New targets for migraine — CGRP, PACAP and electric activity

Migraine medication is often discontinued due to a lack of efficacy and adverse effects

Despite the plethora of medications to treat migraine — including antidepressants, antiepileptics, antihypertensives, and neurotoxins — effective treatment of migraine remains a challenge.¹ A single treatment may not be sufficient, and patients commonly discontinue their medications due to a lack of efficacy and adverse effects.¹ For many of them, migraine remains an intractable disabling disorder.

Increasing understanding of the complex neuropathophysiology underlying the different phases and symptoms of migraine has led to the development of new therapies targeting CGRP and PACAP and innovative neuromodulation techniques. Early clinical trial results suggest these targets have an important role to play in improving outcomes for patients with migraine.

Targeting CGRP

The main CGRP-mAb site of action appears to be outside the brain

CGRP is a 37-amino acid neuropeptide. Canonical CGRP receptors are expressed throughout the nervous system and are important targets for emerging migraine therapies.

Humanized CGRP monoclonal antibodies (CGRP-mAbs) have been found to prevent activation of thinly myelinated A-delta but not unmyelinated C-type meningeal nociceptors.² As CGRP-antibodies do not cross the blood–brain barrier, this selective action is presumed to result from CGRP inhibition outside the brain.²

The trigeminal system has been suggested as a possible site of action for CGRP-antibodies because it lacks blood-brain barrier and is available to circulating molecules.³ It is hypothesized that the C fibers modulate adjacent A-delta fibers in the trigeminal ganglion and dura through axon-to-axon CGRP signaling at the nodes of Ranvier, with CGRP receptor activation modulating ion channel thresholds and rate of nerve firing,³ said Professor David Dodick, Mayo Clinic, Scottsdale, Arizona, USA.

The class of CGRP-mAbs are emerging as preventive therapy for migraine

Precautions when using CGRP-mAbs include:

• hypersensitivity reactions and anaphylaxis
• development of severe constipation with serious complications
• lack of safety data in women who are pregnant or breastfeeding⁴

Targeting PACAP-38

PACAP-38 has been associated with ictal and interictal migraine

PACAP-38 is a vasoactive pro-nociceptive neuropeptide with many actions in the central and peripheral nervous systems including neurotransmission, neuromodulation, regulation of circadian clock, behavioral actions, and learning and memory procession. It has been associated with the ictal and interictal migraine phases,⁵ said Professor Stephen D. Silberstein, Thomas Jefferson University Hospital, Philadelphia, PA. Plasma PACAP-38-like immunoreactivity is significantly lower in the interictal phase in people with migraine compared with healthy controls, and is elevated in the ictal period relative to the interictal period.⁵

PACAP-38 is therefore another new drug target for migraine. mAbs to inhibit PACAP are being investigated in phase 2 clinical trials, but little is known about the clinical consequences.

Modulating neuronal circuitries

Targets for neuromodulation include the cortex, the cervical vagus nerve, and branches of the trigeminal nerve

Minimally invasive and noninvasive neuromodulation techniques are viable treatment options for people with migraine, said Amaal Starling, Mayo Clinic, Scottsdale, Arizona. Multiple devices have undergone clinical trials with efficacy and tolerability, and techniques, with FDA approval, for the treatment of migraine in adults include:

• single pulse transcranial magnetic stimulation (sTMS), which targets the cortex, inhibiting cortical spreading depression (CSD), modulating corticothalamic projections, and reducing excitability of the trigeminothalamic pathway⁶
• noninvasive vagus nerve stimulation (nVNS), which targets the cervical vagus nerve to modulate the nucleus tractus solitarius, hypothalamus, visual cortex, and spinal trigeminal nucleus (STN) and reduce pain-induced activation of neurons in the STN and trigeminal allodynia — it also has a bilateral inhibitory effect on the trigeminal autonomic reflex, anti-inflammatory effects, and decreases CSD
• external trigeminal nerve stimulation (eTNS), which targets supraorbital and supratrochlear branches of the trigeminal nerve to normalize trigeminal nerve modulation, normalize fronto-temporal hypometabolism, and decrease responses to noxious thermal stimulation in the anterior cingulate