Therapeutic strategies that act on the peripheral nervous system in primary headache disorders

ABSTRACT

Introduction: Acute and preventive treatment of primary headache disorders is not completely resolved with regard to efficacy, safety, and tolerability. Hence, peripheral and central neuromodulation can provide therapeutic alternatives in drug-resistant cases. Peripheral targets of neuromodulation include invasive and non-invasive neurostimulation and electrical and chemical nerve and ganglion blockades.

Areas covered: A PubMed search of papers published from January 2012 to October 2018 was conducted. The goal of this review was to analyze the efficacy and safety of invasive (implantable) peripheral neurostimulation methods (the occipital nerve, the cervical branch of vagal nerve, the sphenopalatine ganglion) and non-invasive (transcutaneous) peripheral neurostimulation methods (the occipital nerve, the supraorbital nerve, and the cervical and auricular branches of the vagal nerve), based on the results of published clinical trials and case series. Acting also on the peripheral nervous system, peripheral nerve (i.e. greater occipital nerve) and ganglion (i.e. sphenopalatine ganglion) blockades, botulinum neurotoxin type A-hemagglutinin complex therapies, and calcitonin gene-related peptide-related monoclonal antibody treatments in this patient population are also discussed.

Expert opinion: This review summarizes the latest results on the therapeutic strategies acting on the periphery in primary headache disorders. These therapeutic options are minimally invasive or non-invasive, efficacious, safe, and well tolerated.

KEYWORDS:

• Botulinum neurotoxin type A-hemagglutinin complex
• calcitonin gene-related peptide
• cluster headache
• drug-resistant
• ganglion blockade
• migraine
• monoclonal antibodies
• nerve blockade
• peripheral neurostimulation
• treatment

Article highlights

• The currently available acute and preventive medication in primary headache disorders do not cover the total patient population due to the variation in efficacy, tolerability, and AEs. There is a need for alternative therapeutic options, such as peripheral neuromodulation and drugs acting on the peripheral nervous system (e.g. BoNTA-hemagglutinin complex and CGRP-related mAbs).

• Invasive neurostimulatory techniques, such as implantable ONS (in CM, CCH, SUNCT, SUNA, and HC), implantable SONS+ONS (in CM), implantable cervical VNS (in epileptic patients with headache) and implantable SPG stimulation (in ECH and CCH) are effective and well-tolerated minimally invasive methods.

• Non-invasive neurostimulatory tools, such as transcutaneous ONS (in CM and CH), transcutaneous SONS (in EM), transcutaneous cervical VNS (in EM, CM, ECH, CCH, SUNA, and HC) and transcutaneous auricular VNS (in CM) exhibited beneficial effects and associated with low AE profiles.

• Nerve and ganglion blockades: GON blockade with chemical agents (e.g. bupivacaine, lidocaine, mepivacaine, methylprednisolone, triamcinolone, or betamethasone) is an easily applicable, inexpensive method, and is effective and well tolerated in EM, CM, CCH, and HC. SPG blockade with chemical agents (e.g. bupivacaine, absolute alcohol, or BoNTA-hemagglutinin complex) in CM, ECH, CCH, and HC was effective and well tolerated. SPG blockade with RF ablation in ECH and CCH showed beneficial effect without serious AEs.

• BoNTA-hemagglutinin complex injection administered to fixed-sites (i.e. frontal, temporal, occipital, or neck muscles), a medication approved by the FDA for the prevention of CM, is effective and safe.

• CGRP-related mAbs, fully humanized antibodies targeting CGRP receptor (erenumab) or CGRP itself (eptinezumab, galcanezumab, and fremanezumab), administered subcutaneously or intravenously, were effective compared to placebo without any serious AEs in EM. Long-term safety data are needed.

Acknowledgments

We are grateful to Jennifer Tusz, native speaker (Edmonton, Canada) and Levente Szalardy MD, PhD, medical proofreader, for their valuable contribution in proofreading the manuscript.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by the Economic Development and Innovation Operational Program, Gazdaságfejlesztési és Innovációs Operatív Program, [GINOP-2.3.2-15-2016-00034], financed by the European Union and by the MTA-SZTE Neuroscience Research Group of the Hungarian Academy of Sciences as well as by the University of Szeged. Ministry of Human Capacities, Hungary grant [20391-3/2018/FEKUSTRAT].