84.
17 Ferrari MD, Färkkilä M, Reuter U, et al, and the European COL-144
Investigators. Acute treatment of migraine with the selective
5-HT1F receptor agonist lasmiditan--a randomised proof-of-concept
trial. Cephalalgia 2010; 30: 1170–78.
18 Färkkilä M, Diener HC, Géraud G, et al, and the COL MIG-202
study group. Efficacy and tolerability of lasmiditan, an oral 5-HT(1F)
receptor agonist, for the acute treatment of migraine: a phase 2
randomised, placebo-controlled, parallel-group, dose-ranging study.
Lancet Neurol 2012; 11: 405–13.
19 Chizh B, Palmer J, Lai R, et al. A randomised two-period cross-over
study to investigate the efficacy of the TRPV1 antagonist SB-705498
in acute migraine. Eur J Pain 2009; 13: 202a.
20 Diamond S, Freitag F, Phillips SB, Bernstein JE, Saper JR.
Intranasal civamide for the acute treatment of migraine headache.
Cephalalgia 2000; 20: 597–602.
21 Afridi SK, Giffin NJ, Kaube H, Goadsby PJ. A randomized
controlled trial of intranasal ketamine in migraine with prolonged
aura. Neurology 2013; 80: 642–47.
22 Sang CN, Ramadan NM, Wallihan RG, et al. LY293558, a novel
AMPA/GluR5 antagonist, is efficacious and well-tolerated in acute
migraine. Cephalalgia 2004; 24: 596–602.
23 Gomez-Mancilla B, Brand R, Jürgens TP, et al, and the BGG492
Study Group. Randomized, multicenter trial to assess the efficacy,
safety and tolerability of a single dose of a novel AMPA receptor
antagonist BGG492 for the treatment of acute migraine attacks.
Cephalalgia 2014; 34: 103–13.
24 Johnson KW, Nisenbaun E, Johnson M, Dieckman D,
Clemens-Smith A, Siuda E. Innovative drug development for
headache disorders: glutamate. In: Olesen J, Ramadan N, eds.
Innovative Drug Development for Headache Disoders. Oxford:
Oxford University Press, 2008: 185–94.
25 Goadsby P, Keywood C. Investigation of the role of mGluR5
inhibition in migraine: a proof of concept study of ADX10059 in
acute treatment of migraine. Cephalalgia 2009; 29 (suppl 1): 7.
26 Soleimanpour H, Ghafouri RR, Taheraghdam A, et al. Effectiveness
of intravenous dexamethasone versus propofol for pain relief in the
migraine headache: a prospective double blind randomized clinical
trial. BMC Neurol 2012; 12: 114.
27 Goadsby PJ, Ferrari MD, Csanyi A, Olesen J, Mills JG, and the
Tonabersat TON-01-05 Study Group. Randomized, double-blind,
placebo-controlled, proof-of-concept study of the cortical spreading
depression inhibiting agent tonabersat in migraine prophylaxis.
Cephalalgia 2009; 29: 742–50.
28 Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in
the extracerebral circulation of humans during migraine headache.
Ann Neurol 1990; 28: 183–87.
29 Goadsby PJ, Edvinsson L. The trigeminovascular system and
migraine: studies characterizing cerebrovascular and
neuropeptide changes seen in humans and cats. Ann Neurol 1993;
33: 48–56.
30 Petersen KA, Birk S, Lassen LH, et al. The CGRP-antagonist,
BIBN4096BS does not affect cerebral or systemic haemodynamics
in healthy volunteers. Cephalalgia 2005; 25: 139–47.
31 Doods H, Hallermayer G, Wu D, et al. Pharmacological profile of
BIBN4096BS, the first selective small molecule CGRP antagonist.
Br J Pharmacol 2000; 129: 420–23
32 Luo G, Chen L, Conway CM, et al. Discovery of (5S,6S,9R)-5-amino-
6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-
yl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)
piperidine-1-carboxylate (BMS-927711): an oral calcitonin gene-
related peptide (CGRP) antagonist in clinical trials for treating
migraine. J Med Chem 2012; 55: 10644–51.
33 Peroutka SJ. Clinical trials update. 2013: year in review. Headache
2014; 54: 189–94.
34 Nelson DL, Phebus LA, Johnson KW, et al. Preclinical
pharmacological profile of the selective 5-HT1F receptor agonist
lasmiditan. Cephalalgia 2010; 30: 1159–69.
35 Goadsby PJ, Classey JD. Evidence for serotonin (5-HT)1B, 5-HT1D
and 5-HT1F receptor inhibitory effects on trigeminal neurons with
craniovascular input. Neuroscience 2003; 122: 491–98.
www.thelancet.com/neurology Vol 14 October 2015

36 Bhatt DK, Gupta S, Jansen-Olesen I, Andrews JS, Olesen J. NXN-
188, a selective nNOS inhibitor and a 5-HT1B/1D receptor agonist,
inhibits CGRP release in preclinical migraine models.
Cephalalgia 2013; 33: 87–100.
37 Villalón CM, Olesen J. The role of CGRP in the pathophysiology of
migraine and efficacy of CGRP receptor antagonists as acute
antimigraine drugs. Pharmacol Ther 2009; 124: 309–23.
38 Messlinger K, Lennerz JK, Eberhardt M, Fischer MJ. CGRP and NO
in the trigeminal system: mechanisms and role in headache
generation. Headache 2012; 52: 1411–27.
39 Medve R, Andrews J. Effects of fixed dose combination of nNOS
inhibition and 5HT agonism on progression of migraine with and
without aura. Cephalalgia 2009; 29: 126
40 Hougaard A, Hauge A, Guo S, Tfelt-Hansen P. The nitric oxide
synthase inhibitor and serotonin-receptor agonist NXN-188 during
the aura phase of migraine with aura: a randomized, double-blind,
placebo-controlled cross-over study. Scan J Pain 2012; 4: 48–52.
41 Alderton WK, Angell AD, Craig C, et al. GW274150 and GW273629
are potent and highly selective inhibitors of inducible nitric oxide
synthase in vitro and in vivo. Br J Pharmacol 2005; 145: 301–12.
42 Palmer J, Guillard F, Laurijssens B, Wentz A, Dixon R, Williams P.
A randomised, single-blind, placebo-controlled, adaptive clinical
trial of GW274150, a selective iNOS inhibitor, in the treatment of
acute migraine. Cephalagia 2009; 29: 124
43 Hoye K, Laurijssens B, Harnisch L, et al. Efficacy and tolerability of
the iNOS inhibitor GW274150 administered up to 120 mg daily for
12 weeks in the prophylactic treatment of migraine.
Cephalalgia 2009; 29: 132.
44 Reuter U, Bolay H, Jansen-Olesen I, et al. Delayed inflammation in
rat meninges: implications for migraine pathophysiology.
Brain 2001; 124: 2490–502.
45 Lassen LH, Ashina M, Christiansen I, Ulrich V, Olesen J. Nitric
oxide synthase inhibition in migraine. Lancet 1997; 349: 401–02.
46 Meng J, Ovsepian SV, Wang J, et al. Activation of TRPV1 mediates
calcitonin gene-related peptide release, which excites trigeminal
sensory neurons and is attenuated by a retargeted botulinum toxin
with anti-nociceptive potential. J Neurosci 2009; 29: 4981–92.
47 Summ O, Holland PR, Akerman S, Goadsby PJ. TRPV1 receptor
blockade is ineffective in different in vivo models of migraine.
Cephalalgia 2011; 31: 172–80.
48 Chizh BA, O’Donnell MB, Napolitano A, et al. The effects of the
TRPV1 antagonist SB-705498 on TRPV1 receptor-mediated activity
and inflammatory hyperalgesia in humans. Pain 2007; 132: 132–41.
49 Szolcsányi J, Pintér E. Transient receptor potential vanilloid 1 as a
therapeutic target in analgesia. Expert Opin Ther Targets 2013;
17: 641–57.
50 Sánchez-Porras R, Santos E, Schöll M, et al. The effect of
ketamine on optical and electrical characteristics of spreading
depolarizations in gyrencephalic swine cortex. Neuropharmacology
2014; 84: 52–61.
51 Kaube H, Herzog J, Käufer T, Dichgans M, Diener HC. Ketamine can
stop aura in hemiplegic migraine. Cephalalgia 2000; 20: 270. (abstr).
52 Alt A, Weiss B, Ogden AM, et al. In vitro and in vivo studies in rats
with LY293558 suggest AMPA/kainate receptor blockade as a novel
potential mechanism for the therapeutic treatment of anxiety
disorders. Psychopharmacology (Berl) 2006; 185: 240–47.
53 Weiss B, Alt A, Ogden AM, et al. Pharmacological characterization
of the competitive GLUK5 receptor antagonist
decahydroisoquinoline LY466195 in vitro and in vivo.
J Pharmacol Exp Ther 2006; 318: 772–81.
54 Moshtaghion H, Heiranizadeh N, Rahimdel A, Esmaeili A,
Hashemian H, Hekmatimoghaddam S. The efficacy of propofol vs.
subcutaneous sumatriptan for treatment of acute migraine headaches
in the emergency department: a double-blinded clinical trial. Pain
practice 2014; published online July 12. DOI: 10.1111/papr.12230.
55 Rech MA, Donahey E, Cappiello Dziedzic JM, Oh L, Greenhalgh E.
New drugs of abuse. Pharmacotherapy 2014; 35: 189–97.
56 Smith MI, Read SJ, Chan WN, et al. Repetitive cortical spreading
depression in a gyrencephalic feline brain: inhibition by the novel
benzoylamino-benzopyran SB-220453. Cephalalgia 2000; 20: 546–53.
57 Bradley DP, Smith MI, Netsiri C, et al. Diffusion-weighted MRI
used to detect in vivo modulation of cortical spreading depression:
comparison of sumatriptan and tonabersat. Exp Neurol 2001;
172: 342–53.
www.thelancet.com/neurology Vol 14 October 2015
Review
58 Parsons AA, Bingham S, Raval P, Read S, Thompson M, Upton N.
Tonabersat (SB-220453) a novel benzopyran with anticonvulsant
properties attenuates trigeminal nerve-induced neurovascular
reflexes. Br J Pharmacol 2001; 132: 1549–57.
59 Silberstein SD, Schoenen J, Göbel H, et al. Tonabersat, a gap-
junction modulator: efficacy and safety in two randomized,
placebo-controlled, dose-ranging studies of acute migraine.
Cephalalgia 2009; 29 (suppl 2): 17–27.
60 Hauge AW, Asghar MS, Schytz HW, Christensen K, Olesen J.
Effects of tonabersat on migraine with aura: a randomised,
double-blind, placebo-controlled crossover study. Lancet Neurol
2009; 8: 718–23.
61 Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of
the orexin receptor antagonist filorexant for migraine prophylaxis.
Cephalalgia 2014; 35: 379–88.
62 Stovner LJ, Linde M, Gravdahl GB, et al. A comparative study of
candesartan versus propranolol for migraine prophylaxis: A
randomised, triple-blind, placebo-controlled, double cross-over
study. Cephalalgia 2013; 34: 523–32.
63 Cady RK, Mathew N, Diener HC, Hu P, Haas M, Novak GP, and the
Study Group. Evaluation of carisbamate for the treatment of migraine
in a randomized, double-blind trial. Headache 2009; 49: 216–26.
64 Dodick DW, Goadsby PJ, Spierings EL, Scherer JC, Sweeney SP,
Grayzel DS. Safety and efficacy 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: 885–92.
65 Dodick DW, Goadsby PJ, Silberstein SD, et al, and the ALD403
study investigators. Safety and efficacy 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: 1100–07.
66 Goadsby P, Dodick D, Silberstein S, et al. Randomized, double-
blind, placebo-controlled trial of ALD403, an anti-CGRP peptide
antibody in the prevention of frequent episodic migraine. Headache
2014; 54: 1420 (abstr). http://onlinelibrary.wiley.com/doi/10.1111/
head.12431/epdf (accessed Aug 23, 2015).
67 Shi L, Rao S, King CH, et al. AMG 334, the first potent and selective
human monoclonal antibody antagonist against the CGRP receptor.
Headache 2014; 54: 1417–18 (abstr). http://onlinelibrary.wiley.com/
doi/10.1111/head.12431/epdf (accessed Aug 23, 2015).
68 Lenz R, Silberstein S, Dodick D, et al. Results of a randomized,
double-blind, placebo controlled, phase 2 study to evaluate the
efficacy and safety of AMG 334 for the prevention of episodic
migraine. Cephalalgia 2015; 35: 5.
69 Bigal ME, Escandon R, Bronson M, et al. Safety and tolerability of
LBR-101, a humanized monoclonal antibody that blocks the binding
of CGRP to its receptor: Results of the Phase 1 program. Cephalalgia
2013; 34: 483–92.
70 Diener HC. CGRP as a new target in prevention and treatment of
migraine. Lancet Neurol 2014; 13: 1065–67.
71 Walker C, Eftekhari S, Bower R, et al. A second trigeminal CGRP
receptor: function and expression of the AMY1 receptor.
Ann Clin Transl Neurol 2015; 2: 595–608
72 Smart D, Jerman J. The physiology and pharmacology of the
orexins. Pharmacol Ther 2002; 94: 51–61.
73 Ferguson AV, Samson WK. The orexin/hypocretin system: a critical
regulator of neuroendocrine and autonomic function.
Front Neuroendocrinol 2003; 24: 141–50.
74 Samson WK, Taylor MM, Ferguson AV. Non-sleep effects of
hypocretin/orexin. Sleep Med Rev 2005; 9: 243–52.
75 Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain
and primary headaches. Headache 2007; 47: 951–62.
76 Benjamin L, Levy MJ, Lasalandra MP, et al. Hypothalamic
activation after stimulation of the superior sagittal sinus in the cat:
a Fos study. Neurobiol Dis 2004; 16: 500–05.
77 Bartsch T, Levy MJ, Knight YE, Goadsby PJ. Differential modulation
of nociceptive dural input to [hypocretin] orexin A and B receptor
activation in the posterior hypothalamic area. Pain 2004;
109: 367–78.
78 Robert C, Bourgeais L, Arreto CD, et al. Paraventricular
hypothalamic regulation of trigeminovascular mechanisms involved
in headaches. J Neurosci 2013; 33: 8827–40.
1021
 Review
79 Giffin NJRL, Ruggiero L, Lipton RB, et al. Premonitory symptoms
in migraine: an electronic diary study. Neurology 2003; 60: 935–40.
80 Maniyar FH, Sprenger T, Monteith T, Schankin C, Goadsby PJ.
Brain activations in the premonitory phase of nitroglycerin-
triggered migraine attacks. Brain 2014; 137: 232–41.
81 Winrow CJ, Gotter AL, Cox CD, et al. Pharmacological
characterization of MK-6096—a dual orexin receptor antagonist for
insomnia. Neuropharmacology 2012; 62: 978–87.
82 Herring WJ, Snyder E, Budd K, et al. Orexin receptor antagonism
for treatment of insomnia: a randomized clinical trial of suvorexant.
Neurology 2012; 79: 2265–74.
83 Kishi Y, Ohta S, Kasuya N, Sakita S, Ashikaga T, Isobe M. Ibudilast:
a non-selective PDE inhibitor with multiple actions on blood cells
and the vascular wall. Cardiovasc Drug Rev 2001; 19: 215–25.
84 Rolan P, Hutchinson M, Johnson K. Ibudilast: a review of its
pharmacology, efficacy and safety in respiratory and neurological
disease. Expert Opin Pharmacother 2009; 10: 2897–904.
85 Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic
treatment of migraine with an angiotensin II receptor blocker: a
randomized controlled trial. JAMA 2003; 289: 65–69.
86 Pringsheim T, Davenport W, Mackie G, et al, and the Canadian
Headache Society Prophylactic Guidelines Development Group.
Canadian Headache Society guideline for migraine prophylaxis.
Can J Neurol Sci 2012; 39 (suppl 2): S1–59.
87 Saper JR, Dodick DW, Silberstein SD, McCarville S, Sun M,
Goadsby PJ, and the ONSTIM Investigators. Occipital nerve
stimulation for the treatment of intractable chronic migraine
headache: ONSTIM feasibility study. Cephalalgia 2011; 31: 271–85.
88 Lipton R, Goadsby P, Cady R, et al. PRISM study: occipital nerve
stimualtion for treatment-refractory migraine. Cephalalgia 2009;
29 (suppl 1): 30 (abstr).
89 Cady R, Saper J, Dexter K, Manley HR. A double-blind, placebo-
controlled study of repetitive transnasal sphenopalatine ganglion
blockade with Tx360 as acute treatment for chronic migraine.
Headache 2014; 55: 101–16.
90 Lipton RB, Dodick DW, Silberstein SD, et al. Single-pulse
transcranial magnetic stimulation for acute treatment of migraine
with aura: a randomised, double-blind, parallel-group, sham-
controlled trial. Lancet Neurol 2010; 9: 373–80.
91 Weiner RL, Reed KL. Peripheral neurostimulation for control of
intractable occipital neuralgia. Neuromodulation 1999; 2: 217–21.
92 Matharu MS, Bartsch T, Ward N, Frackowiak RS, Weiner R,
Goadsby PJ. Central neuromodulation in chronic migraine patients
with suboccipital stimulators: a PET study. Brain 2004; 127: 220–30.
93 Goadsby PJ, Schoenen J, Ferrari MD, Silberstein SD, Dodick D.
Towards a definition of intractable headache for use in clinical
practice and trials. Cephalalgia 2006; 26: 1168–70.
94 Trentman TL, Zimmerman RS, Seth N, Hentz JG, Dodick DW.
Stimulation ranges, usage ranges, and paresthesia mapping during
occipital nerve stimulation. Neuromodulation 2008; 11: 56–61.
95 Headache Classification Committee of the International Headache
Society. The International Classification of Headache Disorders,
3rd edition (beta version). Cephalalgia 2013; 33: 629–808.
96 Silberstein SD, Dodick DW, Saper J, et al. Safety and efficacy of
peripheral nerve stimulation of the occipital nerves for the
management of chronic migraine: results from a randomized,
multicenter, double-blinded, controlled study. Cephalalgia 2012;
32: 1165–79.
1022
97 Khan S, Schoenen J, Ashina M. Sphenopalatine ganglion
neuromodulation in migraine: what is the rationale?
Cephalalgia 2014; 34: 382–91.
98 Tepper SJ, Rezai A, Narouze S, Steiner C, Mohajer P, Ansarinia M.
Acute treatment of intractable migraine with sphenopalatine
ganglion electrical stimulation. Headache 2009; 49: 983–89.
99 Chen R, Cros D, Curra A, et al. The clinical diagnostic utility of
transcranial magnetic stimulation: report of an IFCN committee.
Clinical Neurophysiol2008; 119: 504–32.
100 Mohammad Y, Kothari R, Hughes GR, et al. Transcranial magnetic
stimulation (TMS) relieves migraine headache. J Neurol 2006;
13 (suppl 2): 23.
101 Holland P, Schembri C, Fredrick J, Goadsby P. Transcranial
magentic stimulation for the treatment of migraine aura.
Neurology 2009; 92 (suppl 3): A250.
102 Bhola R, Kinsella E, Goadsby P. Update of the UK post market pilot
programme with single pulse transcranial magnetic stimulation
(sTMS) for the acute treatment of migraine. Headache 2014;
54: 1426 (abstr).
103 Dodick DW, Schembri CT, Helmuth M, Aurora SK. Transcranial
magnetic stimulation for migraine: a safety review. Headache 2010;
50: 1153–63.
104 Committee on the Possible Effects of Electromagnetic Fields on
Biologic Systems of the National Research Council. Possible Health
Effects of Exposure to Residential Electric And Magnetic Fields.
Washington (DC): National Academic Press; 1997.
105 Scientific Committee on Emerging and Newly Identified Health
Risks. Possible effects of Electromagnetic Fields (EMF) on Human
Health. EC HCPD, editor. Brussels: European Commission; 2007.
106 Hord ED, Evans MS, Mueed S, Adamolekun B, Naritoku DK. The
effect of vagus nerve stimulation on migraines. J Pain 2003;
4: 530–34.
107 Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve
stimulation help migraine? Cephalalgia 2008; 28: 392–95.
108 Cecchini AP, Mea E, Tullo V, et al. Vagus nerve stimulation in
drug-resistant daily chronic migraine with depression: preliminary
data. Neurol Sci 2009; 30 (suppl 1): S101–04.
109 Mauskop A. Vagus nerve stimulation relieves chronic refractory
migraine and cluster headaches. Cephalalgia 2005; 25: 82–86.
110 Ben-Menachem E, Revesz D, Simon BJ, Silberstein S. Surgically
implanted and non-invasive vagus nerve stimulation: a review of
efficacy, safety and tolerability. Eur J Neurol 2015; published online
Jan 23. DOI:10.1111/ene.12629.
111 Magis D, Gerard P, Schoenen J. Transcutaneous Vagus Nerve
Stimulation (tVNS) for headache prophylaxis: initial experience.
J Headache Pain 2013; 14 (suppl 1): 198.
112 Schoenen J, Vandersmissen B, Jeangette S, et al. Migraine
prevention with a supraorbital transcutaneous stimulator: a
randomized controlled trial. Neurology 2013; 80: 697–704.
113 Magis D, Sava S, d’Elia TS, Baschi R, Schoenen J. Safety and
patients’ satisfaction of transcutaneous supraorbital
neurostimulation (tSNS) with the Cefaly® device in headache
treatment: a survey of 2,313 headache sufferers in the general
population. J Headache Pain 2013; 14: 95.
www.thelancet.com/neurology Vol 14 October 2015