According to recent guidelines from the US Headache Consortium, the goals of acute migraine therapy are to1:
- Treat attacks rapidly and consistently.
- Restore the patient's ability to function.
- Minimize the use of backup and rescue medications.
- Optimize self-care and reduce subsequent use of health care resources.
- Be cost-effective.
- Have minimal or no adverse effects.
How can we best achieve these goals? In this article, I review the evidence to help you determine the most effective approach for your patient. The focus here is not on which medication is best; rather, it is on how to expedite and optimize treatment.
To patients, the most important characteristics of acute migraine therapy are, in descending order: complete pain relief, prevention of recurrence, and rapid onset of pain relief.2 The International Headache Society has suggested that these features be incorporated into a rigorous single clinical end point against which to evaluate acute migraine medications. This end point is defined as a sustained pain-free state that begins within 2 hours after a patient has taken a migraine medication, with no relapse and no use of rescue medication for the next 24 hours. The challenge is to choose the right treatment to meet this goal.
SELECTING A STRATEGY
Treatment decisions have in the past been based on "common sense" rather than randomized prospective evidence. The 3 most widely used strategies are step care across attacks, step care within attacks (also called staged care), and stratified care. A recent study provides strong evidence that a stratified approach yields optimal clinical outcomes.3
Step care across attacks. This model is based on the traditional approach of selecting treatment according to cost. After the physician makes a diagnosis of migraine, he or she selects the least expensive nonspecific medication for the patient to use first and may recommend that the patient use it during several attacks. If it fails to abort the headache, the physician will then "step up" to the next drug, usually another nonspecific agent. This process may continue until a nonspecific medication works, or the physician finally chooses a specific, more effective medication, or the patient does not return to the physician.
An example of agents used successively in this strategy would be:
- Naproxen sodium.
- A combination of aspirin, acetaminophen, and caffeine.
- A combination of isomethep- tene mucate, chlorzoxazone, and acetaminophen.
- A combination of butalbital, aspirin, and caffeine.
- An opioid.
- A triptan.
Insurance companies or managed care organizations may dictate the sequence in which medications are used and may require documentation of medication failure in 3 separate attacks before the next step-up. Some insurance companies mandate the use of ergotamine, then injectable dihydroergotamine, before approving a triptan.
One disadvantage of this approach is that patients have usually tried low-level treatments by the time they reach the physician and may become frustrated at being told to use another nonspecific medication, especially an over-the-counter (OTC) agent. They may lapse from care, an action that, in addition to medical consequences for patients, is likely to have economic and social consequences (such as cost and possible employment problems because of recurrent episodes of disability) for patients as well as their employers.4
Another weakness of the step care approach is that the preordained protocol based on cost ignores the patient's unique needs and disease severity at the point of treatment. An analogous situation would be to treat all patients with asthma-another disease characterized by episodic disabling attacks-first with an OTC epinephrine mist, because it is cheapest. If the asthma does not respond or worsens, the physician might prescribe another inexpensive treatment, such as an oral corticosteroid, followed by a generic inhaler.
The argument in favor of this approach is that it is not cost-effective to use an expensive medication if a less expensive one might work and that the efficacy of the less expensive drug cannot be verified unless the drug is given a fair trial.
Step care within attacks. This strategy calls for starting with a nonspecific, less expensive medication and, in the event of failure, having the patient switch to a specific or more expensive medication during the attack. The patient would use the specific drug only if he felt certain-because the lower-level agent had failed-that the headache was a severe migraine. The specific medication would, in essence, be used as a rescue agent.
Patients often take the staged care approach themselves. They reason that since insurance companies pay for only a limited number of triptan tablets each month, they should use the triptan only when "things are really bad." They start with NSAIDs and other OTC medications or prescribed nonspecific medications and step up to the triptan during the attack only if the lower-level medica-tion fails. The rationale is that if triptans work at any time during an attack, one might as well save them for later.
Stratified care. This strategy matches treatment to a patient's specific needs or the characteristics of the disorder. In the past, treatment was selected according to the features of the attack, such as peak intensity, time to peak intensity, severity of associated symptoms (eg, nausea and vomiting), and time to those symptoms. However, Lipton and colleagues5 have suggested another approach, in which the time loss suffered by the patient and therefore the impact of the headache on his life serves as a surrogate marker for severity, and treatment is selected accordingly. To implement this approach, the authors created the Migraine Disability Assessment (MIDAS) questionnaire, a tool designed to quantify headache-related disability. The MIDAS score is the sum of missed work, home, school, and recreational days as well as days when productivity was reduced by 50% or more.
With the stratified care approach, patients with low disability or time loss are treated with a nonspecific, inexpensive migraine medication, such as aspirin and caffeine or aspirin and metoclopramide. Those who report significant time loss are treated with a migraine-specific medication, such as a triptan.
WHICH STRATEGY IS BEST?
The Disability in Strategies of Care (DISC) study was the first randomized prospective comparison of the 3 strategies described above.3 Patients with episodic migraine were treated with either aspirin, 800 to 1000 mg, and metoclopramide, 10 mg, or zolmitriptan, 2.5 mg, for 6 attacks. The patients were randomized by strategy:
- Patients in the step care across attacks group were told that if the aspirin and metoclopramide combination failed in at least 2 of the first 3 attacks, they could step up to zolmitriptan for the fourth attack and thereafter.
- PPatients in the step care within attacks group could switch to zolmitriptan if, after 2 hours, they did not respond to aspirin plus metoclopramide.
- PPatients in the stratified care co- hort were divided into low- and high- need groups. The low-need patients (MIDAS score less than 11-ie, fewer than 11 days of at least 50% disability in the previous 3 months) were given aspirin and metoclopramide; the high-need patients (MIDAS score higher than 11) were given zolmitriptan.
The primary end points were the 2-hour headache relief rate and the disability time per attack. The study was not meant to evaluate whether nonspecific or specific agents worked best. Rather, the goal was to determine which care strategy worked best and when to use which treatment in which patient. Results showed that all patients in the stratified care group fared significantly better in both main outcome measures. The cost to patients in terms of lost productivity and impaired normal activities was lower with stratified care than with the other strategies.6,7Figure 1 shows a schematic of the benefits of stratified care versus step care.
The results of the study suggest that before initiating treatment, you need to ask patients about time lost from normal activities because of migraine attacks. If time loss is minimal, the patient is a good candidate for nonspecific treatment. If the patient has had more than 10 days of at least 50% disability in the last 3 months, a triptan is recommended as initial therapy.
Evidence for early intervention. In every double-blind, placebo-controlled study of triptans published through 2000, patients were instructed to wait until they reached a moderate to severe level of pain before using the medication (Figure 2). Those who treated their migraines at mild pain were excluded from primary analyses in several placebo-controlled trials of sumatriptan. A post hoc study compared these patients with those who treated at moderate to severe pain.8,9
Patients who treated at moderate to severe pain with sumatriptan, 50 mg, had a pain-free 2-hour response rate of 27% to 31%; the 4-hour response rate was 48% to 56%. Patients who treated at mild pain, however, had a 2-hour pain-free response rate of about 50% and a 4-hour response rate of about 80%. The recurrence rate was also lower in patients who treated at mild pain than in those who treated at moderate to severe pain (13% compared with 18%).
The response with sumatriptan, 100 mg, was even more dramatic. The 2-hour pain-free response for patients who treated at moderate pain was 36%; it was 61% at 4 hours. Of patients who treated at mild pain, 67% were pain free at 2 hours and 91% at 4 hours.
Sustained 2-hour and 4-hour pain-free response rates with early use of sumatriptan were higher (34% and 53%, respectively) than response rates with later treatment (19% and 24%, respectively).8,9
The authors also noted that with sumatriptan, 50 mg, patients experienced a reduction in medication side effects (5.2% in patients who treated at moderate to severe pain compared with zero when these patients treated at mild pain). Adverse events were those typically associated with the use of sumatriptan: tingling, warmth, and tightening.
The reduction in side effects may result from avoidance of allodynia (a state in which nonpainful stimuli are experienced as painful) and central sensitization. Allodynia is believed to be secondary to central sensitization-the recruitment of second- and third-order neurons to firing as a migraine attack progresses.10 At the peak of an attack, all stimuli-including light, noise, smell, movement, and touch-are experienced as painful. It is likely that medications also induce side effects because of this "central windup." Adverse events may be eliminated or reduced if the patient takes a triptan early in the attack, before the recruitment of additional pathways and the development of allodynia.
More supporting evidence. A post hoc study of the naratriptan database reported that patients who treated in the first 90 minutes of an attack were less likely to experience recurrence than those who treated after 2 hours. Achievement of a pain-free state was thought to be associated with the reduced recurrence rate.11
In a 12-month open-label extension study of zolmitriptan, patients who treated at mild pain had better outcomes than those who treated at severe pain.12,13 The same finding was reported with almotriptan.14
The post hoc study results suggest that early intervention that results in greater likelihood of a sustained pain-free effect is a triptan class effect. These data were supported by 2 prospective, placebo-controlled studies of sumatriptan presented at the International Headache Society meeting in June 2001.15 The results of these trials were similar to those of the post hoc studies.16 The prospective studies also allayed the concern that treating at mild pain might result in patients' using triptans for episodic tension-type headache or headaches that would not turn into disabling migraine. The researchers found that in 70% of attacks treated at the mild phase with placebo, patients went on to experience moderate to severe or disabling levels of pain.
A prospective trial of rizatriptan found that patients who treated within 30 minutes of headache onset, compared with those who delayed taking the medication, were more likely to experience headache relief within 30 minutes, were more likely to be largely symptom-free and able to return to normal activities by 1 hour, and less likely to take other prescription medication.17 However, the authors found no difference in headache response at 2 hours with early or delayed use. This may have resulted from the fact that they did not use a pain-free state as an end point.
In a recent post hoc analysis, a significantly larger number of patients were pain-free at 2 hours when they treated mild pain (84%) than when they treated moderate or severe pain (53%).18 Early intervention also resulted in greater consistency of pain relief and lower rates of recurrence.
IMPLICATIONS FOR YOUR PRACTICE
The stratified care strategy is appropriate only in patients with episodicdisabling migraine. Patients with more than 1 or 2 attacks per week and those with chronic daily headache are candidates for prophylaxis to reduce the frequency of attacks.
The preponderance of evidence suggests that the best results with triptan therapy are achieved with early intervention. Patients are more likely to report pain-free and sustained pain-free responses, fewer adverse events, and less recurrence. Because a sustained pain-free result translates into less medication per attack, early intervention is clearly cost-effective. A recent study found that pain intensity strongly influenced the number of triptan tablets used per attack.19 Patients who treated at lower levels of pain used fewer tablets of all kinds-both triptans and rescue medications.
Triptans are contraindicated in patients with vascular disease and hemiplegic or basilar migraine. In patients with risk factors for vascular disease, a standard preoperative functional cardiovascular workup may be warranted before triptan use.
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