Stimulating New Treatments for your Headache Patients

Dr McAllister is Medical Director at the New England Institute for Neurology and Headache and Chief Medical Officer for the New England Institute for Clinical Research and Ki Clinical Research, all in Stamford, Conn.

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I'll start this month's migraine update with a brief quiz.

Which of the following has/have been approved by the Food and Drug Administration (FDA) for the acute treatment of migraine?

A. Sumatriptan

B. Cefaly device

C. Gammacore

D. Spring TMS

E. All of the above

Answer: If you picked E, All of the Above, kudos to you, you’re ahead of the class.

For those who looked at options B, C, and D and wondered what language they were reading, read on, since a new wave of stimulating headache therapies have hit the market in the last few years, and more are coming.

As these devices increase in popularity, the well-informed primary care physician, after reading this article, will be in the know.

The International Neuromodulation Society defines neuromodulation as the alteration of nerve activity through targeted delivery of a stimulus, such as electrical stimulation or chemical agents, to specific neurological sites in the body.

The idea that electricity could be harnessed to treat pain is not new. In the year CE 47 Scribonius Largus advocated fish electrotherapy when he wrote, “To immediately remove and permanently cure headache, a live black torpedo (electric ray) is put on the place which is in pain, until the pain ceases and grows numb.” Indeed, the Greek word for electric fish is narka, as in narcotics.

In 1760 Benjamin Franklin used electric therapy to treat his rheumatism, writing about it in Experiments and Observations of Electricity Made at Philadelphia in America.

From the late 1950s to 1980s functional neurosurgeons used destructive lesions (such as dorsal rhizotomy) for intractable pain, but by the 1990s the idea of stimulation of neural tissue gained a foothold. Early attempts at neuromodulation, such as deep brain stimulation (DBS) for intractable cluster headache were invasive and associated with a not insignificant degree of morbidity and mortality. Newer neuromodulation devices, mostly non-invasive, offer efficacy with little in the way of adverse events.

So far, four non-invasive neuromodulation devices have been approved by the FDA for treatment of primary headache disorders (summarized in Table on last page).

Cefaly is a hand-held transcutaneous SNS device that was FDA approved in 2014 for prevention of migraine, and later shown to be effective for acute treatment as well. It is worn on the forehead for twenty minutes a day to reduce the number of monthly migraines, and applied during an attack to relieve pain.

Cefaly comes in three models: ACUTE, DUAL, and PREVENT, with costs between $349 and $499 to purchase.

A TMS device (Spring TMS, by eNeura) was studied in a randomized, double-blind, sham controlled study in which 182 migraine with aura subjects were randomized to receive a brief pulse of 0.9T TMS or placebo. Increased freedom from pain at 2 hours was noted with early sTMS treatment vs sham stimulation; absence of pain was sustained 24 h and 48 h after treatment. The device is held on the back of the head and when triggered, delivers a brief pulse of electromagnetic energy through the skull.

Spring TMS is rented at a monthly cost of about $200.

gammaCore (by Electrocore)is a non-invasive vagus nerve stimulator (VNS). The handheld device is controlled by the patient, for acute treatment of episodic cluster headache as well as migraine. In clinical trials, some patients felt relief in as littel as 30 minutes; approximately half had complete pain relief at 2 hours and those pain-free at 2 hours remained so for 48 hours.

Monthly rental charges are several hundred dollars.

Most recently, the FDA in May 2019 approved Nerivio Migra (Theranica), a novel, smartphone-controlled neuromodulation device that is worn on the upper arm and blocks migraine pain acutely by conditioned pain modulation. A peripheral nerve stimulation of the median and musculocutaneous nerves sends a subclinical painful signal to the thalamus and activates the descending pain inhibitory pathway. It is approved for acute treatment of migraine with or without aura in adult patients who do not have chronic migraine

Nerivio will be launched in the US later in the year.

Pulsante, an implantable SPG neurostimulator for treatment of chronic cluster headache is approved in Europe, and awaiting FDA clearance in the US. (See Table at right for summary of devices; please click image to enlarge).

Consider neuromodulation for your patients who require treatment of primary headaches but would prefer a drug-free method. These devices are safe, well-tolerated, and proven effective in double-blind, placebo-controlled studies.  (See Table for summary.) The major hurdle is cost and insurance coverage, which is spotty at best. Most of the device companies have free trials and will work with insurance to get coverage, albeit not always successfully.

Neuromodulation for headache is a burgeoning field worth knowing about, and can lead to stimulating doctor-patient discussions (pun intended).

Where does neurostimulation act?

Think of the following pain pathway: sensory pain fibers in the meninges, the face, jaw and sinuses, as well as upper cervical sensory afferents all synapse in the trigeminal nucleus caudalis (TNC) in the brainstem.

Second order neurons then ascend and hit the thalamus (as well as a few other structures like the periaqueductal gray [PAG]), and third order nerves climb yet again to the cortex, where pain is fully processed.

So, starting from the top, transcranial magnetic stimulation (TMS) effects the cortex and thalamocortical circuits, while DBS stimulates the PAG.

Supraorbital nerve stimulation (SNS) modulates facial pain signals into the TNC.

Curled deep behind the nose, the sphenopalatine ganglion (SPG) is a pain superhighway into the TNC, which can be stimulated.

The occipital nerves take posterior cervical sensory information into the TNC, and the vagus nerve, as it courses through the anterior neck, synapses on the TNC and other pain depots such as spinal trigeminal nucleus, nucleus ambiguous, and the nucleus of the solitary tract.

Table. Neuromodulation devices summary