Neuromodulation in Chronic Migraine: Evidence and Recommendations from the GRADE Framework

Abstract

Chronic migraine (CM) affects approximately 2% of the general population and is defined by the persistence of migraine symptoms for at least 15 days per month for at least 3 months. CM is often refractory to common drug treatments and is associated with a significant burden in functions of daily life during ictal phases, productivity loss, and direct costs. Modulation of pain is considered pivotal to reduce its impact and to improve the quality of life among patients with CM. In recent years, neuromodulation in CM has received growing attention; however, there remains no consensus regarding the effectiveness and safety of these procedures. Previous invasive methods such as occipital nerve neurolysis and interruption of the trigeminal dorsal root are not indicated due to high rates of relapsing pain and frequent procedural complications. Although emerging neuromodulation methods, both noninvasive, such as vagus nerve stimulation (VNS), transcranial magnetic stimulation (TMS), remote electrical neuromodulation (REM), and invasive, such as deep brain stimulation (DBS), occipital nerve stimulation (ONS), and high-frequency 10-Hz spinal cord stimulation (HF-10 SNS) have demonstrated promising outcomes in early clinical trials, their use has yet to be integrated into routine clinical practice. In this review, study evidence and strength of recommendations are assessed by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system. Other conditions such as therapeutic risk/benefit, direct and indirect costs, use of resources, and patient/clinician preferences are also evaluated.

Keywords: GRADE; Migraine; Neuromodulation; Remote electrical neuromodulation; Stimulation; Vagus nerve.

Fig. 1

Overview of neuromodulation techniques for migraine treatment, categorized by invasiveness and anatomical target. Neuromodulation approaches can be classified as peripheral or central, and either non-invasive or invasive. Peripheral non-invasive methods include: (1) transcutaneous supraorbital nerve stimulation, administered through 20-min daily sessions, used for both acute and preventive treatment; (2) non-invasive vagus nerve stimulation (nVNS), consisting of 2-min stimulations twice daily, for both acute attacks and prevention; and (3) remote electrical neuromodulation (REN), applied to the upper arm via 45-min sessions every other day, with both acute and preventive applications. Central non-invasive techniques include: (4) transcranial magnetic stimulation (TMS), which can be used in various protocols for either acute or preventive purposes; and (5) transcranial direct current stimulation (tDCS), applied using different electrode montages and stimulation parameters, mainly for preventive treatment. Invasive neuromodulation techniques include: (6) occipital nerve stimulation (ONS), (7) deep brain stimulation (DBS), and (8) high-frequency spinal cord stimulation (HF-SCS), all of which are currently explored as preventive strategies for chronic and refractory migraine. Each technique acts through different mechanisms—modulating cortical excitability, autonomic balance, or central pain networks—and may be tailored to patient characteristics and migraine subtype. Figure permissions: Fig. 1 is original and was created with BioRender.com. Agreement number for use: PN27DQ1OUI