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Noninvasive Neuromodulation in Headache: An Update
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.315998
Keywords: Auricular vagus nerve, migraine, neuromodulation, remote electrical stimulation, supraorbital nerve stimulation, transcranial direct current stimulation, Transcranial magnetic stimulation, vagus nerve stimulation
Migraine and other primary headaches are extremely common neurological conditions, causing significant disability and economic burden worldwide. It is estimated that 47% of the adult population globally has an active headache, whereas 3% is estimated to suffer with a chronic headache that lasts for more than 15 days per month.[1],[2] Migraine is the second most disabling condition worldwide, affecting 17% of women and 6% of men, whereas 2.5%–3% of sufferers transit to chronic migraine (CM) within a year. The annual amount of direct costs spent in the United States for migraine in healthcare has reached 1 billion dollars per year. However, indirect costs related to productivity and earnings loss are by far more significant.[2],[3],[4] On the contrary, cluster headache (CH) is a rarer primary headache condition, but severely painful and disabling affecting up to 0.1% of the population, with a higher prevalence in males and significant psychosocial impact on patients life.[5],[6],[7] The biology of headache disorders is complicated and evolving at different ages.[8],[9] Preclinical and clinical studies suggest an involvement of both peripheral and central mechanisms.[5],[10],[11],[12],[13],[14] Peripherally, activation of the trigeminal nerve is believed to be pivotal for the development of the pain symptoms during a headache attack.[11] The trigeminal nerve is the sensory nerve that supplies facial and intracranial structures with nociceptors. Trigeminal fiber innervations of the dural matter and blood vessels, which form the trigeminovascular system, are considered of significant importance. Some of the effective preventive treatments of migraine are thought to act on the peripheral trigeminovascular system, including botulinum toxin type A,[15] monoclonal anti-calcitonin gene peptide (CGRP) system antibodies, and CGRP antagonists.[16],[17],[18] Centrally, the trigeminal fibers project to second-order neurons in the trigeminocervical complex (TCC), which in turn give rise to the ascending trigeminothalamic pathway, with the majority of the projections being in the ventroposteromedial thalamic nucleus.[19],[20],[21] Both the TCC and the thalamus are important relay areas and targets of current and future therapeutics.[22],[23],[24],[25] In migraine pathophysiology, hypothalamic functional alterations that occur prior to the onset of headache are now considered pivotal for the initiation of an attack.[26],[27] It is unknown which hypothalamic connections and neurotransmitters initiate a migraine attack.[10] The hypothalamus, mainly its posterior part, also appears to be of pivotal interest in the biology of CH.[28],[29],[30] Hypothalamic deep brain stimulation in CH patients was one of the first neuromodulation therapies used in the field of headaches.[31] Another brain area that appears to be of significant importance in migraine biology is the cortex, primarily the occipital area. Functional changes in cortical activity have been shown, along with hypothalamic changes, during the premonitory phase of migraine,[27] whereas connectivity studies suggest impaired functional connectivity between the cortex and the thalamus in migraine patients.[32] The occipital cortex is also involved in the development of migraine aura-transient neurological symptoms that occur in about 30% of migraine patients and usually precede the migraine headache.[33] The biology of migraine aura is believed to be cortical spreading depression, which is a cortical neurovascular event initiated at the occipital cortex.[34] Although various drug treatments and injectables are currently available for treating various headache disorders, they are often accompanied by side effects, insufficient efficacy, and intolerance. A great majority of patients report compliance issues with oral preventive treatments.[35],[36] On the contrary, excessive use of oral abortive medications is known to lead to medication overuse headache (MOH), a common diagnosis in patients with CM.[37],[38] A proportion of patients with CM do not respond/tolerate treatments and have been variously defined as treatment-resistant and refractory migraine.[39] This subgroup of headache patients is generally highly disabled and experience significantly impaired quality of life.[39] Neuromodulation has emerged as an alternative to pharmacological treatments in primary headaches. Invasive modalities are usually offered for medically refractory patients.[40] Noninvasive modalities may be used earlier in the patients' treatment pathway as an alternative or add-on to pharmacological therapies. Compared to medicines, noninvasive neuromodulation devices have theoretically more specific mechanisms of action, better tolerability profile due to the lack of systemic side effects and drug interactions. Barriers to the wider use of these therapies have historically been the lack of robust evidence, largely dictated by the difficulty in producing a reliable sham in clinical trials and the high costs of the devices, which have discouraged some health authorities to cover the cost of these therapies, thereby limiting their wider use. In this paper, we aimed to critically review the evidence so far published for noninvasive neuromodulation treatments in primary headache with a focus on migraine. Central Nervous System acting noninvasive neuromodulation treatments Single-pulse transcranial magnetic stimulation TMS directly stimulates the brain using a copper electromagnetic coil to generate a magnetic pulse. The magnetic pulse passes unimpeded through the nonconductive scalp and skull but produces an electrical current in the electrically conductive neural tissue of the underlying cortex via electromagnetic induction. The current induced by the magnetic pulse is perpendicular to the coil surface due to magnetic flux, at a maximum on the cortical surface and directly proportional to the current passed through the coil. Direct stimulation of the TMS is highly localized to the cortex, as the magnetically induced electrical current rapidly dissipates from the electromagnetic coil, with the greatest current intensity within 1–2 cm of the coil.[41] Thus, the shape of the coil alters the effect of the stimulation. Circular coils have high penetration but limited focal point whereas the overlap between the two coils in a figure-of-eight coil produces a larger peak of induced fields allowing more precise stimulation.[42] Early TMS devices could only produce single-pulse TMS (sTMS) or pairs of TMS pulses (ppTMS) requiring time to recharge the capacitors. However, subsequent improvements lead to the development of repeated pulse TMS (rTMS). This protocol fires trains of hundreds or thousands of pulses across the scalp to produce long-lasting effects in the activated neuronal tissue by neuronal plasticity. Low-frequency (LF) rTMS firing (<1 Hz) has been shown to inhibit cortical activity, whereas high-frequency (HF) firing (>1 Hz) produces facilitation of cortical activity. The studies of rTMS in migraine prevention reported conflicting outcomes.[43] The first hand-held, self-treatment TMS option for migraine was designed to produce a single-pulse the Spring single-pulse TMS device (sTMS) [Figure 1]. The spring TMS is a small (22.4 cm x 13 cm x 6.9 cm), portable (1.4 kg) device capable of outputting a 0.9 T magnetic pulse (1 cm from the surface of the device) from two circular copper coils, inducing a current of approximately 4 mA/cm2. The device can be used as an acute treatment ad libitum, or as a prophylactic treatment starting at two sequential pulses bis in die titrated to a maximum of eight sequential pulses ter in die.
Biological rationale and mechanism of action The rationale for stimulating the occipital cortex, rather than the pre-frontal or somatosensory cortices as with rTMS, is due to its presumed role in migraine pathophysiology. During the pre-ictal and ictal phases, altered cortical activity has been observed particularly in the occipital cortex.[44],[45] In addition, the visual nature of the majority (~90%) of migraine aura suggests an origin for the spread of cortical spreading depolarization (CSD) from the occipital cortex.[46] In general, the cortical response to TMS is dependent on the strength of the pulse applied. Single-pulse TMS (sTMS) applied below the motor endpoint potential (MEP) to cortex caused facilitation of neuronal activity for ~500 ms followed by inhibition for several seconds. Stronger sTMS stimuli (>50%) caused an initial inhibition of neuronal activation for ~100–200 ms, followed by rebound facilitation.[47] sTMS-induced transient facilitation followed by inhibition was suggested to be caused by direct stimulation of excitatory axons which excite inhibitory neurons leading to a rebound inhibition via metabotropic gamma-aminobutyric acid (GABA) receptors.[48] In rodents, sTMS activated inhibitory GABAB fibers in the upper cortical layers which in turn inhibit activity of dendritic pyramidal neurons in layer V. Blocking GABAB receptors was shown to prevent the inhibitory effects of sTMS on the somatosensory cortex.[49] Specifically, in studies where the same stimulating sTMS parameters were used in migraine rodent models, sTMS was shown to block mechanically and chemically induced CSD and increase the threshold of activation of electrically induced CSD, as well as, inhibit glutamate-induced cortical neuronal activity.[50],[51] Both cortical actions were subsequently blocked via pre-application of GABA antagonists suggesting that sTMS enhances inhibitory GABAergic activity, rather than directly suppressing excitatory glutamatergic neurons.[52] Several studies have also suggested that cortical TMS indirectly modulates the thalamus and hypothalamus.[53] In migraine models, sTMS has been shown to block both spontaneous and C-fiber activity of third-order neurons in the VPM thalamic nucleus, potentially by interacting with corticothalamic circuits.[50] Clinical data In 2010, Lipton et al. carried out a randomized, double-blind, parallel-group, two-phase, sham-controlled, multi-center study. Eighty-two migraine with aura (MA) patients treated at least one migraine attack with sTMS were compared against 82 MA patients treated with sham stimulation. Pain freedom at 2 h after treatment showed a 17% therapeutic gain in the sTMS versus the sham treatment. This appeared to be a sustained effect with a greater proportion of the sTMS group remaining pain-free 24- and 48-h post-treatment. There were no reported serious adverse events, whereas minor side effects included headache, migraine, sinusitis, and paraesthesia, and were not significantly different between the two treatment groups.[54] Several post-marketing studies have also looked at sTMS as a prophylactic treatment for migraine. Data from a 3-month UK post-market pilot program showed pain relief in 62% of 190 patients (both migraine with and without aura (MO)). Headache days per month were improved in both episodic (EM) and patients with CM, in addition to reduced attack duration, sTMS showed efficacy in relieving associated migraine symptoms, and a reduction in disability.[55] Subsequently, the eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE), a multi-center, prospective, open-label, observational study, involved 217 patients who used the sTMS device daily for 3 months. Overall, a significant reduction in headache days was seen (–2.75 ± 0.40 from a baseline of 9.06 days), and 46% of patients achieved at least a 50% response rate. There was also a reduction in acute medication use and HIT-6 disability scores.[56] sTMS' efficacy as a preventative treatment has also been studied specifically in adolescents (12–17 years old), in an open-label pilot. Twelve patients completed the trial, with a further nine failing to complete the study (the most common reason for not completing was not returning or completing the baseline headache diary). Patients gave 4x 0.9T pulses twice a day (two pairs of two pulses separated by 15 min intervals) for 12 weeks, with further pulses available for acute treatment. Use of the device was reported as feasible and tolerable. There was also a significant reduction in headache days per month (–4.5 ± 1.7 days) and MIDAS score (–36 ± 14).[57] A smaller study from Canada tested paired-pulse sTMS on 42 migraine patients (both MA and MO) as soon after the start of an attack as possible. After one round of two paired pulses of either high stimulation (50% of the maximum output) or low stimulation (30% maximum output) (using a Caldwell stimulator, max output; 2.3 T, 187 V) 69% of patients showed an improvement, 87% improvement after 2 rounds and 82% after 3 rounds, suggesting a cumulative effect of sTMS. They also suggested a larger effect in MA patients as 100% (10/42) reported immediate pain relief. Finally, they suggested an autonomic effect, with heart rates dropping from 79.05 ± 10.27 to 72.89 ± 11.35 beats/min. However, this study was not well controlled and lacked power. The common adverse events reported included; light-headedness (3.7%), tingling (3.2%), and tinnitus (3.2%).[58] Peripheral Nervous System acting noninvasive neuromodulation treatments Transcranial direct current stimulation Transcranial direct current stimulation (tDCS) is a noninvasive, nonpainful brain stimulation procedure, in which weak direct current (0.1–2 mA) is applied through the skull over cortical areas for 10–30 min. tDCS has been shown effective in neuropsychiatric and neurological conditions such as major depression, as well as, in enhancing learning and memory formation.[59],[60],[61],[62],[63],[64] TDCS can only be applied in a hospital setting and uses stimulation from a positive (anode) and negative (cathode) electrode placed over a target area to manipulate the membrane potential of neurons in the cortex. Anodal stimulation depolarizes the neurons causing cortical excitation, whereas cathodal stimulation hyperpolarizes the neurons decreasing excitation in the cortex.[65] Biological rationale and mechanism of action Similar to the use of TMS, tDCS has been used in migraine treatment due to increasing data supporting cortical altered functionality in patients during and between attacks.[66],[67],[68],[69],[70] Previous work showed that tDCS applied over the motor cortex of human subjects increases the excitability of the motor cortex in a glutamate-dependent manner.[71] Application of direct current over mouse motor cortical slice has shown that DCS enhances synaptic response that depends on the N-methyl-D-aspartate receptor (NMDAR) and brain-derived neurotrophic factor.[72] A more recent important study looking at the molecular actions of tDCS suggested that tDCS-induced plasticity is mediated through astrocytic Ca2+/IP3 signaling.[73] Unfortunately, headache-specific mechanistic studies of tDCS have not been performed and the detailed potential mechanisms of action for tDCS in migraine remain largely unknown. Clinical data tDCS has been shown to modulate activity in the motor and visual cortices in both animal and human models and has prolonged effects.[74],[75],[76] Several studies have investigated tDCS as a prophylactic treatment for migraine. A pilot study treated 10 patients with MO three times a week for 8 weeks, applying anodal tDCS to the visual cortex. A decrease in migraine attack frequency and duration (but not intensity) was seen following tDCS treatment compared to baseline, as well as a decrease in analgesic intake.[77] An randomized control trial (RCT) by Antal et al. applied cathodal stimulation to the visual cortex of 26 patients three times a week for 6 weeks. They showed no change in the frequency of migraine attacks with tDCS treatment compared with the control group, although the duration of attacks and the intensity and number of migraine days were reduced.[78] A similar second RCT treated 10 migraine patients three times a week for 4 weeks. A significant reduction in the number and duration of attacks (but not the intensity) as well as the analgesic intake was seen when compared to the baseline. However, when compared with the control group no differences were seen in the number, duration, or intensity of migraine attacks.[79] Similarly, a recent double-blind randomized study showed no efficacy of tDCS in patients with CM with medication overuse.[80] A recent single-blind, randomized sham-controlled study in EM utilized self-administered anodal tDCS over the visual cortex and showed significant a decrease in the number of monthly migraine days, but not in total headache days or anxiety and depression scores.[81] A study by Rocha et al. also showed nonsignificant outcomes with tDCS when compared against a control group.[79] Thus, the evidence regarding the role of tDCS in migraine is uncertain. tDCS needs to be largely delivered in a hospital setting which further limits its wider adoption in the general clinical practice. Transcutaneous Vagus nerve stimulation Vagus nerve stimulation (VNS) refers to any technique that stimulates invasively or noninvasively the vagus nerve. Over the years it has been used as a treatment in a variety of disorders, including epilepsy, resistant depression, and heart failure. Gammacore [Figure 2] is the main noninvasive transcutaneous vagus nerve stimulator (tVNS) available for the treatment of headache disorders. The small, portable device applies two electrodes to the neck and transcutaneously stimulates the vagus nerve with a 1 ms burst of five kHz sine wave (24 V peak, 60 mA) stimulation repeated at 25 Hz for 90 s.
Biological rationale and mechanism of action The vagus nerve provides parasympathetic innervation to the autonomic nervous system, involved in a variety of autonomic functions including the respiratory, cardiovascular, and nociceptive systems. This stimulation is thought to activate low-threshold myelinated A-fibers, producing an antinociceptive effect on the second-order neurons of the spinothalamic and spino-reticular tracts within the TCC. nVNS in animals has been shown to be able to modulate trigeminal activity, inhibiting the response of TCC neurons to trigeminal stimulation in 48% of neurons, and facilitating activity in 29.5% of neurons and shown to be superior to sham at providing pain freedom up to 60 min post-stimulation and therapeutic benefit up to 120 min.[82] Stimulation of the vagus nerve has also been shown to inhibit cortical spreading depression and it may substantially shorten visual aura.[83],[84] Clinical data in migraine nVNS has been tested for the acute and preventive treatment of migraine. Open-label studies suggested that nVNS could be a beneficial abortive migraine treatment. A study conducted in 48 patients who treated a total of 131 mild-to-moderate migraine attacks showed a pain-relief rate of 38.2% at 1 h and 51.1% at 2 h, whereas the pain-free rate was 17.6% at 1 h and 22.9% at 2 h.[85] When the effect of nVNS was assessed in moderate to severe migraine attacks, the pain-free rate at 2 h was 21% for the first treated attack and the pain-free rate for all moderate or severe attacks was 22%.[86] When studied in a multicenter, randomized, double-blind, parallel-group, sham-controlled study of 243 migraine patients (PRESTO trial), nVNS treatment did not meet the primary endpoint of pain-freedom at 2 h of the first treated attack (30.4% of patients from the verum group versus 19.7% of the sham group, P = 0.067). This is of little surprise given the low percentage of pain freedom in the two open-label studies. The verum group achieved positive but inconsistent results in some of the secondary endpoints including pain relief at 2 h, but not at 30 or 60 min post-nVNS treatment.[87] Gammacore was also evaluated as a migraine preventative treatment in a multicenter, double-blind, sham-controlled pilot study in 59 patients with CM (the EVENT study). Again the primary endpoint of the trial was not met at the end of the double-blind phase: the mean reduction in the number of headache days was at month 2 was –1.4 (nVNS) vs. –0.2 (sham) (Δ = 1.2; P = 0.56).[88] Subsequently, a larger multicenter randomized double-blind trial conducted in 322 EM patients confirmed the poor efficacy of the device in migraine prevention (the PREMIUM trial). At 12 weeks the mean reductions in migraine days per month (primary outcome) were 2.26 for nVNS and 1.80 for sham (P = 0.15). The trial also highlighted issues with suboptimal adherence to treatment and poor sham, which may have biased the results of the study.[89] Real-world experience in a small group of patients has confirmed the lack of efficacy for nVNS as a preventative treatment also in refractory patients with CM.[90] Clinical data in trigeminal autonomic cephalalgias Gammacore is the only noninvasive neuromodulation treatment with published evidence in the trigeminal autonomic cephalalgias (TACs) group. Two randomized double-blind sham-controlled trials (ACT1 and ACT2 studies) were conducted to evaluate the efficacy of nVNS using Gammacore device in CH. The primary endpoint of ACT1 was the response rate, defined as the proportion of subjects who achieved pain relief (pain intensity of 0 or 1) at 15 min after treatment initiation for the first CH attack without rescue medication use through 60 min. Unfortunately, the study did not meet the primary endpoint. Indeed, a response was achieved in 26.7% of nVNS-treated subjects vs. 15.1% of sham-treated subjects (P = 0.1).[91] ACT2 was a smaller study compared to the ACT1 but with a similar design. The primary efficacy endpoint was the proportion of all treated attacks that achieved pain-free status within 15 min after treatment initiation, without rescue treatment. Unfortunately, even in this trial, nVNS (14%) was not superior compared to sham (12%) treatment in the total cohort.[92] In both trials, nVNS was superior to sham in the episodic CH (ECH) group compared, to chronic CH (CCH) group. Given that the current pathophysiological hypotheses for CH suggest that the two subtypes of CH follow the same biology, these results are difficult to explain. It is possible that the vagus nerve pathway plays a minor role in the pathophysiology of CCH. When evaluated as a prophylactic treatment in an open-label small study in CCH, nVNS plus standard of care (SoC) was superior of SoC alone at least for short-term prevention (40% vs. 8.3% responders).[93] Sham-controlled and long-term data would be needed before suggesting Gammacore for prevention of CH. Independent real-world prospective evidence coming from a single headache center in the United Kingdom (UK) suggests the poor effectiveness of nVNS in the difficult-to-treat CCH population, with only one patient out of 12, responding for up to a year to Gammacore therapy.[90] A subsequent company-funded retrospective audit conducted in three headache services in the UK, found opposite results. Indeed, all of the 30 patients analyzed, reported a significant reduction in weekly attacks at 3–6 months follow-up.[94] Interestingly, the greater occipital nerve block (GONB), which is the preventive treatment that has amongst the best evidence of efficacy and tolerability in ECH and CCH, were not tried before using nVNS.[95],[96],[97] A retrospective audit conducted in nine hemicrania continua (HC) and six paroxysmal hemicrania (PH) patients suggested a possible role of Gammacore in their management. In this audit, seven HC patients reported reduced severity of continuous head pain and two patients reported a reduced frequency of headache exacerbations. Among patients with PH, four reported receiving benefits from treatment.[98] Subsequently, eight chronic PH patients who could not tolerate indomethacin, were treated with nVNS. A favorable response, defined as a more than 50% reduction in monthly headache frequency, was observed in 75% of patients at the final follow-up.[99] These, along with other real-world data in HC,[90] support a potential role of n VNS in the preventive treatment of indomethacin responsive headaches. Transcutaneous auricular vagus nerve stimulation A recently developed medical device (VITOS®, VNS Technologies GmbH, Germany) allows for noninvasive, transcutaneous stimulation of the auricular branch of the vagus nerve (auricular t-VNS) using a special ear electrode [Figure 3]. This device may modulate cranial nociceptive signaling, by excitation of myelinated sensory Aβ-fiber afferents in the vagal nerve, activating the nucleus of the solitary tract.[100] The VITOS® device has received the CE mark for treatment of pain (CE0408).
The VITOS device was evaluated in CM in a single-center, prospective, double-blind, randomized, parallel-group, controlled trial. The study consisted of a 4-week screening period (”baseline”) followed by a 12-week randomized, double-blind, parallel-group treatment period with either 1 Hz or 25 Hz tVNS with the VITOS® device. The stimulation parameters were set as pulse width: 250 μs, frequency: 1 Hz or 25 Hz, duty cycle: 30s on, 30 s off. The primary outcome measure was mean change in headache days per 28-day period. The study showed a significant decrease in headache days per 28 days from baseline to evaluation, which was significantly larger in the 1 Hz group than in the 25 Hz group. In the 1 Hz group, the reduction amounted to minus seven days per 28 days (36.4% reduction from baseline), whereas the 25 Hz group reached only − 3.3 days (17.4% reduction from baseline). The number of responders (>50% improvement in headache days) was 29.4% in the 1 Hz group and 13.6% in the 25 Hz group. The number of days with the intake of acute headache medication as well as the MIDAS and HIT-6 scores were significantly reduced in both treatment groups, without any between-group differences. The most frequent treatment-related adverse events were local problems at the stimulation site, such as mild or moderate pain, paresthesia, or pruritus during or after stimulation, and erythema, ulcer, or scab. Treatment-related adverse events leading to discontinuation of the study were stimulation site ulcer (accompanied by pain, paresthesia, or pruritus) in two patients of the 1 Hz group and in on patient of the 25 Hz group.[101] The study findings suggest that auricular t-VNS at 1 Hz for 4 h daily may be effective for CM prevention over a short period of time. The absolute reduction in headache days (7.0) and the difference between groups (2.7 headache days) is comparable to the effects of other licensed CM treatments, such as topiramate and onabotulinum toxin A. The t-VNS treatment also results in a meaningful improvement in the quality of life as assessed by MIDAS and HIT 6. The safety profile was favorable and compliance with daily stimulation was high. In view of this promising initial data, this neuromodulation modality should be explored in future studies. Transcutaneous supraorbital nerve stimulation Cefaly (CEFALY® Technology, Belgium) is a device designed to stimulate the supraorbital and supratrochlear branches of the ophthalmic division of the trigeminal nerve transcutaneously. The Cefaly® headband is applied over the adhesive electrode for transcutaneous transmission of electrical impulses over the forehead bilaterally [Figure 4]. This device produces rectangular biphasic compensated impulses with a width of 250 µS, frequency of 60 Hz, the maximum intensity of 16 mA with a progressive slope from 1 to 16 mA over 14 min. Similar to other LF peripheral nerve stimulator devices, the purpose of Cefaly® is to produce a comfortable tingling sensation over the stimulated area. As the current intensity progressively increases, the patient has the option to stabilize the intensity when the tingling or prickling forehead sensation becomes uncomfortable, to avoid painful stimulation. Cefaly® obtained FDA approval in 2014 for the preventive treatment of migraine and in 2017 for the abortive treatment of migraine episodes. Cefaly® dual neurostimulator can deliver two pre-treatment settings, a HF program aiming to treat acute episodes of migraine that lasts for 60 min and an LF program aiming to prevent migraine symptoms, which delivers one 20-min long stimulation session, preferably in the evening, on a daily basis for 3 months before assessing its efficacy.
Biological rationale and mechanism of action Similarly, to other LF peripheral neurostimulation approaches, it may be postulated that the stimulation of V1 trigeminal branches may improve migraine symptoms by inhibiting nociceptive trigeminal fibers through stimulation of large nonnociceptive fibers as per the gate control theory.[102] An 18-fluorodeoxyglucose positron emission tomography (FDG-PET) study, evaluating the brain metabolic changes before and after 3 months of Cefaly® treatment in EM patients showed a reduction of the hypometabolism in frontotemporal areas, especially in the orbitofrontal (OFC) and rostral anterior cingulate cortices (rACC).[103] Further functional neuroimaging brain research using whole-brain BOLD-fMRI in migraine patients pre- and post-Cefaly® treatment aimed to assess functional response to trigeminal heat stimulation (THS). The study showed a significant positive correlation between ACC BOLD response to noxious THS before eTNS treatment and the decrease of ACC BOLD response to noxious THS after eTNS. Moreover, a significant negative correlation in the migraine group after eTNS treatment between ACC functional activity changes and both the perceived pain ratings during noxious THS and pre-treatment migraine attack frequency has been found.[104] Taken together this initial evidence may suggest a neuromodulatory effect of Cefaly® through the modulation of central pain-controlling areas. Clinical data Acute treatment of episodic migraine The use of Cefaly®as a migraine abortive treatment was studied in a prospective open-label trial. Thirty migraine attacks were treated with Cefaly® for 60 min in 30 patients. Mean pain intensity was significantly reduced in over 50% of the attacks at 1 and 2 h after treatment. No patients took rescue medication within the 2-h observation phase. Within the 24-h follow-up, one-third of patients used a rescue medication. The therapy seems well tolerated by all patients.[105] In view of these promising initial findings, a double-blind, randomized, sham-controlled study was subsequently conducted in a larger number of patients. The study confirmed the statistical superiority of 1-h treatment with Cefaly® compared to sham in reducing migraine pain at 1 h. Furthermore, it supported the safety and good tolerability of this therapy.[106] Preventive treatment of migraine The usefulness of Cefaly® device as a preventive treatment for EM was evaluated in a 3 months pilot study on 10 EM patients, showing positive initial results,[107] which led to a subsequent small prospective, multicenter, double-blinded, randomized, and sham-controlled trial (the PREMICE study). The trial included 67 patients with EM treated with 20 min per day of Cefaly® or sham stimulation over a period of 3 months. Primary outcome measures were a change in monthly migraine days, and secondary outcome measures were changes in migraine and any headache attack frequency, attack severity, use of abortive medications, and migraine-associated symptoms. The patients in the Cefaly® treatment group reported a statistically higher reduction in monthly migraine days (from 6.9 to 4.8) than that of the sham group. About 40% of the patients experienced a 50% reduction in migraine days rate, which was significantly higher than the sham. In the Cefaly® group, there was a marked reduction in the number of migraine attacks, headache days, and acute abortive medication intake per month. No serious adverse events were noticed.[108] A 60-day open-label trial studied the efficacy of Cefaly® in 24 patients with MO who never tried a migraine preventive treatment. Migraine days halved in numbers and migraine attacks in length after the 2-month treatment. Furthermore, the majority of patients obtained at least 50% reduction of monthly migraine attacks and migraine days (respectively, 81% and 75% of patients). No adverse events were reported, and most patients showed good compliance to the treatment.[109] A survey of 2,313 migraine sufferers estimated adverse events (AE) and willingness to continue transcutaneous supraorbital nerve stimulation with the Cefaly® device over a 40-day trial period. The results confirmed that this mode of treatment is safe and well-tolerated for migraine headaches and provides satisfaction to a majority of patients. The most common AEs were local painful paresthesia, sleep disturbances, and headache worsening. Rarely reported adverse effects were nausea and vomiting, inability to keep the eyes open during the stimulation, increased tinnitus during the session, eye redness and tearing, skin irritation or allergic cutaneous reaction to the electrode gel, skin numbness, minor forehead pain, feeling of abrupt electrical variation, and tachycardia.[110] Preliminary evidence in CM was produced through a small prospective open-label study where Cefaly® was tried for 4 months. About one-third of patients responded to the treatment. There was a mean reduction in headache days and acute medication consumption by 57.9% and 68.8%, respectively, compared to baseline, suggesting a potential role of this treatment in patients with CM.[111] Remote electrical neuromodulation Remote electrical neuromodulation (REN) of the upper arm skin is a noninvasive treatment modality recently evaluated in migraine (NerivioMigra®, Theranica Bio-Electronics Ltd., Israel). It is the first noncephalic form of neuromodulation for headache disorders. It has been shown that robust nonpainful conditioning stimuli are sufficient to induce pain inhibition. The therapeutic effect of REN is based on the phenomenon of conditioned pain modulation (CPM), which is an intrinsic analgesic mechanism characterized by inhibition of pain in remote body regions after stimulation of C and Aδ sensory fibers above their depolarization threshold but below the nociceptive threshold.[112] Nerivio (Nerivio, Theranica Bio-Electronics Ltd., Israel) device was designed to stimulate the peripheral nerves of the upper arm for the purpose of REN [Figure 5].[113] This device, controlled by a smartphone application, is applied to the lateral upper arm and produces electrical nonpainful stimulation. It is programmed to deliver 45 min symmetrical, biphasic, square pulses with a pulse width of 50-400 μs, modulated frequency of 80-120-Hz, and patient-controlled output current of up to 40 mA. The postulated underlying mechanism of analgesia is the activation of descending inhibition pathways.[112]
A prospective, double-blinded, randomized, crossover, sham-controlled trial conducted in 71 migraine patients showed that treatment with Nerivio led to 50% pain reduction in 64% of participants compared to 26% of participants in the sham group. About one-third of participants became pain-free with Nerivio treatment compared to 6% of the placebo group. Better results were obtained if stimulation was started at beginning of a migraine episode (within 20 min of pain onset).[112] Similar results emerged from another double-blind, randomized, sham-controlled study conducted in 252 migraine patients. The primary endpoint was the change in the proportion of participants obtaining pain relief at 2 h post-treatment (30–45 min). Relief of the most bothersome symptoms (MBS) was also assessed as one of the key secondary endpoints. Active stimulation was significantly more effective than sham stimulation in achieving pain relief (66.7% vs. 38.8%, pain-freedom (37.4% vs. 18.4%), and MBS relief (46.3% vs. 22.2%) at 2 h post-treatment with sustained effect at 48 h post-treatment. Side effects were experienced by a small proportion of patients without any significant difference from the sham group. Device-related adverse events included warmth sensation, temporary arm/hand numbness, redness, itching, tingling, muscle spasm, and pain in the arm, shoulders, or neck. All device-related adverse events were mild, resolved within 24 h.[113] When compared to standard of care in a post hoc analysis of 99 of the 252 patients, REN was shown to be more effective than usual care.[114]
Noninvasive neuromodulation therapies have relatively compelling pre-clinical data on their different mechanisms of action in primary headaches, primarily migraine. However, when translated in human clinical research, the quality of the studies and outcomes has been less promising. Caveats including study designs, patient selection, lack of outcomes homogeneity, and limited clinical research programs, have created hesitancy in adopting these treatment modalities for routine clinical practice at least in the UK and Europe. These issues along with treatment costs have prevented the widespread use of noninvasive neuromodulation therapies. Nonetheless, these treatments have a role in the arsenal of treatments for primary headache disorders as an alternative to medicines, because of their favorable tolerability profiles. From a health economic point of view, some of these devices have been shown to be cost-effective too. sTMS seems to be cheaper than BoNTA for CM treatment and Gammacore is cost-effective in CH.[115],[116] However, both treatments lack RCT and long-term real-world efficacy data, respectively, in CM and CCH, which would be crucial to understand their role in these conditions, convince clinicians, and influence the health authorities. A summary of the current indications for the different devices in migraine therapy is outlined in [Table 1].[117]
Financial support and sponsorship Nil. Conflicts of interest JL: reports no disclosure; APA: received speaker honoraria and funding for travel from Allergan, MB: reports no disclosure Eli Lilly and eNeura, honoraria for participation in advisory boards sponsored by Allergan and Eli Lilly, sponsorship for educational purposes from eNeura, Allergan, Autonomic Technologies and Novartis, and an equipment grant from eNeura. G.L. has received speaker honoraria, funding for travel and has received honoraria for participation in advisory boards sponsored by Allergan, Novartis, Eli Lilly and TEVA. He has received speaker honoraria, funding for travel from electroCore, Nevro Corp. and Autonomic Technologies.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1]
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