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11. Neuromodulation in Migraine
Like other primary headaches, migraine can be treated by neuromodulation techniques based on electrical stimulation of the nervous system. These neuromodulation techniques can be invasive and noninvasive and have different targets.
11.1 Invasive Neuromodulation in Migraine
11.1.1 Occipital Nerve Stimulation (ONS)
Initially proposed to treat occipital neuralgia, ONS was also used to treat primary headaches including migraine with the same devices as those used to treat neuropathic pain by spinal cord stimulation.
Evidence
Migraine preventative treatment using ONS has been the topic of several randomized controlled trials (RCT), and the results are disappointing. PRISM study was a multicenter, prospective, double-blind, sham-controlled trial promoted by Boston Scientific. It involved 140 subjects with episodic migraine (EM) or chronic migraine (CM) who previously failed of at least two acute treatments and two preventative treatments and regardless presence of medication overuse. There was no significant difference in the primary endpoint that was the reduction in monthly migraine days (−5.5 for the active and −3.9 for the sham, p = 0.29) from baseline to 3 months after implantation, and only the abstract was reported [1]. ONS-STIM trial was a multicenter, prospective, randomized, single-blind, feasibility study promoted by Medtronic. It involved 61 subjects who suffered from CM with a previous failure of at least two preventative treatments, an associated medication overuse being an exclusion criterion. An innovative study design was utilized to compare medical management, preset (sham) stimulation, and adjustable (active) stimulation. This methodology allowed a randomized comparison between groups with a 2:1 active to sham ratio among implanted individuals who had been randomized, and the study was conducted in single blind. Ultimately, 28 were implanted in the adjustable stimulation group, 16 in the preset group, and 17 in the medically managed group. No primary endpoint was specified, but the feasibility of multiple outcome measures for future studies was assessed. After 12 weeks of stimulation, a responder was defined as a subject who achieved at least 50% reduction in the number of headache days per month or a three-point or greater reduction in overall pain intensity compared to baseline. Using this definition, 39% of patients were responders in the adjusted stimulation group compared with 6% in the preset stimulation group (p = 0.032) and 0% in the medically managed group (p = 0.003) [2]. A third trial, promoted by Saint Jude Medical, concerned 157 subjects suffering from CM with previous failure of at least two acute treatments and two preventative treatments and regardless presence of medication overuse. In this multicenter, prospective, double-blind trial, subjects were randomized into two arms according whether they were treated with ONS (105 subjects) or sham stimulation (52 subjects). On the primary endpoint, that was a 50% reduction in mean daily visual analog scale (VAS) scores, this study did not find any significant difference between the ONS arm (17.1%) and stimulation sham arm (13.5%). Nevertheless, this RCT showed significant superiority of ONS regarding a 30% reduction in VAS scores and other secondary endpoints such as the number of headache days per month (−7.3 in active stimulation vs. −4.2 in sham stimulation, p = 0.015) [3]. In addition to these three industrial RCTs, ONS was evaluated in two smaller, academic, monocenter RCTs whose results were in favor of it [4, 5]. Using these five RCTs and seven open series that included at least ten patients, a meta-analysis suggested that the ONS could be effective in the preventative treatment of CM but insisted on the modest effect size with pooled results from the three industrial RCTS showing a mean reduction of 2.59 headache days per month at 3 months compared to sham (95% CI 0.91 to 4.27, I2 = 0%) and probably exaggerated by the bias related to the difficult double-blind respect due to paresthesia induced by ONS in the great occipital nerve territory that is essential to achieve the therapeutic effect [6]. This meta-analysis also insisted on the absence of efficacy data after 3 months, but the long-term results of the study promoted by Saint Jude Medical were subsequently published showing persistent efficacy after 1 year of stimulation [7]. Such an ONS persistent efficacy in CM was also recently reported in an open series involving 53 patients with a mean follow-up of 4 years [8] and another open series involving 37 patients with a mean follow-up of 7 years [9].
Limits
The European Headache Federation stated that in CM, the use of ONS seems “acceptable” although based on limited evidence [10]. In this context, a CE mark to ONS in CM was obtained by Saint Jude Medical for its devices. However, the use of ONS in CM is now limited by the withdrawal of this CE mark. This withdrawal has been justified by a large number of adverse events reducing benefit/risk of ONS in this indication. The mean incidence of total complications of ONS in CM treatment was estimated to 66% [11]. Like any implantable neuromodulation technique, NSO is limited by a risk of immediate or delayed infection. ONS also exposes a risk of early battery depletion due to high-stimulation intensities and the fact that stimulation is most often used continuously during the day and night. Finally, ONS can be complicated by a lead migration secondary to the neck mobility and which, when it occurs, imposes a surgical revision.
Mechanisms of Action
The mechanisms of action of ONS for the prevention of migraine are unknown. The background to propose the ONS in the treatment of migraine (and other primary headaches) was the convergent input from trigeminal and cervical afferents in the trigeminocervical complex (TCC) [12, 13]. Nevertheless, the effect latency observed in many patients suggests a more complex mechanism of action that are also suggested by functional imaging studies. A study using PET showed an activation of the rostro-dorsal pons (where migrainous generators are supposed to be located) associated with an activation of structures involved in the pain matrix, including the anterior cingulate cortex [14]
11.1.2 Others Invasive Neuromodulation Treatments
Sphenopalatine Ganglion Stimulation (SPGS)
A chronically implantable neuromodulation device (“Pulsante”), specifically designed for acute SPGS, has been developed by the company Autonomic Technologies in order to be used on demand. The neurostimulator device is implanted in the pterygopalatine fossae, along the posterior wall of the maxillary bone, and fixed to the zygomatic process with a screwed plate, with the lead being placed in contact with the SPG. The neurostimulator does not contain a battery but is activated and powered by a remote controller using radiofrequency energy. Clinical development of this device mainly concerned the acute treatment of cluster headache [15], but a RCT in acute treatment of migraine has just ended and the results are pending (PATHWAY-M1/NCT01540799 clinicaltrials.gov).
Cervical Spinal Cord Stimulation (CSCS)
The background for CSCS use in primary headaches is the assumption that the application of electrical pulses directly onto the dorsal columns at the C2–C3 vertebral level will provide a neuromodulatory effect on the TCC greater than stimulation of the greater occipital nerve. In a retrospective cohort, a Swiss team reported 12 patients experiencing a 50% response among 17 patients with refractory CM treated by CSCS [16]. A proof of concept trial investigating the safety and efficacy of CSCS in the treatment of refractory CM was carried out few years ago (NCT01653340 clinicaltrials.gov), but results are still pending. Until proper evidence is provided, CSCS is strictly avoided in patients with migraine as stated by EHF [10].
11.2 Noninvasive Neuromodulation in Migraine
11.2.1 Supraorbital Nerve Stimulation (SONS)
The stimulation of the supraorbital nerve is possible by Cefaly©, a noninvasive device which corresponds to a transcutaneous external stimulator specifically developed to stimulate this terminal branch of the trigeminal nerve and which is applied on the forehead.
Evidence
Available evidence supports the Cefaly© use only in the prevention of EM. Data were obtained in the PREMICE study which is an RCT promoted by the manufacturer of this device with a partnership of the Belgian Headache Society [17]. The PREMICE study involved 67 subjects with EM who, after an evaluation period of 1 month, were randomized to use the Cefaly© or a stimulation sham for 3 months. The primary endpoint was the difference of monthly migraine days between the month prior to randomization and the third month of the randomized period. Intention-to-treat analysis showed a significant reduction (from 6.94 to 4.88/29;7% p = 0.023) in the Cefaly© arm and a nonsignificant one (from 6.54 to 6.22/4% p = 0.608) in the sham arm, but the comparison of this reduction between the Cefaly© arm and the sham arm did not reach significance level (p = 0.054). In a covariance analysis, using the number of migraine days before the randomization as a covariate, the significance level was reached, supporting the Cefaly© use in the EM prevention. No evidence is currently available to support the efficacy of Cefaly© in CM prophylaxis, and results of an RCT focused on the acute migraine treatment (NCT03465904 / clinicaltrials.gov) were pending.
Limits
According to evidence, Cefaly© can be used in the preventative treatment of EM with a daily stimulation session lasting 20 min and performed using the second program proposed by this device. SONS induces frontal paresthesia which should not be unpleasant, stimulation intensity remaining under the control of the subject using the Cefaly©. The main advantage of SONS is its safety. An adverse event was reported by only 4.3% of more than 2000 subjects included in a post-marketing study, the most common adverse events being pain at the site of stimulation, paresthesia intolerance, poststimulation headache, or central side effects such as sleep disturbances [18]. Only two patients presented a local allergic reaction, and the manufacturer offers now hypoallergenic electrodes for acrylate allergic subjects. There is no contraindication to the use of Cefaly©, and this device can be used by pregnant women. This device has a CE mark and can be ordered from the manufacturer’s website (www.cephaly.com). However, it is not supported by all health systems, and its price (40-day trial for 49€ and purchase for 295€) can be a limit to its use.
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