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URMC / Obstetrics & Gynecology / UR Medicine Menopause and Women's Health / menoPAUSE Blog / August 2021 / I have had migraines all my life. Now, as I am in menopause, they are less but have not gone away. T

I have had migraines all my life. Now, as I am in menopause, they are less but have not gone away. Triptans and analgesics have not helped much. Is there anything new?

Your Menopause Question: I have had migraines all my life. Now, as I am in menopause, they are less but have not gone away. Triptans and analgesics have not helped much. Is there anything new?

Our Response: If you are among one-third of adult women with migraines, you know the facts (Wang, 2003; Edlow, 2010; and Friedman, 2015). If you never have had a migraine, lucky you. But here is what your friends have dealt with. It may begin a few days before headache pain with changes in yawning, food craving, euphoria, depression, or urinary frequency. The onset of the migraine may be unilateral or bilateral pounding, throbbing pain made worse with movement but also with sensitivity to light, sounds, or odors. Of those with migraines, 65 to 75% will be without aura, but others may experience visual and binocular changes, blind spots, loss of visual fields, sparkles, or floaters. Even without aura, many complain of conjunctival injection, lacrimation, nasal congestion, periorbital swelling, rhinorrhea, salivation, diarrhea, or frequent urination. These symptoms may last up to 48 hours (Edlow, 2010, and Cortelli, 2012).

Unfortunately, migraines are not limited to headaches but often involve visceral functions of the bowel and bladder (Peroutka, 2004, and Cortelli, 2012). Because migraines are mediated principally through the trigeminal nerve complex and parasympathetic system, migraines often are referred to as a trigemino-parasympathetic reflex. Some would even consider this a temporary imbalance of the sympathetic and parasympathetic systems linked to a depletion of sympathetic norepinephrine stores and an increase in other sympathetic cotransmitters such as dopamine, prostaglandins, adenosine triphosphate, and adenosine (Peroutka, 2004). Clearly, migraines are not a one-system disorder.

What brings migraines on is very individual. Changes in weather, fluorescent lights, missed meals, carbohydrates, cheese, wine, or stress are common triggers (Sacco, 2012).

Traditional medical management of migraines reflects the uncertainty that has plagued those individuals. Mild analgesics may suffice for some. Triptans have been successful for many. And, onabotulinumtoxin A (Botox®) has offered significant relief when triptans and other medications have failed (Do, 2018). It is the expanding understanding of the biology of migraines that ultimately will offer true relief.

The story starts in the trigeminal and cervical complex, a structure in the dural spinal horn of our brainstem extending down to C1 and C2 spinal levels (Durham, 2006). The trigeminal nerve, our 5th cranial nerve, in conjunction with our parasympathetic system, controls pain sensation in our face and head. Recall, the brain has no pain fibers of its own, so any pain sensation originates as the trigeminal-vascular complex dilates our dural vessels and pial vessels in our meninges, the membranes that cover our brain and spinal cord. Research now shows that trigeminal nerves stimulate these meningeal vessels by releasing a number of neuropeptide inflammatory proteins including substance P (SP), calcitonin gene-related peptide (CGRP), and pituitaryadenylate cyclase-activating polypeptide (PACAP). Of these, CGRP has received the most attention and has become a prime target for medication development (Durham, 2006; Cortelli, 2012; and Detke, 2018).

Calcitonin gene-related peptide (CGRP) is a potent vasodilator and is involved in mediating pain in the brainstem, thalamus, and cortex in conjunction with release of TNF alpha, the most elevated inflammatory cytokine in migraines (Durham, 2006). Clinical and animal studies demonstrate that administering CGRP produces headache pain, and blocking it reduces the pain (Lauritsen, 2016). How do these observations relate to current migraine medications?

Triptans are serotonin (5HT) agonists that reduce CGRP concentrations when elevated during a migraine, but have no effect on unstimulated trigeminal neurons (Durham, 2006). The mechanism is believed to be by increasing intracellular calcium to regulate CGRP gene expression. Botulinum toxin type A (Botox®) is not a 5HT agonist, but may reduce elevated levels of CGRP, alter receptors and cytokines, and enhance opioidergic transmission (Do, 2018).

The good news is that there are now two types of CGRP inhibitors (Lauritsen, 2016 and Detke, 2018). Three monoclonal antibodies have been FDA approved including Aimovig® (erenumcib-aooe), AJOVY® (fremanexumab) and Emgality® (galcanezumab-gnlm). These are large molecules that do not cross the blood-brain barrier, so they exhibit their actions more slowly. CGRP receptor antagonists are smaller molecules, which are able to enter the brain and work more quickly. The downside is that these medications must be given intravenously, subcutaneously, or intramuscularly, , and safety, as with all new medications, remains under investigation.

It is hopeful that for such a serious health condition that can affect up to one-third of women, compromise time at work and impact quality of life, these newer approaches will target the true mechanism and offer relief from migraines.

James Woods | 8/5/2021

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