NEUROSTIMULATION/NEUROMODULATION UPDATE Meyer and Renee Luskin Andrew Charles, M.D. Professor Luskin Chair in Migraine and Headache Studies Director, UCLA Goldberg Migraine Program David Geffen School of Medicine at UCLA
DISCLOSURES Amgen Consultant Eli Lilly Consultant eneura Medical Advisory di Board Kimberly Clark Consultant St. Jude Medical Clinical trial steering committee Takeda Research Grant Support Trevena Consultant
NEUROSTIMULATION/NEUROMODULATION APPROACHES Supraorbital nerve stimulation Cefaly Device - FDA Approved for migraine prevention (also being investigated as acute therapy) Transcranial magnetic stimulation Spring TMS Device FDA Approved for acute therapy of migraine with aura Spenopalatine ganglion stimulation initially iti investigated t as acute therapy for cluster headache, now being investigated as preventive therapy Vagal nerve stimulation Initially investigated as acute therapy for migraine and cluster, now being studied as preventive therapy
General Concepts of Neurostimulation for Headache Goal is to use peripheral stimulation to provide input to both peripheral and central sites that are involved in headache The fact that input peripheral input may modulate migraine DOES NOT necessarily indicate that there is any pathology at the site of input? Inhibitory or excitatory May depend on frequency, amplitude, other characteristics i of stimulus
PAIN PATHWAYS IN MIGRAINE Meningeal blood vessel Dura Pain Matrix Thalamus Trigeminal ganglion Supraorbital Nerve Peri aqueductal gray Trigeminal cervical complex Upper cervical nerve roots
Upper Neck and Head Pain are Referred to the Same Neurons in the Lower Brainstem Supratentorial dura mater Electrical stimulation Greater occipital nerve Recording electrode Thalamus Trigeminal cervical complex Bartsch T, Goadsby PJ. Cur Pain Headache Rep 2003;7:371-376 376
SUPRAORBITAL NERVE STIMULATION Rationale: Supraorbital nerves are branches of V1 that provide input into central lti trigeminal i nociceptive pathways Many migraine patients experience pain in sensory distribution of these nerves Supraorbital nerve blocks are anecdotally helpful in some patients with migraine Nerve stimulation may relief by stimulation of sensory fibers leading to pain gating, or may cause release of endogenous opioids 1.Ashkenazi A, et al. Peripheral nerve blocks and trigger point injections in headache management a systematic review and suggestions for future research. Headache 2010; 50: 943 52. 2.Reed KL, et al. Combined occipital and supraorbital neurostimulation for the treatment of chronic migraine headaches: initial experience. Cephalalgia 2010; 30: 260 71.
Randomized, sham-controlled study (sham control stimulation with reduced pulse width, frequency, intensity) 67 patients randomized Primary outcome migraine days per month, 50% responder rate
2573 patients who rented Cefaly were surveyed 2313 who used triptans as acute therapy were selected AE reporting on all patients -Discomfort with use of device causing reduced use (1.25%) -Sleepiness during session -Headache after session -Local skin irritation At end of 40 day rental period: -1077 (46.6%) were not satisfied and returned device Of these, use was 48% of recommended time -1236 (53.4%) were satisfied and purchased device
Transcranial Magnetic Stimulation Rationale: Cortical hyperexcitability may be an mechanism of migraine Transcranial magnetic stimulation can modulate the excitability of the cortex TMS can inhibit cortical spreading depression in animal models Repetitive TMS is now FDA approved for treatment of medication refractory depression (10 Hzstimulation of leftdorsolateral prefrontal cortex)
Volume 9, Issue 4, Pages 373-380, April 2010-267 patients intially enrolled, 201 patients randomized -Treatment during aura with 2 pulses -Primary outcome pain free response at 2 hours
119/164 patients reported reduction in acute medication use, average 8.5 +/- 7.7 days reduction
Rationale: Sphenopalatine Ganglion Stimulation SPG is major extracranial parasympathetic ganglion of the head and is involved in cranial autonomic symptoms of primary headaches SPG block is helpful in some patients with primary headache disorders including migraineand and cluster headache SPG stimulation may interrupt parasympathetic outflow to inhibit pain and autonomic symptoms SPG stimulation may modulate sensory processing in the trigeminalnucleus nucleus caudalis
32 patients enrolled, 28 completed randomized period Each cluster attack treated t with full, subperception, or sham stimulation Pain relief and adverse events recorded at 15 minute time intervals Cluster attack frequency also recorded
Significant Adverse Effects Sensory disturbances (localized loss of sensation, hypoesthesia, paresthesia, dysesthesia, allodynia) 81%, resolved with time in 58% Pain (face, cheek, gum, etc.) 38%, resolved in 100% Tooth pain/sensitivity, swelling, trismus,headache More frequent attacks and side switching switching reported
Rationale: Vagal Nerve Stimulation The vagus nerve innervates multiple anatomical structures potentially involved in migraine Branches of cervical nerves innervating the dura may travel withthe the vagus nerve VNS with implanted stimulators found to be effective as acute therapy for migraine and cluster headache VNS reduces allodynia and glutamate release in response to inflammatory soup applied to dura in rats Mauskop. Vagus nerve e stimulation relieves es chronic refractory migraine raineand and cluster headache. Cephalalgia,25:82 86. 86. 2005 Oshinsky et al., Noninvasive vagus nerve stimulation as treatment for trigeminal allodynia. Pain,, 2014
27 patients, 80 attacks All attacks : Moderate to severe pain at baseline 12/54 (22%) pain free at 2 hours, 23/54 (43%) pain relief at 2 hours; Mild pain at baseline 10/26 (38%) pain free at 2 hours; Relevant adverse effects neck twitching (1), raspy voice (1)
Follow up Studies nvns for Prevention of Headache -59 patients enrolled, 49 completed protocol ->15 days of headache per month for previous 3 months -3treatments t t per day 290 second administrations per treatment
Caloric Vestibular Stimulation Warm/cold stimulation of external ear canal with varying controllable waveforms Rationale is that vestibular pathways represent targets for neuromodulation in migraine Data presented at this meeting
COMMON THEMES WITH NEUROSTIMULATION/NEUROMODULATION Multiple stimulation parameters: Amplitude, duration, frequency of stimulation Overlap betweenacute and preventive effects Anatomical targets/mechanisms of action may be broader or different than those originally proposed Further rigorous studies are needed