External trigeminal nerve stimulation for the non-invasive treatment of acute migraine attacks

Abstract

To provide a system and method for acute non-invasive treatment of a migraine attack.SOLUTION: The system comprises at least one skin electrode for placement on the forehead of a patient. The system is configured for providing consecutive biphasic electrical pulses via the at least one skin electrode to the supratrochlear and supraorbital nerves of the ophthalmic nerve branch of the trigeminal nerve during a prolonged time span. Preferably, the time span is at least 10 minutes.SELECTED DRAWING: Figure 2B

Description

Technical Field

[0001] The present invention relates to a system and method for non-invasive treatment of the acute phase of migraine attacks. The system includes at least one skin electrode for placement on a patient's forehead. The system is configured to supply biphasic electrical pulses continuously via the at least one skin electrode to the trochlear nerve and the supraorbital nerve, branches of the ophthalmic nerve of the trigeminal nerve, over a long time span.

Background Art

[0002] Migraine is a common neurobiological disorder characterized by recurrent episodes of headache with hypersensitivity, which can significantly impair the quality of life. Acute treatment is used during migraine attacks for the purpose of stopping or reducing the headache and restoring normal function, whereas preventive treatment is intended to reduce the frequency and severity of attacks.

[0003] Current acute migraine treatments are mainly pharmacological approaches using the most commonly used medications, mainly analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) and triptans. These drugs have several contraindications and are associated with moderate to severe side effects. In patients with frequent and / or long-term migraine attacks, overuse of acute migraine medications can lead to chronification of the headache and medication-overuse headache, which is a harbinger of worse outcomes. Furthermore, some patients (especially those with chronic migraine) may become resistant to conventional migraine medications and thus do not achieve sufficient pain relief. The adverse effects associated with medication and limited efficacy highlight the need for non-pharmacological treatment methods.

[0004] Recent research suggests that nerve stimulation may be a promising modality for treating headache disorders. Several neuromodulatory techniques have been investigated for the treatment of primary headaches. Non-patent document 1 discloses an open-label trial in which percutaneous occipital nerve stimulation (p-ONS) was effective for chronic migraine. Non-patent document 2 discloses the effects of p-ONS on chronic cluster headache. Non-patent document 3 discloses positive results for p-ONS in a controlled comparative study on chronic migraine. Non-patent document 4 discloses that a combination of occipital and supraorbital nerve stimulation shows better efficacy than occipital nerve stimulation alone. Non-patent document 5 discloses that patients' functional status improved perioperatively but declined during long-term follow-up. Non-patent document 6 discloses that sphenopalatine ganglion stimulation (SPG) has yielded positive results in several clinical trials, mainly for the treatment of cluster headache. However, while these invasive neuromodulatory techniques are generally well-tolerated and may be appropriate for refractory migraine and chronic cluster headache, they may not be acceptable for less severe migraine patient categories. Non-patent document 7 discloses that non-invasive vagal nerve stimulation shows clinical benefits that outweigh those of standard treatment for cluster headache. However, non-patent documents 8 and 9 report negative results for non-invasive vagal nerve stimulation in sham-controlled comparative trials for chronic migraine.

[0005] Non-patent document 10 discloses a double-blind, sham-controlled, crossover study using healthy subjects, which found that transcutaneous supraorbital nerve stimulation produces a sedative effect. Subsequently, non-patent document 11 discloses a multicenter, randomized, double-blind, sham-controlled trial clarifying the efficacy and safety of external trigeminal nerve stimulation (e-TNS) for the prevention of sudden migraine. Non-patent document 12 discloses a larger, open-label, randomized trial that confirmed the therapeutic efficacy in migraine prevention. Non-patent document 13 discloses a prospective study of 2313 patients that further confirmed safety and patient satisfaction.

[0006] However, there remains a technological need for safe, non-pharmacological, and non-invasive acute treatments for migraine attacks.

[0007] Patent Document 1 discloses a device for electrotherapy treatment of headaches such as tension headaches and migraines. The electrode support has a shape and size selected to excite the afferent pathways of the supratrochlear and supraorbital nerves, branches of the ophthalmic nerve of the trigeminal nerve, independently of the subject. The electrical circuit includes a programmable signal generator suitable for producing pulses with a duration of 150 μs to 450 μs, with a maximum intensity increase of 0 mA to 20 mA at a rate of 40 μA / s or less and an intensity increase not exceeding 50 μA.

[0008] Patent Document 1 does not disclose the use of a device for the acute treatment of migraine attacks. Furthermore, Patent Document 1 does not disclose a specific treatment period.

[0009] Patent Document 2 discloses an electrotherapy system for stimulating sensory nerves within skin tissue. The system comprises an electrode carrier, a pulse generator, an array of transcutaneous and epidermal electrodes, a pulse processing circuit, and a power supply. The system provides a biphasic pulsed current to the epidermal electrodes and a monophasic pulsed current to each transcutaneous electrode. The document specifically discloses the combined use of transcutaneous and epidermal electrodes. Embodiments disclosed in Patent Document 2 provide an applicable electrode patch that combines both epidermal and transcutaneous electrodes within the same patch. Non-invasive treatment is not possible with such an electrode patch. The system, particularly the epidermal electrodes, is configured to mask pain caused by stimulation via the transcutaneous electrodes. The document does not disclose the treatment of migraines. Furthermore, the document does not disclose the ophthalmic nerve branch of the trigeminal nerve. [Prior art documents] [Patent Documents]

[0010] [Patent Document 1] U.S. Patent Application Publication No. 2009 / 0210028 [Patent Document 2] U.S. Patent Application Publication No. 2010 / 0274327 [Non-patent literature]

[0011] [Non-Patent Document 1] Pain Physician 11(2), 187-200 (2008) [Non-Patent Document 2] Lancet Neurology 6(4), 314-321 (2007) [Non-Patent Document 3] Cephalalgia 31(3), 271-285 (2011) [Non-Patent Document 4] Cephalalgia 30(3), 260-271 (2010) [Non-Patent Document 5] Neuromodulation 19(5), 507-514 (2016)

Non-Patent Document 6

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

Non-Patent Document 11

Non-Patent Document 12

Non-Patent Document 13

Summary of the Invention

Problems to be Solved by the Invention

[0012] The present invention aims to solve at least some of the problems mentioned above. [[ID=

Means for Solving the Problems

[0013] In a first aspect, the present invention provides a non-invasive treatment system for the acute phase of a patient's migraine attack as disclosed in claim 1.

[0014] In a second aspect, the present invention provides a non-invasive treatment method for the acute phase of a patient's migraine attack as disclosed in claim 15.

[0015] The present invention is beneficial for meeting long-standing needs in the art by providing a safe and drug-free non-invasive acute treatment method and system for migraine attacks. The present invention is based on three clinical trials disclosed in the examples.

Brief Description of the Drawings

[0016] [Figure 1] It is a diagram showing the timeline of a forward clinical trial. [Figure 2A] It is a diagram showing a bipolar adhesive electrode to be attached to a patient's forehead. [Figure 2B] It is a diagram showing a power supply device that can be installed on the electrode as shown in Figure 2B. [Figure 2C] It is a diagram showing a power supply device that can be installed on the electrode as shown in Figure 2C. [Figure 2D] It is a diagram showing an alternative bipolar adhesive electrode to be attached to a patient's forehead. [Figure 3] It is a diagram showing the temporal evolution of average pain intensity in a forward clinical trial. [Figure 4] It is a diagram showing a power supply device. [Figure 5] It is a diagram showing a bipolar adhesive electrode. [Figure 6] It is a diagram showing an alternative bipolar adhesive electrode. [Figure 7] It is a diagram showing a power supply device attached to the bipolar adhesive electrode shown in Figure 6. [Figure 8] It is a diagram showing an overview of a clinical trial to determine the effectiveness and safety of home use of the treatment system according to the present invention.

Modes for Carrying Out the Invention

[0017] The present invention relates to a system and method for non-invasive acute treatment of migraine attacks. The present invention is summarized in the corresponding chapter. In the following description, the present invention is described in detail, preferred embodiments are explained, and the present invention is illustrated by examples.

[0018] Unless otherwise defined, all terms used to disclose this invention, including technical and scientific terms, have meanings that are generally understood by those skilled in the art to which this invention pertains. Further guidance includes definitions of terms to better understand the teachings of this invention.

[0019] The following terms used in this specification have the meanings set forth below.

[0020] As used herein, singular forms that do not specify a quantity ("A", "an", and "the") refer to both singular and plural objects unless otherwise clearly indicated by the context. For example, "a compartment" refers to one or more compartments.

[0021] In this specification, "about" when referring to measurable values ​​such as parameters, quantities, and periods means that it includes variations of ±20%, preferably ±10%, more preferably ±5%, even more preferably ±1%, and even more preferably ±0.1% from a specified value, and such variations are within a range suitable for carrying out the disclosed invention. However, it is understood that the values ​​referred to by the modifying phrase "about" are also specifically disclosed.

[0022] As used herein, “comprise,” “comprising,” and “comprises” and “comprised of” are synonymous with “include,” “including,” “includes,” or “contain,” “containing,” and “contains” and are general or unrestricted terms indicating the presence of components, and do not exclude or omit the presence of additional unspecified components, features, elements, parts, or processes known or disclosed in the Art.

[0023] A numerical range described by an endpoint includes all numbers and fractions within that range, and similarly includes the endpoint itself.

[0024] In a first aspect, the present invention provides a system for the acute non-invasive treatment of a patient's migraine attack. The system comprises at least one skin electrode, which is configured to be placed on the patient's forehead. The system is configured to supply continuous biphasic electrical pulses through the at least one skin electrode over a long time span. Preferably, the time span is at least 10 minutes, more preferably at least 25 minutes, even more preferably at least 35 minutes, and even more preferably at least 45 minutes, most preferably at least 55 minutes, for example, a time span of 55 minutes, 60 minutes, 65 minutes, 70 minutes, 75 minutes, 80 minutes, 85 minutes, 90 minutes, 95 minutes, 100 minutes, 105 minutes, 110 minutes, 115 minutes, 120 minutes, 125 minutes, 130 minutes, 135 minutes, 140 minutes, 145 minutes, 150 minutes, 155 minutes, 160 minutes, 165 minutes, 170 minutes, 175 minutes, 180 minutes, 185 minutes, 190 minutes, 195 minutes, 200 minutes, 205 minutes, 210 minutes, 215 minutes, 220 minutes, 225 minutes, 230 minutes, 235 minutes, 240 minutes, or any value exceeding or between them.

[0025] The applicant has found that prolonged treatment, i.e., treatment for at least 10 minutes, preferably at least about 60 minutes, is beneficial for pain relief during migraine attacks in terms of both immediate pain suppression and long-term pain relief after the completion of treatment. Clinical trials disclosed in the Examples support this statement.

[0026] In a preferred embodiment, the biphasic electrical pulse is essentially a rectangular biphasic pulse using zero-electric means. This is advantageous because these types of pulses are easy to generate and do not require net charge transfer to the patient.

[0027] In a preferred embodiment, the system is configured to supply the above-mentioned consecutive biphasic electrical pulses at frequencies of at least 10 Hz and at most 300 Hz, for example, 10 Hz, 20 Hz, 30 Hz, 40 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 110 Hz, 120 Hz, 130 Hz, 140 Hz, 150 Hz, 160 Hz, 170 Hz, 180 Hz, 190 Hz, 200 Hz, 220 Hz, 240 Hz, 260 Hz, 280 Hz, 300 Hz, or any value in between.

[0028] The applicant has found that at a frequency of approximately 100 Hz, pulses can most effectively excite the trigeminal nerve, more specifically the supratrochlear nerve and supraorbital nerve, which are branches of the ophthalmic nerve of the trigeminal nerve, thereby relieving pain and producing an analgesic effect that can treat migraine attacks.

[0029] In one embodiment, the system is configured to supply the above-mentioned consecutive biphasic electrical pulses with frequencies of at least 150 Hz and at most 500 Hz, for example, 150 Hz, 160 Hz, 170 Hz, 180 Hz, 190 Hz, 200 Hz, 210 Hz, 220 Hz, 230 Hz, 240 Hz, 250 Hz, 260 Hz, 270 Hz, 280 Hz, 290 Hz, 300 Hz, 320 Hz, 340 Hz, 360 Hz, 380 Hz, 400 Hz, 420 Hz, 440 Hz, 460 Hz, 480 Hz, 500 Hz, or any value in between. In this embodiment, the system is preferably configured to supply the continuous biphasic electrical pulses at a frequency of at least 200 Hz and at most 400 Hz, more preferably at least 240 Hz and at most 360 Hz, even more preferably at least 250 Hz and at most 350 Hz, even more preferably at least 260 Hz and at most 340 Hz, more preferably 275 Hz and at most 325 Hz, even more preferably at least 290 Hz and at most 310 Hz, and most preferably at about 300 Hz.

[0030] The applicant conducted preliminary tests demonstrating that tripling the frequency from approximately 100 Hz to approximately 300 Hz could potentially further improve the effectiveness of the treatment.

[0031] In a preferred embodiment, at least a portion of the continuous biphasic electrical pulses, preferably each, includes a width of at least 30 μs and at most 1000 μs, preferably at least 100 μs and at most 500 μs, for example, 100 μs, 125 μs, 150 μs, 175 μs, 200 μs, 225 μs, 250 μs, 275 μs, 300 μs, 325 μs, 350 μs, 375 μs, 400 μs, 425 μs, 450 μs, 475 μs, 500 μs, or any value in between.

[0032] The applicant has found that pulses with a width of approximately 250 μs induce a sufficient temporary charge build-up to excite (induce action potentials) the trigeminal nerve, more specifically the supratrochlear and supraorbital nerves, which are branches of the ophthalmic nerve of the trigeminal nerve, thereby relieving pain and treating migraine attacks.

[0033] In a preferred embodiment, the system is configured to linearly increase the amplitude of the consecutive biphasic electrical pulses up to a pre-configured amplitude limit during a first portion of the time span and maintain it during a second subsequent portion of the time span. Preferably, the pre-configured amplitude limit is at least 1 mA and at most 50 mA, more preferably at least 5 mA and at most 25 mA, for example, 5 mA, 6 mA, 7 mA, 8 mA, 9 mA, 10 mA, 11 mA, 12 mA, 13 mA, 14 mA, 15 mA, 16 mA, 17 mA, 18 mA, 19 mA, 20 mA, 21 mA, 22 mA, 23 mA, 24 mA, 25 mA, or any value in between. Preferably, the first portion of the time span is at least 1 minute and at most 30 minutes, more preferably at least 5 minutes and at most 20 minutes, for example 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, or any value in between. The linear amplitude increase during the first portion of the time span described above preferably has a gradient of at least 1.6 μA / s and at most 833 μA / s, preferably at least 8 μA / s and at most 83 μA / s, for example, 8 μA / s, 9 μA / s, 10 μA / s, 11 μA / s, 12 μA / s, 13 μA / s, 14 μA / s, 15 μA / s, 16 μA / s, 17 μA / s, 18 μA / s, 19 μA / s, 20 μA / s, 21 μA / s, 22 μA / s, 23 μA / s, 24 μA / s, 25 μA / s, 26 μA / s, 27 μA / s, 28 μA / s, 29 μA / s, 30 μA / s, or any value in between. The amplitude is preferably ramped up from 0 mA to approximately 16 mA over approximately 14 minutes, and therefore the gradient of the linear amplitude increase is most preferably a value of approximately 19 μA / s.

[0034] The applicant has found that a pulse amplitude of approximately 16 mA presents optimal therapeutic efficacy by enabling maximum spatial recruitment, i.e., excitation (stimulation) of all nerve fibers of the supratrochlear and supraorbital nerves. A gentle linear ramp-up up to a pre-configured amplitude limit is advantageous because it helps the patient gradually adapt to the pre-configured strong stimulation amplitude limit of 16 mA.

[0035] In a preferred embodiment, the system includes a button that can be pressed by the patient. The system is configured such that, by briefly pressing the button during the time span, the biphasic pulse amplitude supplied at or prior to the press of the button is maintained throughout the remainder of the time span. This is advantageous because, during a gentle ramp-up up to a pre-configured amplitude limit, the patient can press the button to maintain the current or past amplitude for the remainder of the treatment time. Thus, the patient can limit the intensity if it becomes too high.

[0036] In a preferred embodiment, the system is further configured to accelerate the ramp-up by pressing the button for several seconds. This is advantageous for patients accustomed to using the system to treat migraine attacks, as it allows for a faster ramp-up and quicker headache relief. By pressing the button for several seconds, an optimal and most effective amplitude of 16 mA can be reached within 30 seconds. Therefore, the system is configured to rapidly increase the amplitude while the button is held down. Once the switch is released, the amplitude stabilizes and remains constant. Pressing the button again increases the intensity again, but only while the button is held down.

[0037] In one embodiment, at least one skin electrode may include two or more skin electrodes configured to be attached to the patient's forehead, establishing two or more contacts to supply the continuous biphasic electrical pulses described above. In the most preferred embodiment, at least one skin electrode comprises a bipolar adhesive electrode having an adhesive side for skin contact and an outer side having two contact areas for establishing electrical contact with an energy supply device. Figure 5 shows an embodiment of such a bipolar adhesive skin electrode. The bipolar adhesive skin electrode further comprises a central projection on which an energy supply device can be placed. Figure 2A shows the placement of the bipolar adhesive skin electrode 6 on the patient's forehead. The bipolar adhesive skin electrode 6 and its placement are therefore adapted to stimulation of the trigeminal nerve, which has three branches: branch 1 of the ophthalmic nerve, branch 4 of the maxillary nerve, and branch 5 of the mandibular nerve. This nerve divides at the forehead into two branches: the internal frontal (or supratrochlear) nerve 2 and the external frontal (or supraorbital) nerve 3. The bipolar adhesive skin electrode has a shape and configuration adapted in particular to stimulation of the supratrochlear and supraorbital nerves, which are branches of the ophthalmic nerve of the trigeminal nerve. Figure 4 shows an embodiment of a head-fixable device comprising two metal contacts (not shown) that can be positioned in electrical contact with the two contact areas of the bipolar adhesive skin electrode. The head-fixable device comprises a recess for placement on the projection of the bipolar adhesive skin electrode. The projection may therefore have a base that connects to the outer surface of the skin electrode at one end and terminates at a wider head portion at the opposite end. The recess of the head-fixable device is preferably configured to be stably placed on the wider head portion. Figure 2B illustrates the placement of the head-fixable device 7 on the bipolar skin electrode. The device comprises a button 8 for initiating treatment and / or limiting the amplitude during the linear increase in the first portion of the time span. The head-fixable device of Figure 2B comprises two legs 9 that provide a fixation function. Alternatively, the fixation function may be achieved by an elastic band. Furthermore, each of the aforementioned legs is equipped with a compartment for housing one AAA battery to supply power to the device. Therefore, the system comprising the device and at least one skin electrode is portable, meaning that the patient can walk around hands-free.

[0038] An alternative embodiment of the power supply device is shown in Figure 2C. The bipolar adhesive skin electrode has a base with a projection, the projection of which is connected to the outer surface of the skin electrode at one end and terminates at the opposite end with a wider head portion. The power supply device has a recess for stably mounting the device on the head portion of the projection. Thus, as can be seen in Figure 2C, the device has no legs. The device also has at least one compartment for housing at least one battery. Alternatively, the device has an internally rechargeable battery. The device also has a button for initiating treatment and / or limiting the amplitude during the linear increase in the first portion of the time span. Thus, the system comprising the device and at least one skin electrode is portable, i.e., the patient can walk around hands-free.

[0039] In another embodiment, the skin electrode comprises a bipolar adhesive electrode having an adhesive side for skin contact and an outer side with two metal contacts for establishing electrical contact and attachment to an energy supply device. The adhesive side may have two adhesive electrode regions. Figure 6 shows an embodiment of such a bipolar adhesive skin electrode. Figure 2D shows the placement of a bipolar adhesive skin electrode 6 having two metal contact areas 11 on the forehead. As described above, the bipolar adhesive skin electrode and its placement are adapted for stimulation of the trigeminal nerve, preferably the supratrochlear and supraorbital nerves, which are branches of the ophthalmic nerve of the trigeminal nerve. Figure 7 shows an embodiment of a power supply device having two metal contacts (not shown) arranged in electrical contact with the two metal contact areas of the bipolar adhesive skin electrode. The metal contacts of the bipolar adhesive electrode or the power supply device are preferably magnetized for attachment of the power supply device to the bipolar adhesive skin electrode. The power supply device includes a button for initiating treatment and / or limiting the amplitude during the linear increase in the first portion of the time span. The system is preferably portable, i.e., the patient can walk around hands-free. The power supply device is preferably without legs. The power supply device is preferably equipped with a rechargeable battery. The power supply device is preferably lightweight, more preferably less than 100 g, for example, weighing 12 g. The power supply device is preferably small, more preferably smaller than 80 mm × 80 mm × 30 mm, for example, 55 mm × 40 mm × 15 mm. The bipolar adhesive electrode is preferably 50 mm to 150 mm long, for example, 94 mm long. The bipolar adhesive electrode is preferably 10 mm to 50 mm high, for example, 30 mm high. The bipolar adhesive electrode is preferably made of a hypoallergenic gel.

[0040] In a preferred embodiment, the power supply device includes a processing unit, a tangible non-transient computer-readable storage medium, and computer-readable instructions for storing information about a treatment session in the storage medium. The power supply device may also include a cable port or module for wireless communication for reading the stored information. The cable port may be a USB port. The wireless communication module may be Bluetooth. 登録商標 It can also be a module.

[0041] In a preferred embodiment, the system includes a tangible non-transient storage medium, such as a programmable electrical circuit, for setting and storing at least one, preferably all, of the following: pulse frequency, pulse width, pulse amplitude, ramp-up time or ramp-up gradient with respect to linear increase in amplitude, and treatment time (i.e., time span).

[0042] Furthermore, the system of the first embodiment of the present invention may be part of a kit, and the kit may also include a drug. The drug preferably includes one or more analgesics, nonsteroidal anti-inflammatory drugs, triptans, ditan, and CGRP antagonists. Depending on the patient's needs, the patient may use combination therapy including the drug and e-TNS. Combination therapy may include the initiation of e-TNS treatment and drug intake at approximately the same time. For example, if e-TNS treatment alone is not sufficiently effective for the patient, combination therapy may include drug intake during or after e-TNS treatment.

[0043] In a second aspect, the present invention provides a method for the acute non-invasive treatment of a patient's migraine attack. The patient has a forehead, a suprachruchal nerve, and a supraorbital nerve. The method includes (a) placing at least one skin electrode on the patient's forehead, and (b) supplying a continuous biphasic electrical pulse over a long time span to the suprachruchal nerve and the supraorbital nerve via the at least one skin electrode.

[0044] Those skilled in the art will understand that all preferred embodiments relating to the above system also relate to the above method. The at least one skin electrode preferably includes the bipolar adhesive electrode mentioned above. The time span is preferably at least 25 minutes. The biphasic electrical pulse is preferably a rectangular biphasic symmetric pulse by essentially zero electrical means. The consecutive biphasic electrical pulses are preferably supplied at a frequency of about 100 Hz. In an alternative preferred embodiment, the consecutive biphasic electrical pulses are supplied at a frequency of about 300 Hz. Each of the consecutive biphasic electrical pulses preferably has a width of about 250 μs. The consecutive biphasic electrical pulses preferably have an amplitude that linearly increases to an amplitude limit over a first portion of the time span and is maintained during a second subsequent portion of the time span, preferably the amplitude limit is one of a predefined amplitude limit of about 16 mA or an amplitude limit of at most 16 mA determined by the patient (button press), preferably the slope of the linear increase is about 19 μA / s.

[0045] The present invention can be further illustrated by the following non-limiting examples. These examples are illustrative of the present invention and are not intended to limit the scope of the present invention, nor should they be construed as limiting the scope of the present invention. [Examples]

[0046] Example 1: Prospective clinical trial A single-center, prospective, open-label clinical trial was conducted at the Columbia University Headache Center (New York, USA). The study was approved by the Columbia University Medical Center Ethics Board (IRB-AAAO9752) and registered in the U.S. Clinical Trials Registry (ClinicalTrials.gov) (Identification Number: NCT02411513). Written informed consent was obtained from all patients participating in the study.

[0047] Patients with migraine, with or without aura, were recruited during standard outpatient visits or at home, provided they experienced a migraine attack with stable pain intensity for at least one hour and lasted for at least three hours, and had not taken acute migraine medication in the previous three hours. The selection criteria were as follows: Adult patients aged 18 to 65 years with a history of sudden or chronic migraine, with or without aura, experiencing headache localized to one or both sides of the frontal, posterior orbital, or periorbital region (or multiple regions), and meeting the diagnostic criteria listed in Chapter 1, Migraine, International Classification of Headache Disorders (ICHD-IIIbeta, 2013), excluding "complex migraine" (i.e., hemiplegic migraine, migraine with brainstem aura, ophthalmoplegic migraine / recurrent painful ophthalmoplegic neuropathy, migraine-associated stroke). The exclusion criteria were as follows: (1) pregnancy; (2) treatment of the head with onabotulinum toxin (e.g., Botox, Dysport, Xeomin) in the past four months; (3) supraorbital nerve block in the past four months; (4) diagnosis of other primary or secondary headache disorders, excluding medication overuse headache; (5) headaches affecting only the temporal or occipital region; (6) opioid use in the past three months; (7) use of migraine relief medication within three hours prior to registration; (8) intolerance to supraorbital nerve stimulation (allodynia); (9) metal or electrical devices implanted in the head; and (10) cardiac pacemakers or implantable or wearable defibrillators.

[0048] Patients were asked to rate the severity of their pain (baseline score) using an 11-point visual analogue scale (VAS) (0 = no pain ~ 10 = maximum pain). The e-TNS device was then attached, and nerve stimulation therapy was initiated, increasing in intensity over the first 14 minutes. Nerve stimulation was then continued for the remaining 55 minutes, including patients who could tolerate the paresthesia for the first 5 minutes (thus reaching a minimum intensity of 7 mA or a minimum electrical charge of 1.75 μC per impulse) without leveling off. Patients who could not tolerate the initial trial phase were not enrolled based on the allodynia exclusion criterion (low nociceptive threshold of the forehead skin). Patients were asked to rate their pain intensity again at the completion of the 1-hour treatment phase (1-hour score) and 1 hour post-treatment (2-hour score). Rescue medication use was recorded with 2-hour markings, and patients were contacted later regarding rescue medication use within 24 hours of e-TNS treatment. Patients who took rescue medication before the end of the post-treatment phase were classified as dropouts. The study plan is shown in Figure 1.

[0049] External trigeminal nerve stimulation (e-TNS) was applied using a Cefaly® nerve stimulator (CEFALY Technology, Ceran, Belgium) for a 60-minute treatment session. The device is a constant current generator for a maximum skin impedance of 2.2 kΩ, delivering rectangular biphasic symmetric pulses by zero electrical means. In this study, the device was programmed with a pulse frequency of 100 Hz and a pulse width of 250 μs, and the total maximum amount of current delivered during a 1-hour treatment session was 1.284 coulombs. The electrical impulse was transmitted transcutaneously via a supraorbital bipolar electrode (30 mm × 94 mm) designed to cover and excite (induce action potentials) both sides of the supratrochlear and supraorbital nerves (see Figures 2 and 5). After 14 minutes, the intensity increased linearly to a maximum of 16 mA, and then remained constant for 46 minutes. If the patient feels the stimulation is too strong, pressing a button on the device once will stabilize the intensity for the remainder of the session (in this case, the patient will receive a lower total current).

[0050] Patients scored their pain intensity using a visual analog scale (VAS) with 11 levels (0 = no pain, 10 = maximum pain). Pain levels were assessed before treatment was applied (baseline score), after 1 hour of treatment (1-hour score), and 2 hours after the start of the treatment phase (2-hour score). Rescue medication use was also recorded at 2 hours and 24 hours. The primary outcome was the mean change in pain intensity after 1 hour of treatment compared to baseline. Secondary outcomes were the mean change in pain intensity at 2 hours after the start of treatment compared to baseline, and the percentage of patients who did not require rescue medication at 2 hours and 24 hours post-treatment.

[0051] The analysis was based on modified intention-to-treat (mITT), meaning the eligible population consisted of patients for whom treatment was applied and for whom baseline severity measurements were available. For each patient, results were calculated using all available data during each period without imputing missing data. A Wilcoxon signed-rank test for paired samples was used to compare baseline with treatment outcomes.

[0052] Table 1 - Demographic characteristics of patients [Table 1]

[0053] The above clinical trial was conducted from April 2015 to October 2015. A total of 35 patients were screened. One patient was excluded due to opioid drug use within the previous three months, and four patients were excluded for failing the nociceptivity test (two patients were excluded because they could not tolerate the initial stimulation, and two patients were excluded because they unintentionally disconnected the device from the electrodes during the trial phase). The remaining 30 patients received the full hour of stimulation, and there were no dropouts during the study (see Figure 1). The demographic characteristics of the patients are shown in Table 1. No adverse events occurred during or within 24 hours after treatment, and no subjective complaints were reported.

[0054] Table 2 shows the study results. There was a statistically significant reduction in pain intensity both after 1 hour of treatment and 2 hours after the start of treatment. No patients used rescue medication at the end of the 2-hour period. Patients were also contacted 24 hours after treatment to report whether they had used rescue medication during that time frame. Of the 26 patients who were contacted, 17 (65.4%) had not used rescue medication within 24 hours after treatment.

[0055] Table 2 - Research results [Table 2]

[0056] Figure 3 shows the change in mean pain intensity. On average, pain intensity decreased from 5.63 to 2.42 after 1 hour of treatment and to 2.66 after 2 hours. This decrease was statistically significant in both cases (p<0.001).

[0057] As shown in Table 2, 76.7% of patients reported more than 50% pain relief within one hour, and 56.7% reported more than 50% within two hours. Six patients (20.0%) reported complete pain relief within one hour, and four patients (13.3%) reported complete pain relief within two hours.

[0058] Regarding nerve stimulation intensity, 17 patients (56.7%) tolerated a maximum intensity of 16 mA (i.e., received a total current of 1.284 coulombs), and 13 patients (43.3%) required the stimulation intensity to be limited to an average of 9.51 mA. A sub-analysis comparing the group of 13 patients with limited current output with the group of 17 patients who received the full electrical dose revealed a difference only in the use of rescue medication within 24 hours, with 50% of patients with partial current output using rescue medication compared to 25% of patients who received the full electrical dose. However, data were only available for 10 and 16 patients in each group, and the above differences were not statistically significant (p=0.234). Baseline pain scores were similar between the two groups (p=0.240): mean score 6.0 for the 13 patients with limited current output during stimulation vs. mean score 5.4 for the 17 patients who received the full electrical dose.

[0059] Regarding safety, no adverse events (AEs) or complaints were reported during the clinical trial, confirming the high level of safety of the above treatment. Furthermore, J. Headache Pain 14, 95 (2013) demonstrated safety in a retrospective study of 2313 patients for the prevention of sudden migraine, with only 4.3% reporting adverse effects (including 2.03% intolerance to paresthesia). In our study, 2 out of 34 patients (5.9%) were not enrolled due to failure to pass the tolerability test. This higher percentage of paresthesia intolerance may be explained by increased allodynia during migraine attacks. Interestingly, there was no increase in skin irritation with the longer 60-minute session compared to the 20-minute session used in the previous study.

[0060] Regarding efficacy, mean pain intensity was significantly reduced by 57.0% after 1 hour of treatment and 52.8% after 2 hours. The similar percentages at the two time points indicate that the pain reduction is well maintained at least 1 hour after the end of nerve stimulation. The percentage of patients not using rescue medication was 100% at 2 hours and 65.4% at 24 hours. While the percentage of patients not taking rescue medication within 24 hours in the placebo group for acute treatment of migraine with medication is usually reported to be around 32%, the populations are not the same and the treatment protocols differ, making any comparison difficult. Therefore, it should be taken into consideration that the above study was open-label and that treatment in a clinic setting may enhance the placebo effect, but these efficacy data are promising. On the other hand, treatment in a clinic ensures the proper application / use of the above device and appropriate data collection. Furthermore, it should be considered that patients were recruited at least 3 hours after the onset of a migraine attack to ensure a stable baseline pain intensity, although acute pharmacological treatment is known to be more effective when used earlier in the migraine attack. Therefore, the e-TNS device may still be effective even when used later in the migraine attack.

[0061] Comparison with published data on other acute migraine treatments is limited due to differences in the clinical trial design. Nevertheless, Cephalalgia 19(4), 232-240 (1999) reported a 26.8% reduction in mean pain VAS score at 1 hour for diclofenac and a 17.1% reduction for sumatriptan, compared to 57.1% for e-TNS in our study. At 2 hours, the mean pain score reduction was 50.5% for diclofenac, 40.0% for sumatriptan, and 52.7% using e-TNS.

[0062] Regarding rescue medication use, a recent review of triptans for acute migraine treatment, Headache 55 Suppl 4, 221-235 (2015), reported that rescue medication use after standard-dose triptans ranged from 20% to 34%, with an average of 37% for NSAIDs, compared to 34.6% for e-TNS between 2 and 24 hours. Despite the limitations of these comparisons due to differences in study design, the data suggest similarities in efficacy regarding rescue medication use. Furthermore, it should be noted that e-TNS treatment was applied later in the migraine attack (at least 3 hours) than the acute-phase migraine medications mentioned above, and showed better efficacy when administered earlier in the attack.

[0063] Example 2: External trigeminal nerve stimulator The device is a small, portable product with legs, designed to be attached to the forehead by mounting bipolar adhesive electrodes on the forehead (Figures 2, 4, and 5). The electrodes are approximately 94 mm long and 30 mm high. Two 1.5 V AAA batteries power the device.

[0064] The device is an external cranial nerve stimulator designed for supraorbital nerve stimulation (also known as external trigeminal nerve stimulation or e-TNS). The electrodes are designed to cover both sides of the supratrochlear and supraorbital nerves, which are branches of the trigeminal nerve. Trigeminal nerve stimulation induces a sedative effect on the central nervous system. The electrical impulses generated by the device induce signals (action potentials) in the supratrochlear and supraorbital nerves of the trigeminal nerve. Repeated excitation of the trigeminal nerve is a neuromodulation of the trigeminal system. Neuromodulation of the trigeminal system induces a sedative effect on the central nervous system and alters the trigeminal nociceptive threshold.

[0065] The device preferably performs a session lasting approximately 60 minutes, during which it generates highly precise electrical impulses that enable stimulation of nerve fibers. The electrical impulses are transmitted transcutaneously via bipolar adhesive electrodes placed on the forehead. The device comprises two metal contacts that can be positioned in contact with two conductive areas on the bipolar adhesive electrodes. The device delivers energy in the form of rectangular biphase pulses. The intensity increases linearly until it reaches a maximum of approximately 16 mA after approximately 14 minutes (and then remains constant for approximately 46 minutes). The pulse frequency is approximately 100 Hz. The pulse width is approximately 250 μs. The device has a button that allows the user to stabilize the intensity by pressing the button if they feel the intensity has become too high.

[0066] The legs of the device may be configured to wrap around and secure the sides of the patient's head. Each of the two legs may have a plastic anti-slip layer. The legs of the device may also be configured to support the device over the ears of the patient's head, either additionally or alternatively.

[0067] In one embodiment, the apparatus and electrodes may be sold as the registered trademark Cefaly® and / or Cefaly® Acute.

[0068] Example 3: Double-blind, randomized, sham-controlled comparative trial The primary objective of this study was to evaluate the efficacy and safety of the device disclosed in Example 2 as an acute treatment for migraine attacks (International Classification of Headache Disorders (ICHD)-III Beta (2013) Chapter 1) with or without aura in patients aged 18 to 65 years in a multicenter, double-blind, randomized, sham-controlled comparative trial.

[0069] A multicenter, prospective, double-blind, randomized, sham-controlled comparative clinical trial was conducted at three study sites. Eligible patients were randomized in a 1:1 ratio to receive either a true (verum) stimulus or a sham stimulus and treated with the device during a 1-hour e-TNS treatment session at the clinic. Pain intensity was scored by patients using a visual analog scale (VAS) before treatment, after the 1-hour treatment session, 2 hours after the beginning of the treatment, and finally 24 hours after the beginning of the treatment. The use of anti-migraine rescue medication was recorded 24 hours after the start of e-TNS treatment. Throughout the various phases, the principal investigator monitored for the occurrence of adverse events (AEs). The primary endpoint was the mean change in pain score at the 1-hour time point compared to baseline. Secondary endpoints included the mean changes in pain score at the 2-hour and 24-hour time points compared to baseline, and the proportion of patients who did not require anti-migraine rescue medication within 24 hours after the start of e-TNS treatment.

[0070] A total of 106 patients with migraine attacks, either with or without aura, were randomized and included in the intention-to-treatment (ITT) analysis. Of these, 99 were eligible for the modified intention-to-treatment (mITT) analysis, i.e., randomized patients who provided measurements of headache pain intensity at baseline and at 1 hour after 1 hour of stimulation therapy.

[0071] In terms of safety, one adverse event (nausea) occurred, but this event was not serious and was completely reversible (nausea resolved spontaneously after 20 minutes). No serious adverse events (SAEs) were reported in any group within 24 hours of the start of treatment, and no subjective complaints or side effects were reported.

[0072] In terms of efficacy, in the ITT analysis, the primary endpoint (mean migraine pain intensity after a 1-hour e-TNS session compared to baseline) was significantly reduced in the true stimulation group compared to the sham stimulation group (-3.46±2.32 vs. -1.78±1.89, p<0.001; or -59% vs. -30%, p<0.001). This pain relief percentage was also significantly reduced in the true stimulation group compared to the sham stimulation group at 2 and 24 hours. Similarly in the mITT analysis, mean migraine pain intensity was significantly reduced in the true stimulation group compared to the sham stimulation group at 1 hour (-3.83±2.13 vs. -1.85±1.89, p<0.001; or -65% vs. -32%, p<0.001), as well as at 2 and 24 hours. Furthermore, the percentage of patients pain-free at the 24-hour time point was significantly higher in the true stimulation group compared to the sham stimulation group (32% vs. 13%, p<0.05), and the 30% of patients experiencing sustained pain relief over 24 hours was significantly higher in the true stimulation group compared to the sham stimulation group (43% vs. 21%, p<0.05). The use of anti-migraine rescue medication within 24 hours of treatment initiation was not significantly lower in the true stimulation group.

[0073] Example 4: Non-invasive home treatment for acute phase This embodiment provides an overview of a single-center, prospective, open-label, phase-1 clinical trial focusing on the acute, non-invasive treatment of migraine attacks in the early stages of migraine onset, administered at home.

[0074] 4.1 Treatment System The treatment system, shown in Figures 2C, 2D, 6, and 7 and discussed above in conjunction with Figures 2C, 2D, 6, and 7, comprises a bipolar adhesive skin electrode and a power supply. The power supply includes a rechargeable battery. The power supply is configured to deliver rectangular biphasic pulses with a frequency of approximately 100 Hz and a width of approximately 250 μs. The power supply is configured to linearly increase the pulse intensity from 0 mA to a maximum of approximately 16 mA for the first approximately 14 minutes of the treatment session, and then maintain a pulse intensity of approximately 16 mA for approximately 106 minutes. The power supply includes a tangible non-transient computer-readable memory system for storing information about the treatment session.

[0075] To perform excitation of the trigeminal nerve into the supratrochlear and supraorbital nerves, electrical pulses generated by a power supply device pass through the metal contacts and skin electrodes of the device. Repeated excitation of the trigeminal nerve is a neuromodulation of the trigeminal nervous system that induces a sedative effect on the central nervous system and alters the nociceptive threshold of the trigeminal nerve, resulting in headache relief during migraine attacks.

[0076] 4.2 Survey Criteria Headache pain severity: To assess the change in pain severity from baseline to 2-24 hours, patients were asked to rate the intensity of their headache on the following scale: Grade 0 = no pain; Grade 1 = mild pain; Grade 2 = moderate pain; and Grade 3 = severe pain. Migraine-related symptoms: Patients also noted the presence of migraine-related symptoms (photophobia, phonophobia, nausea, vomiting) and indicated which symptom was the most bothersome (MBS) at baseline. Rescue medication intake: Patients also recorded any acute rescue medications taken during the 24 hours following the start of the e-TNS session.

[0077] 4.3 Group Criteria The following selection criteria were applied: 1. If you are between 18 and 65 years old on the day you signed the informed consent form, 2. Except for aura without headache, hemiplegic migraine, and brainstem aura migraine, a history of migraine with or without aura for more than one year, according to the diagnostic criteria set out in Chapter 1, Migraine (8) of ICHDIII Beta (2013), 3. Onset of migraines before the age of 50, 4. In the two months prior to screening, 2 to 8 moderate or severe migraine attacks (grade 2 or grade 3) per month. 5. Patients will voluntarily agree to participate in the study by understanding the research procedures and available alternative treatments and providing written informed consent. 6. The patient is able to read and understand written information (instruction sheets, diary forms, and AE collection forms).

[0078] The following exclusion criteria were applied: 1. Patients have difficulty distinguishing between migraine attacks and tension-type headaches. 2. The patient has more than 15 days of headache per month. 3. Patients who have received a supraorbital nerve block in the past four months. 4. Patients who have received Botox treatment in the past four months, 5. Changes in migraine prevention treatment over the past three months. 6. Diagnosis of other primary headache disorders, excluding rare tension-type headaches (less than 4 times per month) 7. Diagnosis of secondary headache disorders, including medication overuse headache. 8. Patients who abuse opioids, or who use recreational drugs or illegal substances, or who have a recent medical history (within the past year) of drug or alcohol abuse or dependence. 9. Metal or electrical devices implanted inside the head, 10. Cardiac pacemakers, or implantable or wearable defibrillators. 11. Patients who have previously used Cefaly® devices, 12. Migraine aura without headache, 13. The patient is currently participating in or has previously participated in a study using the compound or device under investigation during the 30-day period prior to the screening visit. 14. Patients who are unable to properly use and / or perform the treatment system themselves, or who are unable to tolerate the first 20-minute stimulation session during a training session at the research site.

[0079] 4.4 Research Protocol 4.4.1 Patient Recruitment Phase A summary of the study protocol is shown in Figure 8. A total of 60 patients were screened. Patients received training on the practical use of the treatment system (oral explanation, video, and instruction sheets) and performed their first 20-minute treatment session themselves to confirm their ability to use the treatment system appropriately. One patient failed the training test (exclusion criterion 14), so a total of 59 patients were included in the study.

[0080] Patients who met all inclusion criteria and did not meet any exclusion criteria were enrolled in the clinical trial. Patients received a home-use treatment system for treating a single migraine attack, along with a diary and adverse effects forms. The principal investigator instructed patients on how to complete these documents.

[0081] To ensure patients understood the procedure, they completed a practice diary for simulated migraines between screening visits. The principal investigator or clinical trial coordinator then reviewed the diary in detail with the patient.

[0082] 4.4.2 Acute Treatment Phase During the two months following the screening visit, patients were instructed to treat one eligible migraine episode. A migraine is considered eligible if all of the following conditions are met: 1. The severity of the migraine pain is moderate or severe (grade 2 or grade 3). 2. The migraine is associated with at least one of the following migraine-related symptoms: photophobia, phonophobia, nausea, or vomiting. 3. The migraine started more than 4 hours prior to the episode, or the patient woke up due to a migraine. 4. You have not experienced any other migraines or headaches in the past 48 hours. 5. The migraine has not yet resolved on its own; that is, the pain has not yet subsided. 6. I have not taken any acute migraine medication since the onset of my migraines.

[0083] If the patient had a qualifying migraine, they should immediately apply the above system for a full 2-hour treatment session if the migraine was moderate or severe (grade 2 or grade 3).

[0084] In their diaries, patients recorded the grade of headache pain severity. They also recorded migraine-related symptoms (photophobia, phonophobia, nausea, vomiting), indicating which related symptom was the most troublesome (MBS). Patients recorded this data for the duration of each stimulation session immediately before the start of treatment and 2 hours after the start of the treatment session (usually immediately after the device and electrodes were removed, if the session was performed correctly) (2-hour data). Patients were also required to record any auras associated with a qualifying migraine attack. Patients similarly recorded migraine-related symptoms.

[0085] The patient was instructed not to take any acute-phase anti-migraine medications during the two-hour acute-phase treatment phase. Taking medication during the two-hour treatment phase was considered a protocol violation.

[0086] When the treatment system was stopped during the acute treatment phase, restart was not permitted. The duration, intensity, and / or interruption were recorded for each patient by an electronic system built into the power supply unit.

[0087] Patients recorded all adverse events that occurred during the treatment phase on an adverse events sheet. Furthermore, patients were instructed to immediately notify the principal investigator of any severe or serious adverse events caused by the stimulus.

[0088] 4.4.3 Post-treatment phase If, two hours after the start of a treatment session, the migraine was still moderate or severe, or if a moderate or severe headache returned after the initial pain relief (no headache or mild headache pain), the patient was permitted to take rescue medication.

[0089] Patients were required to record the severity of their headache pain and any migraine-related symptoms in a diary during the first 24 hours of each treatment session (24-hour data). They were also instructed to record in their diary any rescue medication they took during the first 24 hours of each treatment session.

[0090] On the adverse effects sheet, patients recorded all adverse effects that occurred within 24 hours of the start of the treatment session. Furthermore, patients were instructed to immediately notify the principal investigator of any severe or serious adverse events caused by the stimulation.

[0091] 4.4.4 Last hospital visit Patients were instructed to return to the research facility approximately four days after their treatment session to return the treatment system, diary, and adverse events report. The principal investigator thoroughly reviewed the written diary to ensure data accuracy (to avoid any missing, unclear, or inconsistent data).

[0092] All adverse events reported on the adverse events form were reviewed by the principal investigator to determine their severity. Furthermore, the principal investigator inquired about any adverse events not reported on the form.

[0093] 4.4.5 Patients conforming to the research protocol Of the 59 patients, 11 did not adhere to the study protocol: Four patients withdrew from the study; One patient's whereabouts are unknown and they did not return; and, Six patients violated the protocol: Two patients did not experience qualifying migraines during the two-month period; Two patients took rescue medication within a two-hour treatment period, and one of them did not report the severity or symptoms of headache during that time. Two patients did not report the severity or symptoms of headache within two hours.

[0094] A total of 48 patients completed the study and were eligible for modified intention-to-treatment (mITT) analysis.

[0095] At baseline, pain intensity was moderate in 68.75% of patients and severe in 31.25%.

[0096] A total of 15 patients (31.25%) experienced migraine attacks with aura, while 33 patients (68.75%) experienced migraine attacks without aura.

[0097] The most frequently reported MBS at baseline was photophobia (56.25%). Nausea and phonophobia were the second most frequently reported MBS at baseline (22.92% and 18.75%, respectively). Only one patient (2.08%) reported vomiting as an MBS at baseline.

[0098] 4.5 Statistical analysis 4.5.1 Hypothesis 1. The above treatment provides relief from pain within 2 hours and from persistent pain within 24 hours. It enables the achievement of pain relief, as measured by [method / measurement]. 2. The above treatment makes it possible to achieve relief from migraine-related symptoms, which is measured by the percentage of patients who are free from BS within 2 hours and who are free from migraine-related symptoms within 2 hours. 3. The above treatment makes it possible to achieve pain relief as measured by pain relief within two hours. 4. The above treatments enable a reduction in the use of rescue medication, which is measured by the use of rescue medication between 2 and 24 hours. 5. No severe adverse effects were observed from a 2-hour e-TNS session using the above treatment system within 24 hours of the start of treatment.

[0099] 4.5.2 Methods of statistical analysis Statistical analysis was performed based on modified treatment intentions (mITT). Patient data were included in the mITT analysis only if all of the following conditions were met: 1. The patient was treated for a qualifying migraine. 2. Patients applied the treatment within at least one minute (patients who stopped the 2-hour treatment session before completion for any reason were included in the mITT analysis if all other conditions were met). 3. Baseline headache pain severity scores and migraine-related symptoms (if multiple) were reported in a diary. 4. Patients reported their headache pain severity score or migraine-related symptoms (if multiple) at 4.2 hours in a diary.

[0100] If a patient took rescue medication between 2 and 24 hours after the start of an e-TNS session, headache pain intensity and the presence of associated symptoms may be affected by the medication. The last value carried forward method (in this case, using the 2-hour value) was applied to headache pain severity and migraine-related symptoms at the 24-hour time point.

[0101] 4.6 Results A total of 17 patients (35.42%) experienced no pain during the 2-hour period. A total of 29 patients (60.42%) did not experience MBS within the 2-hour period. Of the 11 patients with nausea as baseline MSB, 5 (45.45%) did not have MBS at 2 hours; Of the one patient with vomiting as baseline MSB, 0 (0.0%) did not have MBS at 2 hours; Of the 27 patients with photophobia as baseline MSB, 17 (62.96%) did not have MBS at 2 hours; Of the nine patients with phonophobia as baseline MSB, seven (77.78%) did not have MBS at 2 hours; A total of 34 patients (70.83%) achieved pain relief after 2 hours. A total of 22 patients (45.83%) did not have migraine-related symptoms at the 2-hour mark. Half of the patients took rescue medication after their treatment sessions. A total of 12 patients (25.00%) achieved relief from persistent pain after 24 hours.

[0102] On average, patients used the treatment system for 111.23 minutes. A total of 42 patients used the treatment system for the required 120 minutes.

[0103] Of the 59 patients enrolled in the clinical trial, 15 reported at least one adverse event. A total of 21 adverse events were reported. All reported adverse events were not serious and were completely reversible (they resolved without any lasting effects). The most frequently reported adverse events were forehead burning (7 / 21), as well as forehead itchiness, tingling, burning, and / or numbness (5 / 21). Note that four patients discontinued the study due to adverse events: three due to forehead burning and one due to severe tingling inside the head. No serious adverse events were reported throughout the series of trials. No adverse systemic therapeutic effects were observed throughout the series of trials.

[0104] 4.7 Comparison with drugs The present invention compares the treatment with several drugs: [A] Adhesive transdermal microarray (ADAM) zolmitriptan (3.8 mg), data from Spierings et al., Cephalalgia 38(2), 215-224 (2018), http: / / dx.doi.org / 10.1177 / 0333102417737765. [B] Lasmiditan (400 mg), data from Faerkkilae et al., The Lancet Neurology 11(5), 405-413 (2012), http: / / dx.doi.org / 10.1016 / S1474-4422(12)70047-9. [C] Sumatriptan iontophoresis transdermal system, data from Goldstein et al., Headache: The Journal of Head and Face Pain 52(9), 1402-1410 (2012), http: / / dx.doi.org / 10.1111 / j.1526-4610.2012.02198.x. [D] Sumatriptan nasal powder (AVP-825), data from Cady et al., Headache: The Journal of Head and Face Pain 55(1), 88-100 (2015), http: / / dx.doi.org / 10.1111 / head.12472. [E] Transcranial Magnetic Stimulation ** Data from Lipton et al., The Lancet Neurology 9(4), 373-380 (2010), http: / / dx.doi.org / 10.1016 / S1474-4422(10)70054-5. [F] Ubrogepant (100 mg), Voss et al., Cephalalgia 36(9), 887-898 (2016), http: / / dx.doi.org / 10.1177 / 0333102416653233 data.

[0105] A summary of the comparison is provided in Table 3. The table includes the percentage of patients.

[0106] Table 3 - Comparison of results from this study with those of drugs [Table 3] * It has no connection to MBS. ** 75% of patients had no pain or only mild pain at baseline. *** Values ​​are derived from protocol-specific datasets limited to patients with moderate or severe pain at baseline, while other values ​​are derived from the mITT dataset. **** Treatment-related adverse events occurred in 5% of cases.

[0107] As measured by pain relief within two hours, the treatment system of the present invention enables the achievement of pain relief. The results are better than those reported for other acute treatments, excluding ADAM zolmitriptan and transcranial magnetic stimulation. The 24-hour sustained pain relief associated with the treatment system of the present invention is limited by a high percentage of rescue medication intake, but is within the range reported for other acute treatments (20%–30%).

[0108] As measured by the percentage of patients who are free from migraine-related symptoms within two hours and the percentage of patients who are free from migraine-related symptoms within two hours, the treatment system of the present invention makes it possible to achieve relief from migraine-related symptoms. The results are better than those reported for other acute treatments other than ADAM zolmitriptan.

[0109] The treatment system of the present invention enables pain relief, as measured by pain relief within two hours. The results are better than those reported for other acute treatments, excluding ADAM zolmitriptan and transcranial magnetic stimulation.

[0110] The therapeutic system of the present invention is associated with a higher rate of rescue drug intake within 2 to 24 hours compared to triptans, but is similar to the rates reported for transcranial magnetic stimulation.

[0111] In terms of safety, the therapeutic system of the present invention is associated with a significantly better level of safety than triptans. Compared to ADAM zolmitriptan, the triptan with the best efficacy results, the number of patients experiencing at least one adverse event is significantly lower with respect to the therapeutic system of the present invention (18.6%, compared to 51.8% for ADAM zolmitriptan).

[0112] Based on these findings, the treatment system of the present invention appears to have a better efficacy / safety ratio among the currently available interrupt therapies for migraine. Since many patients are known to be prone to the abuse of acute-phase anti-migraine medications, a major factor in the chronicity of migraines, this safe, effective, drug-free, non-invasive acute-phase anti-migraine treatment would represent an advance in the management of migraine patients.

[0113] In one embodiment, the treatment system, bipolar adhesive electrodes, and / or power supply device may be marketed under the registered trademarks Cefaly®, Cefaly® Acute, and / or Cefaly® Abortive Program. [Explanation of Symbols]

[0114] Figure 1 0 h 0 hours 5 min 1 h 1 hour 2 h 2 hours 24 hours 24 hours Screening Treatment phase Neurostimulation using Cefaly™ Cefaly® Post-treatment phase No treatment Follow-up Baseline pain score Nociceptive test 1-hour pain score 2-hour pain score / rescue medication intake 24-hour rescue medication intake Figure 3 Mean pain intensity baseline 1 hour 2 hours Figure 8 Recruitment phase Acute treatment phase Acute treatment phase Post-treatment phase Screening love, going to the clinic for screening Meet the inclusion criteria and not meet the exclusion criteria 1-13. Failed screening and not included in the trial. e-TNS 20-minute training session Training session succeeded. Included for the acute treatment phase One qualifying migraine during the 2 months following the screening visit. Baseline measurements (pain intensity and migraine-associated symptoms) A 2-hour e-TNS session using the Cefaly™ Abortive Program device. 2-hour measurements (pain intensity and migraine-associated symptoms) 24-hour follow-up 24-hour measurements (pain intensity, migraine-related symptoms, and medication intake) Final visit

Claims

1. A non-invasive treatment system for the acute phase of migraine attacks in the user, A skin electrode configured to supply continuous biphasic electrical pulses, The device is equipped with a button that is releasably coupled to the skin electrode and can be pressed by the user. By pressing a pressable button, the amplitude of the consecutive biphasic electrical pulses can be linearly increased to a pre-configured amplitude limit during a first portion of the time span, and the pre-configured amplitude limit can be maintained during a second subsequent portion of the time span, A device configured to maintain the amplitude of the continuous biphasic electrical pulses at or prior to the amplitude at the time the user presses and releases the button during a first portion of the time span, A system equipped with, A system in which the device is configured to rapidly increase the amplitude of the continuous biphasic electrical pulses up to the pre-configured amplitude limit when a button pressable by the user is pressed continuously for several seconds.

2. The system according to claim 1, wherein the device is configured to maintain the amplitude of the consecutive biphasic electrical pulses at the pre-configured amplitude limit during the second subsequent portion of the time span if no button pressable by the user is pressed during the first portion of the time span.

3. The system according to claim 1, wherein the time span is at least 10 minutes.

4. The system according to claim 1, wherein the device is configured to set one or more of the pulse frequency of the continuous biphase electrical pulses, the pulse width of the continuous biphase electrical pulses, the pulse amplitude of the continuous biphase electrical pulses, the pulse ramp-up time of the continuous biphase electrical pulses, the pulse ramp-up gradient of the continuous biphase electrical pulses, and the time span.

5. The system according to claim 1, wherein the pulse frequency of the continuous biphasic electrical pulses is approximately 80 Hz to approximately 300 Hz.

6. The system according to claim 1, wherein the pulse width of the continuous biphasic electrical pulses is approximately 250 μs.

7. The system according to claim 1, wherein the skin electrode includes an adhesive.

8. The system according to claim 7, wherein the adhesive comprises a hypoallergenic gel.

9. The system according to claim 1, wherein the skin electrode is configured to be attached to the user's forehead.

10. The system according to claim 1, wherein the system is configured to deliver the continuous biphasic electrical pulses to the user's trigeminal nerve.

11. The system according to claim 1, wherein the pre-configured amplitude upper limit is approximately 5mA to approximately 25mA.

12. The system according to claim 1, wherein the first portion of the time span is approximately 5 minutes to approximately 20 minutes.

13. The system according to claim 1, wherein the device is configured to increase the amplitude of the continuous biphasic electrical pulses to the pre-configured amplitude upper limit within 30 seconds when a button pressable by the user is pressed continuously for several seconds.

14. The system according to claim 1, wherein the device is configured to maintain a constant amplitude of the continuous biphasic electrical pulses when a button pressable by the user is repeatedly pressed and then released.

15. The system according to claim 1, wherein the apparatus is configured to linearly increase the amplitude of the continuous biphasic electrical pulses up to the pre-configured upper amplitude limit with a gradient of approximately 8 μA / s to approximately 83 μA / s.

16. The system according to claim 1, wherein the device comprises a wireless communication module.

17. The system according to claim 1, wherein the device is configured to initiate the continuous biphasic electrical pulses when a button pressable by the user is pressed before the first portion of the time span.

18. The system according to claim 1, wherein the skin electrode comprises a bipolar electrode.

19. The system according to claim 1, wherein the device is configured to be electrically coupled to the skin electrode.

20. The system according to claim 1, wherein the device is configured to be magnetically coupled to the skin electrode.

21. The system according to claim 1, wherein the skin electrode comprises two conductive areas, the device further comprises two metal contacts, and the two metal contacts of the device are releasably coupled to the two conductive areas of the skin electrode.

Images