Starting with Zeus’ Headache
If for a peculiar reason, you ask a question, could gods, the divinities, ever get sick? Would they ever have had diarrhea, cold, high fever, hypertension, cardiac arrest, etc.? Then you might start looking through stories of the Great Greek Mythology for an answer. You would find that none was mentioned rather than headache. Zeus, the supreme boss of all divinities of Mt. Olympus, one day, suffered atrocious headache. He was desperately in pain and no one could help him until his son, Hephaestus, to take a sledgehammer and split open Zeus’s skull. That was how the Goddess Athena came to her birth by springing out from the crack of Zeus skull and brought the resolution of Zeus’ unbearable headache. Headache is a condition of such complex with 150 different types. They are categorized as primary headache and secondary headache. Primary headache is referred to those headache originated to the dysfunction of patients’ heads, like Tension-type headache, migraine headache. Secondary headache is for those headaches as symptoms caused by an underlying medical condition, like sinus headaches, medication overuse headache, brain bleeding. Therefore, the treatment of headaches may differ based the diagnostic type of headache. Tylenol is helpful for sinus headaches, but it would not help Zeus’ headache without letting Athena born out of his skull.
Migraine is one of the most common headaches. There have been about close to ten possible theories proposed for the pathological mechanism of migraine. Vascular theory contributes vasodilation to the cause of pain; neurovascular theory explains the activation of certain neurons and inflammation the cause of pain and so on. There are also several types of migraine variants.
Medicines for migraine acute treatment and for migraine prophylaxis are very different
The acute treatment of migraine is also termed abortive therapy. For moderate migraine, NSAIDS, such as naproxen, ketorola., are commonly used. Analgesics like Tylenol and opioids, dopamine antagonists like prochlorperazine originally for nausea/vomiting are also options. A group of chemically related medicine termed triptan includes five drugs is used for moderate to severe migraine. Sumatriptan among triptan members is usually the most common treatment. Its efficacy has been used to evaluate other agents in development for acute treatment of migraine.
When the frequency of migraine attacks is more than 2 days per month or each migraine attack lasts longer than 24 hours, and several other indicative manifestations, prophylactic therapy needs to be considered. It is quite perplexing to look at the list of prophylactic medications. Some are the medicines used for hypertension (beta blocker, propranolol), some are for psychological depression (Tricyclic antidepressants, like amitriptyline), some are for epilepsy (topiramate, divalproex), a neurotoxin (botulinum toxin, Botox) is also an option. Recently, a top migraine specialist, Dr. Keven Webber, who hosts a podcast program of headache management, talked about that an anti-hypertension drug candesartan and antidepressant venlafaxine were effective in migraine prophylaxis. Those medicines have very different pharmacological mechanisms of actions, originally for treating totally unrelated diseases. However, they have been found effective for preventing migraine. What is the rational of those medicines for the effect? There are no answers. That is because the causative mechanism of migraine has been poorly understood. For all the years, the empirical approach of trial and error seems the way to find a drug for migraine prophylaxis. The drugs of first line options in include beta blockers (like propranolol) , tricyclic antidepressants ( like amitriptyline ), divalproex ( Depakote) and topiramate ( Topamax). Topiramate has been used to evaluate the efficacy of developed agents for migraine prophylaxis.
The latest medications for migraine: CGRP inhibitors
Since 2018, a group of medicines targets calcitonin gene-related peptide ( abbreviation: CGRP) and its receptor for migraine management has emerged. Scientists first discovered a peptide called Calcitonin Gene Related Peptide ( CGRP). CGRP is a potent blood vessel dilator. When this peptide is released at high levels from primary trigeminal nerves, CGRP binds its receptor – CGRP receptor, blood vessel dilation and migraine occurs. Scientists postulated if they were able to interrupt the interaction between CGRP and its receptor, either by blocking the receptor’s binding site, or attack the peptide CGRP, they may be able to find a treatment for migraine. This is exactly how a series of wonderful CGRP inhibitors for the management of migraine have been developed.
CGRP inhibitors include two groups of medicines. One group is members of CGRP monoclonal antibodies, used by injection route. Another group is members of small molecule termed gepants, used by oral route.
CGRP – Targeted Monoclonal antibody, injectable for migraine prophylaxis:
- Erenumab (Aimovig) , is targeting CGRP receptor, blocking receptor biding site of ligand peptide. It was first approved by FDA in 2018. It is administered by subcutaneous injection monthly.
- Fremanezumab (Ajovy), is attaching the ligand peptide- CGRP, so it is not able to interact with its receptor. It is administered by subcutaneous injection. The low dosage form is injected monthly, and the high dosage form is injected once every three months.
- Galcanezumab ( Emgality), is attaching CGRP, similar to fremanezub. It is subcutaneously injected monthly.
- Eptinezumab (Vyypti), is attaching the ligand peptide CGRP, similar to fremanezub. It is administered intravenously every 3 months.
CGRP receptor gepant blockers .They block CGRP receptor, similar to what erenumab does. The medicines of this group are oral tablets for migraine prophylaxis, or/and for acute treatment of migraine:
- Rimegepant ( Nurtec ODT ) This is the only CGRP blocker approved by FDA for both migraine acute treatment and prophylaxis. For acute treatment, the tablet is taken orally one time dose as needed at the first sign of migraine, providing 24 hours of freedom of headache. For migraine prophylaxis, the tablet is taken every other day. (ODT = oral dissolvable tablet)
- Ubrogepant (Ubrelvy) Oral tablet is approved for migraine acute treatment, not for prophylaxis. It is taken at onset of migraine, repeated once after 2 hours as needed. It provides 24 hours relief.
- Atogepant Quilpta oral tablet is approved for migraine prophylaxis, not for acute treatment. The drug has several dosages, taken once daily.
Because of the understanding of the CGRP’s role in the pathophysiology of migraine, a therapeutic target has been found and aimed for the treatments of migraine. Those CGRP inhibitors have good efficacy in the management of various chronic migraine, periodic migraine or cluster headache. They are able to prevent 50% of monthly migraine days. Their adverse effects are basically similar to placebo. They are primarily considered not having drug and drug interactions, which means they can be taken with any other medicines concomitantly either for uncontrollable migraine, or other health conditions if needed.
The simple facts in comparison of CGRP inhibitors with preexisting migraine medications
There are trials after a trial to answer the questions such as: how much better are CGRP inhibitors in comparison with the pre-existing medicines for acute treatment and prophylaxis of migraine? Which CGRP inhibitor is better than others? If I attempted to cite the statistic data and crack wise in this writing, I would probably need a few doses of a migraine medicine for myself. However, some simple conclusions in those studies can be pinpointed to get the picture.
For acute treatment of migraine, Sumatriptan (Imitrex) has been the first line drug of choice. The efficacy of Rimegepant ( Nurtec ODT) for acute treatment is comparable and slightly less than that of sumatrptian. However, Sumatriptan is contraindicated with uncontrolled hypertension, cardiovascular disease. Serotonin syndrome, which is a dangerous adverse effect, is a warning in the label of sumatriptan (but Dr. Keven Webber commented that the warning was purely theoretical).
For migraine prophylaxis, topiramate ( Topamax) has been the first line, high efficacy drug of choice . Erenumab (Aimovig) once per month injection was compared with topiramate in high oral dose twice daily in a trial, the result showed that Erenumab was more efficacious than topiramate. The side effects of topiramate also caused more patients’ discontinuation of the prophylactic therapy. Two additional side notes are worth of mentioning. Both erenumab and topiramate may require up to 3 months’ administration to reach maximal prevention. When compared with amitriptyline which is another first line drug of choice, topiramate was at least as effective as amitriptyline, and patients with topiramate had better quality of life than amitriptyline.
Clinical data have showed the efficacy of each CGRP inhibitors for prophylactic therapy is similar, fulfilling the end point of 50% reduction of days of migraine per month. A report of rating by patients who received Erenumab (Aimovig) or rimegipant (Nurtec ODT) showed that Nurtec ODT had higher rating than erenumab (Aimovig), although was only to represent patients’ preference. Erenumab was believed having no risk of worsening hypertension in its clinical trial. However, three years after its approval, FDA added a new warning of a risk causing new-onset hypertension and worsening preexisting hypertension. To be clear, it is a warning for caution, not a black box warning. (If FDA gives a drug a black box warning, then you need to be careful) Other CGRP monoclonal antibodies (Fremanezumab, Galcanezumab, etc ) do not have such a warning . They may have one or two insignificant drug-drug interactions. Rimegepant (Nurtec ODT) and other gepants do not carry any risk warning. None of CGRP inhibitors has contraindications. Wow! Their tolerability and safety profile are simply amazing.
CGRP inhibitors do not carry the risk of medication overuse. Medical overuse is also called medication induced rebound headaches. All preexisting-medicines for acute treatment of migraine potentially carry this risk if a patient takes medications for pain relief of migraine on frequent basis, for example, an acute medication is taken more than 3 days per week for long term, he is prone to suffer the rebound headache. The patient would experience headache upon awakening, relieved briefly once acute medication is given. However, headache returns when the effect of medication wanes off. Patients of medication overuse may suffer more than 15 headache days per month. In my practice, I used to have the opportunity to care a few patients who developed medication overuse with their acute medications. One patient always finished one month’s supply of Imitrex (sumatriptan) 9 tablet package just 2 – 3 weeks, then beseeched for early prescription refill. She explained if she stopped taking the medicine, her migraine would paralyze her. Some other patients had the medication overuse with another popular, inexpensive medicine called Fioricet. Fioricet is a combo of butabital, acetaminophen ( Tylenol) and caffeine. Its use for acute migraine relief should be limited no more than 2 days per week. But some patients have taken it regularly, in a pattern of preventing migraine. There are two CGRP inhibitors approved by FDA for migraine acute treatment, rimegepant ( Nurtec ODT) and Ubrogepant (Ubrelvy) . Neither possesses the risk of causing medication overuse. Instead, they are the important options of treating patients who suffer medication overuse.
All clinical data have indicated that CGRP inhibitors are efficacious, very few side effects, and basically no interaction with other drugs and no contraindications in the treatment of migraine. However, they are not given the status of the first line option either for migraine acute treatment or prophylaxis by FDA. With all therapeutic superiority over the preexisting medications, why are CGRP inhibitors listed as drug options of second line? It seems that the Cost—Effect Ratio is the reason. They are expensive in comparison with preexisting medications for migraine. Patients are required to be treated at least two different medications from the firs line, if the treatments fail, then those medication of CGRP inhibitors could be applied for medical insurance coverage. Without insurance, the cost of out of packet is at least $550 monthly.
A finalized comment
It is a long stretch from talking about Zeus’ headache to the latest medications of CGRP inhibitors for migraine. Although those two seem not having much relevancy to each other, the Zeus’ case tells the importance of differentiating various types of headaches in order to select an effective treatment. The process of developing CGRP inhibitors for the treatment of migraine is a classic story for a brilliant new drug discovery. Nurtec ODT and other members of this class are such wonderful medications. In the time when their low cost generics are available, they will inevitably be the top choice for migraine management.
Key Ref:
Calcitonin Gene-Related Peptide (CGRP)-Targeted Monoclonal Antibodies and Antagonists in Migraine: Current Evidence and Rationale , Fred Cohen, Hsiangkuo Yuan, and Stephen D. Silberste, BioDrugs. 2022; 36(3): 341–358.
CGRP inhibitors: Uses, Common Brands and Safety Info; Chad Shaffer; SingleCare.com 04/05/2022
An Overview of New Biologics for Migraine Prophylaxis; Philip Harvey,Pooja Shah, Scott Shipley, South Jordan, US Pharm. 2020;45(1):21-24.
Novartis’ Aimovig tops topiramate in migraine face-off Phil Taylor, Pharmaphorum.com/news November 4, 2020
Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs David W Dodick 1, Fred Freitag, James Banks, Joel Saper, Jim Xiang, Marcia Rupnow, David Biondi, Steven J Greenberg, Joseph Hulihan, Clin Ther., 2009 Mar;31(3):542-59.
http://www.drugs.com compare › aimovig-vs-nurtec-odt
GEPANTS (NURTEC, QULIPTA) VS. CGRP MONOCLONAL ANTIBODIES (AIMOVIG, AJOVY, EMGALITY, VYEPTI) FOR MIGRAINE PREVENTION. WHICH ARE BETTER? Dr. Eric Baron https://virtualheadachespecialist.com October 8, 2022
In Brief: Hypertension with Erenumab (Aimovig), Med Lett Drugs Ther. 2021 Apr 5;63(1621):56
Note from Medscape : Migraine Headache Treatment & Management
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