Purpose of Review <p>This review provides evidence for the mechanism of action (MOA) of Remote Electrical Neuromodulation (REN), a non-pharmacological therapeutic technology for treating migraine and other symptoms manifested by certain idiopathic pain diseases. It discusses the main physiological and anatomical aspects associated with conditioned pain modulation (CPM), and how REN is applied for the treatment of migraine pain and other symptoms.</p> Recent Findings <p>The REN wearable device (Nerivio^®) is FDA cleared for acute and preventive treatment of migraine in patients aged 8 years and above, and CE marked in patients aged 12 and above. In brief, the REN MOA is formulated on the observed concept that one of the descending pain inhibition mechanisms in the brain, known as CPM, is deficient among people diagnosed with certain idiopathic pain disorders, such as migraine. Hence, these people are more vulnerable to otherwise innocent external stimuli, which are misinterpreted in the brain as painful and can thus trigger a migraine attack, often presenting with increased pain sensitivity (hyperalgesia) and headache. Research has revealed that descending inhibitory mechanisms can be externally activated under certain conditions. REN operates through applying electrical stimulation with parameters designed to activate A-delta and C nociceptive nerve fibers in the skin to optimize this response, thereby enhancing CPM and increasing pain inhibition by releasing norepinephrine and serotonin.</p> Summary <p>Based on current evidence, the review presents medical practitioners and researchers with a detailed explanation of the REN MOA in treating and preventing migraine, and potentially other idiopathic pain disorders.</p>