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tVNS in the management of headache and pain

  • Andreas Straube
    Correspondence
    Corresponding author at: LMU, University Hospital, Department of Neurology, Munich, Ludwig-Maximilian-University Munich, 81377 Munich, Germany.
    Affiliations
    Department of Neurology, University Hospital LMU, Munich, Ludwig-Maximilian-University, Munich, 81377 Munich, Germany
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  • Ozan Eren
    Affiliations
    Department of Neurology, University Hospital LMU, Munich, Ludwig-Maximilian-University, Munich, 81377 Munich, Germany
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      Abstract

      First clinical observations of the therapeutic effect of vagus nerve stimulation were of patients who were treated for refractory epilepsy with a fully implanted vagus nerve stimulator, who also reported an improvement of their migraine and cluster headache. With the development of non-invasive vagus nerve stimulation, first clinical studies concerning a possible therapeutic effect in migraine and cluster headache were performed. In a controlled study, transcutaneous cervical vagus nerve stimulation (tcVNS) showed a significant but limited effect in acute treatment of a migraine attack. There was no significant prophylactic effect in episodic migraine. Concerning cluster headache, there was a clear beneficial effect in the prophylaxis of chronic cluster headache and in the attack treatment in episodic cluster headache. There are fewer studies in the literature on the effect of transcutaneous auricular vagus nerve stimulation (taVNS), with a partial overlap with studies on electrical ear acupuncture. In a small controlled clinical trial, there was a significant effect of taVNS in the prevention of chronic migraine. In less defined clinical studies, there were some positive signs that the method may be beneficial in chronic back pain and in unspecific gastro-intestinal pain in adolescents.
      Based on the available evidence, it is probable that vagus nerve stimulation can have a clinically meaningful influence on pain syndromes, but there are still several questions (e.g. frequency of the stimulation; duration of the stimulation; differential effects of auricular vagus stimulation and cervical vagus stimulation) to answer before vagus stimulation can be used widely in the clinic.

      Abbreviations:

      paVNS (percutaneous auricular vagus nerve stimulation), tVNS (transcutaneous vagus nerve stimulation), taVNS (transcutaneous auricular vagus nerve stimulation), tcVNS (transcutaneous cervical vagus nerve stimulation)

      Keywords

      1. Introduction

      The vagus nerve is one of the essential parts of the parasympathetic system and carries motoric nerve fibers for the control of the vocal cords as well as autonomic fibers that control heart and stomach and gut. More than 70% of the fibers in the nerve are afferent fibers and only 20-30% efferent fibers. In most studies, the left cervical vagus nerve is stimulated based on safety concerns, since the left vagus nerve innervates more the atrial-ventricular node and the right the sinus-atrial node (
      • Chen M.
      • Yu L.
      • Ouyang F.
      • Liu Q.
      • Wang Z.
      • Wang S.
      • Zhou L.
      • Jiang H.
      • Zhou S.
      The right side or left side of noninvasive transcutaneous vagus nerve stimulation: based on conventional wisdom or scientific evidence?.
      ). Due to the current spread and the much lower thresholds for the stimulation of the myelinated afferent fibers, it becomes clear that only the afferent fibers can be stimulated with the non-invasive stimulation. Consequently, the majority of recent clinical studies used bilateral stimulation. Based on these facts, it is not obvious that the vagus nerve is involved in the processing of noxious stimuli. However, physiological investigations in the 1980s and 1990s revealed that stimulation of the left vagus nerve has a modulatory effect on somatic pain and on headache (
      • Ammons W.S.
      • Blair R.W.
      • Foreman R.D.
      Vagal afferent inhibition of primate thoracic spinothalamic neurons.
      ;
      • Randich A.
      • Gebhart G.F.
      Vagal afferent modulation of nociception.
      ). Stimulation of the left vagus nerve inhibited the activity of primate spinothalamic neurons related to cardiac pain (
      • Ammons W.S.
      • Blair R.W.
      • Foreman R.D.
      Vagal afferent inhibition of primate thoracic spinothalamic neurons.
      ). The effect was eliminated by bilateral cervical vagotomy, in line with the idea that vagal afferents to the brainstem are activated and the effect on the spinothalamic neurons is then carried forward by descending spinal pathways (
      • Ammons W.S.
      • Blair R.W.
      • Foreman R.D.
      Vagal afferent inhibition of primate thoracic spinothalamic neurons.
      ). Further, it was shown that the vagal input to the nucleus tractus solitary and other brainstem relays is critical here. This implies the involvement of descending spinal serotonergic and noradrenergic pathways which are known as the descending anti-nociceptive system (
      • Randich A.
      • Gebhart G.F.
      Vagal afferent modulation of nociception.
      ). Concerning the influence of vagal stimulation on headache, there are several experimental studies, mostly in rats, which show an inhibitory influence of the stimulation of cardiac vagal afferents on the activity of spinal trigeminal nociceptive neurons which respond to the painful stimulation of the oro-facial skin and the tooth pulp (
      • Bossut D.F.
      • Maixner W.
      Effects of cardiac vagal afferent electrostimulation on the responses of trigeminal and trigeminothalamic neurons to noxious orofacial stimulation.
      ;
      • Lyubashina O.A.
      • Sokolov A.Y.
      • Panteleev S.S.
      Vagal afferent modulation of spinal trigeminal neuronal responses to dural electrical stimulation in rats.
      ). Later it was shown that this inhibitory effect was at least partially mediated by an opioidergic mechanism and can be blocked by naloxone (
      • Takeda M.
      • Tanimoto T.
      • Ojima K.
      • Matsumoto S.
      Suppressive effect of vagal afferents on the activity of the trigeminal spinal neurons related to the jaw-opening reflex in rats: involvement of the endogenous opioid system.
      ). Continuous vagus nerve stimulation was also able to reduce pain behavior after formalin injection into the mystacial vibrissae in rats and the associated c-Fos expression in the caudal trigeminal nucleus (
      • Bohotin C.
      • Scholsem M.
      • Multon S.
      • Martin D.
      • Bohotin V.
      • Schoenen J.
      Vagus nerve stimulation in awake rats reduces formalin-induced nociceptive behaviour and fos-immunoreactivity in trigeminal nucleus caudalis.
      ). Based on the experimental results, in 2001 first reports of the effect of vagus nerve stimulation on nociception in humans were reported. In these case series, patients who were implanted with a vagus nerve stimulator for medical refractory seizures reported on a reduction in migraine headache or showed a reduction in pain perception in experimental settings. In ten patients with left vagus nerve stimulation for medically intractable epilepsy,
      • Kirchner A.
      • Birklein F.
      • Stefan H.
      • Handwerker H.O.
      Left vagus nerve stimulation suppresses experimentally induced pain.
      tested pain perception by using quantitative sensory testing (QST). Vagus nerve stimulation diminished the increase in pain perception during trains of pain stimuli (“wind up”) and also reduced the pain due to tonic pressure stimuli. There was no effect on pinprick and heat stimulation. In a survey including 62 patients, 4 patients had episodic migraine and all of them reported a reduction of migraine attacks under the vagal stimulation (
      • Hord E.D.
      • Evans M.S.
      • Mueed S.
      • Adamolekun B.
      • Naritoku D.K.
      The effect of vagus nerve stimulation on migraines.
      ). In a similar approach,
      • Lenaerts M.E.
      • Oommen K.J.
      • Couch J.R.
      • Skaggs V.
      Can vagus nerve stimulation help migraine?.
      retrospectively analyzed 34 patients who were initially implanted for seizure treatment. Ten of these patients also had migraine and the attack frequency was analyzed. Eight showed a reduction of attacks of at least 50%; two did not respond.
      • Mauskop A.
      Vagus nerve stimulation relieves chronic refractory migraine and cluster headaches.
      described 6 patients who were treated for headache with an implanted vagus nerve stimulator. Four of them showed excellent or good improvement on the stimulation, two did not benefit.
      Based on clinical observations of the benefit of invasive vagal nerve stimulation on migraine and cluster headache in individual cases, first studies investigating the effect of non-invasive vagal nerve stimulation on migraine and cluster headache were initiated. For other chronic pain syndromes, the literature is more anecdotal. In the following, we will discuss the literature on non-invasive vagal stimulation at the neck (nVNS) in the form of transcutaneous auricular stimulation of the sensory vagus nerve (taVNS), transcutaneous cervical stimulation of the sensory vagus nerve (tcVNS) and for the sake of completeness also the minimally invasive form of percutaneous auricular vagus nerve stimulation (paVNS). The review is based on a search in the databank PubMed under the items “non-invasive vagus nerve stimulation AND migraine OR cluster headache OR pain syndrome” and “transcutaneous auricular/cervical vagus nerve stimulation AND migraine OR cluster headache OR pain syndrome”. The paper will discuss possible mechanisms by which tVNS influences migraine and cluster headache, as well as clinical experience with non-invasive vagus nerve stimulation in the acute and preventive treatment of headache and somatic pain.

      2. Vagus nerve stimulation

      2.1 Transcutaneous cervical vagus nerve stimulation (tcVNS)

      TcVNS is studied in open uncontrolled case series as well as in controlled studies by using the GammaCore® battery-powered handheld device. In order to stimulate the vagus nerve, the device is placed ventrally to the sternocleidomastoid muscle on the left or right side. When activated by the patient, the device gives an adjustable low-voltage electrical stimulation with a burst of 5 kHz sine waves every 40 ms (25 Hz) for a duration, in most studies, of 120 s. For sham stimulation, the device was set at 0.1 Hz biphasic stimulation. The stimulation was repeated 2–3 times in some studies. The patients were asked to use the maximum tolerated output intensity which normally causes contractions of the platysma muscle.
      In migraine, there are studies published concerning acute as well as preventive treatment. In a first open uncontrolled study, 30 patients were enrolled. The patients treated up to four attacks with two 90s stimulation on the right cervical vagal nerve (
      • Goadsby P.
      • Grosberg B.
      • Mauskop A.
      • Cady R.
      • Simmons K.
      Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.
      ). No severe adverse event was reported; some patients complained about short-lasting redness of the stimulation site or neck twitching or a raspy voice. In the mean across all attacks, the pain-free rate at 2 h, the gold standard in attack treatment studies, was 22%. This rate is comparable to the data in some of the controlled phase 3 studies using triptans or naproxen (
      • Goadsby P.
      • Grosberg B.
      • Mauskop A.
      • Cady R.
      • Simmons K.
      Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.
      ).
      In order to confirm these results, a randomized study (PRESTO) was done (
      • Tassorelli C.
      • Grazzi L.
      • de Tommaso M.
      • Pierangeli G.
      • Martelletti P.
      • Rainero I.
      • Dorlas S.
      • Geppetti P.
      • Ambrosini A.
      • Sarchielli P.
      • Liebler E.
      • Barbanti P.
      PRESTO Study Group
      Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study.
      ). A total of 248 patients with episodic migraine were included and randomized in a verum and a sham group. The active group stimulated bilaterally for 120 s each and in the sham group the above-described 0.1 Hz stimulation was applied. The stimulation was started within 20 min after beginning of the headache and the effect was assessed after 15, 30, 60 and 120 min and 24 and 48 h. The main outcome was that the active stimulation was superior to the sham stimulation in pain-free responder rates at 30 (12.7% vs. 4.2%) and 60 (21.0% vs. 10.0%) minutes and also with a strong tendency at 120 min (30.4% vs. 19.7%). The secondary endpoints concerning pain relief showed similar results with 40.8% reporting pain relief at 120 min (
      • Tassorelli C.
      • Grazzi L.
      • de Tommaso M.
      • Pierangeli G.
      • Martelletti P.
      • Rainero I.
      • Dorlas S.
      • Geppetti P.
      • Ambrosini A.
      • Sarchielli P.
      • Liebler E.
      • Barbanti P.
      PRESTO Study Group
      Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study.
      ). The side effects were similar to the open study. Overall, the result confirmed the findings from the open study in which the pain-free data were in the range of the values seen in the studies with medication. The pain relief data are somewhat lower than the percentage in the medication trials. A limitation which is more or less given in all studies using electrical stimulation is establishing a sham stimulation which does surely not have an effect and is also not easily recognized as a sham stimulation. Using different stimulation frequencies does not exclude the possibility that the different stimulation frequencies have a biological effect.
      Beside the optimization of acute attack treatment, there is a recommendation in national and international guidelines to start preventive treatment in episodic migraine with more than 4 headache days/month. The PREMIUM trial was a controlled, double-blind, randomized study for the preventive treatment of episodic migraine with tcVNS (
      • Diener H.C.
      • Goadsby P.J.
      • Ashina M.
      • Al-Karagholi M.A.
      • Sinclair A.
      • Mitsikostas D.
      • Magis D.
      • Pozo-Rosich P.
      • Irimia Sieira P.
      • Làinez M.J.
      • Gaul C.
      • Silver N.
      • Hoffmann J.
      • Marin J.
      • Liebler E.
      • Ferrari M.D.
      Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial.
      ). The study protocol started with a 4-week baseline period, followed by a 12-week double-blind period and then a 24-week open-label phase. The intervention was a daily application of two 120 s stimulations at the cervical vagus nerve 3 times a day either with a stimulator or a sham device. The analysis included 332 patients (about 8 migraine days at baseline). There was no difference between the verum and the sham group (reduction of migraine days by 2.26 compared to 1.80). In a post hoc analysis, only including patients with minimal stimulation on 67% of the days showed a significant difference (-2.27 vs. -1.53 days). This result can be interpreted as indicating that there is a dose effect for the vagus nerve stimulation.
      In addition to studies on the use of tcVNS in migraine, several studies concerning cluster headache were performed. One of the first studies was published in 2015 (
      • Nesbitt A.D.
      • Marin J.C.
      • Tompkins E.
      • Ruttledge M.H.
      • Goadsby P.J.
      Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment.
      ). In this open uncontrolled study, 19 patients (11 chronic cluster headache, 8 episodic) were included. The patients could use the device for acute attack treatment by stimulating 3 times for 120 s ipsilaterally to the cluster attack side and for preventive use 2 to 3 times in the morning and late afternoon. Fifteen patients reported some improvement, four stated that there was no effect. 47% of the attacks were halted within 11 min. In terms of the preventive effect, there was a reduction of the mean attack frequency from 4.5/24 h to 2.6/24 h. These effects were investigated more deeply in controlled, randomized, double-blind studies (ACT1 and ACT2 study) (
      • Silberstein S.D.
      • Mechtler L.L.
      • Kudrow D.B.
      • Calhoun A.H.
      • McClure C.
      • Saper J.R.
      • Liebler E.J.
      • Rubenstein Engel E.
      • Tepper S.J.
      Non–invasive vagus nerve stimulation for the ACute treatment of cluster headache: findings from the randomized, double-blind, sham-controlled ACT1 study.
      ;
      • Goadsby P.J.
      • de Coo I.F.
      • Silver N.
      • Tyagi A.
      • Ahmed F.
      • Gaul C.
      • Jensen R.H.
      • Diener H.C.
      • Solbach K.
      • Straube A.
      • Liebler E.
      • Marin J.C.
      • Ferrari M.D.
      ACT2 Study Group
      Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study.
      ). ACT1 was a double-blind, prospective study including 150 patients with episodic or chronic cluster headache that were randomized for a duration up to one month or five attacks treated either with tcVNS (3x120sec right side of the neck) or sham (which elicited a slight tingling sensation without stimulation of the vagus nerve) (
      • Silberstein S.D.
      • Yuan H.
      • Najib U.
      • Ailani J.
      • Morais A.L.
      • Mathew P.G.
      • Liebler E.
      • Tassorelli C.
      • Diener H.C.
      Non-invasive vagus nerve stimulation for primary headache: a clinical update.
      ). A total of 60 patients (episodic n = 38, chronic n = 22) were randomized to the verum group, 73 were sham-treated (episodic n = 47, chronic n = 26). The primary endpoint “response rate” (pain-free 15 min after treatment) was only significant for the episodic cluster headache group compared to sham (34.2% vs. 10.6%; p = 0.008), but not for patients with chronic cluster headache. No severe adverse events occurred.
      In ACT2, in a 2-week double-blind phase, the patients received non-invasive vagus nerve stimulation (3x120sec ipsilateral to the cluster headache early at the attack onset) or sham stimulation (see ACT1). A total of 48 patients were randomized to the verum group and 44 to the sham treatment. In both groups, about 1/3 of the patients had an episodic and 2/3 a chronic form. The stimulation again only showed a significant benefit in the subgroup with episodic cluster headache (48% vs. 6%; proportion of pain-free status after 15 min in all stimulated attacks); there was no significant difference for chronic cluster headache. No severe adverse events were reported.
      In contrast to the negative finding concerning the acute attack treatment in chronic cluster headache, there was a significant improvement in the prevention of attacks in chronic cluster headache with non-invasive vagus nerve stimulation (
      • Gaul C.
      • Diener H.C.
      • Silver N.
      • Magis D.
      • Reuter U.
      • Andersson A.
      • Liebler E.J.
      • Straube A.
      PREVA study group. non-invasive vagus nerve stimulation for PREVention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study.
      ). In this study (PREVA), 97 patients with chronic cluster headache were randomized into two groups after a two-week baseline phase. One group received their standard medical treatment plus the vagal stimulation (3 times 120 s stimulation 2 times a day), the control group went on with their standard care for 4 weeks and after that could also receive the vagus nerve stimulation in a cross-over design. The primary endpoint was the reduction of cluster attacks in the last two weeks of the randomized phase compared to the number of attacks in the 1-week run-in phase. The reduction was also calculated for the 2 last weeks of the extension phase, when the control group also received vagus nerve stimulation. The intervention group showed a significant larger reduction in weekly cluster attacks (-5.9) compared to the group with the usual standard care (-2.1). The number of patients with an improvement of at least 50% was also higher in the group with vagal stimulation (40% versus 8.3%). Further, in the subjects with measurable observations (modified ITT (mITT)) the number of responders (improvement by 50%) increased in the control group in the extension phase when they were allowed to use the vagal stimulation from 8.5% to 21.6%. The net effect of reduction in chronic cluster headache attacks was 3.8 which is nominally larger than the reduction that was seen in the recently published study concerning the preventive effect of prednisone, but which solely included episodic cluster headache patients (−2.4) (
      • Obermann M.
      • Nägel S.
      • Ose C.
      • Sonuc N.
      • Scherag A.
      • Storch P.
      • Gaul C.
      • Böger A.
      • Kraya T.
      • Jansen J.P.
      • Straube A.
      • Freilinger T.
      • Kaube H.
      • Jürgens T.P.
      • Diener H.C.
      • Katsarava Z.
      • Kleinschnitz C.
      • Holle D.
      Safety and efficacy of prednisone versus placebo in short-term prevention of episodic cluster headache: a multicentre, double-blind, randomised controlled trial.
      ). In a further analysis of the data, it was shown that the improvement was seen starting with the second week of vagal stimulation and that the primary intervention group was better than the control group at all time points. The percentage of patients with a 100% reduction was 8% in the intervention group and 0% in the control group (
      • Gaul C.
      • Magis D.
      • Liebler E.
      • Straube A.
      Effects of non-invasive vagus nerve stimulation on attack frequency over time and expanded response rates in patients with chronic cluster headache: a post hoc analysis of the randomised, controlled PREVA study.
      ). The data were confirmed due to later open case series of 30 patients who were treated in England in the period from 2012 to 2016. Here the attack frequency before start of the stimulation was 26.6 attacks and fell to 9.5 attacks/week afterwards (
      • Marin J.
      • Giffin N.
      • Consiglio E.
      • McClure C.
      • Liebler E.
      • Davies B.
      Non-invasive vagus nerve stimulation for treatment of cluster headache: early UK clinical experience.
      ).
      Concerning other trigemino-autonome headaches, there are some single case reports which reported a benefit of ipsilateral stimulation, especially in hemicrania continua (
      • Eren O.
      • Straube A.
      • Schöberl F.
      • Schankin C.
      Hemicrania continua: beneficial effect of non-invasive vagus nerve stimulation in a patient with a contraindication for indomethacin.
      ;
      • Tso A.R.
      • Marin J.
      • Goadsby P.J.
      Noninvasive vagus nerve stimulation for treatment of indomethacin-sensitive headaches.
      ;
      • Trimboli M.
      • Al-Kaisy A.
      • Andreou A.P.
      • Murphy M.
      • Lambru G.
      Non-invasive vagus nerve stimulation for the management of refractory primary chronic headaches: a real-world experience.
      ).

      2.2 Transcutaneous auricular vagus nerve stimulation

      The scientific rationale behind the stimulation of the auricular branch of the vagus nerve is that the same parasympathetic brainstem center can be assessed as with the vagus nerve stimulation at the neck. Evidence from fMRI studies showed that electrical stimulation of the auricular branch of the vagus nerve causes an activation in the areas of the central vagus projections (nucleus tractus solitary, spinal trigeminal nucleus, dorsal raphe, locus coeruleus, parabrachial area, amygdala and nucleus accumbens as well as cortical activation). The hippocampus and hypothalamus showed a deactivation (
      • Frangos E.
      • Ellrich J.
      • Komisaruk B.R.
      Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans.
      ). The auricular branch is the only sensory nerve of the vagus nerve which innervates some surface areas and the skin of the cymba conchae is exclusively innervated by the sensory vagal afferents (
      • Ellrich J.
      Transcutaneous auricular vagus nerve stimulation.
      ). Like the non-invasive vagus nerve stimulation, electrical stimulation of this area activates mostly and exclusively the larger myelinated sensory Aβ fibers (
      • Ellrich J.
      Transcutaneous auricular vagus nerve stimulation.
      ). Most clinical studies used the NEMOS® device. In contrast to the non-invasive neck stimulation, the stimulation was done with 25 Hz or 1 Hz and for 4 h a day with minimum stimulation intervals of 1 h.
      There is only a limited number of studies on the clinical benefit of taVNS. In one monocentric controlled, blinded and randomized study, 46 patients with chronic migraine (more than 15 headache days per month and at least 8 of these with migraine-type headache or response to migraine medication) were included (
      • Straube A.
      • Ellrich J.
      • Eren O.
      • Blum B.
      • Ruscheweyh R.
      Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.
      ). Forty patients completed the study. After a baseline period of 4 weeks, the patients were randomized to receive 1 Hz or 25 Hz stimulation of the auricular branch of the vagus nerve. The stimulation was delivered by the NEMOS® device using a specially designed electrode to the concha of the left outer ear. The patients were asked to use an intensity which elicited a non-painful tingling sensation and the daily stimulation duration should be 4 h in total. The primary endpoint was the change in headache days in a 28-day period starting 4 weeks before the end of the study compared to the 28 days in the baseline period. Secondary outcome parameter were the percentage of patients with at least 50% improvement and the changes in the MIDAS, HIT-6 questionnaires and the number of adverse events. 46 patients were included in the study, with 6 patients dropping out during the study. Somewhat astonishingly and contrary to the primary hypothesis, the group with 1 Hz stimulation showed a significantly larger reduction in headache days per 4 weeks (19.1; -7.0 days) than the group with the 25 Hz stimulation which is the gold standard for stimulation with implanted stimulators (19.2 days at baseline; -3.3 days). 29.4% of the 1 Hz group and only 13.3% of the 25 Hz group showed a reduction of at least 50%. No serious adverse events were reported (
      • Straube A.
      • Ellrich J.
      • Eren O.
      • Blum B.
      • Ruscheweyh R.
      Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.
      ).
      The reduction in the 1 Hz group of about 7.0 days (after 12 weeks) is comparable to the effect seen in the large PREEMPT trial for the effect of onabotulinumtoxinA. (-8.4 days after 24 weeks) (
      • Dodick D.W.
      • Turkel C.C.
      • DeGryse R.E.
      • Aurora S.K.
      • Silberstein S.D.
      • Lipton R.B.
      • Diener H.C.
      • Brin M.F.
      PREEMPT chronic migraine study group. OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program.
      ). Unfortunately, no further clinical studies concerning the preventive effect in migraine or cluster headache have been published. In an fMRI study,
      • Zhang Y.
      • Huang Y.
      • Li H.
      • Yan Z.
      • Zhang Y.
      • Liu X.
      • Hou X.
      • Chen W.
      • Tu Y.
      • Hodges S.
      • Chen H.
      • Liu B.
      • Kong J.
      Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study.
      report that the patients with taVNS (1 Hz stimulation) compared to the patients with sham taVNS showed a reduction in intensity and frequency of migraine days after 4 weeks treatment, supporting the results described above.
      There is also an effect of taVNS on pain perception beyond the trigeminal supply area. In an experimental setting using QST (quantitative sensory testing), healthy subjects were tested during continuous taVNS stimulation with 25 Hz. Under stimulation there were increased pressure and mechanical pain thresholds as well as reduced pain perception during sustained painful heat stimulation on the hand compared to the sham condition (
      • Busch V.
      • Zeman F.
      • Heckel A.
      • Menne F.
      • Ellrich J.
      • Eichhammer P.
      The effect of transcutaneous vagus nerve stimulation on pain perception–an experimental study.
      ).
      Another study investigated the effect of electrical stimulated auricular acupuncture (compared to classic auricular acupuncture) on chronic low back pain. The study is therefore not a typical tVNS study given the fact that minimally invasive subcutaneous microneedles were used for percutaneous auricular vagus nerve stimulation (paVNS) but gives some indication of a possible effect of tVNS in chronic back pain. In total 61 patients were analyzed: 31 patients received electrical stimulation, 30 served as a control group. In both groups, 3 auricular acupuncture points were inserted with single-use needles and the needles were removed after two days. In the stimulation group, the needles were connected to an electrical stimulator and the stimulation frequency was 1 Hz. Stimulation was done once a week for 48 h for 6 weeks and the patients were followed up until the end of 3 months. Several standard pain questionnaires were used for the assessment. Both groups improved, but the pain reduction was significantly better over the whole study period in the group with the active stimulation. This also translated into less use of analgesics and more patients returning to full-time employment. No severe adverse events were reported (
      • Sator-Katzenschlager S.M.
      • Scharbert G.
      • Kozek-Langenecker S.A.
      • Szeles J.C.
      • Finster G.
      • Schiesser A.W.
      • Heinze G.
      • Kress H.G.
      The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture.
      ).
      A frequent problem, especially in adolescents, is unspecific gastro-intestinal pain. In a study with 115 patients, the effect of paVNS or sham stimulation over a period of 4 weeks was tested. The stimulated group had a larger reduction of the worse pain than the sham group. This reduction was sustained over the treatment period. Some side effects were reported, most often irritation or skin problems at the stimulation site (
      • Kovacic K.
      • Hainsworth K.
      • Sood M.
      • Chelimsky G.
      • Unteutsch R.
      • Nugent M.
      • Simpson P.
      • Miranda A.
      Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial.
      ).

      3. Discussion

      Both vagal stimulations, tcVNS and taVNS, showed a positive effect on pain perception in different pain syndromes or experimental settings in some studies. The studies on both stimulation types included only a limited number of patients. A further limitation is that most clinical syndromes were only investigated in one study, thus there is no information about the reliability of the results. In recent years, two reviews and meta-analyses of the available studies were published. In a review concerning neuromodulation techniques for acute and preventive migraine treatment, the authors concluded that vagus nerve stimulation had no significant effect and the heterogeneity was high (
      • Moisset X.
      • Pereira B.
      • Ciampi de Andrade D.
      • Fontaine D.
      • Lantéri-Minet M.
      • Mawet J.
      Neuromodulation techniques for acute and preventive migraine treatment: a systematic review and meta-analysis of randomized controlled trials.
      ). In another review,
      • Lai Y.H.
      • Huang Y.C.
      • Huang L.T.
      • Chen R.M.
      • Chen C.
      Cervical noninvasive vagus nerve stimulation for migraine and cluster headache: a systematic review and meta-analysis.
      analyzed 6 published randomized controlled trials on the effect of tcVNS on migraine and cluster headache. They stated that there is a significant effect of tcVNS on treatment of acute migraine and cluster attacks, but no significant effect on headache days in episodic migraine. Based on the very good tolerability of both stimulation methods (tcVNS and taVNS), some authors stated that the vagal stimulation should be seen as a preferred option in the treatment of acute migraine attacks or cluster attacks in episodic cluster headache as well as an option in the preventive treatment in chronic cluster headache (
      • Silberstein S.D.
      • Yuan H.
      • Najib U.
      • Ailani J.
      • Morais A.L.
      • Mathew P.G.
      • Liebler E.
      • Tassorelli C.
      • Diener H.C.
      Non-invasive vagus nerve stimulation for primary headache: a clinical update.
      ) (Table 1, Table 2) .
      Table 1Summary of the clinical studies published for tVNS and paVNS.
      Pain syndromeStimulation typeFrequency/durationStudy typeNResultLiterature
      MigrainetcVNSacute, twice 90scase30Positive: Pain-free rate at 2 h was 22%
      • Goadsby P.
      • Grosberg B.
      • Mauskop A.
      • Cady R.
      • Simmons K.
      Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.
      Episodic migrainetcVNSacute, bilaterally 120 sRCT248Positive: Significant pain-free responder rates at 30 and 60 min, tendency for 120 min (PE). Significant for pain relief (120 min) and percentage of pain intensity reduction (60 and 120 min) (SE)
      • Tassorelli C.
      • Grazzi L.
      • de Tommaso M.
      • Pierangeli G.
      • Martelletti P.
      • Rainero I.
      • Dorlas S.
      • Geppetti P.
      • Ambrosini A.
      • Sarchielli P.
      • Liebler E.
      • Barbanti P.
      PRESTO Study Group
      Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study.
      Episodic migrainetcVNSacute and preventive, twice 120 s 3 times a dayRCT332no difference in reduction of migraine days (PE)
      • Diener H.C.
      • Goadsby P.J.
      • Ashina M.
      • Al-Karagholi M.A.
      • Sinclair A.
      • Mitsikostas D.
      • Magis D.
      • Pozo-Rosich P.
      • Irimia Sieira P.
      • Làinez M.J.
      • Gaul C.
      • Silver N.
      • Hoffmann J.
      • Marin J.
      • Liebler E.
      • Ferrari M.D.
      Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial.
      Cluster headachetcVNSpreventive and acute, 3 times for 120 s and 2 to 3 times a dayCase19Positive:

      reduction of mean attack frequency and painfree in 47% at 11 min.
      • Nesbitt A.D.
      • Marin J.C.
      • Tompkins E.
      • Ruttledge M.H.
      • Goadsby P.J.
      Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment.
      Cluster headachetcVNSacute, 3 times 120 sRCT92only positive in episodic cluster headache with significant higher proportion of pain-free status after 15 min in all stimulated attacks (48% vs. 6%).
      • Goadsby P.J.
      • de Coo I.F.
      • Silver N.
      • Tyagi A.
      • Ahmed F.
      • Gaul C.
      • Jensen R.H.
      • Diener H.C.
      • Solbach K.
      • Straube A.
      • Liebler E.
      • Marin J.C.
      • Ferrari M.D.
      ACT2 Study Group
      Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study.
      Chronic cluster headachetcVNSpreventive, 2 times 3 stimulation for 120 s eachRCT97Significant reduction in weekly cluster attacks (-5.9 vs. -2.1) and improvement of at least 50% (40% versus 8.3%) in the group with vagal stimulation.
      • Gaul C.
      • Diener H.C.
      • Silver N.
      • Magis D.
      • Reuter U.
      • Andersson A.
      • Liebler E.J.
      • Straube A.
      PREVA study group. non-invasive vagus nerve stimulation for PREVention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study.
      Episodic and chronic cluster headachetcVNSacute, 3 times 120 sRCT150only positive in episodic cluster headache with significant reduction in response rate (PE). Significant SE were sustained treatment response rate, responder and pain-free rate for >50% of treated attacks, change in attack duration.
      • Silberstein S.D.
      • Yuan H.
      • Najib U.
      • Ailani J.
      • Morais A.L.
      • Mathew P.G.
      • Liebler E.
      • Tassorelli C.
      • Diener H.C.
      Non-invasive vagus nerve stimulation for primary headache: a clinical update.
      Chronic migrainetaVNSpreventive, 4 h daily 1 HzRCT46Significant reduction in headache days (-7 vs. -3.3.), no difference in SE.
      • Straube A.
      • Ellrich J.
      • Eren O.
      • Blum B.
      • Ruscheweyh R.
      Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.
      Episodic migrainetaVNSpreventive, 3 sessions per week for 30 min; 1 HzRCT70Significant

      reduction in number of migraine days, pain intensity and migraine attack times after 4 weeks.
      • Zhang Y.
      • Huang Y.
      • Li H.
      • Yan Z.
      • Zhang Y.
      • Liu X.
      • Hou X.
      • Chen W.
      • Tu Y.
      • Hodges S.
      • Chen H.
      • Liu B.
      • Kong J.
      Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study.
      Chronic low back painpaVNStherapy; 48 h per week for 6 weeks; 1 HzRCT61Significant

      pain reduction in the group with active stimulation and also significant less use of analgesics. Additionally, improvement in psychological well-being, physical activity, quality of sleep and return to employment.
      • Sator-Katzenschlager S.M.
      • Scharbert G.
      • Kozek-Langenecker S.A.
      • Szeles J.C.
      • Finster G.
      • Schiesser A.W.
      • Heinze G.
      • Kress H.G.
      The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture.
      Functional gastro-intestinal disorders (adolescents)paVNStherapy; 4 weeksRCT115Significant larger reduction of worse pain in the active group
      • Kovacic K.
      • Hainsworth K.
      • Sood M.
      • Chelimsky G.
      • Unteutsch R.
      • Nugent M.
      • Simpson P.
      • Miranda A.
      Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial.
      paVNS = percutaneous auricular vagus nerve stimulation.
      tVNS = transcutaneous vagus nerve stimulation.
      taVNS = transcutaneous auricular vagus nerve stimulation.
      tcVNS = transcutaneous cervical vagus nerve stimulation.
      PE = Primary endpoint.
      SE = Secondary endpoint.
      Table 2Study rating.
      StudySelection biasStudy designConfoundersBlindingData collection methodWithdrawals and dropoutsGlobal ratingClassification of evidence
      • Goadsby P.
      • Grosberg B.
      • Mauskop A.
      • Cady R.
      • Simmons K.
      Effect of noninvasive vagus nerve stimulation on acute migraine: an open-label pilot study.
      13 (open label single arm)n.a.n.a.113IV
      • Tassorelli C.
      • Grazzi L.
      • de Tommaso M.
      • Pierangeli G.
      • Martelletti P.
      • Rainero I.
      • Dorlas S.
      • Geppetti P.
      • Ambrosini A.
      • Sarchielli P.
      • Liebler E.
      • Barbanti P.
      PRESTO Study Group
      Noninvasive vagus nerve stimulation as acute therapy for migraine: the randomized PRESTO study.
      11 (RCT)11111I
      • Diener H.C.
      • Goadsby P.J.
      • Ashina M.
      • Al-Karagholi M.A.
      • Sinclair A.
      • Mitsikostas D.
      • Magis D.
      • Pozo-Rosich P.
      • Irimia Sieira P.
      • Làinez M.J.
      • Gaul C.
      • Silver N.
      • Hoffmann J.
      • Marin J.
      • Liebler E.
      • Ferrari M.D.
      Non-invasive vagus nerve stimulation (nVNS) for the preventive treatment of episodic migraine: the multicentre, double-blind, randomised, sham-controlled PREMIUM trial.
      11 (RCT)11111I
      • Nesbitt A.D.
      • Marin J.C.
      • Tompkins E.
      • Ruttledge M.H.
      • Goadsby P.J.
      Initial use of a novel noninvasive vagus nerve stimulator for cluster headache treatment.
      13 (open label single arm)n.a.n.a.113IV
      • Goadsby P.J.
      • de Coo I.F.
      • Silver N.
      • Tyagi A.
      • Ahmed F.
      • Gaul C.
      • Jensen R.H.
      • Diener H.C.
      • Solbach K.
      • Straube A.
      • Liebler E.
      • Marin J.C.
      • Ferrari M.D.
      ACT2 Study Group
      Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: a randomized, double-blind, sham-controlled ACT2 study.
      11 (RCT)11111I
      • Gaul C.
      • Diener H.C.
      • Silver N.
      • Magis D.
      • Reuter U.
      • Andersson A.
      • Liebler E.J.
      • Straube A.
      PREVA study group. non-invasive vagus nerve stimulation for PREVention and acute treatment of chronic cluster headache (PREVA): a randomised controlled study.
      12 (open label, randomized, controlled, parallel group)1n.a.112III
      • Silberstein S.D.
      • Yuan H.
      • Najib U.
      • Ailani J.
      • Morais A.L.
      • Mathew P.G.
      • Liebler E.
      • Tassorelli C.
      • Diener H.C.
      Non-invasive vagus nerve stimulation for primary headache: a clinical update.
      11 (RCT)11111I
      • Straube A.
      • Ellrich J.
      • Eren O.
      • Blum B.
      • Ruscheweyh R.
      Treatment of chronic migraine with transcutaneous stimulation of the auricular branch of the vagal nerve (auricular t-VNS): a randomized, monocentric clinical trial.
      11 (RCT)11111I
      • Zhang Y.
      • Huang Y.
      • Li H.
      • Yan Z.
      • Zhang Y.
      • Liu X.
      • Hou X.
      • Chen W.
      • Tu Y.
      • Hodges S.
      • Chen H.
      • Liu B.
      • Kong J.
      Transcutaneous auricular vagus nerve stimulation (taVNS) for migraine: an fMRI study.
      12 (single blinded crossover design)12112II
      • Sator-Katzenschlager S.M.
      • Scharbert G.
      • Kozek-Langenecker S.A.
      • Szeles J.C.
      • Finster G.
      • Schiesser A.W.
      • Heinze G.
      • Kress H.G.
      The short- and long-term benefit in chronic low back pain through adjuvant electrical versus manual auricular acupuncture.
      11 (RCT)21212II
      • Kovacic K.
      • Hainsworth K.
      • Sood M.
      • Chelimsky G.
      • Unteutsch R.
      • Nugent M.
      • Simpson P.
      • Miranda A.
      Neurostimulation for abdominal pain-related functional gastrointestinal disorders in adolescents: a randomised, double-blind, sham-controlled trial.
      11 (RCT)11111I
      1 = strong, 2 = moderate, 3 = weak according to the “Effective Public Health Practice Project Quality Assessment Tool” (
      • Armijo-Olivo S.
      • Stiles C.R.
      • Hagen N.A.
      • Biondo P.D.
      • Cummings G.G.
      Assessment of study quality for systematic reviews: a comparison of the Cochrane collaboration risk of bias tool and the effective public health practice project quality assessment tool: methodological research.
      ); n.a. = not applicable. Classification of evidence according to AAN 2017 edition clinical practice guideline process manual and criteria for rating (1.30.17).
      Several issues have still not been addressed, mainly regarding the stimulation technique itself: 1) the best stimulation frequency, 2) the optimal stimulation duration, 3) whether there is a differential effect of tcVNS and taVNS in a specific pain condition. Answering these questions will be important before vagal stimulation procedures will result in patient specific treatment protocols to find broad clinical acceptance and use. Then, there will be the question of non-responders. Who are they and what is different? Maybe, these will lead to clinical implications and even better stimulation schemes or less use for inappropriate patients.
      To achieve this, another point is crucial for further research: The classification of reporting standards to ensure better reporting and easier comparison of findings across different studies (
      • Farmer A.D.
      • Strzelczyk A.
      • Finisguerra A.
      • Gourine A.V.
      • Gharabaghi A.
      • Hasan A.
      • Burger A.M.
      • Jaramillo A.M.
      • Mertens A.
      • Majid A.
      • Verkuil B.
      • Badran B.W.
      • Ventura-Bort C.
      • Gaul C.
      • Beste C.
      • Warren C.M.
      • Quintana D.S.
      • Hämmerer D.
      • Freri E.
      • Frangos E.
      • Tobaldini E.
      • Kaniusas E.
      • Rosenow F.
      • Capone F.
      • Panetsos F.
      • Ackland G.L.
      • Kaithwas G.
      • O’Leary G.H.
      • Genheimer H.
      • Jacobs H.I.L.
      • Van Diest I.
      • Schoenen J.
      • Redgrave J.
      • Fang J.
      • Deuchars J.
      • Széles J.C.
      • Thayer J.F.
      • More K.
      • Vonck K.
      • Steenbergen L.
      • Vianna L.C.
      • McTeague L.M.
      • Ludwig M.
      • Veldhuizen M.G.
      • De Couck M.
      • Casazza M.
      • Keute M.
      • Bikson M.
      • Andreatta M.
      • D’Agostini M.
      • Weymar M.
      • Betts M.
      • Prigge M.
      • Kaess M.
      • Roden M.
      • Thai M.
      • Schuster N.M.
      • Montano N.
      • Hansen N.
      • Kroemer N.B.
      • Rong P.
      • Fischer R.
      • Howland R.H.
      • Sclocco R.
      • Sellaro R.
      • Garcia R.G.
      • Bauer S.
      • Gancheva S.
      • Stavrakis S.
      • Kampusch S.
      • Deuchars S.A.
      • Wehner S.
      • Laborde S.
      • Usichenko T.
      • Polak T.
      • Zaehle T.
      • Borges U.
      • Teckentrup V.
      • Jandackova V.K.
      • Napadow V.
      • Koenig J.
      International consensus based review and recommendations for minimum reporting standards in research on transcutaneous vagus nerve stimulation (Version 2020).
      ). This is even more important as the fields of interest go far beyond headaches in various areas of autonomic research and VNS, thus better understanding possibly can complement each other in the future.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Declaration of competing interest

      Prof. Dr. Straube reports personal fees from Allergan, Bayer, Sanofi, Desitin, Electrocore, Eli Lilly, Teva Pharmaceuticals, and grants from the German Research Council, Kröner-Fresenius Foundation, Ludwig-Maximilian University, Friedrich-Baur Foundation outside the submitted work.
      Dr. Eren reports personal fees from Electrocore, Lilly, Novartis and grants from the Deutsche Migräne- und Kopfschmerzgesellschaft, Eye on Vision Foundation, Friedrich-Baur Foundation outside the submitted work.

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