Future Treatments: Ditan Tablet and Oral Gepants

Key Points

  • introduction
  • how these medicines differ from monoclonal anti-CGRP antibody injections/intravenous (IV) infusion
  • experts agree that they do not appear to cause medication overuse headaches
  • Dr. Lawrence Robbins discusses lasmiditan in the Journal - Practical Pain Management
  • The World Migraine Summit interviews Dr. Uwe Reuter from Berlin on how Ditans differ from Triptans
  • comparing Ditans to Triptans

Introduction

Ditans and Gepants are new migraine treatments that differ slightly from existing therapies. These new medications provide additional options for people with migraine for whom other medications may put them at risk of side effects. 1

Ditans and Gepants are medicines that can be taken both acutely and preventatively. They come as a tablet to be taken at the start of an attack to treat pain and associated migraine symptoms (e.g. pain, nausea, light/noise sensitivity) or preventatively. 1

How do these medicines differ from monoclonal CGRP injections/infusion?

Calcitonin gene-related peptide (CGRP) is a protein that plays a role in causing the pain associated with migraine. The anti-CGRP injections are monoclonal antibodies (3 are injections and 1 an intravenous infusion), all are approved by Health Canada, while the oral CGRP antagonists that are pending Health Canada approval are atogepant and ubrogepant, both from drug-maker Abbvie Canada. 2

 

A third Gepant rimegepant (Nurtec™ ODT) "orally disintegrating tablets" are available in the U.S. and are pending approval in Canada - as of the writing of this document.

According to The Migraine Trust, they do not appear to cause medication overuse headache, and do not appear to have significant side effects. 3

Ditan Tablet

Wikipedia suggests Ditans are a class of abortive medication for the treatment of migraines. Ditans selectively bind to the 5-T1F receptor subtype 4

In the publication Practical Pain Management, Dr. Lawrence Robbins a renowned headache specialist suggests lasmiditan (Reyvow) in the U.S. is a newly approved (October 2019) migraine abortive tablet. It is a "Ditan," that is an antagonist at the 5-HT 1F serotonin receptor. Lasmiditan does not constrict the coronary or cerebral vessels and offers an alternative for those who cannot take the Triptans. As with the Gepant use, there are patients who may respond to lasmiditan, who do not do well with the Triptans. Lasmiditan, available in 50- and 100-mg tablets, is a controlled (Schedule V) substance. Patients are cautioned not to drive for 8 hours after using lasmiditan. It is indicated for only one dose per day. Dizziness has been one of the prominent side effects recorded so far. 5

The World Migraine Summit in an interview with Professor Uwe Reuter who is a professor of neurology at Charité University Hospital of Berlin, remarks on Ditans and why they differ from Triptans.

Dr. Reuter comments "they’re very different drugs. You can say that a Ditan is the sister to a triptan, and the major differences are that Ditans penetrate into the central nervous system, meaning they go across the blood-brain barrier right into your brain and they get into the brain. Also, they don’t have vasoconstricting activity, meaning they don’t constrict your vessels around your heart, which is a theoretical possibility with the Triptans. There’s still that possibility, and we are looking for drugs that avoid vascular action, so that’s why a Ditan might be an advantage to the patient. And the results you see with Ditans are typically in the range of what we see with Triptans. So these drugs are not much better but also not much worse. They’re simply a different opportunity for patients who can’t tolerate Triptans, who don’t respond to Triptans, or who don’t like the feeling of taking a Triptan." 6

Further Comparing Ditans to Triptans

Dr. Jessica Alaini from the American Migraine Foundation still considers Triptans a "gold standard medication" for acute treatment of migraine, which she would give to patients of the appropriate age who don’t have vascular conditions like uncontrolled blood pressure or a prior stroke or heart attack. 7

She further comments "I think of Ditans as a relative of the Triptans, like a younger sister, younger brother," she says. Triptans act on two specific receptors that are found on sensory nerves, but one of the receptors is also on blood vessels, she says, and "can sometimes come with constriction of blood vessels which if diseased or prone to spasm, could lead to complications. 7

Lasmiditan (Reyvow) (approved in the U.S. ) should be used no more than once a day. Because of the possible side effects — dizziness and sleepiness — patients should not drive or perform other activities requiring mental alertness for eight hours after use. Animal studies suggest lasmiditan may not be safe in pregnancy, and thus should be avoided by women who are or may become pregnant. 8

Given the restrictions, this drug might be a choice for non-pregnant patients who cannot take Triptans and want to treat a headache at the end of the day when going to bed anyway, or when the usual treatment of headache involves a period of sleep. 8

According to Migraine Canada, lasmiditan will NOT be coming to Canada. 9

Oral Gepants

Gepants work to block CGRP from attaching to its receptor and initiating those pain signals. Gepants are different from the 3 injectable, and 1 intravenous infusion anti-CGRP monoclonal antibodies in a few ways. Gepants are oral pills or dissolvable tablets versus an injectable/infusion. 10

According to the Migraine Trust, Gepants work to block CGRP from attaching to its receptor on the nerves involved in initiating pain signals. Compared to a Triptan, the proportion of people who will be pain free in 2 hours is smaller, but with the lack of an effect on other systems (for example they do not constrict blood vessels), their side effect rate is much less. They will be beneficial to the significant group of people who cannot take a Triptan for those reasons. 11

uprogepant (Ubrelvy) (a Gepant) trials in the New England Medical Journal

In December of 2019 headache specialists published an article in the New England Journal of Medicine on uprogepant (an emerging Gepant). In there trial of 50-mg and 100-mg doses of ubrogepant for acute migraine treatment, the percentage of participants who had freedom from pain and absence of the most bothersome migraine-associated symptom (the co-primary end points) was higher among participants who received either dose of ubrogepant than among those who received placebo (a dummy pill). Freedom from pain occurred within 2 hours after a dose in approximately 20% of participants in each of the ubrogepant groups, as compared with 12% in the placebo group. Absence of the most bothersome symptom associated with migraine at 2 hours occurred in 38% of participants who received ubrogepant, as compared with 28% who received placebo. 12

ubrogepant (Ubrelvy) aborts 20% of attacks at two doses - Migraine Again -

The American Migraine Foundation has written an article on the topic of Ditans and Gepants. Please keep in mind that this is a U.S. article, and some medicines may not be available in Canada. Some are pending approval from Health Canada or are listed as another name. Access the article here.

As Migraine Canada points out, as of the writing of this article the Gepants (rimegepant and uprogepant) are currently not available in Canada (as of February 2021). 13

For Canadian resources refer to:

a) Migraine Canada - www.migrainecanada.org
b) Migraine Québec - www.migrainequebec.org - francais
c) Help for Headaches - www.headache-help.org
d) Chronic Migraine Facebook Support group

References

  1. American Migraine Foundation, How Gepants and Ditans compliment existing therapies? - 2020
  2. Dr. Paul Cooper Headache Neurologist London Ontario
  3. The Migraine Trust: Ditans and Gepants, 2020
  4. Wikipedia - Ditan definition, 2020
  5. Dr. Lawrence Robbins, Practical Pain Management, New migraine medications: Oral Gepants, Ditan tablet, and more. May 2020
  6. The World Migraine Summit, interview: Ditans and Gepants, Dr. Uwe Reuter, Berlin, 2020
  7. Dr. Jessica Ailani, How Gepants and Ditans compliment existing therapies? 2020
  8. Harvard Health Publishing: lasmiditan: New first-in-class drug treatment approved for migraine, 2020
  9. Migraine Canada, lasmiditan not coming to Canada - March 2021
  10. American Migraine Foundation, how Gepants and Ditans compliment existing therapies, April 2020
  11. The Migraine Trust, Gepants: how do they work? 2020
  12. N Engl J Med 2019; 381:2230-2241 - Ubrogepant for the treatment of Migraine, December 2019
  13. Migraine Canada, Gepants pending approval - 2020

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