Headache Horizons: Headache Pharmacology and Novel Therapeutics Update

Substantial advances in acute and preventive treatments for headache have been made in the past several years. With the advent of these advances, it is important to review their pharmacologic implications. Understanding the pharmacokinetic properties of acute and preventive treatments can help optimize migraine control. In addition to drug–drug interactions, comorbid conditions must be considered (eg, hypertension, Raynaud disease). This review focuses on newer-generation medications and their clinical pharmacologic implications. Product label information as well as updated scientific data that provide clarity on drug-related interactions are discussed (Table).

General Pharmacokinetic Considerations

The terms “adverse event” and “side effect” are often used interchangeably, but there are subtle differences in their definitions. Adverse events are undesired and unexpected pharmacologic reactions that occur when a medicine is administered correctly (eg, lactic acidosis from metformin). Side effects are secondary unwanted, but expected effects that occur in concert with the goal of drug therapy (eg, drowsiness from an antihistamine).

Several factors affect hepatic CPY450 metabolism. Most orally administered medications undergo first-pass hepatic metabolism, and higher doses of substrates can saturate metabolic pathways. Metabolites after biotransformation may be inactive, active, or rarely, toxic. Genetic variations in CYP450 can alter drug clearance and affect plasma concentrations. With polypharmacy, inhibition and induction effects on specific enzymes may create interactions.

More recently, other metabolic pathways have come to our attention with newer migraine treatments. Permeability glycoprotein 1 (PG1) is a membrane transport protein. Relevant substrates for this include atogepant, rimegepant, ubrogepant, topiramate, and verapamil. These glycoproteins “pump out” their substrates from the brain. Breast cancer resistant peptide (BCRP), another metabolic pathway, exhibits reflux action similar to PG1. Relevant substrates include atogepant, rimegepant, and ubrogepant. A third important transport system is the organic anion transport peptide (OATP); its substrate includes atogepant, whereas zavegepant is metabolized by sodium-taurocholate co-transporting polypeptide (NTCP), a key transporter in the enterohepatic circulation of bile acids. Hepatically active medications such as rosuvastatin may be affected by this.

Other considerations include a key compound found in grapefruit juice, furanocoumarins, which can inhibit CYP3A4 and PG1.

Current Pharmacologic Migraine Treatments: Food and Drug Administration Label Information, Updated Scientific Studies, and Real-World Safety Data

Gepants (Acute and Prevention)

Gepants are small molecules that block calcitonin gene-related peptide (CGRP). Telcagepant was the first molecule in the class, but because of its hepatic enzyme effects, it was discontinued. The molecular structure containing phenyl-glyoxal precursor was believed to be responsible for these hepatic effects.

Ubrogepant (Acute). Based on the product label, strong CYP3A4 inhibitors, such as ketoconazole, itraconazole, or clarithromycin, should not be used with Ubrevly (ubrogepant; Allergan, Irvine, CA). With moderate inhibitors, such as verapamil, a dose adjustment is suggested. However, in a study of a single and supratherapeutic dose of ubrogepant, there was no effect on cardiac repolarization in healthy adults.¹

Avoidance of ubrogepant is recommended with strong CYP3A4 inducers such as phenytoin and barbiturates.

Rimegepant (Acute and Prevention). With Nurtec (rimegepant; Pfizer, New York, NY), strong CYP3A4 inhibitors and inducers should be avoided. Both gepants are substrates for PG1 and BCRP and per the label there can be an increased exposure to the gepant. Avoiding use with inhibitors (eg, verapamil, carvedilol, curcumin) is suggested. However, in a drug interaction study presented at the 2021 annual meeting of the American Headache Society, strong PG1 inhibitors such as cyclosporine and quinidine only moderately increased rimegepant exposure and were believed to be safe and well tolerated. BCRP inhibition was also believed to have minimal influence on rimegepant exposure.²

The recently updated label for rimegepant includes data on breastmilk and plasma pharmacokinetics of a single 75-mg dose in healthy lactating women. Findings showed a relevant infant dose of <1% of the maternal dose.³

Zavegepant (Acute). Coadministration of Zavzpret (zavegepant; Pfizer, New York, NY) with inhibitors or inducers of OATP1B3 or NTCP may result in significant increase or decrease in exposure or absorption of zavegepant.

Atogepant (Prevention). The product label of Qulipta (atogepant; AbbVie, Lake Bluff, IL) includes dosing recommendations. The 10-mg dose is recommended with strong CYP3A4 inhibitors. The 30-mg and 60-mg daily dose are recommended for strong and moderate CYP3A4 inducers. For OATP inhibitors, 10 mg and 30 mg once daily are recommended. In chronic migraine, where only the 60-mg dose was studied, use should be avoided with strong CYP3A4 inhibitors, and with strong, moderate, or weak inducers. With OATP inhibitors, 30 mg once daily is suggested.

A recent study examining the coadministration of atogepant and topiramate (a mild inducer of CYP3A4) showed only marginally lower atogepant concentrations, as well as marginally lower topiramate concentrations.⁴ In another study of atogepant administration with quinidine gluconate (a strong PG1 inhibitor), no important pharmacokinetic interaction was noted.⁵

Polytherapy with Gepants

In clinical practice, we typically combine various medications, with no guidelines available for this practice. In a safety and tolerability drug–drug interaction study with concomitant use of atogepant and ubrogepant, no new safety concerns were identified.⁶

Coadministration of ubrogepant with anti-CGRP monoclonal antibody injections in a small drug interaction study did not reveal any serious adverse events, the pharmacokinetic profile of ubrogepant was not substantially changed, and no safety concerns were identified when given with erenumab or galcanezumab.⁷

Postmarketing surveillance has shown the occurrence of Raynaud phenomenon with use of small molecule oral CGRP blockers.⁸

Monoclonal Antibodies Targeting CGRP

Monoclonal antibodies targeting CGRP include Aimovig (erenumab; Amgen, Thousand Oaks, CA), Emgality (galcanezumab; Eli Lilly, Indianapolis, IN), Ajovy (fremanezumab; Teva Pharmaceuticals, Parsippany–Troy Hills, NJ), and Vyepti (eptinezumab; Lundbeck Pharmaceuticals, Deerfield, IL). They are primarily metabolized through the reticuloendothelial system, also known as the mononuclear phagocyte system. Because they are not metabolized by the CYP450 system, no important drug–drug interactions are likely. There are limited data on combining 2 different CGRP blockers for prevention. However, antibody–antibody interactions are unlikely to occur because immunoglobulin G clearance is dependent on FcRn saturation, which is unlikely at therapeutic doses.

Case reports of Raynaud phenomenon have been published in the monoclonal antibodies class.⁹ A prospective follow-up study looking at blood pressure in individuals with migraine showed that a majority of participants remained within normal blood pressure limits, although there was an estimated mean increase in blood pressure (systolic, 5.2 mm Hg; diastolic, 3.5 mm Hg).¹⁰

Lasmiditan

Lasmiditan is in a novel class called ditans. It has a high affinity and selectivity for the 5-HT1F receptor acting in the trigeminal system and does not cause vasoconstriction because of its low affinity for 5-HT1B receptors. There is a boxed warning against driving for 8 hours after use. A dose-dependent increase in dizziness is its most common side effect, possibly because 1F receptors are found in the central nervous system as well as the peripheral nervous system. Although there may be some drawbacks to lasmiditan use because of this mechanism, there may also be benefit in migraine efficacy, because both peripheral and central sensitization play a role in migraine pathophysiology. The bradycardic effect of some beta-blockers may be increased with the use of lasmiditan, per the product label, which states that 200 mg of lasmiditan taken with propranolol decreased heart rate by 5 beats per minute. The label reports the standard increased risk of serotonin syndrome when combined with other serotonin medication, but the 2010 American Headache Society position paper on the topic should be consulted for realistic guidance on this rare event. ¹¹

Dihydroergotamine Nasal Spray

Although dihydroergotamine (DHE) has been used for decades, a newer delivery mechanism using a precision olfactory delivery device minimizes the dose used by having it absorbed through the vasculature in the upper nasal passages while preserving some favorable pharmacokinetics. The product label is similar to the label for the traditional intravenous DHE; therefore, it is contraindicated with strong CYP3A4 inhibitors. For example, erythromycin combined with DHE can result in vasospasms leading to cerebral or peripheral ischemia. Propranolol, another migraine preventive agent, may potentiate the vasoconstriction effect of ergotamine by blocking the vasodilation effects of epinephrine.

Conclusion

Understanding the mechanisms of action of headache medicine therapeutics is important for providers and people with migraine. Sometimes, optimizing an individual’s condition involves polypharmacy. Combination trials are rarely performed, but polypharmacy is common in clinical practice, especially for people with refractory headache disorders. The potential for drug–drug interactions must be kept in mind; however, without dedicated studies, whether these theoretical reactions will occur is unclear. Nevertheless, caution is advised. Expanding beyond drug–drug interactions, drug–disease interactions reported in postmarketing surveillance must be considered. Adverse drug event reporting should be considered, when appropriate, to help advance our understanding of drug mechanisms and improve medication safety for people with headache.