Migraine Review Non-invasive neuromodulation for migraine and cluster headache: a systematic review of clinical trials Uwe Reuter,‍ ‍ 1 Candace McClure,2 Eric Liebler,3 Patricia Pozo-Rosich4,5 ►► Additional material is Abstract or concomitantly with pharmacological treatment. published online only. To view Non-invasive neuromodulation therapies for migraine Non-invasive neuromodulation also offers a novel please visit the journal online (http://​dx.​doi.​org/​10.​1136/​ and cluster headache are a practical and safe alternative alternative for those in sensitive patient populations jnnp-​2018-​320113). to pharmacologics. Comparisons of these therapies (eg, pregnant women or adolescents), or for those are difficult because of the heterogeneity in study affected by poor tolerability or lack of efficacy with 1 Department of Neurology, designs. In this systematic review of clinical trials, the pharmacologics. Charité–Universitätsmedizin Comparisons among the expanding number of scientific rigour and clinical relevance of the available Berlin, Berlin, Germany 2 North American Science data were assessed to inform clinical decisions about non-invasive neuromodulation device trials are Associates, Minneapolis, non-invasive neuromodulation. PubMed, Cochrane challenging because of the heterogeneity of clin- Minnesota, USA Library and ​ClinicalTrials.​gov databases and the WHO’s ical study designs and range of predefined efficacy 3 electroCore, Inc, Basking Ridge, International Clinical Trials Registry Platform were outcomes. These inconsistencies among the non-in- New Jersey, USA 4 Headache and Craniofacial Pain searched for relevant clinical studies of non-invasive vasive neuromodulation trials may be due in part Unit, Neurology Department, neuromodulation devices for migraine and cluster to the absence of guidelines for conducting trials Hospital Universitari Vall headache (1 January 1990 to 31 January 2018), and 71 in primary headache. While such guidelines are in d’Hebron, Barcelona, Spain were identified. This analysis compared study designs development, clinicians should currently base their 5 Headache Research Group, treatment decisions on the best available evidence using recommendations of the International Headache VHIR, Universitat Autònoma de Barcelona, Barcelona, Spain Society for pharmacological clinical trials, the only from rigorous clinical trials. Until non-invasive available guidelines for migraine and cluster headache. neuromodulation-specific study recommendations Correspondence to Non-invasive vagus nerve stimulation (nVNS), single- become available, neuromodulation trials designed Dr Uwe Reuter, Department transcranial magnetic stimulation and external trigeminal and conducted in accordance with existing guide- of Neurology, Charité– nerve stimulation (all with regulatory clearance) were lines of the International Headache Society (IHS) Universitätsmedizin Berlin, for controlled studies of pharmacological therapies well studied compared with the other devices, for Berlin 10117, Germany; ​uwe.​ reuter@​charite.​de which studies frequently lacked proper blinding, sham continue to provide the greatest scientific rigour controls and sufficient population sizes. nVNS studies and consistency.7 Adherence to future guidelines Received 30 November 2018 demonstrated the most consistent adherence to available currently under development will allow for greater Revised 21 January 2019 guidelines. Studies of all neuromodulation devices should uniformity among studies to help clinicians make Accepted 22 January 2019 Published Online First 1 March strive to achieve the same high level of scientific rigour informed decisions on appropriate treatment 2019 to allow for proper comparison across devices. Device- options for their patients. specific guidelines for migraine and cluster headache will be soon available, but adherence to current guidelines Objective for pharmacological trials will remain a key consideration The objective of this article was to systematically for investigators and clinicians. review the clinical study designs of non-inva- sive neuromodulation trials for the treatment of migraine and cluster headache in order to assess the scientific rigour and clinical relevance of these devices and their associated clinical data. Clinicians Introduction and investigators can use this assessment to make Non-invasive neuromodulation alters neural informed decisions on treatment options and design activity through the stimulation of nerves or neural more rigorous studies for patients with migraine tissue. This technology is emerging as a practical and cluster headache. and safe alternative to conventional pharmacolog- ical interventions for the treatment of migraine Methods/literature search strategy and cluster headache.1 The demonstrated efficacy Four databases were systematically searched for and safety of several non-invasive neuromodula- clinical trials in the non-invasive neuromodula- tion therapies, including non-invasive vagus nerve tion of migraine and cluster headaches: ​PubMed.​ stimulation (nVNS), external trigeminal nerve gov, the Cochrane Library, ​ClinicalTrials.​gov and © Author(s) (or their stimulation (e-TNS) and single-pulse transcra- employer(s)) 2019. Re-use the WHO’s International Clinical Trials Registry permitted under CC BY-NC. No nial magnetic stimulation (sTMS), has generated Platform (WHO-ICTRP). The Preferred Reporting commercial re-use. See rights interest among clinicians and patients.2 3 The clear- Items for Systematic Reviews and Meta-Anal- and permissions. Published ance of these therapies by CE mark in the European yses (PRISMA) methodology was followed in this by BMJ. Union and the US Food and Drug Administration review.8 To cite: Reuter U, McClure C, (FDA) provides an alternative for the treatment of Liebler E, et al. J Neurol primary headache.4–6 These devices could present a Identification of research studies Neurosurg Psychiatry unique flexible treatment option because they can Medline through ​ PubMed.​ gov was systemat- 2019;90:796–804. be used as an early therapy, either independently ically searched for all clinical trials assessing 796 Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 Migraine review’ in Publication Type; and ‘1990’ to ‘2018’ in publication Table 1 Clinical trial neuromodulation devices analysis inclusion and year. A search limit was placed on ‘trials’ only. exclusion criteria ClinicalTrials.​ ​ gov was systematically searched for all clin- Inclusion Exclusion ical trials (ie, all types of recruitment status) assessing neuro- Non-invasive devices Invasive devices modulation OR neurostimulation OR stimulation treatments ►► Transcutaneous ►► Implanted in migraine OR headache (ie, Condition or disease) between ►► Transcranial ►► Percutaneous 1 January 1990 and 31 January 2018. The WHO-ICTRP was ►► External ►► Requiring surgical procedures also searched for all clinical trials (ie, all types of recruitment Neuromodulation device Non−peer review or registry publications status) assessing neuromodulation OR neurostimulation OR ►► Neurostimulation ►► News articles ►► Stimulation ►► Abstracts and posters stimulation (ie, Intervention) treatments in migraine OR head- ►► Electrical or magnetic ►► Conference proceedings ache (ie, Condition) between 1 January 1990 and 31 January Patients with migraine or cluster Secondary headache-related indications 2018. Since the neurologic effect can be excitatory or inhibitory, headache as defined by International ►► Traumatic brain injury the preferred term is neuromodulation rather than neurostimu- Classification of Headache Disorders ►► Cervical injury lation, which is used in this review. Clinical trial registration is Published/registered between 1 January ►► Substance abuse/withdrawal currently required by the US FDA for approval and clearance of 1990 and 31 January 2018 ►► Non-specific or facial pain devices and by the International Committee of Medical Journal ►► Infection Editors as a condition of consideration for publication.9–11 Human clinical trials only Observational or diagnostic only The broad search term ‘headache’ was used instead of ‘cluster English-language articles or registries Review articles headache’ to provide comprehensive search results and minimise exclusion of relevant studies. ‘Non-invasive’ was not specified in the search because studies often do not explicitly categorise neuromodulation treatments in migraine and cluster headache treatments in this manner and instead use implied terminology that were published between 1 January 1990 and 31 January (eg, transcutaneous, transcranial, external). 2018. Search terms were ‘neuromodulation OR neurostimu- lation OR stimulation’ and ‘migraine OR headache’; publica- Screening tion type ‘clinical trial NOT review’; and language ‘English’. Trials from WHO-ICTRP were cross-referenced with those The Cochrane Library was searched for ‘neuromodulation OR from ​ClinicalTrials.​gov, and duplicates were removed to create neurostimulation OR stimulation’ in Title, Abstract, Keywords; a master list of unique clinical trials. Research articles from ‘migraine OR headache’ in Title, Abstract, Keywords; ‘NOT PubMed and the Cochrane Library were matched to a registered Table 2 Non-invasive neuromodulation clinical trials in acute migraine treatments Percentage of studies evaluating IHS- Enrolled Both aura and Blinded Sham- recommended endpoints population no aura patients studies controlled Device type* Studies (n) (total n) included (%) (n)† studies (n) Primary (%)‡ Secondary (%)‡ Electrical nerve stimulation  Non-invasive vagus nerve stimulation 4 396 100 2 2 100 100 (nVNS)  External trigeminal nerve stimulation 3 196 100 1 1 33 100 (e-TNS)  Occipital and supraorbital 3 106 100 2 3 0 100 transcutaneous nerve stimulation (OS-TNS)  Transcranial direct current stimulation 1 32 100 0 0 0 0 (tDCS)  Transcranial alternating current 1 40 100 1 1 100 0 stimulation  Auricular transcutaneous vagus nerve 1 50 100 1 1 0 0 stimulation Magnetic stimulation  Single-pulse transcranial magnetic 2 309 50 2 1 50 50 stimulation (sTMS)  Repetitive transcranial magnetic 1 201 0 1 1 100 100 stimulation (rTMS) Other  Conditioned pain modulation 3 476 100 3 3 0 33  (CPM)  Intranasal kinetic oscillation 1 36 100 1 1 0 0 stimulation *All references for studies in this table are listed in the online supplementary references. †Double-blind or better. ‡Percentage of efficacy studies in which either a primary or a secondary endpoint recommended by the International Headache Society was used. Safety studies were excluded from this calculation. IHS, International Headache Society. Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 797 Migraine clinical trial12; matched data were combined as a single record predefined IHS-recommended endpoints. For acute and preven- for analysis. tive migraine treatments, the number of studies conforming to the IHS recommendation to include both patients with aura Inclusion and exclusion criteria and without aura was also examined.16 IHS recommendations A list of a priori inclusion and exclusion criteria was applied for controlled trials of drugs in migraine and cluster headache to ensure that only relevant studies were evaluated (table 1). were used to evaluate whether the recommended primary and Only clinical trials of neuromodulation devices in patients secondary endpoints were evaluated in the identified studies for with migraine or cluster headache, as defined by the Interna- each device.16–18 tional Classification of Headache Disorders Third Edition (or All devices that are both CE marked and cleared by the FDA earlier editions when applicable), were eligible.13–15 Studies for migraine and cluster headache as well as devices used in more with patient populations that comprised comorbidities were than two studies for either the acute or preventive treatment of excluded. Only trials evaluating a non-invasive treatment of the migraine are reported in the Results section for all applicable central or peripheral nervous system in migraine and cluster study indications. The remaining devices that had two studies or headache were included for analysis. Invasive neuromodulation fewer are presented only in tables 2 and 3. All devices in cluster therapies were excluded from this review because these treat- headache were reported in the Results section. ments are reserved for intractable diseases and are considered separate from standard of care options. Studies that were obser- Results vational or diagnostic only or that used any invasive device Search results including acupuncture were excluded, as were studies that had Of the 647 studies identified in the systematic search, 509 were only healthy patient populations or patients with non-specific screened for eligibility, and 71 fulfilled the specified inclusion pain. Only studies reported in peer-reviewed publications and/ criteria (figure 1). Fifteen published studies were not regis- or properly registered clinical trials were included; posters and tered with ​ClinicalTrials.​gov or another WHO primary registry. congress abstracts were excluded from formal analysis. Sixteen published studies had a corresponding registration and Two reviewers independently reviewed the inclusion of studies thus fulfilled the ethical recommendations for reporting results according to a priori inclusion criteria. Data were independently of clinical trials.19 The remaining 40 studies were registered with​ categorised by the same reviewers and confirmed by a third ClinicalTrials.​gov (34 studies) or another WHO primary registry reviewer. The same two reviewers evaluated the data and results (six studies) without a corresponding publication. of the clinical trials included in this assessment. The search identified non-invasive neuromodulation clinical trials in the acute treatment of migraine (20 studies), migraine Data collection and analysis prevention (48 studies), acute treatment of cluster headache (2 The data collected in this systematic review were categorised by studies) and cluster headache prevention (2 studies). One study type of headache treatment and indication. The elements eval- evaluated both acute and preventive interventions in migraine. uated were the total patient population among all studies and The complete list of studies is available as online supplementary whether each study was blinded, was sham controlled and used references. Table 3 Non-invasive neuromodulation clinical trials in preventive migraine treatments Percentage of studies evaluating IHS- Enrolled Both aura and Blinded Sham- recommended endpoints population no aura patients studies controlled Device type* Studies (n) (total n) included (%) (n)† studies (n) Primary (%)‡ Secondary (%)‡ Electrical nerve stimulation  Transcranial direct current stimulation (tDCS) 18 855 94 15 15 50 72  Non-invasive vagus nerve stimulation (nVNS) 4 626 100 3 3 100 33  External trigeminal nerve stimulation (e-TNS) 3 194 100 1 1 33 100  Transcutaneous electrical nerve stimulation 2 76 100 0 0 0 50  Transcutaneous supraorbital nerve stimulation 1 80 100 1 1 100 100  Auricular transcutaneous vagus nerve 1 58 100 1 1 0 100 stimulation  Cranial electrotherapy stimulation 1 68 100 1 1 100 100 Magnetic stimulation  Repetitive transcranial magnetic stimulation 10 416 90 5 8 30 80  (rTMS)  Single-pulse transcranial magnetic stimulation 1 263 100 0 0 0 100 (sTMS)  Deep transcranial magnetic stimulation 1 14 100 0 0 0 100 Other  Caloric vestibular stimulation (CVS) 3 291 67 2 2 100 67  Intranasal kinetic oscillation stimulation 2 220 100 2 2 100 100  Auditory biofeedback 1 40 100 0 0 0 0 *All references for studies in this table are listed in the online supplementary references. †Double-blind or better. ‡Percentage of efficacy studies in which either a primary or a secondary endpoint recommended by the International Headache Society was used. Safety studies were excluded from this calculation. IHS, International Headache Society. 798 Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 Migraine these criteria are as follows: nVNS, e-TNS, repetitive transcra- nial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), occipital and supraorbital transcutaneous nerve stimulation (OS-TNS), conditioned pain modulation (CPM) and caloric vestibular stimulation (CVS). sTMS was evaluated in only three studies (ie, two in acute treatment; one in preventive treatment) but is included because of its CE mark and FDA clearance as both an acute and preventive treatment for migraine. Non-invasive vagus nerve stimulation nVNS was examined in 10 studies for the treatment of primary headache: four studies of the acute treatment of migraine, four studies in migraine prevention, two studies in acute cluster head- ache treatment and one study in cluster headache prevention. One nVNS study included acute and preventive migraine treat- ment regimens and was assessed in both interventions. Four studies were registered on ​ClinicalTrials.​gov or another WHO primary registry but were not yet published, whereas six studies were both published and registered. Migraine In the acute treatment of migraine (table 2), the four nVNS Figure 1 Flow diagram of trial selection. *Trials were excluded because studies had a total population of 396 patients who had migraine study objectives were mechanistic only. ICTRP, International Clinical Trials with and without aura. Two of the acute nVNS trials used Registry Platform.*Trials were excluded because study objectives were blinding and sham controls along with the IHS-recommended mechanistic only. primary and secondary efficacy endpoints; the remaining two acute nVNS trials were exclusively safety studies and were not This analysis compares clinical trial designs of non-invasive included in the assessment of efficacy endpoints. One nVNS neuromodulation devices with the available guidelines from study (​ClinicalTrials.​ gov identifier: NCT02378844) evaluated the IHS for acute and preventive pharmacological treatment both acute and preventive treatment regimens and included of migraine and cluster headache.16–18 Developed as guidelines patients with either episodic or chronic migraine; the IHS recom- for the design of pharmacological clinical trials, the current IHS mends excluding patients with chronic migraine from acute recommendations do not specifically address therapeutic devices. treatment studies, but the primary and secondary endpoints of These guidelines were determined as the most rigorous standard this study were focused on evaluating migraine prevention.20 In against which to assess the quality of non-invasive neuromodu- migraine prevention (table 3), the four nVNS studies had a total lation studies in the treatment of migraine and cluster headache. population of 626 patients who had migraine with and without Devices with more than two studies for an indication are aura. Three of the preventive nVNS trials used blinding and reported. Six devices each had two or fewer studies in the sham controls along with at least one of the IHS-recommended acute treatment of migraine (table 2), and eight devices each primary efficacy endpoints; one trial used the pertinent IHS-rec- had two or fewer studies in migraine prevention (table 3). All ommended secondary efficacy endpoints. One preventive nVNS devices with studies evaluating the treatment of cluster head- trial was designed as a safety study and was not included in the ache are presented in table 4. The devices reported based on assessment of efficacy endpoints. Table 4 Non-invasive neuromodulation clinical trials in acute and preventive cluster headache treatments Percentage of studies evaluating IHS- recommended endpoints Enrolled population Blinded studies Sham-controlled Primary endpoint Secondary endpoint Device type* Studies (n) (total n) (n)† studies (n) (%)‡ (%)‡ Acute cluster headache treatments  Non-invasive vagus nerve stimulation (nVNS) 2 253 2 2 100 100 Preventive cluster headache treatments  Non-invasive vagus nerve stimulation (nVNS) 1§ 97 0 0 100 100  Transcranial direct current stimulation (tDCS) 1 32 0 0 0 100 *All references for studies in this table are listed in the online supplementary references. †Double-blind or better. ‡Percentage of efficacy studies in which either a primary or a secondary endpoint recommended by the International Headache Society was used. Safety studies were excluded from this calculation. §Marin et al’s study (used for recent Food and Drug Administration clearance) not included here as it was published outside of predefined date range. IHS, International Headache Society. Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 799 Migraine Cluster headache Repetitive transcranial magnetic stimulation nVNS is the only identified non-invasive neuromodulation Migraine device that has been evaluated in the acute treatment of cluster rTMS was evaluated in 11 studies for the acute and preventive headache (table 4). The two nVNS studies had a total population treatment of migraine. Four studies were registered on ​Clin- of 253 patients, were blinded and sham controlled and adhered icalTrials.​gov or another WHO primary registry but were not to the IHS-recommended primary and secondary efficacy published; one study was published and registered; six studies endpoints. In cluster headache prevention (table 4), one study were published without registration. with a population sample size of 97 patients was randomised In the acute treatment of migraine (table 2), one rTMS study and controlled, but not blinded or sham controlled. This study of 201 patients was identified. The rTMS study was blinded adhered to the IHS-recommended primary and secondary effi- and sham controlled and included only patients with aura. The cacy endpoints. rTMS study used IHS-recommended primary and secondary efficacy endpoints. In migraine prevention (table 3), 10 rTMS studies with a total population of 416 patients were identi- External trigeminal nerve stimulation fied. Nine studies on rTMS for preventive treatment evaluated Migraine patients with migraine with and without aura, five studies were e-TNS was examined in six studies for the acute or preventive blinded and eight studies were sham controlled. Thirty per cent treatment of migraine. Four studies were registered on C ​ linical- of the preventive rTMS studies used IHS-recommended primary Trials.​gov, one study was published and registered and one study efficacy endpoints, and 80% used IHS-recommended secondary was published without registration. efficacy endpoints. In the acute treatment of migraine (table 2), the three e-TNS studies had a total population of 196 patients with and without Cluster headache aura; one study was blinded and sham controlled. One acute No studies of the rTMS device for the treatment of cluster head- e-TNS study used a primary endpoint recommended by the ache were identified. IHS. All three studies used at least one IHS-recommended secondary efficacy endpoint. Contrary to IHS recommendations for studies in acute migraine treatment, two of these studies Transcranial direct current stimulation included patients with chronic migraine. In preventive migraine tDCS was evaluated in 20 studies for the acute and preventive (table 3), the three e-TNS studies had a total population of 194 treatment of migraine and for chronic cluster headache preven- patients with and without aura; one study was blinded and sham tion. Fifteen studies were registered on C ​ linicalTrials.​ gov or controlled. One preventive e-TNS study used a primary efficacy another WHO primary registry but were not published; one endpoint recommended by the IHS; all three studies used at least study was published and registered; four studies were published one IHS-recommended secondary efficacy endpoint. without registration. Migraine Cluster headache In the acute treatment of migraine (table 2), the single tDCS No e-TNS studies for the treatment of cluster headache were study had a population of 32 patients with and without aura; identified. the study was neither blinded nor sham controlled and did not evaluate IHS-recommended primary and secondary endpoints. In migraine prevention (table 3), 18 studies were evaluated Single-pulse transcranial magnetic stimulation with a total population of 855 patients. Seventeen studies had Migraine patients with and without aura, 15 studies were blinded and 15 sTMS was evaluated in three studies for the acute and preventive studies were sham controlled. Fifty per cent of the studies used treatment of migraine. Two studies were published and regis- an IHS-recommended primary efficacy endpoint, and 72% used tered; one study was published without registration. an IHS-recommended secondary efficacy endpoint. In the acute treatment of migraine (table 2), the two sTMS studies had a total population of 309 patients. One study used Cluster headache patients with and without aura. Both acute studies were blinded, In cluster headache prevention (table 4), one tDCS study was and one used a sham control. One acute sTMS study used the identified. The study included 32 patients and was not blinded IHS-recommended primary and secondary efficacy endpoints. or sham controlled. An IHS-recommended primary efficacy One sTMS study in the acute treatment of migraine did not endpoint was not used, but three IHS-recommended secondary adhere to the IHS recommendation of excluding patients with efficacy endpoints were used. chronic migraine. The preventive sTMS study evaluated 263 patients (table 3) with either episodic or chronic migraine, both with or without aura. The study was not blinded or Occipital and supraorbital transcutaneous nerve stimulation sham controlled. A reduction in headache days rather than the Migraine IHS-recommended reduction in migraine days was used as the OS-TNS was evaluated in three studies of the acute treatment of primary efficacy endpoint. Three IHS-recommended secondary migraine (table 2), which were registered on C ​ linicalTrials.​gov efficacy endpoints for the prevention of either episodic or but not published. These studies had a total population of 106 chronic migraine were used. patients who had migraine with and without aura. All were sham controlled, but only two of the three were blinded. None of the OS-TNS studies used the IHS-recommended primary endpoint, Cluster headache but all used at least one IHS-recommended secondary endpoint. No sTMS studies for the treatment of cluster headache were Two of the acute studies did not comply with the IHS recom- identified. mendation to exclude patients with chronic migraine. 800 Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 Migraine Cluster headache treatment of migraine, Tassorelli et al’s21 study of nVNS (n=285) No studies of the OS-TNS device for the treatment of cluster and Lipton et al’s28 study of sTMS (n=267), had comparable headache were identified. population sample sizes, with the e-TNS pivotal trial having enrolled a smaller number of patients (n=106).26 Of all iden- Conditioned pain modulation tified clinical studies of migraine prevention, the PREMIUM Migraine study of nVNS had the largest population sample (n=479).20 33 CPM was evaluated in three studies of the acute treatment of The pivotal trials by Starling et al29 for sTMS and by Schoenen migraine (table 2): two studies were only registered on ​Clinical- et al27 for e-TNS used population sample sizes of 263 and 84 Trials.​gov, and one study was both published and registered. The patients, respectively. The nVNS and e-TNS pivotal trials in the three CPM studies had a total population of 476 patients, and all acute treatment of migraine and all three key migraine preven- three consisted of patients with migraine with and without aura tion studies followed the IHS recommendation to enrol patients and were blinded and sham controlled. None of the CPM studies both with and without aura, whereas the acute sTMS study eval- used the IHS-recommended primary endpoint, and only one uated only patients with aura. All three pivotal studies of the used at least one of the IHS-recommended secondary endpoints. acute treatment of migraine as well as the PREMIUM preven- tive nVNS trial and the pivotal study of preventive e-TNS were blinded and sham controlled. The pivotal study of sTMS in Cluster headache migraine prevention was an open-label trial and used an esti- No studies of the CPM device for the treatment of cluster head- mate of the placebo effect that was statistically derived according ache were identified. to historical controls (ie, performance goal) rather than a sham control group. Caloric vestibular stimulation The pivotal studies of acute nVNS and sTMS evaluated the Migraine IHS-recommended primary endpoint of pain freedom at 2 hours. CVS was evaluated in three studies of migraine prevention The acute e-TNS pivotal study predefined its primary endpoint (table 3); two studies were registered on ​ClinicalTrials.​gov but as the change in visual analogue scale pain score at 1 hour and not published; one study was both published and registered. used pain freedom at 2 hours as a secondary endpoint. Ther- The three CVS studies had a total population of 291 patients; apeutic effects on the pain-free response rate at 2 hours were two studies enrolled patients with migraine with and without comparable among the three pivotal studies of acute treatment, aura. Two studies were blinded and sham controlled. All three with significance (vs sham) demonstrated for sTMS (active, studies used at least one of the IHS-recommended primary effi- 39%; sham, 22%; p=0.0179)28 but not for nVNS (active, cacy endpoints; two of the CVS studies used at least one of the 30.4%; sham, 19.7%; p=0.067)21 or e-TNS (active, 19%; sham, IHS-recommended secondary efficacy endpoints. 8%; p=0.136).26 The IHS-recommended primary endpoint of the reduction in migraine days (from run-in to the third month Cluster headache of therapy) was used in the key migraine prevention trials for No studies of the CVS device for the treatment of cluster head- both nVNS (active, –2.26 days; sham, –1.80 days; p=0.146)33 ache were identified. and e-TNS (active, –2.06 days; sham, –0.32 days; p=0.054),27 whereas the pivotal preventive sTMS study used the reduction in Discussion headache days as the primary endpoint and did not evaluate the We conducted a comprehensive systematic review of non-inva- reduction in migraine-specific pain.29 sive neuromodulation clinical trials in migraine and cluster head- Interpretation of the acute and preventive findings across the ache using the PRISMA criteria to ensure an unbiased analysis of three devices is challenging because of differences in patient all relevant studies. This analysis used the current IHS recom- characteristics, rescue medication use and sham devices used mendations for drug studies as a benchmark for scientific rigour in the trials. The acute sTMS study results represent those of in the absence of guidelines specific to non-invasive neuro- an aura population, whereas the acute nVNS and e-TNS results modulation16–18 and further demonstrated the heterogeneity are from a population composed of patients both with and of study designs and endpoints in clinical trials with non-inva- without aura. The acute e-TNS study allowed rescue medi- sive neuromodulation. The IHS guidelines for acute treatment cation use within 24 hours after treatment, whereas the acute studies of migraine recommend the assessment of migraine pain nVNS and sTMS studies defined requirements to delay rescue at a consistent time point (ie, pain freedom at 2 hours) after the medication use for 2 hours.21 26 28 The therapeutic difference intervention, and guidelines for studies of preventive migraine between nVNS and sham in both the acute and preventive nVNS treatments recommend one of three clinically relevant outcomes studies was likely affected by the elevated effects in the sham (ie, change in migraine days, change in moderate to severe head- groups. The sham device that was used in the nVNS trials was ache days, or responder rate), with the remaining two recom- shown in a separate study to be partially active according to its mended as secondary endpoints. observed inhibitory effects on the trigeminal autonomic reflex.34 In our systematic search, we identified pivotal studies for This heterogeneity in the pivotal studies of nVNS, e-TNS and the three non-invasive neuromodulation therapies with regula- sTMS makes the comparison of these devices and their efficacy tory clearance for migraine and/or cluster headache (ie, nVNS, outcomes difficult. e-TNS, sTMS), which are the focus of this discussion. Pivotal The nVNS device is the only non-invasive neuromodulation studies are clinical trials intended to provide evidence for regu- therapy currently cleared for acute and preventive use in cluster latory approval. Publications of these studies for the available headache. Only one other device (ie, tDCS for preventive use) devices were assessed using the criteria provided by the Euro- has been evaluated in a study of cluster headache. The two pivotal pean Federation of Neurological Societies (EFNS; table 5).21–30 studies of nVNS for acute cluster headache treatment (ACT1 and Studies with a published classification of evidence by the Amer- ACT2) evaluated primary endpoints consistent with IHS recom- ican Academy of Neurology were also assessed alongside the mendations: pain relief at 15 min for the first attack without EFNS criteria.21 27 31 32 Two of the pivotal studies in the acute rescue medication use through 60 min and pain freedom at 15 Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 801 Migraine Table 5 Clinical evidence of available devices AAN Classification Device Study Authors CE marked FDA cleared of Evidence GRADE 21 nVNS Acute migraine Tassorelli et al Yes Yes I High treatment* Migraine Silberstein et al Yes No II Low prevention*† (EVENT)31 Acute CH Silberstein et al Yes Yes¶ NA High treatment (ACT1)22 Goadsby et al23 NA High CH prevention‡ Gaul et al24 Yes Yes NA High Marin et al25 NA Moderate e-TNS Acute migraine Chou et al26 Yes Yes NA Moderate treatment Migraine Schoenen et al27 Yes Yes III Moderate prevention* Acute CH NA No No NA NA treatment§ CH prevention§ NA No No NA NA sTMS Acute migraine Lipton et al28 Yes Yes NA Moderate treatment Migraine Starling et al29 Yes Yes NA Low prevention Acute CH NA No No NA NA treatment§ CH prevention§ NA No No NA NA *AAN Classification of Evidence is published for this study. †The EVENT study was not a pivotal study. ‡Marin et al’s study published outside of predefined date range; included here based on recent FDA clearance. §No studies identified. ¶FDA cleared for episodic CH only. AAN, American Academy of Neurology;ACT, acute CH treatment; CH, cluster headache;FDA, Food and Drug Administration; GRADE, Grading of Recommendations Assessment, Development and Evaluation; NA, not available; e-TNS, external trigeminal nerve stimulation; nVNS, non-invasive vagus nerve stimulation; sTMS, single-pulse transcranial magnetic stimulation. min among all attacks without rescue medication use through 15 of this review to compare the results of these clinical trials as min.22 23 Significant therapeutic benefits were observed for the they are heterogeneous. episodic cluster headache cohorts of both ACT1 (active, 34.2%; The results of this review suggest several considerations for sham, 10.6%; p=0.008)22 and ACT2 (active, 48.0%; sham, the ongoing development of clinical trial guidelines for non-in- 6.0%; p<0.01)23 but not for the total populations or chronic vasive neuromodulation devices in primary headache. First, in cluster headache cohorts. The two pivotal studies of nVNS for an acute setting, the IHS emphasis on the first attack may not preventive use in cluster headache evaluated the frequency of be optimal for non-invasive neuromodulation devices. These attacks per week as the primary endpoint,24 25 which is consis- devices require patient training to ensure proper administra- tent with IHS recommendations.18 The PREVA24 study indicated tion, which may not be complete at the first attack. To allow for a significantly greater reduction in the number of attacks per complete patient training with non-invasive neuromodulation week versus controls (−5.9 vs −2.1, respectively) for a mean devices, it may be advisable to assess the efficacy of multiple therapeutic gain of 3.9 fewer attacks per week (p=0.02). Marin attacks or after proper administration is demonstrated. Second, et al’s25 study demonstrated a decrease in mean attack frequency the mechanisms of preventive neuromodulation (eg, electrical from 26.6 attacks per week before initiation of nVNS treatment or magnetic) treatments in primary headache are indirect, and to 9.5 attacks per week (p<0.01) afterward. efficacy may be multidimensional when considering the different The scope of this systematic review was limited by the hetero- pathophysiologies of migraine and cluster headache. The full geneity among the clinical trials analysed and the unavailability preventive potential of a neuromodulation regimen may be best of many of the study results, which precluded a formal system- captured with an observational time period equal to that of the atic meta-analysis of all identified studies. Thirty-seven of the 41 IHS-recommended period for pharmacological therapies (ie, a studies that were registered with ​ClinicalTrials.​gov or another minimum 12 weeks). Third, reproducibility is needed to support registry but not published did not have results available, and the validity of efficacy outcomes in all therapeutic trials. Many some did not comprehensively report all study design compo- neuromodulation devices have not yet been evaluated in multiple nents examined. Studies evaluated in this review are hetero- randomised controlled studies. The field of neuromodulation geneous in both study design and statistical power (ie, patient would benefit if more devices were evaluated in more than one population sample size), which affects the ability to interpret rigorous study to support efficacy outcomes. Lastly, appropriate and compare the true effects.35 36 Uniform use of prespecified blinding is a particular challenge in non-invasive neuromodu- outcome measures and other study design components is essen- lation trials. Ideally, the sham device should mimic the active tial for conducting meta-analyses and cost-benefit analyses to device as closely as possible while avoiding any inadvertent compare different treatment interventions. It was not the scope nerve activity. Sham devices with an active signal risk producing 802 Reuter U, et al. J Neurol Neurosurg Psychiatry 2019;90:796–804. doi:10.1136/jnnp-2018-320113 Migraine an active therapeutic effect, which could diminish the ability to Federation. He is on the editorial boards of The Journal of Headache and Pain and achieve significant treatment differences. The suggested modifi- Frontiers in Neurology. cations to clinical design elements recommended in this review Patient consent for publication Not required. could support scientific rigour and inform the development of Provenance and peer review Not commissioned; externally peer reviewed. recommendations for non-invasive neuromodulation studies in Open access This is an open access article distributed in accordance with the migraine and cluster headache. Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which The efficacy and low side effect burden of non-invasive permits others to distribute, remix, adapt, build upon this work non-commercially, neuromodulation make it a practical, tolerable and safe thera- and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use peutic option for patients and clinicians, but efficacy may vary is non-commercial. See: http://​creativecommons.​org/​licenses/​by-​nc/​4.​0/. across the different devices. Greater rigour and consistency among non-invasive neuromodulation studies are needed to improve clinicians’ ability to select the appropriate option for References their patients. Development of guidelines for evaluating the effi- 1 Martel MO, Finan PH, Dolman AJ, et al. Self-reports of medication side effects cacy of non-invasive neuromodulation therapies is under way. and pain-related activity interference in patients with chronic pain. PAIN Well-designed studies, such as those for nVNS that consistently 2015;156:1–1100. 2 Schwedt TJ, Vargas B. Neurostimulation for treatment of migraine and cluster adhere to stringent IHS recommendations for pharmacological headache. Pain Med 2015;16:1827–34. trials, may help in the design of future clinical trials until neuro- 3 Martelletti P, Jensen RH, Antal A, et al. Neuromodulation of chronic headaches: modulation-specific guidelines are established. position statement from the European headache Federation. J Headache Pain 2013;14. 4 electroCore, Inc. gammaCore®-S [Instructions for Use. Basking Ridge, NJ: electroCore, Inc., 2018. Conclusions 5 Cefaly US Inc. Cefaly dual. Available: https://www.​cefaly.​us/. Updated 2018 [Accessed In this systematic review of non-invasive neuromodulation device 16 Nov 2018]. studies in the acute and preventive treatment of migraine and 6 eNeura Inc. sTMS miniTM [Instructions for Use]. Sunnyvale, CA: eNeura Inc., 2018. cluster headache, nVNS studies demonstrated the most consis- 7 Hougaard A, Tfelt-Hansen P. Are the current IHS guidelines for migraine drug trials being followed? J Headache Pain 2010;11:457–68. tent adherence to IHS recommendations. Future trials should 8 Moher D, Liberati A, Tetzlaff J, et al. Preferred reporting items for systematic reviews be rigorously designed to facilitate comparisons across devices. and meta-analyses: the PRISMA statement. BMJ 2009;339:b2535. Guidelines specific to evaluating non-invasive neuromodulation 9 Clinical trials registration and results information submission. Available: https://www.​ therapies for the treatment of migraine and cluster headache will federalregister.​gov/​documents/​2016/​09/​21/​2016-​22129/​clinical-​trials-​registration-​ and-​results-​information-​submission [Accessed 15 Aug 2018]. soon be available, but adherence to current recommendations 10 Section 801 of the food and drug administration amendments act of 2007. Available: for pharmacological trials will minimise heterogeneity among https://www.​gpo.​gov/​fdsys/​pkg/​PLAW-​110publ85/​pdf/​PLAW-​110publ85.​pdf#​page=​ neuromodulation studies. 82 [Accessed 15 Aug 2018]. 11 International Committee of Medical Journal Editors. Clinical trials. Available: http:// Acknowledgements Technical and editorial support for this manuscript was www.​icmje.​org/​recommendations/​browse/​publishing-​and-​editorial-​issues/​clinical-​trial-​ provided by Mark Skopin, PhD, Stefanie Dorlas, BMath, BEd, and Martin Kurtev, MS, registration.​html. Identifier. [Accessed 15 Aug 2018]. of MedLogix Communications. 12 Bashir R, Bourgeois FT, Dunn AG. A systematic review of the processes used to link clinical trial registrations to their published results. Syst Rev 2017;6. Contributors UR, EL and PP-R provided detailed input into the development 13 Classification and diagnostic criteria for headache disorders, cranial neuralgias and of the manuscript. UR conceptualised the manuscript. All authors participated facial pain. Headache classification Committee of the International Headache Society. in data collection, interpretation, and validation and had full access to all data Cephalalgia 1988;8(suppl 7):1–96. in the manuscript. All authors reviewed, critiqued and contributed to revision 14 Headache Classification Subcommittee of the International Headache Society. The of the manuscript content and provided approval of the final manuscript draft. International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Professional medical writing, data and editorial support (ie, technical editing, suppl 1:9–160. copyediting, preparation of tables and figures and clerical assistance) from MedLogix 15 Headache Classification Committee of the International Headache Society. The Communications was funded by electroCore. The principal author, UR, takes International Classification of Headache Disorders: 3rd edition. Cephalalgia responsibility for the data, analyses and interpretation, and conduct of the research. 2018;38:1–211. Funding This review was sponsored by electroCore. An employee of the sponsor 16 Tfelt-Hansen P, Pascual J, Ramadan N, et al. Guidelines for controlled trials of drugs in was involved in data collection, interpretation and validation. All authors, including migraine: third edition. A guide for Investigators. Cephalalgia 2012;32:6–38. an employee of the study sponsor, drafted and/or revised the manuscript and 17 Tassorelli C, Diener H-C, Dodick DW, et al. Guidelines of the International Headache approved the final version for submission. Professional medical writing, data and Society for controlled trials of preventive treatment of chronic migraine in adults. editorial support (ie, technical editing, copyediting, preparation of tables and figures Cephalalgia 2018;38:815–32. and clerical assistance) from MedLogix Communications was funded by electroCore. 18 Lipton RB, Micieli G, Russell D, et al. Guidelines for controlled trials of drugs in cluster headache. Cephalalgia 1995;15:452–62. Competing interests PP-R has received honoraria as a consultant and speaker 19 World Health Organization, 2015. WHO statement on public disclosure of clinical for Allergan, Amgen, Almirall, Chiesi, Eli Lilly, Janssen Cilag, Medscape, MSD, trial results. Available: http://www.​who.​int/​ictrp/​results/​WHO_​Statement_​results_​ Novartis, and Teva. Her research group has received research grants from Allergan reporting_​clinical_​trials.​pdf?​ua=​1. Updated April 9 [Accessed 16 Aug 2018]. and has received funding for clinical trials from Alder, Boehringer Ingelheim, MSD, 20 ​ClinicalTrials.​gov. A randomized, sham-controlled study of gammaCore® (nVNS) electroCore, Eli Lilly, Janssen Cilag, Novartis, and Teva. She is a trustee member of for prevention of episodic migraine. Available: https://​clinicaltrials.​gov/​ct2/​show/​ the board of the International Headache Society, a member of the Council of the NCT02378844 [Accessed 2 Apr 2018]. European Headache Federation, and coordinator of the Spanish Headache Study 21 Tassorelli C, Grazzi L, de Tommaso M, et al. Noninvasive vagus nerve stimulation Group of the Spanish Neurological Society. She is on the editorial board of Revista as acute therapy for migraine: The randomized PRESTO study. Neurology de Neurologia. She is an editor for Frontiers in Neurology and The Journal of 2018;91:e364–73. Headache and Pain. She is a member of the Clinical Trials Guidelines Committee of 22 Silberstein SD, Mechtler LL, Kudrow DB, et al. Non-Invasive Vagus Nerve Stimulation the International Headache Society. She has edited the Guidelines for the Diagnosis for the ACute Treatment of Cluster Headache: Findings From the Randomized, Double- and Treatment of Headache of the Spanish Neurological Society. She is the founder Blind, Sham-Controlled ACT1 Study. Headache: The Journal of Head and Face Pain of www.​midolordecabeza.​org. She does not own stocks in any pharmaceutical 2016;56:1317–32. company. CM is an employee of North American Science Associates, Inc. EL is 23 Goadsby PJ, de Coo IF, Silver N, et al. 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