NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE

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1 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE INTERVENTIONAL PROCEDURES PROGRAMME Interventional procedure overview of transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine Migraines are severe headaches, usually felt as a throbbing pain at the front or side of the head, which can be accompanied by nausea and sensitivity to light. They may last for several hours. In this procedure, the patient wears a small device positioned on their forehead with an adhesive electrode. It stimulates the nerves under the skin of the forehead to relieve pain and reduce the number of migraine attacks. Introduction The National Institute for Health and Care Excellence (NICE) has prepared this interventional procedure (IP) overview to help members of the Interventional Procedures Advisory Committee (IPAC) make recommendations about the safety and efficacy of an interventional procedure. It is based on a rapid review of the medical literature and specialist opinion. It should not be regarded as a definitive assessment of the procedure. Date prepared This IP overview was prepared in July Procedure name Transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine Specialist societies British Association for the Study of Headache Association of British Neurologists. preventing migraine Page 1 of 29

2 Description Indications and current treatment Migraines are severe headaches that may last for hours, days or longer, often accompanied by nausea, photophobia, phonophobia and the perception of unpleasant odours. In some people, migraines may be accompanied by an aura, characterised by the focal neurological symptoms that usually precede or sometimes accompany the headache. The International Headache Society s international classification of headache disorders classifies migraine types. The usual treatment option for patients with migraine is medical therapy, either to stop or prevent attacks. Treatments for acute migraine attacks include medications such as analgesics, triptans and anti-emetics (as recommended in NICE s guideline on headaches in over 12s). Treatments to stop or reduce the frequency of migraine attacks include medications such as beta-blockers, tricyclic antidepressants and antiepileptics. Invasive treatments are reserved for patients with distressing symptoms that are refractory to medical treatments. These include invasive treatments such as nerve blocks, botulinum toxin (see NICE s technology appraisal guidance on botulinum toxin type A for the prevention of headaches in adults with chronic migraine), acupuncture or occipital nerve stimulation. What the procedure involves Transcutaneous supraorbital nerve stimulation uses small electrical currents to stimulate the supraorbital nerve. It aims to relieve headache, and when used regularly, to reduce the severity and the frequency of migraine attacks. Therapy is administered by the patient, using a small battery-operated device (a headband with a central button) connected to a self-adhesive electrode patch applied to the forehead above the eyebrows. When the device is activated, small electrical impulses stimulate the supraorbital nerves (branches of the ophthalmic nerve, the first division of the trigeminal nerve). The intensity of the electrical pulses increases periodically and this can be adjusted by the patient. Stimulation is applied for approximately 20 minutes daily. The device can be used to treat acute migraine attacks and for prophylaxis between attacks. preventing migraine Page 2 of 29

3 Literature review Rapid review of literature The medical literature was searched to identify studies and reviews relevant to transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine. The following databases were searched, covering the period from their start to 28 July.2015: MEDLINE, PREMEDLINE, EMBASE, Cochrane Library and other databases. Trial registries and the Internet were also searched. No language restriction was applied to the searches (see appendix C for details of search strategy). Relevant published studies identified during consultation or resolution that are published after this date may also be considered for inclusion. The following selection criteria (table 1) were applied to the abstracts identified by the literature search. Where selection criteria could not be determined from the abstracts the full paper was retrieved. Table 1 Inclusion criteria for identification of relevant studies Characteristic Publication type Patient Intervention/test Outcome Language Criteria Clinical studies were included. Emphasis was placed on identifying good quality studies. Abstracts were excluded where no clinical outcomes were reported, or where the paper was a review, editorial, or a laboratory or animal study. Conference abstracts were also excluded because of the difficulty of appraising study methodology, unless they reported specific adverse events that were not available in the published literature. Patients with migraine. Transcutaneous supraorbital electrical neurostimulation. Articles were retrieved if the abstract contained information relevant to the safety and/or efficacy. Non-English-language articles were excluded unless they were thought to add substantively to the English-language evidence base. List of studies included in the IP overview This IP overview is based on 2405 patients from 1 randomised controlled trial, 1 case series and 1 Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database adverse event report. Other studies that were considered to be relevant to the procedure but were not included in the main extraction table (table 2) have been listed in appendix A. preventing migraine Page 3 of 29

4 Table 2 Summary of key efficacy and safety findings on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine Study 1 Schoenen J (2013, 2016) Details Study type Country Recruitment period Study population and number Double-blind randomised sham-controlled trial Belgium (multicentre) (PREMICE trial) n=67 (34 transcutaneous supraorbital neurostimulation [tsns] vs 33 sham) Indication: migraine prevention Migraine with aura: tsns=10, sham=10; migraine without aura: tsns=24, sham n=23 Age and sex Mean 36.79±10.63 years; female 91% (61/67) Patient selection criteria Inclusion criteria: years old, with migraine with or without aura (ICHD-II code 1.2 or 1.1, and at least 2 attacks per month. Technique Follow-up Conflict of interest/source of funding Exclusion criteria: use of a preventive antimigraine treatment in the previous 3 months, failure on> 3 wellestablished preventive drug treatments, medication overuse headache (ICHD-II 8.2), frequent chronic tension type headache (International Classification of Headache Disorders-ii 2.2/2.3) and other severe neurologic or psychiatric disorders. Sham and tsns (with a Cefaly device) treatments were delivered with a self-adhesive electrode placed on the forehead covering the supratrochlear and supraorbital nerves bilaterally. Impulses were delivered at a frequency of 1 Hz for sham and 60 Hz for tsns and intensity 1 ma for sham and 16 ma for tsns. Daily sessions lasted for 20 minutes during 3 months. An intermediate visit was done after 45 days and a final visit at the end of the study. 3 months First author is a consultant for ATI redwood California, advisory member for ST Jude, Allergan, and ATI; received research grants from Medtronic and Cyberonics. One author is a scientific advisor for Allergan. The study was funded by Walloon Region DH06, research convention from National Fund for Scientific Research, and a grant from the University of Liege. STX Med provided the devices. Analysis Follow-up issues: complete follow-up Study design issues: small study, conducted by members of Belgian Headache Society in 5 tertiary headache clinics. After a run-in phase of 1 month (during which no preventive treatment was used and headache data were collected in a diary) those meeting the inclusion criteria were randomised 1:1 to receive sham or tsns. Treatment allocation was concealed; patients and neurologists were blinded from randomisation. Devices and electrodes were identical, programmed by manufacturers, coded and randomly distributed in blocks of 2 tsns and 2 sham stimulators. Everyone had some degree of electrical stimulation but sensory perceptions were different. Headache diaries recorded headache occurrence and its severity on a 4-point scale (presence of an aura, nausea, phonophobia or photophobia and acute antimigraine drug intake). A database was created from these diaries by 2 independent investigators. Data were analysed on an intention-to-treat and per-protocol basis. Migraine days not separated by at least 1 headache-free day were considered to belong to the same migraine attack. Study population issues: patients in both groups had similar characteristics. Those in the tsns group were slightly younger (by 4.47 years) than those in the sham group. Other issues: Authors state that partial unblinding might have occurred in the study. They also state that patients had 4 attacks or 7 migraine days per month and are representative of most patients in the general population who need preventive treatment. preventing migraine Page 4 of 29

5 Key efficacy and safety findings Efficacy Number of patients analysed: 67 (34 tsns vs 33 sham) Outcome measures (intention-to-treat analyses) Change in monthly migraine days^ tsns mean± SD Sham mean± SD Comparison between the 2 groups Baseline 6.94± ± months 4.88± ±2.99 p value ~ 50% responder rate* % (n) (13) (4) Safety No adverse events or side effects occurred in either group. p value % responder rate** % (n) 58.8 (20) 27.3 (9) p value Change in monthly migraine attack frequency Baseline 4.37± ± months 3.55± ±1.89 p value Change in monthly frequency of any headache++ Baseline 7.78± ± months 5.27± ±3.20 p value Severity of migraine days^ Baseline 1.96± ± months 1.80± ±0.53 p value Change in monthly acute anti-migraine drug intake Baseline 11.45± ± months 7.25± ±5.69 p value * a >50% reduction of monthly migraine days; ** >25% improvement in migraine days ~ difference becomes significant (p=0.044) when baseline migraine days are considered as a covariate ^ defined as a day with headache fulfilling ICHD-II criteria for migraine, except for duration if treated ^^measured on a 4-point scale (0-3, 3 indicating severe pain prohibiting daily activities) ++ a headache of grade 1 severity without associated symptoms and not treated with an acute medication Patient satisfaction 3 months after treatment tsns % (n) Sham % (n) Very satisfied 29.4 (10) 18.2 (6) Moderately satisfied 41.2 (14) 21.1 (7) Not satisfied 21.2 (7) 51.5 (17) Not available 8.8 (3) 9.1 (3) Device compliance (usage recorded in the device) The mean numbers of sessions were 61.7% (55.54 sessions, 1,110 minutes) in tsns group and 54.4% (49 sessions, 980 minutes) in the sham group. The difference between the 2 groups was not significant. A rank analysis of covariance showed that age and disease duration did not influence study outcomes 2. Abbreviations used: ICHD, International Classification of Headache Disorders; tsns, transcutaneous supraorbital neurostimulation. preventing migraine Page 5 of 29

6 Study 2 Magis (2015) Details Study type Country Recruitment period Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding Case series (survey) prospective registry France, Belgium and Switzerland n=2313 patients with headache (migraine according to ICHD-II criteria) Age years; 70.9% 91641/2313) female Only patients using specific anti-migraine drugs (triptans) and most likely suffering from migraine were included in the survey. Patients had transcutaneous supraorbital neurostimulation (with a Cefaly device) for a 40-day period using a unit rented via the internet. Stimulation was delivered with an external self-adhesive electrode placed on the forehead. Impulses with a frequency of 60 Hz and intensity of 16mA were generated. All were given leaflets advising them to have at least 1 session daily for 20 minutes to obtain an effect. For 40 days the minimum total time of use recommended was 800 minutes. A built-in electronic system recorded the total time of use. 29 months Not reported Analysis Follow-up issues: Study design issues: lack of a control group, patient satisfaction and self-reported adverse events were monitored by phone interviews. It was not clear at what time point the outcomes were assessed. A built-in electronic system allowed the total duration of use or compliance in patients who returned the device after the trial period to be assessed. Study population issues: no precise diagnosis of patients, authors assumption was that all patients had migraine based on the fact that they used triptans as an abortive therapy. It was not clear if they had episodic or chronic migraine, migraine with or without aura; tension-type, medication overuse or cluster headaches. They did not have any regular neurological follow-up. Other issues: Authors state that some patients in whom the device was effective might not have purchased the device for financial reasons and this would have led to an overestimation of the proportion of non-satisfied subjects. preventing migraine Page 6 of 29

7 Key efficacy and safety findings Efficacy Number of patients analysed: 2313 Average rental period (from day the device was received until they were actually contacted to answer the questions): 58.2± 33.6 days. Patient satisfaction and compliance: 53.4% (1236/2313) patients were satisfied and wanted to continue the treatment. They purchased the device. 46.6% (1077/2313) were not satisfied and returned the device, but the compliance showed that they used it only for 48.6% of the recommended time. Safety 1 or more adverse events (minor and fully reversible, some patients reported more than one event) IP 1293 [IPG559] % (n) 4.3 (99/2313) Do not like the feeling and do not want to continue using the device 1.25 (29/2313) Local pain/intolerance to paraesthesia (all stopped the treatment) 2.03 (47/2313) Dental pain during/beginning of the session 0.09 (3/2313) Cervical pain during sessions 0.04 (1/2313) Cervical pain with nausea after the first 2 sessions 0.04 (1/2313) Strong paraesthesia feeling on the left side 0.04 (1/2313) Strong paraesthesia feeling on the right side 0.04 (1/2313) More head pain when using the device during a headache 0.04 (1/2313) Slight pain at one eyebrow during the first session 0.04 (1/2313) Forehead skin burning sensation during a session 0.04 (1/2313) Arousal and sleep changes 0.82 (19/2313) Sleepiness during the session 0.52 (12/99) Fatigue 0.13 (3/99) Insomnia 0.17 (4/99) Tension-type headache after stimulation 0.52 (12/2313) Skin problems 0.38 (9/2313) Reversible forehead skin irritation 0.22 (5/2313) Transient local skin allergy 0.09 (2/2313) Feeling of contusion on the forehead during a few days 0.09 (2/2313) Other Inability to keep eyes open during sessions 0.09 (2/2313) Red eye after a session 0.04 (1/2313) Eyes weeping during a session 0.04 (1/2313) Feeling of stress during stimulation 0.09 (3/2313) Pre-existing tinnitus increased during the session 0.04 (1/2313) Tinnitus appearing after the session 0.04 (1/2313) Wake up during night with a feeling of anxiety and tremor 0.04 (1/2313) Vertigo during first session 0.04 (1/2313) Short feeling of electrical shock 0.04 (1/2313) Vomiting after a session 0.04 (1/2313) Nausea and vertigo during session 0.04 (1/2313) Nausea during sessions 0.04 (1/2313) Forehead and cranial anaesthesia feeling during a few hours after a session 0.04 (1/2313) Pressure feeling between the eyebrows during sessions 0.04 (1/2313) Numbness at the back of the head after a session 0.04 (1/2313) Subjective tachycardia during a session 0.04 (1/2313) Migraine feeling during sessions 0.04 (1/2313) Abbreviations used: ICHD, International Classification of Headache Disorders; tsns, transcutaneous supraorbital neurostimulation. preventing migraine Page 7 of 29

8 Study 3 Russo A (2015) Details Study type Country Case series Italy Recruitment period Study population and number n=24 patients with migraine without aura disease duration: 8.3 years Age and sex mean age 32.9 years; 75% female (15/20) Patient selection criteria Technique Follow-up Conflict of interest/source of funding Patients with migraine with aura (according to ICHD criteria) who had <5 attacks per month, who had never taken any anti-migraine preventive drugs, were included. Patients with any other type of headache, somatic or psychiatric conditions and intake of daily medication were excluded. Transcutaneous supraorbital neurostimulation (with a Cefaly device) was delivered with a high frequency (60Hz, 250 µs and 16 ma intensity) tsns and sessions lasted 20 minutes per day. Triptans and NSAIDs were taken by patients as rescue medication. 60 days Stx Med provided the devices, not industry sponsored. 2 authors received an honorarium and funding for travel from pharma companies. Analysis Analysis Follow-up issues: baseline was followed by a 60-day treatment period. Four patients were excluded from the analysis because of non-compliance i.e. they did not use the device for >800 minutes during the treatment period. Study design issues: prospective study in an outpatient headache clinic, small sample size. Baseline characteristics were determined using data from the 28-day baseline diaries. During the treatment period, patients filled in diaries and recorded data on outcomes. Compliance was assessed by a built-in electronic system that recorded usage of the stimulators by each patient. preventing migraine Page 8 of 29

9 Key efficacy and safety findings Efficacy Number of patients analysed: 24 Baseline Follow-up p value Frequency of migraine attacks per month (mean ± SD) NR NR <0.001 Safety Adverse events: none Frequency of migraine days* per month (mean ± SD) 4.5± ±0.28 <0.001 Headache Impact Test (HIT)-6 rating (mean ± SD) 62.3± ±1.4 <0.001 Monthly intake of rescue medication(mean ± SD) 5.6± ±0.3 <0.001 NSAID intake (mean ± SD) 3.2± ± Triptans intake (mean ± SD) 2.4± ± Pain intensity during migraine attacks ( measured on a VAS 0-10, 0 no pain; 10 severe pain) % of patients having at least a 50% reduction in monthly migraine attacks % of patients having at least a 50% reduction in monthly migraine days 8.0± ± % 75% Compliance and satisfaction with treatment 100% *A migraine day is defined as a day without headache fulfilling ICHD-III criteria for migraine without aura, except for duration, if the attack was treated. Migraine days not separated by at least 1 headache-free day were considered to belong to the same migraine attack. Abbreviations used: tsns, transcutaneous supraorbital neurostimulation; NSAID, non-steroidal anti-inflammatory drugs; NR, not reported; SD, standard deviation; VAS, visual analogue scale. preventing migraine Page 9 of 29

10 Study 4 MAUDE database Details Study type Country Study population and number Age and sex Patient selection criteria Technique Follow-up Conflict of interest/source of funding MAUDE adverse event report USA n=1 Not reported Not reported Patient tested transcutaneous supraorbital neurostimulation (with a Cefaly device) Not reported Analysis Key efficacy and safety findings Safety Number of patients analysed: 1 Event date: 08/01/2014 Event type: Injury, reported by a physician Event description: Cefaly device was prescribed to a patient by a neurologist to help decrease the frequency of headaches which the patient had for many years. Patient purchased and tested the device as described in the manufacturer s instructions on a day that she was completely well. The intensity of the power was set to the lowest setting. Approximately 17 minutes after starting the device on the lowest setting, the patient began to experience weakness in jaw muscles and upper extremities (proximally more than distally) and to a lesser extent, proximal lower extremity muscles. Patient also developed significant dizziness. These symptoms increased until the use of the device was discontinued. After shutting the device off, the muscle weakness and dizziness did not immediately stop. It took a period of approximately 2 hours for complete resolution of these symptoms. Abbreviations used: tsns, transcutaneous supraorbital neurostimulation. preventing migraine Page 10 of 29

11 Efficacy Change in monthly migraine days A multicentre double-blind randomised controlled trial (RCT) of 67 patients compared transcutaneous supraorbital neurostimulation (tsns; n=34) against sham treatment (n=33). In the intention-to-treat analysis, there was a statistically significant decrease in the mean number of migraine days between baseline and 3 months after treatment in the tsns group (6.94±3.04 to 4.88 ±3.46; p=0.023), but not in the sham group (6.54±2.61 to 6.22±2.99; p=0.608). The difference between the 2 groups was not statistically significant (p=0.054) 1. A case series of 20 patients with migraine without aura reported a statistically significant decrease in the frequency of migraine days per month from 4.5±0.24 at baseline to 2.06±0.28 at 60-day follow-up (p<0.001) 3. Responder rate (reduction in monthly migraine days) In the RCT of 67 patients the 50% responder rate (defined as the percentage of patients having a greater than 50% reduction in monthly migraine days) was statistically significantly higher in the tsns group than in the sham group (38% [n=13] versus 12% [n=4]; p=0.023) in the intention-to-treat analysis. The percentage of patients with at least a 25% reduction (moderate improvement) in migraine days was also statistically significantly higher in the tsns group than in the sham group (59% [n=20] versus 27% [n=9], p=0.014) 1. The case series of 20 patients reported a 50% reduction in monthly migraine attacks and migraine days in 81% and 75% of patients respectively at 60-day follow-up 3. Reduction in monthly migraine attacks In the RCT of 67 patients (intention-to-treat analysis), the monthly migraine attack frequency was 4.37±1.87 at baseline and 3.55±2.94 at 3 months (p=0.058) in the tsns group, and 4.04±1.52 at baseline and 3.89±1.89 at 3 months (p=0.516) in the sham group. The difference between the 2 groups was statistically significant (p=0.044) 1. The case series of 20 patients reported a significant decrease in the frequency of migraine attacks per month at 60-day follow-up (p<0.001) 3. Reduction in any headache days In the RCT of 67 patients (intention-to-treat analysis), there was a statistically significant decrease in monthly days with any headache between baseline and 3 months after treatment in the tsns group (7.78±4.00 to 5.27±3.55; p=0.011), preventing migraine Page 11 of 29

12 but not in the sham group (6.72±2.63 to 6.49±3.20; p=0.674). The difference between the 2 groups was statistically significant (p=0.041) 1. Reduction in mean headache severity per migraine day In the RCT of 67 patients (intention-to-treat analysis), the mean headache severity per migraine day (on a 4-point scale, 0 indicating no pain and 3 indicating severe pain prohibiting daily activities) was 1.96±0.46 at baseline and 1.8±0.60 at 3 months (p=0.131) in the tsns group, and 1.78±0.41 at baseline and 1.73±0.53 at 3 months (p=0.443) in the sham group. The difference between the 2 groups was not statistically significant (p=0.301) 1. In the case series of 20 patients there was a statistically significant reduction in average pain intensity (measured on a visual analogue scale from 0 10, 0 indicating no pain and 10 indicating severe pain) during migraine attacks, from 8.0±0.1 at baseline to 6.7±0.2 at 60-day follow-up (p=0.002) 3. Reduction in acute migraine drug intake In the RCT of 67 patients (intention-to-treat analysis), there was a statistically significant decrease in the monthly intake of migraine drugs for acute attacks in the tsns group (11.45±8.35 to 7.25±7.31; p=0.0057), but not in the sham group (9.24±4.75 to 9.28±5.69; p=0.822). There difference between the 2 groups was statistically significant (p=0.0072) 1. In the case series of 20 patients, there was a statistically significant reduction in the use of rescue drugs from 5.6±0.4 medications at baseline to 2.2±0.3 at 60- day follow-up (p<0.001). Statistically significant reductions were also seen in the intake of non-steroidal anti-inflammatory drugs, from 3.2±0.6 medications at baseline to 1.3±0.4 at 60-day follow-up (p=0.02), and in triptans, from 2.4±0.7 medications at baseline to 0.9±0.3 at 60-day follow-up (p=0.04) 3. Patient satisfaction In the RCT of 67 patients the percentage of very or moderately satisfied patients was higher in the tsns group (70%) than in the sham group (39%) 1. The case series of 20 patients reported 100% satisfaction with tsns treatment at 60-day follow-up 3. Safety Minor adverse events One or more adverse events (minor and reversible) were reported in 4% (99/2,313) of patients in a case series of 2,313 patients. Some patients reported more than 1 event 2. preventing migraine Page 12 of 29

13 Local pain or intolerance to paraesthesia Local pain or intolerance to paraesthesia induced by the electrical stimulation was reported in 2% (47/2,313) of patients in the case series of 2,313 patients. All patients stopped the treatment 2. Skin problems Skin problems were reported in less than 1% (9/2,313) of patients in the case series of 2,313 patients. These included transient local skin allergy in 2 patients, reversible forehead skin irritation in 5 patients, and a feeling of bruising on the forehead in 2 patients 2. Arousal and sleep changes Arousal and sleep changes were reported in less than 1% (19/2,313) of patients in the case series of 2,313 patients. These included insomnia in 4 patients, fatigue in 3 patients and sleepiness in 12 patients 2. Headache after a session Tension-type headache was reported in less than 1% (12/2,313) of patients in the case series of 2,313 patients 2. Weakness in jaw muscles and upper extremities Weakness in jaw muscles and in upper and lower extremity muscles was reported in 1 patient 17 minutes after starting the device on the lowest setting. The patient also developed significant dizziness. These symptoms increased until the use of the device was stopped. After stopping the device, the muscle weakness and dizziness took approximately 2 hours to resolve completely. This adverse event was reported in the Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database by a physician 4. Validity and generalisability of the studies There were limited data available on the efficacy and safety of transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine. Existing assessments of this procedure There were no published assessments from other organisations identified at the time of the literature search. preventing migraine Page 13 of 29

14 Related NICE guidance Below is a list of NICE guidance related to this procedure. Appendix B gives details of the recommendations made in each piece of guidance listed. Interventional procedures Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. NICE interventional procedure guidance 552 (2016). Available from Repetitive transcranial magnetic stimulation for depression. NICE interventional procedure guidance 542 (2015). Available from Implantation of a sphenopalatine ganglion stimulation device for chronic cluster headache. NICE interventional procedure guidance 527 (2015). Available from Transcranial magnetic stimulation for treating and preventing migraine. NICE interventional procedure guidance 477 (2014). Available from Occipital nerve stimulation for intractable chronic migraine. NICE interventional procedure guidance 452 (2013). Available from Deep brain stimulation for intractable trigeminal autonomic cephalalgias. NICE interventional procedure guidance 381 (2011). Available from Percutaneous closure of patent foramen ovale for recurrent migraine. NICE interventional procedure guidance 370 (2010). Available from Vagus nerve stimulation for treatment-resistant depression. NICE interventional procedure guidance 330 (2009). Available from preventing migraine Page 14 of 29

15 Technology appraisals Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. NICE technology appraisal guidance 260 (2012). Available from NICE guidelines Headaches in over 12s: diagnosis and management. NICE guideline 150 (2012). Available from Specialist advisers opinions Specialist advice was sought from consultants who have been nominated or ratified by their Specialist Society or Royal College. The advice received is their individual opinion and is not intended to represent the view of the society. The advice provided by Specialist Advisers, in the form of the completed questionnaires, is normally published in full on the NICE website during public consultation, except in circumstances but not limited to, where comments are considered voluminous, or publication would be unlawful or inappropriate. Three Specialist Advisor Questionnaires for transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine were submitted and can be found on the NICE website. Patient commentators opinions NICE s Public Involvement Programme sent 53 questionnaires to 2 NHS trusts for distribution to patients who had the procedure (or their carers). NICE received 20 completed questionnaires. The patient commentators views on the procedure were consistent with the published evidence and the opinions of the specialist advisers. Issues for consideration by IPAC Ongoing trial NCT : Open trial on the prevention of chronic migraines with the CEFALY device. Study type: interventional single group assignment; Indication: chronic migraine; primary outcomes: mean change from baseline in frequency of headache days, change from baseline in acute medication preventing migraine Page 15 of 29

16 intake, overall acute headache pain medication use; estimated enrolment: 50; Location: USA; study start date: February 2015; Primary completion date: August Status: recruiting. Application of electrodes and stimulator via an invasive surgical procedure for supraorbital nerve stimulation is out of the scope for this review. There is no published evidence on the use of tsns for chronic headaches. preventing migraine Page 16 of 29

17 References 1. Schoenen J, Vandersmissen B et al. (2013). Migraine prevention with a supraorbital transcutaneous stimulator. A randomized controlled trial. Neurology, 80: Schoenen JE (2016). Migraine prevention with a supraorbital transcutaneous stimulator: a randomised controlled trial. Neurology 86, Magis D, Sava S et al. (2013) Safety and patients satisfaction of transcutaneous Supraorbital NeuroStimulation (tsns) with the Cefaly device in headache treatment: a survey of 2313 headache sufferers in the general population. The Journal of Headache and Pain / Russo A, Tessitore A et al. (2015). Transcutaneous supraorbital neurostimulation in de novo patients with migraine without aura: the first Italian experience. The Journal of Headache and Pain 16:69, FDA (MAUDE database) Date searched MAUDE Adverse Event Report: CEFALY TECHNOLOGY CEFALY DRFOI ID= preventing migraine Page 17 of 29

18 Appendix A: Additional papers on transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine The following table outlines the studies that are considered potentially relevant to the IP overview but were not included in the main data extraction table (table 2). It is by no means an exhaustive list of potentially relevant studies. preventing migraine Page 18 of 29

19 Article Number of patients/follow-up Direction of conclusions Reasons for noninclusion in table 2 Meng FG, Zhang JG et al (2013). Author response to editorial. Migraine prevention with a supraorbital transcutaneous stimulator: a randomised controlled trial (2013) Neurology 81 (12) 1102 Goldberg SW and Nahas SJ (2015) Supratrochlear and supraorbital nerve stimulation for chronic headache: a review. Curr Pain Headache Rep 19: 26 Review of literature on supraorbital and supratrochlear nerve stimulation for chronic headache. Solomon S Guglielmo KM (1985) Treatment of headache by transcutaneous electrical stimulation. Headache 25 (1): 12-5 General review Haane D YP and Koehler PJ (2014). Nociception specific supraorbital nerve stimulation may prevent cluster headache attacks: serendipity in a blink reflex study. Cephalagia 34 (ca11), Serendipity study n=7 A cluster headache pathophysiology study using 2 hourly nociception specific, bilateral transcutaneous supraorbital stimulation to elicit blink reflexes with or without oxygen treatment. The authors discovered by chance that this could have a prophylactic effect in chronic cluster headache. Not studied for the purpose of treating cluster headache. Riederer F, Penning S et al (2015). Transcutaneous Supraorbital Nerve Stimulation (t-sns) with the Cefaly Device for Migraine Prevention: A Review of the Available Data. Pain and Therapy 4 (2) Review of t-sns with CEFALY Among the different noninvasive neurostimulation methods, only transcutaneous supraorbital nerve stimulation (t- SNS) with the Cefaly device has randomized controlled trialbased evidence for safety and efficacy and obtained FDA approval for the prevention of episodic migraine. In a doubleblinded, randomized, shamcontrolled trial on 67 episodic migraine patients (mean pretreatment migraine days/month: 6.9), the 50% responder rate after 3 months was significantly higher in the active group (38.2%) than in the sham group (12.1%); attack frequency and total headache days were also significantly reduced, but not Review preventing migraine Page 19 of 29

20 headache severity. Acute antimigraine drug intake was reduced by 36.7% in the active group. Statistical sub-analysis suggested that t-sns was more effective in patients with a higher attack frequency. In a large survey on 2313 Cefaly users about safety and satisfaction only 4.3% of subjects reported side effects, all of which were minor and fully reversible, the most frequent being intolerance to the paresthesia feeling and the most severe an allergic skin reaction to the electrode gel. The efficacy/safety ratio of the Cefaly device was therefore most favorable, especially when compared to preventive antimigraine drugs. The therapeutic efficacy of t-sns with Cefaly with low-frequency migraine (<5 attacks/month) was recently confirmed in an open randomized trial. No published data are available in chronic migraine. According to preliminary results of a fluorodeoxyglucose-positron emission tomography study, Cefaly might exert its effect in migraine by increasing activity in crucial areas of the limbic system and salience matrix such as orbitofrontal and anterior cingulate cortices. preventing migraine Page 20 of 29

21 Appendix B: Related NICE guidance for transcutaneous electrical stimulation of the supraorbital nerve for treating and preventing migraine Guidance Interventional procedures Recommendations Transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. NICE interventional procedure guidance 552 (2016) 1.1 Current evidence on the safety of transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine raises no major concerns. The evidence on efficacy is limited in quantity and quality. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Clinicians wishing to do transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine (see section 7.2). 1.3 NICE encourages further research on transcutaneous stimulation of the cervical branch of the vagus nerve for cluster headache and migraine. Studies should describe whether the procedure is used for treatment or prevention, and whether it is used for cluster headache or migraine. Clinicians should clearly document details of patient selection and the treatment regimen. Outcome measures should include changes in the number and severity of cluster headache or migraine episodes, medication use, quality of life in the short and long term, side effects, acceptability, and device durability. NICE may update this guidance on publication of further evidence. Repetitive transcranial magnetic stimulation for depression. NICE interventional procedure guidance 542 (2015) 1.1 The evidence on repetitive transcranial magnetic stimulation for depression shows no major safety concerns. The evidence on its efficacy in the short-term is adequate, although the clinical response is variable. Repetitive transcranial magnetic stimulation for depression may be used with normal arrangements for clinical governance and audit. 1.2 During the consent process, clinicians should, in particular, inform patients about the other treatment options available, and make sure that patients understand the possibility the procedure may not give them preventing migraine Page 21 of 29

22 benefit. 1.3 NICE encourages publication of further evidence on patient selection, details of the precise type and regime of stimulation used, the use of maintenance treatment and long-term outcomes. Implantation of a sphenopalatine ganglion stimulation device for chronic cluster headache. NICE interventional procedure guidance 527 (2015) Current evidence on the efficacy of implantation of a sphenopalatine ganglion stimulation device for chronic cluster headache, in the short term (up to 2 months), is adequate. With regard to safety, a variety of complications have been documented, most of which occur early and resolve; surgical revision of the implanted system is sometimes needed. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Clinicians wishing to implant a sphenopalatine ganglion stimulation device for chronic cluster headache should: Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and long term efficacy and provide them with clear written information. Patients should be informed about other treatment options. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having sphenopalatine ganglion stimulation (see section 7.2). 1.3 The selection of patients for implantation of a sphenopalatine ganglion stimulation device and their management should be done by multidisciplinary teams specialising in refractory headache. 1.4 Clinicians should enter details about all patients being implanted with a sphenopalatine ganglion stimulation device onto the national Neuromodulation register hosted by the National Institute for Cardiovascular Outcomes Research (NICOR). Clinical outcomes should also be reviewed locally. 1.5 NICE encourages further research on sphenopalatine ganglion stimulation for chronic cluster headache. Reported outcomes should include long term efficacy and device durability. Transcranial magnetic stimulation for treating and preventing migraine. NICE interventional procedure guidance 477 (2014). Transcranial magnetic stimulation (TMS) has been evaluated for use during the aura before a migraine episode or at the start of a migraine episode, with the intention of stopping or reducing the severity of the episode ('treatment'); or at planned intervals, with the intention of reducing the frequency and/or severity of migraine episodes ('prevention'). preventing migraine Page 22 of 29

23 1.1 Evidence on the efficacy of TMS for the treatment of migraine is limited in quantity and for the prevention of migraine is limited in both quality and quantity. Evidence on its safety in the short and medium term is adequate but there is uncertainty about the safety of long-term or frequent use of TMS. Therefore, this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Patient selection should normally be done in specialist headache clinics and the procedure should only be used under the direction of clinicians specialising in the management of headache. 1.3 Patients should be informed that TMS is not intended to provide a cure for migraine and that reduction in symptoms may be modest. 1.4 Clinicians wishing to undertake TMS for treating and preventing migraine should take the following actions. Inform the clinical governance leads in their NHS trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's information for the public is recommended. Audit and review clinical outcomes of all patients having TMS for the treatment and prevention of migraine (see section 7.1). 1.5 NICE encourages further research on TMS for treating and preventing migraine. Data should be collected for all patients not entered into controlled trials. Studies should describe clearly whether its use is for treatment or prevention. They should report details of patient selection and the dose and frequency of use. Outcome measures should include the number and severity of migraine episodes, and quality of life in both the short and long term. The development of any neurological disorders (such as epilepsy) in the short or longer term after starting treatment should be documented. Occipital nerve stimulation for intractable chronic migraine. NICE interventional procedure guidance 452 (2013). 1.1 The evidence on occipital nerve stimulation (ONS) for intractable chronic migraine shows some efficacy in the short term but there is very little evidence about long term outcomes. With regard to safety, there is a risk of complications, needing further surgery. Therefore, this procedure should only be used with special arrangements for clinical governance, consent, and audit or research. 1.2 Clinicians wishing to undertake ONS for intractable chronic migraine should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients understand the uncertainty about the procedure's safety and efficacy, and provide them with clear written information. In addition, the use of NICE's information for preventing migraine Page 23 of 29

24 the public is recommended. 1.3 Selection of patients for treatment using ONS for intractable chronic migraine should be done by a multidisciplinary team, including specialists in headache, pain management and neurosurgery. 1.4 Clinicians should enter details about all patients undergoing ONS for intractable chronic migraine onto the UK Neuromodulation Register when access to that database is available. They should audit and review clinical outcomes locally and should document and consider their relationship to patient characteristics. 1.5 NICE encourages publication of further information from comparative studies and from collaborative data collection to guide future use of this procedure and to provide patients with the best possible advice. Publications should include full details of any complications, and of adjunctive or subsequent treatments. Outcomes should include measures of pain, function and quality of life, particularly in the long term. 1.6 NICE may review the procedure on publication of further evidence. Deep brain stimulation for intractable trigeminal autonomic cephalalgias. NICE interventional procedure guidance 381 (2011). 1.1 Current evidence on the efficacy of deep brain stimulation (DBS) for intractable trigeminal autonomic cephalalgias (TACs) is limited and inconsistent, and the evidence on safety shows that there are serious but well-known side effects. Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Clinicians wishing to undertake DBS for intractable TACs should take the following actions: Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's efficacy. They should be specifically informed that DBS may not control their headache symptoms and they should be fully informed about the possible risks associated with the procedure, including the small risk of death. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having DBS for intractable TACs (see section 3.1). 1.3 Patient selection for DBS for intractable TACs should be carried out by a multidisciplinary team specialising in pain management. 1.4 Further research studies should clearly define patient selection and report the intensity and duration of stimulation, medication use and quality of life, in addition to documenting the effects on headache symptoms as clearly as possible. Percutaneous closure of patent foramen ovale for recurrent preventing migraine Page 24 of 29

25 migraine. NICE interventional procedure guidance 370 (2010) 1.1 Current evidence on the efficacy of percutaneous closure of patent foramen ovale (PFO) for recurrent migraine is inadequate in quality and quantity. The evidence on safety shows a small incidence of wellrecognised but sometimes serious adverse events, including device embolisation and device prolapse (each reported in less than 1% of patients). Therefore this procedure should only be used with special arrangements for clinical governance, consent and audit or research. 1.2 Clinicians wishing to undertake percutaneous closure of PFO for recurrent migraine should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and their carers understand the uncertainty about the procedure's efficacy and the possibility of serious complications. Clinicians should provide them with clear written information. In addition, the use of NICE's information for patients ('Understanding NICE guidance') is recommended. 1.3 Patient selection for percutaneous closure of PFO for recurrent migraine should be carried out by a neurologist or other specialist in headache followed by an interventional cardiologist. Use of this procedure should be restricted to patients who are severely affected by recurrent, refractory migraine. 1.4 The procedure should be done by an interventional cardiologist and supporting team with specific training in the procedure. 1.5 The procedure should only be carried out in units where there are arrangements for emergency cardiac surgical support in the event of complications. 1.6 Data on all patients having this procedure should be submitted to the UK Central Cardiac Audit Database. 1.7 NICE encourages further research into this procedure, which should investigate the uncertainty surrounding the aetiology and natural history of migraine in patients with PFO. NICE may review this procedure on publication of further evidence. Vagus nerve stimulation for treatment-resistant depression. NICE interventional procedure guidance 330 (2009) 1.1 Current evidence on the safety and efficacy of vagus nerve stimulation (VNS) for treatment-resistant depression is inadequate in quantity and quality. Therefore this procedure should be used only with special arrangements for clinical governance, consent and audit or research. It should be used only in patients with treatment-resistant depression. 1.2 Clinicians wishing to undertake VNS for treatment-resistant depression should take the following actions. Inform the clinical governance leads in their Trusts. Ensure that patients and/or their parents/carers understand the uncertainty about the procedure's safety and efficacy and provide them with clear written information. In addition, the use of NICE's preventing migraine Page 25 of 29

26 information for patients ('Understanding NICE guidance') is recommended. Audit and review clinical outcomes of all patients having VNS for treatment-resistant depression (see section 3.1). 1.3 Patient selection and management should be carried out by a multidisciplinary team including a psychiatrist and a surgeon (usually a neurosurgeon), with other relevant specialists (for example, a clinical psychologist and an appropriately trained technician). Technology appraisals NICE guidelines 1.4 NICE encourages further research into VNS for treatment-resistant depression. Research outcomes should include depression rating scales, objective measures of depressive symptoms and patientreported quality of life. NICE may review the procedure on publication of further evidence. Botulinum toxin type A for the prevention of headaches in adults with chronic migraine. NICE technology appraisal guidance 260 (2012) 1.1 Botulinum toxin type A is recommended as an option for the prophylaxis of headaches in adults with chronic migraine (defined as headaches on at least 15 days per month of which at least 8 days are with migraine): that has not responded to at least three prior pharmacological prophylaxis therapies and whose condition is appropriately managed for medication overuse. 1.2 Treatment with botulinum toxin type A that is recommended according to 1.1 should be stopped in people whose condition: is not adequately responding to treatment (defined as less than a 30% reduction in headache days per month after two treatment cycles) or has changed to episodic migraine (defined as fewer than 15 headache days per month) for three consecutive months. 1.3 People currently receiving botulinum toxin type A that is not recommended according to 1.1 and 1.2 should have the option to continue treatment until they and their clinician consider it appropriate to stop. Headaches in over 12s: diagnosis and management. NICE guideline 150 (2012). 1.3 Management Cluster headache Acute treatment Discuss the need for neuroimaging for people with a first bout of cluster headache with a GP with a special interest in headache or a neurologist Offer oxygen and/or a subcutaneous or nasal triptan for the acute preventing migraine Page 26 of 29