Migraine Tip of the Month: Optimal Pharmacologic Treatment of Acute Migraine Headache: Update
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Match your medication to your headache’s intensity
As most migraineurs know well from personal experience, not all migraine episodes are created equal.
For those 20 to 25% of the migraine population who at least occasionally have migrainous aura, an episode of migraine may involve only aura and no associated headache whatsoever. Or perhaps they may experience only aura and a prominent postdrome, the latter that final phase of a migraine episode which, for those who may have had the experience, closely resembles a hangover. For more on the different phases of a migraine episode, go to our Spring 2019 issue, wherein an article describes in some detail the different phases of a compleat migraine episode.
Migraine is the “Baskin-Robbins of headache”; it comes in all flavors. Very few patients will find monotherapy with a single medication to be effective for all of their migraine headaches. Migraine – and the intensity of migraine headache, specifically – is rarely stereotyped, and oral medication often is simply too slow to deal effectively with a more advanced and severe headache. Such headaches typically require intranasal or injectable medication. On the other hand, intranasal and injectable medication intended for acute migraine headache of moderate to severe intensity is not appropriate treatment for a migraine headache that is in its early stages and still mild to moderate in intensity. You don’t use a BB gun to bring down a charging water buffalo, and you don’t use a shotgun to eliminate an annoying mosquito.
Optimal treatment of acute migraine headache is typically a “three layer cake”: something for early stage headache to nip the migraine episode in the bud, something for a headache which is beginning to escalate and something for “rescue” if the headache is through the roof or if nausea and vomiting are so prominent as to exclude an oral therapy. There are various ways to bake that cake, but one commonly employed option is to prescribe (1) a non-steroidal anti-inflammatory drug (NSAID) with a caffeinated beverage for early/mild headache, (2) either that same NSAID/caffeine combo along with a fast-onset oral triptan vs an oral gepant (rimegepant/Nurtec, ubrogepant/Ubrelvy) for a headache “on the rise”, and (3) either subcutaneously self-injected sumatriptan, subcutaneously self-injected dihydroergotamine (DHE/Brekiya) or intranasally administered zolmitriptan (Zomig), DHE (Trudhesa) or zavegepant (Zavzpret) for “rescue”.
Two commonly asked questions:
If I’m taking a medication for migraine prevention, is it all right for me to continue to use my usual as needed medication for any acute headaches I may have?
Absolutely! If your migraine burden has increased to the point that a course of prevention therapy for stabilization is indicated, rapidly and effectively treating any acute “breakthrough” headaches that occur will play a key supporting role in reducing the hypersensitivity of the biologic circuitry that is generating your headaches. Prolonged episodes of severe migraine headache will work against the prevention medication’s effort to calm down that circuitry, and snuffing out an acute migraine headache early, soon after the circuitry ignites, will assist the prevention medication in the desensitization effort. Rarely is a prevention medication so effective that it entirely eliminates migraine episodes. Expect breakthrough headaches, and treat them aggressively.
But I’m having headaches almost every day. If I use medication to treat every one of those headaches, won’t I start having rebound headaches? Treat acute migraine attacks aggressively, but don’t overuse acute medication? How can I manage to do both?
An excellent question. Medication overuse headache (MOH; commonly referred to as “rebound” headache) occurs when a migraineur uses a given medication or class of medications intended for acute treatment so frequently that the overuse itself begins to generate headache that adds to the existing migraine burden. This happens insidiously, without a dramatic escalation of headache but instead with a gradual overall increase in headache burden.
Ironically, it is the triptans, the first of the modern “designer drugs” for migraine, that appear to have the highest potential for producing MOH and to do so more rapidly than other medications commonly used to treat acute migraine. Persistent use of a triptan preparation more than 9 days a month is sufficient to cause MOH and thus amplify the burden imposed by migraine itself. A sneakier culprit is plain old acetaminophen (present in such OTC preparations as Tylenol and Excedrin), easily obtainable and, at least in the short run, often quite helpful in controlling acute headache. Taken more than 15 days a month on a regular basis, however, acetaminophen faithfully produces MOH. Interestingly, the anti-CGRP “gepants” used for acute migraine treatment – Nurtec, Ubrelvy, Zavzpret – do not appear to have the potential for producing MOH.
In treating an acute migraine headache, keep in mind the pharmacokinetics of the medication you are administering. The most important components of a medication’s pharmacokinetics involve its bioavailability, Tmax, Cmax and half-life. Put simply, bioavailability can be defined as the percentage of an administered medication that has the potential to make its way to its therapeutic target. Tmax relates to how quickly after administration a medication reaches its maximum concentration, and Cmax relates to what is the maximum blood or brain concentration of the medication that is achieved. Half-life refers to how much time is required for 1/2 of the medication administered to be cleared from the body.
For example, subcutaneously injected sumatriptan is a particularly effective medication for “rescue” from an acute migraine headache of moderate to severe intensity because of its fast Tmax, high bioavailability and the high concentration of medication achieved. The Tmax for injectable sumatriptan is about 10 to 15 minutes (vs 1-2 hours for the oral formulation of the drug). Working in combination with a high Cmax, this Ferrari-like characteristic of injectable sumatriptan provides it the speed required to catch up with a rapidly escalating migraine headache or a headache that has already built to become moderate to severe in intensity. With a Tmax of 1-2 hours, the oral formulation of sumatriptan – 1 of the 5 “fast-onset” oral triptans– is simply too slow.
On the downside, the half-life of injectable sumatriptan is only about 2 hours; it will be essentially gone from the body within 8 hours, and it may decline to a subtherapeutic level well before it vanishes entirely. As such, the incidence of early recurrent headache following initially successful treatment with injectable sumatriptan is as high as 40%, and recurrence is especially high if the headache being treated is reduced but not eliminated. On the front end, the longer one waits to administer injectable sumatriptan after the headache has reached the moderate to severe level of intensity, the lower the chance of obtaining complete (or even satisfactory) headache relief and the higher the chance of early headache recurrence. In any event, expect and be prepared to treat headache recurrence following initially successful treatment with subcutaneous sumatriptan. Such recurrence is not a “rebound” headache provoked by the sumatriptan itself; it is, rather, a case of an acute headache successfully treated with injectable sumatriptan recurring as sumatriptan exits the body and the smoldering migraine circuitry is free to reignite.
This also can be a problem with all 5 of the “fast-onset” oral triptans. Not only are they often too slow to catch up with an advanced migraine headache, but their relatively short half-lives (about 2 to 4 hours) may predispose to early headache recurrence. Their initial effectiveness may be amplified by co-administration of a nonsteroidal anti-inflammatory drug (NSAID), and with their typically longer half-lives the NSAIDs also may may mitigate to some extent the risk of early headache recurrence. These observations led to the development of two orally administered compounds, Treximet (sumatriptan plus naproxen sodium) and Symbravo (rizatriptan plus meloxicam – see this issue’s “migraine treatments of the month”). Whether these compounds are more effective than their individual components taken simultaneously but separately remains unknown; there have been published no meaningful results from active comparator trials.
There are two so-called “slow onset” oral triptans, naratriptan and frovatriptan. Each has a Tmax somewhat slower than the than that of the 5 fast-onset oral triptans, and each has a longer half-life; the half-life of frovatriptan is about 26 hours, at least 4 times that of naratriptan, and – not surprisingly – the incidence of early headache recurrence is correspondingly low relative to all the other triptans. Given that the array of side effects that occur with the triptans – chest pressure, neck squeezing, jaw tightness, facial tingling, etc. – is likely to be a function of Tmax and Cmax, these slow-acting oral triptans are “gentler” than their oral brethern and much less likely to produce side effects than fast Tmax/high Cmax injectable sumatriptan. On the downside, they are also less effective and less rapidly effective than the other triptans. A positive note: each may have a niche indication for use in the “mini-prophylaxis” of menstrual migraine.
Not only does the effectiveness of a given therapy vary according to its pharmacokinetics and when that treatment is administered in the course of a migraine attack, but – especially for the triptans, be they orally, intranasally or subcutaneously administered – the occurrence and intensity of side effects also will vary. The later a triptan is administered, the less effective it is likely to be and the more likely it is to cause side effects.
While the triptans generally are a very safe class of medications, the side effects they cause can be annoying or even alarming. If one does not know that the chest pressure caused by a triptan is a consequence of spasm within the smooth muscle of the esophagus, is benign in origin and will resolve spontaneously, the individual understandably may assume he/she is having a heart attack. And it’s off to the ER, where chaos, expense and unnecessary diagnostic intervention may ensue.
The effectiveness of a given therapy often depends upon its route of administration. As emphasized previously, oral therapies will be inconsistently effective at best for a migraine headache that has advanced to become moderate to severe in intensity; such headaches call for intranasal or subcutaneously self-injected therapy. While the pointlessness of administering an oral therapy when migraine-associated nausea and vomiting are prominent may be obvious, a less obvious saboteur of efficacy is the phenomenon of gastroparesis (delayed passage of stomach contents to the small intestine). Chronic gastroparesis is surprisingly common in migraine, and it increases during acute migraine. If the gastroparesis is severe, any oral therapy administered may not make its way to the small intestine to be absorbed quickly enough or in a high enough amount to be effective. Similar issues can arise in patients who have had gastric bypass or gastric sleeve surgery for obesity. If impaired gastrointestinal (GI) absorption could be consistently producing treatment failure, it may be time to try taking oral metoclopramide (Reglan), a gastric stimulant, 10-20 minutes prior to an anti-migraine oral therapy or switching to a non-oral route of administration.
A final word about “rescue”…
While intranasal medications are more rapidly acting and more effective than their oral counterparts for treating moderate to severe intensity migraine headache, they are less effective than the injectable medications for “rescue” from these more advanced headaches. Subcutaneously self-administered DHE per auto-injector (Brekiya) – see this issue’s “migraine treatments of the month“ – now offers an interesting alternative to injectable sumatriptan for “rescue”. Brekiya’s Tmax is nearly as fast as that of injectable sumatriptan, and with its significantly longer half-life the incidence of early headache recurrence is much lower. Because there is an at least theoretical risk of arterial vasoconstriction with both the triptans and the ergotamines, one should wait at least 6 hours after administering a triptan before administering Brekiya and at least 24 hours after administering Brekiya before administering a triptan.Especially for those migraineurs who require a “rescue” medication for acute, severe migraine headaches and have found subcutaneously injectable sumatriptan to be ineffective - or effective but associated with a high frequency of early headache recurrence - Brekiya represents an attractive new alternative.
All this may sound complicated, but it’s actually pretty simple. It boils down to having multiple weapons for acute migraine headache available in your arsenal and then using the right medication(s) at the right time.
