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HEADACHE: Edited by Peter J. Goadsby

Neuromodulation in primary headaches: current evidence and integration into clinical practice

Rimmele, Florian; Jürgens, Tim P.

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Current Opinion in Neurology: June 2020 - Volume 33 - Issue 3 - p 329-337
doi: 10.1097/WCO.0000000000000820
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Abstract

INTRODUCTION

Neuromodulatory techniques have enlarged our armamentarium for the treatment of primary headaches. However, their role has recently been challenged by new compounds, such as monoclonal antibodies to calcitonin gen-related peptide and its receptor, gepants, and ditans, which have been proven effective in a large number of well designed, adequately powered randomized controlled trials. First reports on the use of neuromodulation techniques date back to Ancient Greece and Rome, where Dioscorides, Galen, and Scribonius Largus used electric eels and rays to treat headaches [1]. With the increasing availability of electricity in the 19th century, external application for headaches regained attention. The first commercially available battery-powered device for transcutaneous electrical nerve stimulation was introduced in 1919. It was not until 1967 neurostimulators were implanted for invasive pain therapy and not before the late 1990s that occipital nerve stimulation (ONS) was used in occipital headaches [2]. Deep brain stimulation (DBS) for the treatment of chronic cluster headache (CCH) was not established until 2001 [3]. Lately, noninvasive approaches have gained popularity over invasive methods. Both approaches targeting peripheral and central targets using either intermittent or continuous stimulation are currently applied in either acute or preventive stimulation (or both) (Fig. 1; Table 1). 

FIGURE 1
FIGURE 1:
Invasive and noninvasive as well as peripheral and central methods of neuromodulation with their active agents. PAG, Periaqueductal gray; RVM, rostral ventral medulla; TMS, transcranial magnetic stimulation; TNC, trigeminal caudal nucleus; TCC, trigeminal cervical complex.
Table 1
Table 1:
Overview of relevant neuromodulating procedures in the treatment of headache and facial pain
Box 1
Box 1:
no caption available

INVASIVE PERIPHERAL TREATMENT METHODS

These include ONS and sphenopalatine ganglion stimulation (SPGS).

Occipital nerve stimulation

Pathophysiological considerations

Peripheral (such as a frequency-dependent modulation of conduction velocity, segmental gating of nociceptive input, modulation of trigemino-cervical connectivity) and central effects (such as modulation of descending inhibitory networks and other parts of the ‘pain matrix’ by activation of ascending second-order neurons) have been discussed (see [4] for further details). Recent studies confirmed modulation of mechanically induced activity of central thalamic neurons (neuronal spike frequency and burst activity) by ONS in a rat model of chronic migraine [5] (Fig. 1). Migraine: A recent meta-analysis from 2018 [6▪] which included the Occipital nerve stimulation for the treatment of intractable chronic migrain headache study by Saper et al.[7] and another study on chronic migraine by Silberstein et al.[8] did not find any significant effects for the endpoints responder rate (reduction of headache days by ≥50%) and headache intensity. However, the reduction of headache days/month and migraine disability assessment scores was more pronounced with active ONS. Owing to a presumably high risk of systematic errors, scientific evidence was judged low. Chen et al.[9] reported similar findings in a metaanalysis from 2015 with significant differences between active ONS and placebo stimulation only for the number of days with prolonged headaches (≥4 h) of moderate to severe intensity. Due to the large number of device related adverse events and high rate of surgical revisions [8] the Conformité Européenne mark for ‘refractory chronic migraine’ was withdrawn by the notified body in 2011. Another system was not certified until 2018 for the indication ‘refractory chronic cluster headache’ in 2018. A prospective long-term open study on chronic migraine with an average follow-up of 9.4 years [10] initially included 37 patients with response to a prior occipital nerve block. Thirty-five responded to external occipital nerve stimulation and received a fully implanted system leading to reduction of pain intensity reduced by 4.9 points out of 10. Five patients were pain-free. Seven patients required explantation of the system. In an open, prospective study from the United Kingdom, 53 patients with refractory chronic migraine and a mean follow-up of 42 months reported a decrease of moderate to severe headache days by 8.51 per month (P < 0.001) [11]. An increasing body of evidence suggests that prior occipital interventions are predictive of therapeutic efficacy, such as occipital nerve blocks [12▪], occipital transcutaneous electrical nerve stimulation [13], and percutaneous electrical field stimulation [14▪].

Cluster headache

So far, no randomized, controlled studies have been published on the efficacy of ONS in cluster headaches. However, countless case series and open studies have been published on the effectiveness of ONS in patients with refractory and chronic progression. A systematic review from 2018 [6▪] based on eight earlier case series [15–22] reported a reduction of attacks frequency of 40–95%, responder rates from 20–92% and pain intensity of 17–60% with an average follow-up of was 18.5 months.

Sphenopalatine ganglion stimulation

Pathophysiological considerations

It remains ambiguous whether SPGS exerts its disruptive effects on the trigemino-parasympathic loop by blocking efferent parasympathic fibers or a rapid depletion of neurotransmitters (Table 1).

Migraine

With the exception of one case series showing acute effectiveness, no further studies have been published for migraine [23].

Cluster headache

Based on numerous studies on interventions targeting the ganglion sphenopalatinum (SPG), a small pilot study (n = 5) using SPG stimulation reduced the pain effectively (≥50%) in 14 of 18 treated attacks (78%) [24]. This led to the development of an implantable microstimulator for intermittent stimulation. In a first multicenter study (pathway cluster headache-1) conducted in Europe in patients with refractory CCH (n = 32) active, subthreshold (below perception threshold) and sham stimulation [25]) led to a statistically significant reduction of pain using active stimulation (67.1%) compared with the control conditions (7.4 and 7.3%, P < 0.001). Furthermore, a significant reduction of attack frequency was also found. A long-term follow-up study showed sustained acute and preventive effects [26]. The pathway cluster headache-2 study in the United States (n = 93) revealed a relevant reduction in pain within 15 min in 62.46% of attacks over 992 attacks using active stimulation compared with an active control (P = 0.008) using transcutaneous electrical stimulation. Similarly, the weekly attack frequency was reduced by 2.9 (P = 0.03) [27▪▪] with active stimulation illustrating both acute and preventive therapeutic effects. Side-effects were transient, light to moderate, and related to implantation (trigeminal sensory disorders, postoperative pain, and swelling) in 73% of patients. As of April 19th, 2019, Autonomic Technologies, Inc. had stopped business and discontinued distribution and technical support. At present, there is no system available for SPGS.

INVASIVE CENTRAL TREATMENT METHODS

Deep brain stimulation of the posterior hypothalamus is the only established approach for primary headaches.

Deep brain stimulation of the posterior hypothalamus

Pathophysiological considerations

The posterior hypothalamus has been found to play a pivotal role in the pathophysiology of cluster headache in clinical and hormonal studies as well as structural and functional imaging studies [28]. Imaging studies point to a functional modulation of pain processing networks [28]. Neurophysiological data studies did not reveal short-term changes of DBS, but lateralized neuroplastic changes after long-term stimulation [29] (Fig. 1).

Cluster headache

The first successful implantation in a medication-refractory patient dates back to 2001 [1,3]. The target coordinates lie between the posterior hypothalamus and the midbrain tegmentum. In the open phase of the only randomized, controlled study therapeutic effects were detectable in the experimental phase [30]. However, case series and prospective, open studies have reported effectiveness [31–33]. Although DBS is well tolerated by most patients over the course of years, it is associated with potentially serious side-effects because of its invasive nature [34], such as intracerebral hemorrhage, loss of consciousness, diplopia, and infections.

NONINVASIVE PERIPHERAL TREATMENT METHODS

These include trigeminal, vagal, and extracranial targets.

Stimulation of the supraorbital and supratrochlear nerve

Pathophysiological considerations

Peripheral and central effects are discussed with special emphasis on the role of the trigemino-cervical complex and modulatory effects on the descending inhibitory systems [35]. Recent imaging studies suggest a relevant modulation of the anterior cingulate cortex [36] (Table 1).

Migraine

In the tricentric ACME study [37▪▪] (n = 109) a significant absolute and relative reduction in pain intensity was found within 60 min (−59%) in the active compared with sham stimulation (−30%) (P < 0.001). The corresponding 50% responder rate was 63 versus 31% (P < 0.01). There were no serious side-effects and no device-related side-effects.

In 2013, transcutaneous stimulation of supraorbital and supratrochlear nerve (tSNS) had already shown efficacy in episodic migraine in the multicenter PREvention of MIgraine using the supraorbital transcutaneous stimulator CEfaly study (PREMICE study) [38] (n = 67; 20 min daily for 3 months). The number of headache days per month, decreased from 6.94 by 2.06 (P = 0.0023) with active, but only by 0.32 from 6.54 with sham stimulation (P = 0.608). However, comparing both groups statistical significance was missed by a narrow margin (P = 0.054). The 50% responder rate was 38 versus 12% (P = 0.014).

Cluster headache

In the absence of controlled trials, only a small case series suggests effectiveness in cluster headache [39].

Transcutaneous vagal nerve stimulation

Pathophysiological considerations

Stimulation of cervical and auricular vagal branches is thought to modulate the trigemino-cervical complex relayed by vagal nuclei. A recent functional MRI study has revealed a complex central regulatory network modulated by cervical transcutaneous vagus nerve stimulation (tVNS) in humans. tVNS caused increased activity in the left pons nucleus and a reduced activity in the right parahippocampal gyrus. Furthermore, it led to a loss in functional connectivity between both spinal trigeminal nuclei and the right parahippocampal gyrus and a gain in functional connectivity between the left pons and the right hypothalamus [40▪▪] (Fig. 1).

Migraine

Acute treatment

The multicenter PRESTO study [41▪▪] (bilateral stimulation for 120 s) in episodic migraine (n = 248) failed to showed significant differences for the primary endpoint (pain freedom at 120 min) with 30.4% for active versus 19.7% for sham stimulation (P = 0.067), unlike pain freedom at 30 and 60 min (12.7 versus 4.2%, P = 0.012; 21.0 versus 10.0%, P = 0.023). Fifty percent responder rates for pain reduction and freedom of pain 120 min after stimulation were significantly higher in the verum group (32.4 versus 18.2%, P = 0.02, and 47.6 versus 32.3%, P = 0.026).

Migraine

Preventive treatment

The multicenter EVENT study [42] in chronic migraine (n = 59) showed that active or sham stimulation over two months did not change the number of headache days/month from baseline to month 2 (−1.4, P = 0.44; −0.2; P = 0.72). Only an analysis of responders yielded significant results with the inherent risk of a selection bias due study dropouts (n = 11) in the experimental phase. The side-effects were mainly transient and minor to moderate, the most frequent were pain and paresthesia in the face, gastrointestinal symptoms, and pharyngitis. The multicenter PREMIUM study [43▪] in episodic migraines with and without aura (n = 447) using active stimulation or active placebo on both sides of the neck for 120 s three times a day over a course of 12 weeks yielded no significant differences for the primary endpoint (reduction of migraine days per month) (2.26 versus 1.80, P = 0.15). The device-related side-effects were mild and transient [43▪].

Auricular tVNS [44] in chronic migraine (n = 46) revealed surprisingly that presumably active stimulation (25 Hz for 4 h/day in the external ear canal) was inferior to the putative sham condition (1 Hz) (−6.9 versus −3.3 days; P = 0.035). The rate of side-effects was considerably higher in the 25 Hz group (71 versus 50%). The most side-effects rated mild to moderate included slight localized pain, paraesthesia, pruritus, and cutaneous ulcerations.

Cluster headache

Acute treatment

In the multicenter Acute cluster headache treatment study (ACT1) study [45], 38 patients with episodic cluster headache (ECH) and 22 with CCH received 3 × 120 min of active cervical stimulation (25 Hz) and 47 with ECH and 26 with CCH sham stimulation (0.1 Hz). The primary endpoint (relevant improvement within 15 min) did not differ between both groups (26.7 versus 15.1%, P = 0.1). A subgroup analysis revealed significant effects for ECH (34.2 versus 10.6%; P = 0.008) whereas no significant changes were found for those with CCH (13.6 versus 23.1%; P = 0.48). Forty-eight percent of the study participants had at least one side-effect (mostly localized irritation of the stimulation site, skin irritation, dysgeusia).

In the ACT2 study, 48 patients were treated with active stimulation (14 ECH, 34 CCH) and 44 with placebo stimulation (13 ECH and 31 CCH) [46▪]. As in the ACT1 study, the primary endpoint (no pain within 15 min) was not achieved (13.5 versus 11.5%; P = 0.71). Similarly, significant differences were found in ECH only (48 versus 6%; P < 0.01).

Preventive treatment

In the open, randomized, and prospective PREVenti study stimulation (3 × 120 s/day at 25 Hz) and stable SOC (mostly verapamil) in CCH (n = 48) was more effective than SOC (n = 48) each over a period of four weeks [47] in reducing the average number of cluster attacks per week (−5.9 versus −2.1, P = 0.02). The rate of adverse events did not differ (52 or 49%) and included dizziness, headaches, nasopharyngitis, oropharyngeal, and neck pain.

Remote electrical neurostimulation

Pathophysiological considerations

REN is thought to convey its effects by conditioned pain modulation via activation of descending inhibition pathways (Fig. 1).

Migraine

Acute treatment

In a crossover pilot study, 71 patients were included treating 299 attacks with stimulation REN at the upper arm starting within 20 min after onset of an attack for 20 min with varying pulse widths (100, 150, and 200 μs). Sixty-four percent of participants reported a reduction of pain of at least 50% with active stimulation compared with 26% (P = 0.005) using sham stimulation [48▪]. Earlier stimulation yielded better outcomes. In a confirmatory multicenter study (n = 202) active stimulation applied to the upper arm for 30–45 min within 1 h after attack onset [49▪▪] led to pain relief within 2 h in 66.7 versus 38.8% using active sham stimulation (P < 0.0001). Tolerability did not differ between both groups (P = 0.499).

NONINVASIVE CENTRAL TREATMENT METHODS

Recent systematic reviews and metaanalyses suggest favorable effects of transcranial magnetic stimulation over transcranial direct current stimulation (tDCS) regarding various endpoints (such as headache frequency, duration, and intensity) [50▪] with excitatory stimulation of the primary motor cortex (M1) considered most effective [51▪]. However, high-quality studies using standardized protocols are lacking.

Pathophysiological considerations

Transcranial magnetic stimulation and tDCS convey their effects by activation of a top-down cascade directly involving parts of the ‘pain matrix’ and other higher order structures such as M1 which modulate downstream targets involved in headache pathophysiology (Fig. 1).

Transcranial magnetic stimulation

Migraine

Acute treatment

Migraine patients experiencing a visual aura during 30% of their attacks followed by moderate-to-severe headaches in at least 90% received two occipital single pulses within 1 h after aura onset [52]. After 2 h, 39% from the verum group reported pain freedom compared with 22% from the sham group (P = 0.0179). Side-effects included sinusitis and paraesthesia.

Preventive treatment with single pulses

In the multicenter, prospective, open ESPOUSE study [53], repeat single pulses in migraines without and without aura (n = 132) reduced headache days significantly (−2.75 days) in week 9–12 which was statistically significant (P < 0.001) compared with a ‘statistical placebo’ (two randomized, controlled clinical trials with topiramate for migraines, and the PREMICE).

Preventive treatment with repetitive transcranial magnetic stimulation

Trials on rTMS efficacy [54–57] and metaanalyses [50▪,58,59] yielded heterogeneous results attributable to different stimulation paradigms, including target region, stimulation frequency, and intensity. As there is no portable rTMS device, its use in a routine clinical setting remains difficult.

Cluster headache

Apart from a ‘naturalistic’ study [60] (n = 19) with 10–20 min treatments for two weeks with a significant reduction of attack frequency solid evidence is missing.

Transcranial direct current stimulation

Migraine

A metaanalysis from 2016 did not find any significant effects for the endpoints pain intensity, migraine attacks, use of painkillers, and side-effects [58]. In a double-blind study [61] on refractory chronic migraine (n = 13), active stimulation (three times a week for four weeks) over M1 or the dorsolateral prefrontal cortex (DLPFC) at 2 mA for 20 min significantly lower HIT-6 scores after DLPFC stimulation were found compared with M1 and sham stimulation. Small group sizes were problematic (n = 3–6). Occipital cathodic tDCS in menstrual migraine (n = 16) for 20 min with 2 mA on each of the five days leading to expected menstruation [62] did not reduce the number of attacks compared with sham stimulation. The most frequent side-effect was paresthesia. Again, sample size was low.

Cluster headache

Only uncontrolled data [63▪] on refractory CCH (n = 31) are available showing that active tDCS for 20 min over the anterior cingular cortex at 2 mA on a daily basis for four to eight weeks leads to a decrease in attack frequency of 35% (P < 0.001).

INTEGRATION INTO ESTABLISHED TREATMENT ALGORITHMS

Based on the regulatory limitations (Table 2) and the evidence shown above (Table 3), it is difficult to integrate neuromodulatory approaches into established treatment algorithms for migraine and cluster headache.

Table 2
Table 2:
Currently available neuromodulatory systems which have been tested in published randomized controlled trials with CE mark and/or FDA clearance
Table 3
Table 3:
Effectiveness of the individual neuromodulating methods in the acute and preventive treatment of migraines and cluster headache

NONINVASIVE METHODS

Migraine

With limited positive data suggesting acute efficacy in acute treatment for tVNS, preventive use in chronic migraine was disappointing [42]. Acute tSNS is supported by a positive study, whereas the trial on preventive effects did not formally meet its endpoint. Single-pulse TMS has shown acute efficacy in migraine with aura only. No clear recommendations can be given for the other approaches. In the absence of comparative studies and the limited evidence of combined use with conventional pharmaceuticals [64▪], the role noninvasive neuromodulation in current algorithms is unclear and should be based upon the patients’ preference. They may be considered in case of contraindications, failure of conventional pharmaceuticals, polypharmacy, and pregnancy or breastfeeding.

Recent studies raise doubt on stimulating pathophysiologically relevant cranial structures only, as demonstrated by REN [48▪,65], which is more feasible for longer stimulation in daily life.

Cluster headache

tVNS has shown efficacy in acute treatment of ECH [45,46▪] and preventive treatments in addition to standard treatment in CCH [47]. There is insufficient evidence for the remaining procedures. tVNS should especially be considered in cases of contraindications to or overuse of triptans.

INVASIVE METHODS

Migraine

In the absence of an approved method and ambiguous data from controlled trials, ONS seems acceptable only in highly refractory cases. Beforehand, noninvasive neuromodulation, minimally invasive procedures (occipital nerve blocks), monoclonal antibodies, and multimodal treatment approaches [66] should have been tried and failed.

Cluster headache

With a Conformité Européenne-marked system available, ONS is the method of choice in CCH if tVNS and occipital nerve blocks have failed. Data on the monoclonal antibodies fremanezumab and galcanezumab are positive only for galcanezumab in ECH with approved by the FDA [67–69]. Following the manufacturer's insolvency, SPGS is currently unavailable.

CONCEPTIONAL CONSIDERATIONS

One major shortcoming is the limited number of well-designed and adequately powered trials. Effective blinding is difficult in peripheral approaches given the induction of paresthesia in the receptive field. Alleged ‘active placebo’ paradigms have been used successfully in some trials [27▪▪] but emerged as equally or even more effective than the putative ‘active stimulation’ in others [44,70▪▪]. Thus, additional inactive placebo conditions or more preceding research is necessary.

The manufacturer's closure of business had profound reverberations for patients with SPGS. This illustrates the need for compulsory backup plans (including repositories for essential technical equipment) for any implanted device in the future.

CONCLUSION

Neuromodulation is a helpful addition with noninvasive procedures being used increasingly. The integration into established treatment algorithms is difficult. The limited number of sufficiently powered randomized controlled trials and the lack of head-to-head studies with conventional preventives remain relevant methodological limitations.

Acknowledgements

None.

Financial support and sponsorship

None.

Conflicts of interest

F.R. has received honoraria from Novartis and Pharm Allergan. T.P.J. has received honoraria from Hormosan Pharma, Lilly, Novartis, Teva, Pharm Allergan, Autonomic Technologies and Sanofi (to TPJ).

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

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Keywords:

cluster headache; migraine; occipital nerve stimulation; supraorbital nerve stimulation; transcranial magnetic stimulation; vagus nerve stimulation

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