The aim of this systematic review was to investigate whether external trigeminal nerve stimulation (e-TNS), as a preventive or acute therapy, is more effective and safer than standard drug therapy or placebo with respect to improvement in migraine episodes, quality of life (QoL), satisfaction, and side effects.

A systematic literature search was conducted in the following four databases: Medline via Ovid, Embase, The Cochrane Library, CRD (DARE, NHS-EED, HTA). The search was limited to prospective studies and articles published in English or German, but not to publication year. After deduplication, 433 citations remained for abstract screening. Seven further publications were found by hand search, resulting in 440 references overall. An additional search of clinical trial registries search yielded 70 results, of which seven proved relevant. The manufacturer provided no further publications.

For the assessment of clinical effectiveness, two studies met the inclusion criteria. One randomised controlled trial (RCT) for the preventive use of e-TNS and one RCT for the acute treatment use of e-TNS. Concerning prevention, the results from the "preventive study" (34 e-TNS patients) suggest that e-TNS is more effective than sham treatment in episodic migraine patients when measured by reduction of migraine attacks (0.67 less migraine attacks per month), migraine days (1.74 less migraine days per month), headache days (2.28 less headache days per month), acute antimigraine drug intake (4.24 less instances of acute drug intake per month), improvement in responder rate of migraine days (26.2% more response to verum treatment) and satisfaction (31.2% difference in satisfaction with the control group). Concerning acute treatment, the "acute study" showed that e-TNS caused more improvement in pain reduction than sham on a VAS scale (out of 11 points) at 1/2/24 hours post-acute treatment (1.68/1.02/1.08 more improvement points, respectively). Concerning the minimal clinically important difference (MCID) however, it remains unclear if the improvement measured is of clinical importance because the results oscillate around the lower end of the clinically meaningful benefit threshold. There was also an increase of one intervention group (IG) patient in acute antimigraine drug intake at two hours post-acute treatment compared to control (CG), and a decrease of three verum patients compared to control at 24 hours.

For the assessment of safety, seven studies met the inclusion criteria. Two RCTs (described above), and five prospective case series (three for prevention with a total of 84 patients and two for acute treatment with a total of 95 patients). Concerning safety, in both the prevention and acute treatment studies, no serious adverse device effects occurred. In terms of adverse device effects in the prevention studies, two studies reported that there were none, while intolerance to paraesthesia (burning sensation) was reported in 34.3% of patients. Furthermore, headache after stimulation as well as neck tension were reported in one study, where headache occurred in 8.7% of patients, while there was neck tension in 4.3%. In terms of adverse device effects in the acute treatment studies, one study reported that there were none, while intolerance to paraesthesia was documented in two acute treatment studies in 5.8% (IG n=52) vs. 1.9% (CG n=54) and 11.9% of patients. Nausea after stimulation was reported in two studies in 1.9% (IG n=52) vs. 0% (CG n=54) and 3.5% of patients. Furthermore, arousal changes (insomnia, sleepiness/fatigue, drowsiness), dizziness, vomiting, pain in the jaw, discomfort in teeth, pain in eyes, and cold feet occurred in one study in 1.7% of patients. In the same study, 18.3% of patients reported skin allergy/irritation.

Given the small size of the highly selective sample of patients included in the evidence base (as compared to the large burden of disease that migraine creates), the conclusions about effectiveness and the positive safety profile appear to be inflated. The target population of e-TNS are not only patients refractory to medication, but mainly drug responsive patients, which makes replacing the use of medication a main objective of e-TNS. That is why larger controlled trials with best practice interventions (for prevention as well as acute treatment use of e-TNS) as comparators are necessary for potentially considering e-TNS to be part of the standard practice. The inclusion in the catalogue of benefits is currently not recommended.