Migraine and calcitonin-gene related peptide

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By Ken Sharlin

The U.S. Food and Drug Administration recently approved the fourth new drug to treat migraine since May 2018. It has been nearly a decade since the approval of any new migraine medicines, and for those patients in the conventional care system, these new treatments are a welcome sigh of relief. What makes each of these medications unique is that they all target calcitonin gene-related peptide (CGRP). But what about patients who are seeking a more natural solution to their migraines?

By the time Steve came to see me he had tried at least two conventional preventative migraine medications with no success. His condition had already affected his life in a big way. He was looking for something different. As I considered options to help him, I wanted to know how if addressing CGRP might be the right solution. The first step was to roll up my sleeves and learn about CGRP.

CGRP is a neuropeptide expressed in 35 to 50 percent of neurons in the trigeminal ganglia. However, CGRP also has activity in the central nervous system. In addition to the trigeminal ganglion, CGRP receptors can be found in the heart and gastrointestinal tract.

CGRP is a mediator of inflammation and a modulator of pain signals transmitted by the trigeminal nerve. There are several observations that gave researchers a clue that CGRP plays a key role in migraine. Elevated CGRP levels have been reported in the serum and saliva during migraines and has also been observed between attacks. Intravenous injection of CGRP causes moderate to severe migraine-like headaches in migraine-susceptible individuals, but not in those without a history of migraine. CGRP-induced migraine can be reversed by a triptan, such as the commercially available drug sumatriptan. The final observation that CGRP is implicated in migraine is that compounds, which block the receptor for CGRP are effective in the treatment of migraine.

CGRP plays a role in neurogenic inflammation. The process of neurogenic inflammation is central to our understanding of migraine pathophysiology and involves the release of inflammatory mediators. When CGRP triggers degranulation of dural mast cells, and glia of the trigeminal ganglia and nerve, there is release of proinflammatory cytokines such as TNF-alpha and interleukins -1beta and -6. These compounds activate neurons that transmit pain signals, including in the pain sensitive nerve endings in the meningeal layer around the brain and optic nerves. CGRP also acts as a potent dilator of vascular beds, including the intracranial arteries, through direct action on smooth muscle cells and stimulation of endothelial nitric oxide. From a more clinical perspective, it appears that CGRP plays a key role in the experience of light sensitivity during migraine, central sensitization, the underlying mechanism for chronic pain, and the aura phase of migraine.

One study published in 2016 looked at the effects that certain foods have on CGRP secretion. The researchers evaluated grape pomace extract which comes from the solid remains of grapes (skin, pulp, seeds, and stems) after the juice has been pressed out of the fruit, ginger, and S-petasin from butterbur. All three substances decreased the secretion of CGRP, but the most potent effect came from the higher doses of pomace. Additionally, a study of butterbur published in the journal Neurology in 2004 found that the proportion of patients with a 50 percent or greater reduction in attack frequency over four months was 68 percent for those treated with butterbur at a dose of 75 milligrams twice per day. Importantly, butterbur extract has been shown to contain pyrrolizidine alkaloids (PA), a substance that causes hepatotoxicity in humans, so it is important to seek out a PA-free butterbur formulation when using it as a supplement.

Another study published in 2010 found that rats fed high cacao diets had a repressed inflammatory response to acute and chronic stimulation of trigeminal ganglion neurons, and that cacao decreased the expression of CGRP. Flavanols are thought to provide the anti-inflammatory effect of cacao, but it is interesting to note that anecdotally chocolate is sometimes a trigger for migraine. This raises the question whether it is the cacao in chocolate that is a trigger or other additives.

Coenzyme Q is also thought to exert its positive effect on migraine in part by decreasing CGRP.  Researchers from Trabiz University in Iran found that 400 milligrams per day of coenzyme Q10 had a significant improvement in frequency, severity, and duration of migraine among 23 migraine sufferers compared to placebo.

Lastly, whereas women are three times more likely to get migraine compared to men it turns out that varying levels of estrogen influence serotonin neurotransmission and CGRP levels which probably predisposes them to migraine attacks. Modulation of the normal estrogen drop through menses with bioidentical estradiol may help prevent menstrual migraine.

When I met Steve, the 26-year-old gentleman from the beginning of this story, he reported a history of migraine going back five years. The first flare up was triggered while performing CPR as a medic. He told me that all of his headaches are triggered by exertion hard enough to raise his blood pressure and heart rate. Attacks begin with seeing spots, and over 20 minutes he gradually loses his vision. When vision returns the headaches comes on. Frequency varied, but migraines could last up to two days. Since he had to be sedentary to avoid migraine it cost him a career. He wanted to be a firefighter but had to give up that dream because his migraines would incapacitate him for two days. In his case, 200 milligrams coenzyme q twice per day with the option to add 75 milligrams butterbur twice per day resonated with his desire for a more natural solution. Though results are still pending, I’ll be monitoring him in the coming weeks. When he returns to my office with his migraine diary, I will be excited to see what this CGRP-oriented prevention strategy may offer to help him gain his life back.

References

Aggarwal M, Puri V, Puri S. (2012) Serotonin and CGRP in Migraine. Ann Neurosci. Retrieved from:  http://annalsofneurosciences.org/journal/index.php/annal/article/view/441

Cady RJ, Durham PL. (2010) Cocoa Enriched Diets Enhance Expression of Phosphatases and Decrease Expression of Inflammatory Molecules in Trigeminal Ganglion Neurons. Brain Res. Retrieved from: https://www.sciencedirect.com/science/article/abs/pii/S0006899310002350?via%3Dihub

Dahri M, Tarighat-Esfanjani A, Asghari-Jafarabadi M, Hashemilar M. (2019) Oral coenzyme Q10 supplementation in patients with migraine: Effects on clinical features and inflammatory markers. Nutr Neurosci. Retrieved from: https://www.tandfonline.com/doi/full/10.1080/1028415X.2017.1421039

Dodick DW, Lipton RB, Ailani J, et al. (2019) Ubrogepant for the Treatment of Migraine. N Engl J Med. Retrieved from: https://www.nejm.org/doi/10.1056/NEJMoa1813049

Dodick DW, Silberstein SD, Bigal ME, et al. (2018) Effect of Fremanezumab Compared with Placebo for Prevention of Episodic Migraine: A Randomized Clinical Trial. JAMA. Retried from: https://jamanetwork.com/journals/jama/fullarticle/2681193

Lipton RB, Göbel H, Einhäupl KM, Wilks K, Mauskop A. (2004) Petasites hybridus root (butterbur) is an effective preventive treatment for migraine. Neurology. Retrieved from: https://n.neurology.org/content/63/12/2240

Menstrual Migraine Treatment. American Migraine Foundation. Retrieved from https://americanmigrainefoundation.org/resource-library/menstrual-migraine/

Skljarevski V, Matharu M, Millen BA, Ossipov MH, Kim B-K, Yang JY. (2018) Efficacy and safety of galcanezumab for the prevention of episodic migraine: Results of the EVOLVE-2 Phase 3 randomized controlled clinical trial. Cephalalgia. Retrieved from: https://journals.sagepub.com/doi/10.1177/0333102418779543

Slavin M, Bourguignon J, Jackson K, Orciga M-A. (2016) Impact of Food Components on in vitro Calcitonin Gene-Related Peptide Secretion—A Potential Mechanism for Dietary Influence on Migraine. Nutrients. Retrieved from: https://www.mdpi.com/2072-6643/8/7/406

Stauffer VL, Dodick DW, Zhang Q, Carter JN, Ailani J, Conley RR. (2018) Evaluation of Galcanezumab for the Prevention of Episodic Migraine: The EVOLVE-1 Randomized Clinical Trial. JAMA Neurol. Retrieved from: https://jamanetwork.com/journals/jamaneurology/fullarticle/2681442