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  • Review Article
  • Published:

New strategies for the treatment and prevention of primary headache disorders

Nature Reviews Neurology volume 12, pages 635–650 (2016)Cite this article

Subjects

Key Points

  • Calcitonin gene-related peptide (CGRP) is the best-validated therapeutic target for migraine

  • Monoclonal antibodies (mAbs) against CGRP or its receptor hold promise for migraine prevention, and small-molecule CGRP antagonists hold promise for acute and/or preventive treatment

  • Four mAbs targeting CGRP or its receptor have been effective in phase II studies and are being studied in phase III trials for migraine prevention

  • Non-oral systems to deliver triptans and dihydroergotamine mesylate for acute migraine treatment bypass hurdles posed by nausea, gastric stasis, and first-pass metabolism

  • Noninvasive electrical and electromagnetic neurostimulators for primary headache disorders are available for clinical use, but regulatory approval varies by country, and patients might be required to cover costs

  • For patients with intractable, medically refractory primary headache disorders, implantable neurostimulators targeting peripheral nerves, the sphenopalatine ganglion, and high cervical spinal cord are being studied

Abstract

The primary headache disorders, which include migraine, cluster headache and tension-type headache, are among the most common diseases and leading causes of disability worldwide. The available treatment options for primary headache disorders have unsatisfactory rates of efficacy, tolerability and patient adherence. In this Review, we discuss promising new approaches for the prevention of primary headache disorders, such as monoclonal antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor, and small-molecule CGRP receptor antagonists. Neuromodulation approaches employing noninvasive or implantable devices also show promise for treating primary headache disorders. Noninvasive treatments, such as transcranial magnetic stimulation and transcutaneous peripheral nerve stimulation, are delivered by devices that patients can self-administer. Implantable devices targeting the occipital nerves, sphenopalatine ganglion or high cervical spinal cord are placed using percutaneous and/or surgical procedures, and are powered either wirelessly or by surgically implanted batteries. These new and emerging treatments have the potential to address unmet patient needs and reduce headache-associated disability.

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Figure 1: CGRP levels during migraine attacks.
Figure 2: Nasal administration of sumatriptan via Onzetra Xsail.
Figure 3: Non-invasive neuromodulation treatments.
Figure 4: Implantable neuromodulation treatments.
Figure 5: High cervical spinal cord stimulators.

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Authors and Affiliations

  1. Department of Anesthesia, Center for Pain Medicine, Critical Care, and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, 15 Parkman Street, Boston, 02114, Massachusetts, USA

    Nathaniel M. Schuster

  2. Department of Neurology, David Geffen School of Medicine at UCLA, 710 Westwood Plaza, Los Angeles, 90095, California, USA

    Alan M. Rapoport

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Contributions

N.M.S. and A.M.R. contributed equally to researching data for the article, discussion of the article's content, and writing and editing the manuscript before submission.

Corresponding author

Correspondence to Nathaniel M. Schuster.

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Competing interests

N.M.S. received an American Headache Society travel grant with funding from Avanir. A.M.R. serves on the speaker's bureaus of Avanir, Depomed and Teva, consults for Eli Lilly and serves on the advisory boards of Autonomic Technologies, Doctor Reddy's, Pernix, Teva and Zosano.

PowerPoint slides

Glossary

CGRP receptor

The calcitonin gene-related peptide (CGRP) receptor is a complex between the calcitonin receptor-like receptor and the receptor activity-modifying protein 1 (RAMP1). Expression of the CGRP receptor has been confirmed in the vasculature, the trigeminal ganglion, and the spinal trigeminal complex of the brainstem.

LY2951742

A fully humanized anti-calcitonin gene-related peptide IgG4 monoclonal antibody with a 28-day half-life (also known as galcanezumab).

Fast-track status

Fast-track status is granted by the FDA to investigational drugs anticipated to fill an unmet need in treating a serious condition.

ALD403

A genetically engineered, desialylated, humanized anti-calcitonin gene-related peptide IgG1 antibody with a 31-day half-life.

TEV-48125

A fully humanized anti-calcitonin gene-related peptide IgG2a monoclonal antibody with a half-life of 40–48 days (previously known as LBR-101).

AMG 334

A human IgG2 monoclonal antibody that is targeted against the calcitonin gene-related peptide receptor. AMG 334 has a half-life of 21 days.

Ubrogepant

An orally administered small-molecule calcitonin gene-related peptide antagonist for the acute treatment of migraine (also known as MK-1602).

MK-8031

An orally administered small-molecule calcitonin gene-related peptide antagonist for the prevention of migraine.

Acute treatments

Treatments that are used as needed while experiencing a headache, with the purpose of aborting the headache. These treatments include simple analgesics, triptans, and ergot derivatives such as dihydroergotamine mesylate.

Paraesthesia

An abnormal sensation, often described as a 'pins and needles' feeling, that can be caused by medications or by damage, compression, or stimulation of peripheral nerves.

Double-dummy

A double-dummy study is a form of double-blind study that is used when the two treatments being studied cannot be made to appear identical. For example, it can be used to compare an inhaled medication with an oral medication. All participants are administered two treatments — one inhaled and one oral. Participants are randomly assigned to receive either the active inhaled treatment and placebo oral treatment or the placebo inhaled treatment and active oral treatment.

Atypical triptan sensations

Atypical triptan sensations are often reported following the use of triptans. Atypical triptan sensations include tightness and tingling in the chest, limbs and face. They are benign, but can be mistaken for much more serious conditions.

Cutaneous allodynia

In cutaneous allodynia, central sensitization to pain causes normally non-noxious tactile stimuli to skin (such as showering, shaving, brushing the hair or wearing tight clothing) to be experienced as painful.

Status migrainosus

A migraine attack lasting more than 72h.

Hemicrania continua

A primary headache disorder that results in continuous pain in one side of the face and head, with associated ipsilateral autonomic symptoms.

Lead migration

The displacement of an electrical neurostimulation lead following implantation. Lead migration is the most common complication following the surgical implantation of a peripheral nerve stimulator or spinal cord stimulator.

Sphenopalatine ganglion

The sphenopalatine ganglion, also known as the pterygopalatine ganglion, sits in the pterygopalatine fossa and contains parasympathetic nerve bodies and postsynaptic sympathetic fibres.

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Schuster, N., Rapoport, A. New strategies for the treatment and prevention of primary headache disorders. Nat Rev Neurol 12, 635–650 (2016). https://doi.org/10.1038/nrneurol.2016.143

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