Rescue Therapy for Acute Migraine, Part 3
Rescue Therapy for Acute Migraine, Part 3
This section is intended as a general discussion of all the studies presented in this 3-part review of physician-administered rescue therapy for acute migraine in the ED, urgent care, and headache clinic infusion center settings. The conclusions are based on the current paper and those published previously in this journal.
Analysis of the large number of studies presented in this review confirms that a definitive and optimally effective ED migraine rescue regimen cannot be determined on the basis of current published data. In an attempt to compare migraine treatments without relying solely on the pair-wise comparisons typical of the methodology used in the studies reviewed, the author determined and compared weighted averages of the percentages of pain relief. These weighted averages were computed for all medications for which there were 2 or more randomized trials with the medication used as a single agent (that is, was not combined with any other medications). The following lists these average percentages of pain relief from greatest to least (total number of patients represented is in parentheses): droperidol 82% (229), sumatriptan 78% (351), prochlorperazine 77% (312), tramadol 76% (37), metamizole (not available in the USA) 75% (164), metoclopramide IV 70% (184), DHE 67% (188), chlorpromazine 65% (158), ketorolac 30 mg IV 60% (77), meperidine 58% (79), metoclopramide IM 45% (128), magnesium 43% (169), ketorolac 60 mg IM 37% (64), and valproate 32% (39) (Fig. 1). Of note, promethazine is not listed here in this analysis because it was only studied in combination with meperidine.
(Enlarge Image)
Figure 1.
Weighted averages of the percentages of pain relief for all medications for which there were ≥2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous.
The weighted averages for percentages of patients who were pain free were also computed for all medications for which there were 2 or more randomized trials where the medication was used as a single agent. These are presented from greatest to least as follows (total number of patients represented is in parentheses): 53% for both prochlorperazine (90) and chlorpromazine (115), droperidol 40% (214), magnesium 36% (91), sumatriptan 35% (166), tramadol 32% (37), and DHE 21% (34) (Fig. 2). Magnesium fared much better in this analysis than in the analysis of headache relief.
(Enlarge Image)
Figure 2.
Weighted averages of the percentages of pain free for all medications for which there were ≥2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous.
The choice of headache treatment should be based on considerations of efficacy, side effects, and cost. The calculated expense of a treatment should include not only immediate ED treatment, but also the hidden costs of continuing headache, early headache recurrence, functional disability, return trips to the ED, and the need for follow-up care in an outpatient clinic. Headache recurs in more than 50% of patients after ED discharge. Ducharme et al found that those who are pain free at discharge are significantly less likely to have recurrence, but Friedman et al could not independently support this finding. When they looked at their ED records for administered medications, Sheftell et al also reported a link between low recurrence and pain-free response with naratriptan PO. Overall, it seems reasonable that a concerted effort should be made to discharge patients from the ED pain free.
Parenterally administered dopamine antagonists are not only effective anti-emetics but also can reduce or terminate migraine headache. As a class, however, they frequently cause side effects (including sedation, akathisia, and dystonia) that can outlast the symptoms of the migraine itself and thereby prolong patients' functional disability. There is a need to pre-dose patients receiving phenothiazines (especially chlorpromazine) with IV fluid to prevent postural hypotension, as well as with a drug possessing anticholinergic properties to reduce the likelihood of extrapyramidal side effects. Droperidol and haloperidol are not recommended as first-line therapy because of potential QTc prolongation and the consequent need for electrocardiogram monitoring.
For a variety of reasons (discussed in some detail earlier in this paper), opiates/opioids generally are not recommended as first-line treatment for migraine. One argument used in support of using opioids for first-line treatment is that they are quick to administer and act rapidly, such that patients can be discharged in a timely fashion. It remains unclear, however, whether the use of opioids does indeed save time. Coleman et al assessed migraine treatment patterns in 5 linked Canadian EDs. Opiates/opioids were used as first-line treatment for 59.6% of the migraine patients. The odds of receiving an opioid as first-line therapy was increased in patients who took medications prior to ED admission and was decreased in patients who had a longer-lasting headache or a more urgent triage score. Those who received opioids first line spent less total time in the ED (177 minutes vs 237 minutes, P < .001). This contrasts with the findings of Tornabene et al, who found that patients who received opioids spent more time in their ED than patients who did not (160 minutes vs 125 minutes, P = .015), regardless of whether they often sought treatment for headache in the ED.
Sumatriptan SQ, a relatively migraine-specific medication, is as effective as droperidol and prochlorperazine in providing pain relief. When limited to patients with no contraindications, it is very well tolerated. Adverse events are generally limited to transient chest tightness, shoulder pain, and neck pain, all of which rarely outlast the migraine pain itself and require no treatment to resolve.
An argument can be made for the use of fixed drug combinations to treat migraine. These combinations can target multiple symptoms and have synergistic effects, and there is also the possibility that 1 or more medications can counteract side effects of another medication when they are combined. One such combination is DHE combined with metoclopramide intravenously, with the latter treating the nausea induced by the former. Both of these medications were individually as effective as chlorpromazine in providing pain relief, although the combination did not appear to have additional pain-relieving effects.
Magnesium can be an effective agent in migraine treatment, either alone or as adjuvant treatment, especially in those patients who have aura. It provided as much freedom from migraine pain (with and without aura) as did sumatriptan or ketorolac IV, although average pain relief was relatively low, only surpassing ketorolac IM and valproate.
There is some support for using corticosteroids to prevent headache recurrence, especially if the presenting migraine has lasted longer than 72 hours. The optimal regimen likely involves IV doses in the ED followed by oral dosing for several days post-discharge.
It is recommended that all future studies be randomized and double blinded (including double dummy). For those rescue treatments for which there have been insufficient studies employing a placebo arm, it is recommended that this be done to ascertain effectiveness more accurately. When drug combinations are compared, the same second agent should be used in both or all arms. An ideal design for studying drug combinations would have 4 arms: drug A/placebo B, drug B/placebo A, drug A/drug B, and placebo A/placebo B. Recording of headache status should be done at 2 hours (in addition to any other outcome measures), even if this involves the patient reporting their status post-discharge, in order to determine the percent pain free at 2 hours. All studies should include 24–72 hour follow-up evaluations.
In summary, the ideal acute migraine rescue therapy administered in the urgent care or ED setting would provide complete headache relief, possess no side effects, and prevent early headache recurrence. Because no such therapy currently exists, treatment must be tailored to the needs of the individual patient.
Triptans and DHE are most effective in injectable formulations and should be avoided in those at risk for vascular complications. DHE is particularly effective when given IV but can cause increased nausea.
NSAIDs such as ketorolac have the advantage of being appropriate for patients with vascular risk factors, and they do not cause sedation. They can be combined with most other treatments for increased efficacy.
Dopamine antagonists can be given alone or with other agents. As this review indicates, they are surprisingly effective for migraine, even late in the attack, and they are inexpensive. When used alone, prochlorperazine, droperidol, and metoclopramide were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, but they commonly cause side effects that are especially unpleasant for patients (notably dystonia and akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when considering only paired comparisons. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to droperidol and prochlorperazine.
Once again, opiate/opioid rescue sometimes can be effective, but such therapy also may lead to early headache recurrence, central sensitization, sedation, nausea and dizziness, as well as raise concerns for overuse and abuse. While commonly administered for treatment of acute migraine, ideally, these medications should be a last resort.
Magnesium can be an effective treatment for migraineurs with aura and can reduce the photophobia and phonophobia of all migraineurs. It can be added on to any of the said medications to boost effectiveness without sedation. Magnesium also can be very useful as a therapy for pregnancy-associated migraine.
General Discussion and Conclusions
This section is intended as a general discussion of all the studies presented in this 3-part review of physician-administered rescue therapy for acute migraine in the ED, urgent care, and headache clinic infusion center settings. The conclusions are based on the current paper and those published previously in this journal.
Analysis of the large number of studies presented in this review confirms that a definitive and optimally effective ED migraine rescue regimen cannot be determined on the basis of current published data. In an attempt to compare migraine treatments without relying solely on the pair-wise comparisons typical of the methodology used in the studies reviewed, the author determined and compared weighted averages of the percentages of pain relief. These weighted averages were computed for all medications for which there were 2 or more randomized trials with the medication used as a single agent (that is, was not combined with any other medications). The following lists these average percentages of pain relief from greatest to least (total number of patients represented is in parentheses): droperidol 82% (229), sumatriptan 78% (351), prochlorperazine 77% (312), tramadol 76% (37), metamizole (not available in the USA) 75% (164), metoclopramide IV 70% (184), DHE 67% (188), chlorpromazine 65% (158), ketorolac 30 mg IV 60% (77), meperidine 58% (79), metoclopramide IM 45% (128), magnesium 43% (169), ketorolac 60 mg IM 37% (64), and valproate 32% (39) (Fig. 1). Of note, promethazine is not listed here in this analysis because it was only studied in combination with meperidine.
(Enlarge Image)
Figure 1.
Weighted averages of the percentages of pain relief for all medications for which there were ≥2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous.
The weighted averages for percentages of patients who were pain free were also computed for all medications for which there were 2 or more randomized trials where the medication was used as a single agent. These are presented from greatest to least as follows (total number of patients represented is in parentheses): 53% for both prochlorperazine (90) and chlorpromazine (115), droperidol 40% (214), magnesium 36% (91), sumatriptan 35% (166), tramadol 32% (37), and DHE 21% (34) (Fig. 2). Magnesium fared much better in this analysis than in the analysis of headache relief.
(Enlarge Image)
Figure 2.
Weighted averages of the percentages of pain free for all medications for which there were ≥2 randomized trials with the medication used as a single agent. DHE = dihydroergotamine; IM = intramuscular; IV = intravenous.
The choice of headache treatment should be based on considerations of efficacy, side effects, and cost. The calculated expense of a treatment should include not only immediate ED treatment, but also the hidden costs of continuing headache, early headache recurrence, functional disability, return trips to the ED, and the need for follow-up care in an outpatient clinic. Headache recurs in more than 50% of patients after ED discharge. Ducharme et al found that those who are pain free at discharge are significantly less likely to have recurrence, but Friedman et al could not independently support this finding. When they looked at their ED records for administered medications, Sheftell et al also reported a link between low recurrence and pain-free response with naratriptan PO. Overall, it seems reasonable that a concerted effort should be made to discharge patients from the ED pain free.
Parenterally administered dopamine antagonists are not only effective anti-emetics but also can reduce or terminate migraine headache. As a class, however, they frequently cause side effects (including sedation, akathisia, and dystonia) that can outlast the symptoms of the migraine itself and thereby prolong patients' functional disability. There is a need to pre-dose patients receiving phenothiazines (especially chlorpromazine) with IV fluid to prevent postural hypotension, as well as with a drug possessing anticholinergic properties to reduce the likelihood of extrapyramidal side effects. Droperidol and haloperidol are not recommended as first-line therapy because of potential QTc prolongation and the consequent need for electrocardiogram monitoring.
For a variety of reasons (discussed in some detail earlier in this paper), opiates/opioids generally are not recommended as first-line treatment for migraine. One argument used in support of using opioids for first-line treatment is that they are quick to administer and act rapidly, such that patients can be discharged in a timely fashion. It remains unclear, however, whether the use of opioids does indeed save time. Coleman et al assessed migraine treatment patterns in 5 linked Canadian EDs. Opiates/opioids were used as first-line treatment for 59.6% of the migraine patients. The odds of receiving an opioid as first-line therapy was increased in patients who took medications prior to ED admission and was decreased in patients who had a longer-lasting headache or a more urgent triage score. Those who received opioids first line spent less total time in the ED (177 minutes vs 237 minutes, P < .001). This contrasts with the findings of Tornabene et al, who found that patients who received opioids spent more time in their ED than patients who did not (160 minutes vs 125 minutes, P = .015), regardless of whether they often sought treatment for headache in the ED.
Sumatriptan SQ, a relatively migraine-specific medication, is as effective as droperidol and prochlorperazine in providing pain relief. When limited to patients with no contraindications, it is very well tolerated. Adverse events are generally limited to transient chest tightness, shoulder pain, and neck pain, all of which rarely outlast the migraine pain itself and require no treatment to resolve.
An argument can be made for the use of fixed drug combinations to treat migraine. These combinations can target multiple symptoms and have synergistic effects, and there is also the possibility that 1 or more medications can counteract side effects of another medication when they are combined. One such combination is DHE combined with metoclopramide intravenously, with the latter treating the nausea induced by the former. Both of these medications were individually as effective as chlorpromazine in providing pain relief, although the combination did not appear to have additional pain-relieving effects.
Magnesium can be an effective agent in migraine treatment, either alone or as adjuvant treatment, especially in those patients who have aura. It provided as much freedom from migraine pain (with and without aura) as did sumatriptan or ketorolac IV, although average pain relief was relatively low, only surpassing ketorolac IM and valproate.
There is some support for using corticosteroids to prevent headache recurrence, especially if the presenting migraine has lasted longer than 72 hours. The optimal regimen likely involves IV doses in the ED followed by oral dosing for several days post-discharge.
It is recommended that all future studies be randomized and double blinded (including double dummy). For those rescue treatments for which there have been insufficient studies employing a placebo arm, it is recommended that this be done to ascertain effectiveness more accurately. When drug combinations are compared, the same second agent should be used in both or all arms. An ideal design for studying drug combinations would have 4 arms: drug A/placebo B, drug B/placebo A, drug A/drug B, and placebo A/placebo B. Recording of headache status should be done at 2 hours (in addition to any other outcome measures), even if this involves the patient reporting their status post-discharge, in order to determine the percent pain free at 2 hours. All studies should include 24–72 hour follow-up evaluations.
In summary, the ideal acute migraine rescue therapy administered in the urgent care or ED setting would provide complete headache relief, possess no side effects, and prevent early headache recurrence. Because no such therapy currently exists, treatment must be tailored to the needs of the individual patient.
Triptans and DHE are most effective in injectable formulations and should be avoided in those at risk for vascular complications. DHE is particularly effective when given IV but can cause increased nausea.
NSAIDs such as ketorolac have the advantage of being appropriate for patients with vascular risk factors, and they do not cause sedation. They can be combined with most other treatments for increased efficacy.
Dopamine antagonists can be given alone or with other agents. As this review indicates, they are surprisingly effective for migraine, even late in the attack, and they are inexpensive. When used alone, prochlorperazine, droperidol, and metoclopramide were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, but they commonly cause side effects that are especially unpleasant for patients (notably dystonia and akathisia). Metoclopramide was equivalent to prochlorperazine, and, when combined with diphenhydramine, was superior in efficacy to triptans and NSAIDs. Meperidine was arguably equivalent when compared with ketorolac and DHE but was inferior to chlorpromazine and equivalent to the other neuroleptics. Sumatriptan was inferior or equivalent to the neuroleptics and equivalent to DHE when considering only paired comparisons. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to droperidol and prochlorperazine.
Once again, opiate/opioid rescue sometimes can be effective, but such therapy also may lead to early headache recurrence, central sensitization, sedation, nausea and dizziness, as well as raise concerns for overuse and abuse. While commonly administered for treatment of acute migraine, ideally, these medications should be a last resort.
Magnesium can be an effective treatment for migraineurs with aura and can reduce the photophobia and phonophobia of all migraineurs. It can be added on to any of the said medications to boost effectiveness without sedation. Magnesium also can be very useful as a therapy for pregnancy-associated migraine.
