Migraine Therapeutics: Slow Progress Towards Precision Medicine

Introduction

The ergot alkaloids ergotamine and dihydroergotamine were the first two agents used in the treatment of acute migraine. Ergotamine, which was first isolated from ergot by Stoll in Switzerland in 1918, was first used in the treatment of migraine by Maier, also in Switzerland, in 1925. Dihydroergotamine on the other hand was first introduced in 1943 (1). It is noted that the FDA approval dates for these two ergot alkaloids are not readily available. Subsequently, it wasn’t until the early 1990’s that a new pharmacologic class would be introduced for the treatment of acute migraine, the triptans.

In addition to drugs for the acute treatment of migraine, there have been approvals of new molecule treatments for the prevention of migraine, involving three pharmacologic classes. This has involved approvals in the late 1990’s and early 2000’s for antiepileptic agents, for botulinum toxin in 2010, and for beta adrenergic blockers; note that the FDA approval dates for the beta adrenergic blockers are not readily available.

Drug Approvals

There have been a total of 15 new molecule approvals for migraine therapeutics, in 5 broad pharmacologic classes. The first pharmacologic class, the ergot alkaloids, as been in use since the 1940’s, but the exact approval years for ergotamine and dihydroergotamine are not readily available, while the third drug in this class, Sansert (methysergide) was approved in 1962, but later withdrawn from the market due to toxicities. In keeping with our convention, included are approved new molecules for this indication, although they might have been previously approved for another indication, i.e., two antiepileptic drugs, two beta-adrenergic blockers, and one botulinum toxin. Note that all 5 of the approved drugs of these last three pharmacologic classes were for migraine prophylaxis. Refer to the accompanying chart below (click for a larger chart). The new molecule drug approvals are listed below:

  • Ergot Alkaloids: 3 new molecules; Ergotamine and Dihydroergotamine (FDA approval years not readily available) and Sansert (methysergide, 1962)
  • Triptans: 7 new molecules; Imitrex (sumatriptan, 1992), Zomig (zolmitriptan, 1997), Amerge (naratriptan, 1998), Maxalt (rizatriptan, 1998), Axert (almotriptan, 2001), Frova (frovatriptan, 2001), and Relpax (eletriptan, 2002).
  • Antiepileptic Agents: 2 new molecules; Depakote (divalproex, 1996) and Topamax (topiramate, 2004).
  • Beta Adrenergic Blockers: 2 new molecules; Inderal (propranolol) and Blocadren (timolol), (FDA approval years not readily available, but placed around 1985 as placeholders).
  • Botulinum Toxin: 1 new molecule; Botox (onabotulinumtoxin A, 2010).

Comments

The history of ergot alkaloids and their use in migraine represents one of the fascinating chapters in classic pharmacology. It is noteworthy, however, that after ergot alkaloids, there has only been one new pharmacologic class introduced for the treatment of migraine, the triptans. Below are a few general comments about the current status of migraine therapeutics:

  • There are two pharmacologic classes for migraine treatment, i.e., ergot alkaloids and triptans, and three pharmacologic classes for migraine prophylaxis, i.e., antiepileptic agents, beta adrenergic blockers, and botulinum toxin.
  • A new drug molecule for migraine treatment hasn’t been approved since 2002, a triptan, and a new drug molecule for migraine prophylaxis hasn’t been approved since 2010, a botulinum toxin.
  • It is noteworthy that there are few other therapeutic classes with more off-label uses than migraine, and these off-label drugs are frequently listed in recommended drugs for migraine. These unapproved drugs include tricyclic antidepressants, other beta adrenergic blockers, and other antiepileptic agents.
  • It is also noteworthy that anti-migraine drugs and treatments are not infrequently used in combination with other pharmacologic classes, such as antiemetics, NSAID’s, and caffeine.
  • These last two comments are likely related to the nature of migraine, its etiology and multifaceted pathophysiology and symptomatology.

Conclusions

Migraine is a multifaceted, episodic CNS disorder, with complex symptomatology and a genetic component. Previously, it was thought to be related to vascular dysfunction, but more recently, it is thought to include cortical spreading depression. At the very least, the efficacy of disparate pharmacologic classes would attest to complex etiology and pathophysiology. Clearly, there is a great need for detailed understanding of the precise biologic mechanisms underlying the pathophysiology of migraine, including the different components of its symptomatology. As has previously been discussed, progress in other CNS therapeutic classes has been slow – Schizophrenia and Depression (2), Attention Deficit Hyperacticity Disorder (3) – suggesting a need for more basic research to identify new precision medicine-based therapeutic options for these – and other – CNS disorders.

References

  1. Tfelt-Hansen PC, Koehler PJ. History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward. Cephalalgia, 28(8):877-886, 2008.
  2. TRI-instirute,org: Slow Progress in Psychopharmacologic Therapeutics, Sep 2014, http://tri-institute.org/?p=184.
  3. TRI-institute.org: ADHD Therapeutics: Slow and Limited Progress, Nov 2015, http://tri-institute.org/?p=742.

Refer to Progression of Modern Therapeutics (2014 Report) available under Reports on this website, which includes the methodology used.