REVIEW

CURRENT
OPINION Noninvasive neuromodulation in cluster headache
Miguel J.A. Lainez a and Rigmor Jensen b

Purpose of review
Neuromodulation is an alternative in the management of medically intractable cluster headache patients.
Most of the techniques are invasive, but in the last 2 years, some studies using a noninvasive device have
been presented. The objective of this article is to review the data using this approach.
Recent findings
Techniques as occipital nerve stimulation or sphenopalatine ganglion stimulation are recommended as first-
line therapy in refractory cluster patients, but they are invasive and maybe associated with complications.
Noninvasive vagal nerve stimulation with an external device has been tried in cluster patients. Results from
clinical practice and a single randomized clinical trial have been presented showing a reduction of the
number of cluster attacks/week in the patients treated with the device. The rate of adverse events was low
and most of them were mild.
Summary
In the last decade, invasive neuromodulation treatments have demonstrated good efficacy in cluster
refractory patients. Noninvasive approaches such as the noninvasive vagal nerve stimulation have shown
efficacy in one trial and could be an easier alternative in the management of this debilitating headache.
We need to replicate these results with further controlled studies and conduct basic research in order to
clarify the mechanism of action.
Keywords
cluster headache, neuromodulation, noninvasive stimulation, vagal stimulation

INTRODUCTION drug-resistant attacks [4]. Although subcutaneous

Cluster headache is a severe, debilitating disorder
with pain that ranks among the most severe known
to humans [1]. It is well defined in the third edition
of The International Classification of Headache Dis-
orders (ICHD-3 beta 2013); typically is presented
with accompanying autonomic symptoms ipsilat-
eral to the pain, including conjunctival injection,
lacrimation, nasal congestion, rhinorrhea, eyelid or
periorbital edema, forehead and facial sweating,
mitosis or ptosis, and a sense of restlessness or
agitation. Cluster headaches can occur up to eight
times a day and each attack typically last between
15 min and 3 h. Episodic cluster headache occurs in
periods lasting 1 week to 1 year, separated by pain-
free periods of 1 month or longer [2]. Approximately
1015% of patients are suffering from chronic clus-
ter headache (CCH), with headaches occurring
without remission or with remission lasting less
than 1 month during a year. Although cluster head-
ache is an invalidating and clinically clear-cut dis-
order, it is still frequently unrecognized and/or
mistaken for other disorders [3].
Patients with cluster headaches have few thera-
peutic options and further, 1020% patients develop
triptan injections [5] and inhaled high-flow oxygen
[6] provide relief to some patients some of the time,
the next attacks are not prevented and many patients
are severely affected and disabled. Sumatriptan is
contraindicated in ischemic heart disease, stroke,
uncontrolled hypertension, and peripheral vascular
disease. Furthermore, triptans are limited to a maxi-
mum of twice-daily dosing, the injectable form is very
expensive and not available in many countries.
Although oxygen-inhalation therapy (100%, 12 L/
min for 15 min via a face mask) can be effective in
the early stage of the attack [6], it may be associated
with attack recurrence and it has significant practical
a
Department of Neurology, Clinic University Hospital, Catholic University
of Valencia, Valencia, Spain and bDepartment of Neurology, Danish
Headache Center, Glostrup Hospital, University of Copenhagen, Copen-
hagen, Denmark
Correspondence to Miguel J.A. Lainez, MD, PhD, Department of Neu-
rology, Hospital Clnico Universitario, Universidad Catolica de Valencia,
Avda. Blasco Ibanez, 17 46010 Valencia, Spain. Tel: +34 961973981;
fax: +34 963900321; e-mail: miguel.lainez@sen.es
Curr Opin Neurol 2015, 28:271276
DOI:10.1097/WCO.0000000000000196

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Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

Headache
KEY POINTS

Cluster headache is one of most debilitating headache
syndromes, especially when it is refractory to
medical treatment.

Invasive neuromodulation treatments have demonstrated
good efficacy in the management of medically
refractory patients, but with potential complications for
the patient.

nVNS has been efficacious reducing the number of
attacks with good tolerability.

nVNS could be an interesting alternative, but the results
should be replicated in randomized controlled studies.
limitations because of the size and cumbersomeness
of the required oxygen tanks.
The socioeconomic burden of cluster headache
on individuals and society is quite high because of
the direct costs of healthcare services, and the indi-
rect costs of lost work days and decreased work
efficacy. A Danish report showed that 43.5% of
cluster patients had seen specialists, approximately
30% had missed work, and 78% reported restrictions
in daily living [7]. A recent German study showed
that a patient with typical CCH cost the healthcare
system over s21,000 per year [8].
The often brief duration of cluster attacks makes
abortive therapy a challenge. Transition treatments
with steroids and preventive medications, such as
verapamil, lithium carbonate, divalproex sodium
(valproate), and topiramate among others, are
almost always provided to patients. The side-effects
of these preventive medications can be significant,
ranging from nausea and fatigue to hypotension,
bradycardia, atrioventricular block, paresthesias, or
psychomotor slowing, and although these medi-
cations may be better tolerated when used for cluster
headache than other headache types [9], the adverse
events are a limiting factor in the treatment. None of
these preventive medications are, however,
approved by the U.S. Food and Drug Administration
for the treatment of cluster headache. Given the
relentless nature of their disorder, cluster patients
desperately continue to search for new, effective
therapies to treat their headaches.
NEUROSTIMULATION
The use of electrical stimulation of the nervous sys-
tem for the treatment of headaches is not new. In the
first century A.D., the physician Scribonius Largus
used the electric fish Torpedo marmorata to reduce
head pain of Claudius, the Roman emperor [10].
272 www.co-neurology.com
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Modern neurostimulation had its genesis in a parallel
expansion of functional neurosurgery, which
focused on the placement of ablative brain lesions
to treat disabling symptoms of movement disorders.
Initially, with a view to avoiding ablative lesions,
the neuromodulation techniques started using deep
brain stimulation (DBS), which is a surgical therapy
that involves the delivery of an electrical current to
one or more brain targets. With time, stimulation
techniques changed their target and now DBS is not
always deep, not always brain, and not always simply
stimulation; a more accurate term for this field may
be electrical neuro-network modulation [11].
Electrical neuromodulation refers to adjustable
manipulation of central or peripheral pain pathways
with electrical current for the purpose of reversible
modification of the nociceptive system function
using implantable devices. Many targets for treating
craniofacial pain via neuromodulation have been
described, including trigeminal nerve and ganglion,
vagus nerve, sphenopalatine ganglion (SPG), per-
ipheral (occipital) nerves, cervical spinal cord, peri-
aqueductal gray matter, hypothalamus, and motor
cortex [12].
The basis for peripheral stimulation started with
the publication of the Gate Control Theory of pain
modulation in 1965, by Melzack and Wall [13], that
provided a conceptual mechanistic foundation for
considering direct electrical stimulation of the spi-
nal cord and peripheral nerves as a potential treat-
ment for chronic pain. Electrical stimulation of
peripheral nerves results in pain modulation by
direct effects on the stimulated nerve and secondary
effects on the central nervous system [14].
Peripheral nerve stimulation (PNS) therapies for
chronic pain developed in parallel to spinal cord
stimulation. Over the 1970s and 1980s, some studies
showed positive responses to open surgical PNS
implants in patients with various neuropathic pain
syndromes [15], with few studies including isolated
patients with occipital neuralgia. Attention to the
potential of this methodology as a treatment for head
pain came after a publication that showed that
implanted occipital nerve stimulators (ONS) with
percutaneously placed leads could be an alternative
in the treatment for intractable occipital neuralgia
[16].
NEUROSTIMULATION INVASIVE
TECHNIQUES
In the treatment of refractory cluster headache,
both DBS and PNS have been used. DBS of the
posteriorinferior hypothalamus has been proposed
by Leone et al. [17] after the identification of the
presumed generator of the pain in the posterior
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 Noninvasive neuromodulation in cluster headache Lainez and Jensen
hypothalamus. Until now, around 60 patients treated
with this technique have been reported in the liter-
ature but the total number of implants is unknown, as
a register of all patients with DBS is not established. In
60% of the reported cases, the attack frequency
decreased more than 50%, including 3040% of
patients who were pain-free [18,19]. In a sham-con-
trolled study for 1 month, there was, however, no
effect between active and sham stimulation but prob-
ably the observation period was too short [20]. A
follow-up series of 17 patients with DBS after 8.7
years demonstrated long-term effect in 70% of
patients, hereof pain freedom in six patients and
remission to episodic clusters in an other six patients
&
[21 ]. DBS implant is not a riskless procedure; one
patient died and oculomotor and other compli-
cations have been described.
Bilateral ONS has been also used in patients with
refractory CCH with good results in the first studies
published [22,23]. More than 90 patients have now
been reported with a reduction of more than 50% of
attacks in around 70% of patients. Complications
such as electrode migration were frequent in more
than 30% of patients and there was also a risk of
infection of 35% of patients [18,19]. Thus, ONS for
treatment of refractory CCH is a costly treatment
option with a significant complication rate, but also
with substantial benefit in an important percentage
of patients [24].
SPG has been over the years a target for various
lesional therapies to treat cluster patients. After
positive proof of concept studies using a removable
electrode to stimulate SPG, an implantable micro-
stimulator has been developed. The stimulator is
activated on demand by a remote controller using
radiofrequency energy. A randomized, sham-con-
trolled study of 32 patients was performed to evaluate
further the use of SPG stimulation for the acute treat-
&
ment of CCH [25 ]. Of the 32 medically refractory
patients, 28 completed the randomized experimental
period. Although the study was designed for acute
treatment, a preventive response was observed in
some patients. Overall, 68% of patients experienced
an acute response, a frequency response, or both. In
this study, the majority of adverse events were sen-
sory disturbances related to the implantation pro-
cedure, which typically resolved or remained mild in
nature at 3 months following the implant procedure.
Spinal cord stimulation has been tried in a small
group of eight patients with similar results to ONS,
but with a higher rate of lead-related complications
[26]. Yet, there is no evidence for spinal cord stimu-
lation in cluster headache and is not recommended
&
by the European Headache Federation [27 ].
At this moment, ONS and SPG stimulation tech-
niques are recommended as first-line therapy in
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&
refractory cluster patients [27 ]. However, the
implants require surgical expertise, are relatively
costly, and are still restricted to a minority of cluster
headache patients. Furthermore, they do not resolve
the problem in around 30% of these medically
refractory patients and, although ONS and SPG
are not as invasive as DBS, complications are not
infrequent, most of them not being serious but
uncomfortable for the patients.
NONINVASIVE NEUROSTIMULATION
TECHNIQUES
Consequently, it is important to develop new strat-
egies that are less invasive and easier to use for the
patient. In this way, in the last year we have known
the first results of some studies using a noninvasive
vagus nerve stimulator (nVNS). Figure 1 illustrates
the different stimulation techniques used in cluster
headache.
The implantable VNS seems to work in migraine
attacks [28]. The first evidence of a possible role of
the vagus stimulation was reported in two refractory
cluster patients who improved significantly after
been implanted with a VNS [29], but this is also
an invasive method.
A novel portable, lightweight, noninvasive, bat-
tery-driven device (gammaCore), designed for
patients to self-administer transcutaneous stimulus
in the vagus nerve has been developed [30]. The
nVNS device produces a low-voltage electric signal
consisting of five 5000 Hz pulses occurring at a rate
of 25 Hz for 120 s per dose. When applied against the
skin of the neck, the device delivers a peak voltage of
24 V and a maximum output current of 60 mA;
Deep brain stimulation (DBS)
Sphenopalatine ganglion
stimulation (SPG)
Occipital nerve
stimulation (ONS)
Noninvasive vagus nerve
stimulation (nVNS)
FIGURE 1. Neuromodulation techniques.
www.co-neurology.com 273
Headache
amplitude of the stimulation can be adjusted by the
user. In the last 2 years, some studies using this
device in patients with cluster headache have been
presented in headache meetings.
The first one is an open study in which patients
with medically intractable cluster headache attend-
ing headache centers in the United Kingdom and
Ireland were offered the nVNS device for treatment
in an unbiased fashion. The patients used the device
both as prophylactic (2 times in a day) and as acute
therapy. They analyzed 14 of 17 patients that used
the device for an average period of 13 weeks (range
226). Seven were chronic and seven episodic and
nine were male. Thirteen felt there was an overall
improvement in their condition since using the
device, stating a mean estimated subjective
improvement of 60% (SD 30) from baseline. One
patients condition remained the same. Seven were
able to reduce significantly or stop their previous
abortive treatment, five had reduced it and two
required the same amount as previously. Five were
very satisfied, eight satisfied, and one equivocally
satisfied after using the device. All 14 would recom-
mend the treatment to others [31].
nVNS has been tried in a multicenter trial: the
prevention and acute treatment of CCH (PREVA
&
study) [32 ]. It was a prospective, randomized, con-
trolled study that compared the adjunctive use of
nVNS with patientss standard of care (SoC) versus
SoC alone in patients with CCH. The study composed
of three phases: 2-week run-in, 4-week randomized
(1 : 1; nVNS vs. SoC), and 4-week extension. Patients
randomized to nVNS delivered three 2-min stimu-
lations prophylactically twice daily (mandatory) to
the right side of the neck, and optionally they could
use the stimulator (three doses) as symptomatic
therapy for the cluster headache attack at the onset
of pain or other symptoms. If the cluster headache
attack treated with nVNS was not aborted within 15
min, the patients were instructed to use their stand-
ard acute rescue medication for the rescue treatment
of cluster headache attack.
The primary efficacy end point was the reduction
in number of cluster headache attacks/week during
the last 2 weeks of the randomized phase versus the
run-in phase. Additional end points included the
proportion of patients with more than 50% reduction
in cluster headache attacks/week (response rate) and
rescue medication use; safety was assessed by
monitoring the frequency of adverse events.
Of the 114 patients in the run-in phase 97 were
randomly assigned to receive nVNS plus SoC or SoC
alone. Seventy percent of patients were male and the
mean age was 45 years. Data from 93 patients (n 45
nVNS; n 48 SoC) was included in the intention-to-
treat population. Number of cluster headache
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attacks/week was significantly reduced in patients
treated with nVNS compared with patients treated
with SoC only (7.6 vs. 2.0; P 0.002). Further-
more, significantly more nVNS than SoC-treated
patients were considered treatment responders
(34.4% vs. 7.1%; P 0.003). nVNS was associated
with less use of sumatriptan and oxygen as rescue
medications. The rate of adverse events was very
similar in both groups and most of them were mild.
In the open-label phase of the PREVA study [33],
during the extension phase, patients delivered three
consecutive 90-s stimulations prophylactically
twice daily (mandatory, right-side only) and option-
ally at the onset of a cluster headache attack (two
stimulations on headache side, one on opposite
side) for rescue treatment. Efficacy end points eval-
uated in the extension phase were the mean number
of all cluster headache attacks, pain intensity (range:
no pain to very severe pain), treatment success rate,
and use of rescue medication. A total of 97 patients,
across 10 European sites, were randomized to treat-
ment; 90 entered the extension phase and results
from 71 were presented. Patients who continued
with nVNS (n 30) had an additional 1.8-day
attacks reduction per week (P 0.03); patients
who received nVNS for first time in the open phase
had a 4.4-day reduction. Surprisingly, no significant
change in cluster headache attack duration and
intensity were observed during the open-label phase
and there were no differences in the use of sympto-
matic medications. The tolerability was similar to
that of the previous phase, with the majority of
adverse events being mild or moderate. In summary,
in the extension phase, the patients with adjuvant
nVNS treatment sustained or improved the response
and the patients who initiated the prophylactic
treatment with nVNS showed also clinical benefits
consistent with the data of the randomized phase.
The quality-of-life was also measured in the
PREVA study [34]. From the 97 patients who were
randomized to treatment, data from 93 patients
(n 45 nVNS; n 48 SoC) was included in the effi-
cacy analysis population. Compared with patients
treated with SoC alone, patients also treated with
nVNS reported greater overall improvements in EQ-
5D-3L, HIT-6, and HADS scores from the end of run-
in to the end of the randomized phase.
One of the important critics to this study is that
there is no placebo arm. Although some reports
suggest that response to placebo is low in patients
with cluster headache, it is necessary to know that a
proportion of patients can improve with natural
history. Another important issue is how relevant
are these results in clinical practice and is it a val-
uable alternative to the conventional treatment
strategies.
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 Noninvasive neuromodulation in cluster headache Lainez and Jensen
Concerning the mechanism of action, it is well
known that there are numerous connections
between the nucleus tractus solitarius and spinal
trigeminal nucleus [35]. Early studies suggest that
inhibition of pain by VNS occurs by direct inhibition
of vagal afferents to the caudal trigeminal nucleus
[36] in line with the acute effect of VNS; in animal
models it has been demonstrated that electrical,
chemical, and physiologic activation of vagal affer-
ents produces analgesics effects [37]. More recent
evidence suggests that VNS may also inhibit pain by
reducing the glutamate levels in the trigeminal
nucleus caudalis [38], which is more in line with
the longer lasting preventive effect of VNS.
CONCLUSION
We need to find new alternatives in the treatment of
cluster headache. In the last decade, invasive neuro-
modulation treatments have demonstrated good effi-
cacy in the management of medically refractory
patients. Noninvasive techniques are in develop-
ment. Noninvasive approaches such as the nVNS
have shown efficacy in one trial and could be an
interesting alternative in the management of this
debilitating headache. We need to replicate these
results with further sham-controlled studies and, in
parallel, conduct basic research (or studies) in order to
clarify the mechanism of action. Both invasive and
noninvasive strategies for neuromodulation are
promising and a very interesting avenue in the treat-
ment of cluster headaches.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
M.J.A.L. has received grants/research supports and hon-
oraria for consulting or participation in speaker bureau
from: Autonomic Technologies, Allergan, Boehringer,
Electrocore, Lupin, Medtronic, Terumo and Otsuka.
R.J. has given lectures for Allergan, Pfizer, ATI, Berlin-
Chemie, and is a present member of the advisory board
for ElectroCore and Autonomic Technologies.
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