Transcutaneous supraorbital neurostimulation in “de novo” patients with migraine without aura: the first Italian experience

Taken together, our results provide evidence that daily treatment with tSNS has a
preventive effect in patients with MwoA experiencing a low frequency of attacks and
drug-naïve for any pharmacological anti-migraine preventive therapies. This preventive
effect has been achieved after a relatively short-term (i.e., 60-days) tSNS treatment. Furthermore, the tSNS seems to be devoid of AE and patients
with MwoA exhibit a high level of both compliance and satisfaction with the treatment.

The goals of the pharmacological anti-migraine preventive therapies include reduction
of migraine attack frequency, intensity, duration and disability; improvement of health-related
quality of life and avoiding of migraine attacks escalation and medication misuse
14]. However, migraine patients could reasonably decide not to use pharmacological anti-migraine
preventive therapies for different reasons such as negative attitudes towards medication
in general and fear of medication side-effects 15], 16]. Among these latter, the increase of weight (especially in female patients) and/or
sedation seems to be the most important factors 16], 17]. Unfortunately, in the last decade, there have been no new migraine preventive drugs,
with a good level of efficacy and safety, that can be used in clinical practice.

In this context, neurostimulation has inaugurated a new era in headache management
and offers an alternative to pharmacological therapy. Neurostimulation treatments
were first experimented in patients with refractory or intractable headaches, then
they have been applied as an alternative to acute or preventive therapies when pharmacological
strategies produce unsatisfactory effects or are associated to unacceptable AE 2]. Recently, a 3-month treatment with tSNS was estimated superior to sham stimulation
for episodic migraine prevention in a randomized trial in a large cohort of patients
8]. Moreover, although a reduced vigilance in healthy volunteers due to tSNS treatment
was evidenced 18], tSNS was considered a safe and well-tolerated headache treatment, providing a high
rate of satisfaction in patients with migraine which used the device for a 40-day
period 9].

By comparison, tSNS appears not to match the preventive benefits seen, for example,
with topiramate, a first choice drug in migraine preventive treatment. Indeed, topiramate
can decrease the number of migraine days by 44 % as opposed to a 25 % reduction of
days using tSNS, and the number of migraine attacks in the course of topiramate treatment
was reduced by 48 %, while the tSNS reduced the number of migraine attacks by 19 %
19], 20]. Nevertheless, we believe there is a need to further evaluate whether tSNS could
exhibit a more robust efficacy in specific migraine patients sub-groups or clinical
phenotypes.

Our data demonstrate that preventive treatment with tSNS may have a strong benefit
in a selected population of patients with MwoA, characterized by low migraine frequency.
We believe that these patients could be more prone to successfully respond to tSNS
due to a minor impact of migraine burden on pain pathways. Indeed, converging evidence
suggest that repeated migraine attacks are related to functional and structural changes
induced by dural nociceptors stimulations 21]. Specifically, a high frequency of migraine attacks may be related to trigemino-spinal
central sensitization and impaired descending pain inhibitory controls 22]. Moreover, the above-mentioned pathophysiological mechanisms seem to be associated
with an atypical stimulus-induced activation of brainstem, subcortical, and cortical
regions involved in sensory processing both during and between migraine attacks 22]. Finally, tSNS could be more efficacious in those patients where the pain processing
network has not been already influenced by previous pharmacological preventive therapies.
It is a common experience that some migraine medications work better in patients drug-naïve
for any pharmacological anti-migraine therapies, compared with those with a past marred
by previous preventive treatments. Indeed, it is well-known that pharmacological anti-migraine
preventive therapies, including antiepileptic drugs, beta-blockers, tricyclic antidepressants
and calcium-channel blockers, tend to modify activities in both central and peripheral
nervous system 23].

Our findings are in line with previous data of tSNS efficacy in patients with migraine
8]. Interestingly, in our patients both migraine attacks frequency and migraine days
per month showed a percentage of at least 50 % of reduction, that is usually considered
clinically relevant 24], in respectively 81 and 75 % of patients, between run-in and 60-days of treatment.

Furthermore, the remaining attacks exhibited a significant reduction in both the average
of pain intensity and their impact on patients’ quality of life.

As a consequence of the significant improvement of migraine burden in patients with
MwoA, a reduced total intake of rescue medications has been noticed during the 60-days
tSNS treatment. Specifically, a significant reduction has been observed in both NSAID
(including acetaminophen) and triptans intake in our patients.

Our findings are also in line with previous data of compliance, safety and satisfaction
with tSNS treatment in patients with migraine 8], 9]. All patients with MwoA showed a very high compliance levels to treatment and no
AE occurred during the tSNS period. Finally, all patients reported that they were
willing to continue tSNS treatment even after the end of the study.

We are aware that the present study is not exempt from some limitations. First of
all, we did not use a tSNS sham device and, therefore, we cannot rule-out the possible
role of a placebo-effect on primary and secondary outcomes in our study. In particular,
several factors may contribute to the remedial efficacy of tSNS in our patients such
as alternative form of medical therapy, patients naïve to preventive treatment and
observation period limited to no more than two months. However, the placebo-effect
seems to have a lower impact in the prophylactic treatment than in the acute treatment
of migraine attacks. This could be due to the inherent variability in response measured
over a period of months compared with one measured over a period of hours 25]. Moreover, the effective tSNS superiority respect to sham stimulation for the prevention
of migraine headaches has been extensively demonstrated in a previous randomised controlled
trial in a large cohort of patients with migraine 8]. Nevertheless, in partial disagreement with our findings, Schoenen and colleagues
8] did not show statistically significant effect on migraine attacks at two months,
although ameliorating effect on migraine severity vanished in sham treated patients
and amplified in effectively treated patients at this time of the study. We suggest
that a greater migraine severity (i.e., frequency of migraine per month and disease duration) and, probably, previous pharmacological
anti-migraine preventive therapies may cause a different impact on pain pathways in
the two migraine populations and consequent different response to the tSNS treatment.
Second, the lack of blinding may weaken the results of the present study. However,
empirical evidence shows that although double-blind randomized controlled trials are
the gold standard for proving efficacy of a therapeutic procedure, they often suffer
from lack of generalizability 26]. Therefore, we believe that our data, in addition to the previous effectiveness and
safety results of double-blind randomized controlled studies 8], could provide additional information which may be useful in everyday clinical practice
26]. Finally, although our results are consistent with previous studies 8], 9], our sample size was relatively small. Therefore, further studies are needed to corroborate
our findings and to explore tSNS efficacy and tolerability in patients with migraine
compared with preventive treatments used in clinical practice.