Rescue Therapy for Acute Migraine, Part 1

Triptans, Dihydroergotamine, and Magnesium

Nancy E. Kelley, MD, PhD; Deborah E. Tepper, MD

Disclosures

Headache. 2012;52(1):114-128. 

In This Article

Triptan, DHE, and Magnesium

When treatments from 2 different classes of medications were compared, a summary of results appears under both classes (for example, a study comparing DHE to sumatriptan would appear under both DHE and triptans), but details of the results will only appear under one class. Where combinations of medications were used, all members of the combination are represented within their own medication class.

Triptans

Two triptans (sumatriptan and rizatriptan) have been studied for treatment of acute migraine in the ED setting. These triptans act primarily as selective serotonin 1B/D (5HT1B/1D) agonists on extracerebral arteries. 5HT1B constricts blood vessels dilated by CGRP, and 5-HT1D further inhibits CGRP release from the activated peripheral nociceptive C-fibers.[24] The triptans also inhibit the release of inflammatory peptides in the meninges and interfere with the transduction of pain signals to the TNC.

The serum concentration of sumatriptan administered subcutaneously (SQ) peaks between 10–12 minutes and is 97% bio-available.[25] Rizatriptan reaches maximum concentration faster than other oral triptans.[26] Triptans generally have been found to be safe and efficacious in the outpatient treatment of acute migraines. Their most common side effects are chest pressure, neck tightness, limb heaviness, tingling, dizziness, and flushing. Triptans are contraindicated for patients who have vascular disease, basilar/hemiplegic migraine, or uncontrolled hypertension, are pregnant or at risk for pregnancy (Pregnancy Class C), or have used a different triptan or ergotamine/DHE within the previous 24 hours.[27] Because triptans do not affect the 5HT2A serotonin receptors, there is likely to be no risk of serotonin syndrome when used in monotherapy and no increased risk from combination with serotonin reuptake inhibitors.[28]

Seven randomized, double-blind studies compared sumatriptan 6 mg SQ with placebo or various other agents. One compared sumatriptan 20 mg nasal with ketorolac 30 mg IV. There was one study involving rizatriptan 10 mg orally dissolvable tablets and one with sumatriptan 6 mg SQ, neither of which used a placebo or comparison group; these were included because they were carried out in an ED setting with a relatively large number of patients (98 and 147, respectively).

Hay et al[29] used rizatriptan orally dissolvable 10 mg tablets to treat 98 migraine patients in the ED and found that 73.5% were pain-free at 2 hours and 93% had headache relief. Miner et al[30] determined the efficacy of sumatriptan 6 mg SC for patients with three headache diagnoses: migraine (M; n = 84), probable migraine (pM; n = 45), and tension-type headaches (TTH; n = 18). Headache relief at 1 hour was similar across the groups (M 60% vs pM 56% vs TTH 67%, P = .61). Headache persisted at 48 hours in 66%. Common side effects included chest/neck tightness (8%), followed by drowsiness, increased head pain, and nausea (all 4%).

Akpunonu[31] found pain relief was greater with sumatriptan SQ 6 mg compared with placebo (70% vs 35%, P < .01). Side effects, most commonly "dizziness" or vertigo and tingling, were reported in 52% for sumatriptan SQ vs 27% for placebo. Five of 88 patients in the sumatriptan group reported benign chest tightness that resolved within 1 hour without treatment. Winner et al[32] compared sumatriptan SQ 6 mg with DHE SQ. Each medication could be repeated once at 2 hours. More patients taking sumatriptan had pain relief at 2 hours (85.3% vs 73.1%, P = .002), but this advantage had dissipated at 3 hours (sumatriptan 86% vs DHE 90%). Common side effects included injection site discomfort (DHE 38.4% vs sumatriptan 17.7%), nausea (15.9% vs 5.9%), vomiting (6.5% vs 3.8%), and chest pain (0.9% vs 5.9%).

Four studies compared sumatriptan with an anti-emetic. Kelly et al[33] compared sumatriptan SQ 6 mg with chlorpromazine 12.5 mg IV (repeated up to 37.5 mg). All patients received IV metoclopramide 10 mg. At 2 hours, there was no difference in pain reduction as measured via VAS (sumatriptan −63.3 mm vs chlorpromazine −54.3 mm). No dystonia was reported. Friedman et al[34] compared sumatriptan SQ 6 mg with IV metoclopramide 20 mg (repeated up to 80 mg) combined with IV diphenhydramine 25 mg. Pain reduction (11-PPS) at 2 hours was similar (sumatriptan −6.3 vs metoclopramide/diphenhydramine −7.2), but the percentage pain-free was greater with metoclopramide/diphenhydramine (59% vs 35%, P = .04). Common side effects included weakness, drowsiness, and a feeling of heaviness, the last greater for sumatriptan (11% vs 0%, P = .05). Friedman et al[35] compared sumatriptan SQ 6 mg to trimethobenzamide 200 mg intramuscular (IM) plus diphenhydramine 25 mg IM. Pain reduction (11-PPS) at 2 hours was similar (trimethobenzamide/diphenhydramine −4.4 vs sumatriptan −6.1). Kostic et al[36] compared sumatriptan SQ 6 mg to prochlorperazine 10 mg IV plus diphenhydramine 12.5 mg SQ. Pain reduction (VAS) at 80 minutes favored prochlorperazine/diphenhydramine (−73 vs −50, P < .05). Nine of 31 patients in the prochlorperazine/diphenhydramine group reported restlessness, but none needed treatment.

Meredith[37] compared sumatriptan 20 mg nasal spray to ketorolac 30 mg IV. Mean pain reduction (VAS) at 1 hour favored ketorolac over sumatriptan (−71.5 vs −22.9, P < .05). Jakubowski et al[38] compared sumatriptan SQ 6 mg to ketorolac 15 mg IV bolused twice successively (30 mg total) for the delayed treatment (4 hours) of migraine with cutaneous allodynia. No patient in the sumatriptan group was pain-free after 2 hours compared with 64% in the ketorolac group at 1 hour (P < .05). Table 1 summarizes details of the studies involving sumatriptan and rizatriptan.

DHE

DHE is an ergot extract that activates 5HT1B and 5HT1D receptors, as do the triptans, but DHE can also activate 5HT1A, 5HT2A, 5HT1F, 5HT2C, 5HT3, and dopamine1- and dopamine2-receptor subtypes. DHE can block activation of the TNC by blocking the release of prostaglandins from the glia[39] and is associated with a low headache recurrence rate.

While DHE has fewer side effects than ergotamine tartrate, its predecessor, it can still cause nausea, vomiting, diarrhea, abdominal cramping, vasoconstriction, and leg pain. The appearance of nausea suggests that the patient has been given too high a dose of DHE, mediated by activation of the 5HT2 and 5HT3 receptors. DHE is generally non-sedating. It can be easily mixed with lidocaine to prevent injection site burning. As with the triptans, DHE is contraindicated for patients who have vascular disease, basilar/hemiplegic migraine, or uncontrolled hypertension, are pregnant or at risk (Pregnancy Class X), or have used a triptan or ergotamine within the previous 24 hours.[28] Because DHE, unlike the triptans, does affect the 5HT2A serotonin receptor, there may be a risk of serotonin syndrome when used in combination with serotonin reuptake inhibitors.

Three studies compared DHE 1 mg IV or SQ as a single agent with other single agents or with combinations of DHE and an anti-emetic, and an additional seven studies compared a combination of DHE 0.5–1.0 mg IV plus an anti-emetic (usually metoclopramide 5–10 mg IV) with another active agent. Bell et al[40] compared DHE 1 mg IV (could be repeated once) with chlorpromazine 12.5 mg IV (repeated up to 37.5 mg) and to lidocaine 50 mg IV (repeated up to 150 mg). Although there was no difference in the pain-free rate, pain reduction (11-PPS) was greater for chlorpromazine than for lidocaine or DHE (−79.5% vs −50% vs −36.7%, P < .05). As stated previously, Winner et al[33] showed that DHE 1 mg SQ afforded less headache relief at 2 hours than sumatriptan 6 mg SQ (73.1% vs 8.3%, P = .002), but there was no difference at 4 hours. Saadah[41] compared DHE 1 mg IV with DHE 0.5 mg plus prochlorperazine 5 mg, DHE 1 mg plus prochlorperazine 10 mg, and DHE 1 mg plus prochlorperazine 3.5 mg. The percentage pain-free at 4 hours for DHE 1 mg alone was 83%, DHE 0.5 mg + prochlorperazine 5 mg 80%, DHE 1 mg + prochlorperazine 3.5 mg 89%, and DHE 1 mg + prochlorperazine 10 mg 95%. Side effects were reported in 100% of the patients receiving DHE alone, with the most common being sedation (30%), nausea (67%), and chest discomfort (75%).

Haugh et al[42] showed that DHE 1 mg IV plus metoclopramide 10 mg IV was not more effective than DHE 1 mg IV alone in the percentage of patients with headache relief at 1 hour (38%). Klapper and Stanton[43] compared DHE 0.75–1 mg IV plus metoclopramide 5–10 mg IV with dexamethasone 6 mg IV plus metoclopramide 5–10 mg IV and with placebo/normal saline IV. Headache relief at 30 minutes was equal for DHE/metoclopramide (82%) and dexamethasone/metoclopramide (78%) vs placebo (20%, P < .002). Edwards et al[44] showed that DHE 1 mg IV plus metoclopramide 10 mg IV was similar in headache relief at 4 hours to valproate 500 mg IV (60%). Klapper and Stanton[45] found that DHE 1 mg IV plus metoclopramide 5 mg IV produced more headache relief at 1 hour than ketorolac 60 mg IM (78% vs 33%, P = .031). Belgrade et al[46] compared DHE 1 mg plus metoclopramide 10 mg IV with meperidine 75 mg IM plus hydroxyzine 50 mg IM and with butorphanol 2 mg IM. Pain reduction (VAS) was greater with DHE/metoclopramide (−59) and butorphanol (−54) vs meperidine/hydroxyzine (−37, P < .01). There were more patients with >90% pain reduction with DHE/metoclopramide (38%) than butorphanol (16%) or meperidine/hydroxyzine (0%, P < .01). The most common side effect with meperidine/hydroxyzine was sedation (18%). With DHE/metoclopramide nausea (33%), dysphoria (43%), restlessness (19%), and flushing (29%) were the most common side effects; with butorphanol, it was dizziness (21%) and nausea (26%). Klapper and Stanton[47] compared DHE 1 mg plus metoclopramide 10 mg IV with meperidine 75 mg plus hydroxyzine 75 mg IM. Pain reduction (4-PPS) was greater in the DHE plus metoclopramide group (−2.14 vs −0.86, P = .006). Scherl and Wilson[48] showed that DHE 0.5 mg plus metoclopramide 10 mg IV was equally effective in providing 1 hour headache relief as meperidine 75 mg plus promethazine 25 mg IM (86.2% vs 77.2%); there were more lethargy and dizziness reported with promethazine/meperidine (7.2% vs 3.9%, P = .006).

Carleton et al[49] compared DHE 1 mg IV plus hydroxyzine 0.7 mg/kg (could repeat once) with meperidine 1.5 mg/kg plus hydroxyzine 0.7 mg/kg. Pain reduction (VAS) was similar in the two groups (DHE −41 vs meperidine −45, P = .81). Dizziness (DHE 2% vs meperidine 15%, P < .05) and drowsiness (DHE 21.5% vs meperidine 22.6%) were the most common side effects. Callaham and Raskin[50] pretreated all their study participants with prochlorperazine 5 mg IV, and after 30 minutes, average pain (11-PPS) dropped from 10.0 to 6.3 (NS). Three patients dropped out of the study at this point because of sufficient pain relief, and the remaining patients were randomized to receive either DHE 0.75 mg IV or NS placebo IV. Additional pain relief at 30 minutes was similar (5.2 vs 4.7). At this point, another seven patients left the study because of sufficient pain relief, four in DHE group and three in the placebo group. Then, the patients who had received DHE were given placebo and vice versa. A half hour later, those patients receiving DHE in the first round had more pain relief (2.5 vs 4.7, P = .05). Table 2 summarizes the DHE studies.

Magnesium

Magnesium can affect a number of neurochemical processes that are known to be involved in migraine pathophysiology. Magnesium maintains calcium homeostasis by binding to N-methyl-D-aspartate glutamate receptors, modulates the release of substance P, and regulates the production of nitric oxide.[51] Ionized magnesium can affect vascular tone[52] and inhibits cortical spreading depression in rats.[53]

Mauskop et al[54] found that 80% of patients treated with magnesium 1 g IV were pain-free 15 minutes postinfusion (P < .001). Of the 20% requiring rescue medications, the majority had chronic migraine (88%), and only 37.5% had low ionized magnesium (0.54 mmol/L or lower) compared with 89% who had sustained pain-freedom at 24 hours. Almost all patients experienced brief flushing with magnesium. Demirkaya et al[55] compared magnesium 1 g IV with placebo/normal saline IV. Seventy percent of the patients had migraine with aura. A greater percentage receiving magnesium group was pain-free at 30 minutes (86.6% vs 6.6%; P < .0001). Mild side effects of flushing and face/neck burning were experienced by 86.6% of the patients in both groups.

Cete et al[56] compared magnesium 2 g IV with metoclopramide 10 mg IV and with placebo/NS IV. Pain reduction (VAS) was similar for metoclopramide vs magnesium vs placebo (−38 vs −33 vs −24), but a smaller percentage in the metoclopramide and magnesium groups required rescue medications vs the placebo group (38% and 44% vs 65%; P = .04). Three percent of those taking metoclopramide complained of dystonia, and 8% taking magnesium complained of flushing. Corbo et al[57] compared magnesium 2 g IV with placebo/NS IV. All patients received metoclopramide 20 mg IV (repeated up to 60 mg). Pain reduction (VAS) was not different between the groups (magnesium −55 vs placebo −71), but return to normal functioning on a 4-point disability scale was greater for the placebo group (magnesium 8% vs placebo 17%; P < .05). The most common side effect noted was flushing (magnesium 48% vs placebo 22%, not significant). Bigal et al[58] compared magnesium 1 g IV with placebo/NS IV. Although they did have significantly less photophobia and phonophobia, for patients without aura, headache relief at 1 hour was not greater with magnesium compared with placebo (33.3% vs 16.6%). Patients with aura had greater headache relief at 1 hour with magnesium (50% vs 13.3%; P < .05). Ginder et al[59] compared magnesium 2 g IV with prochlorperazine 10 mg IV for undifferentiated acute headache. At 30 minutes postinfusion, prochlorperazine provided greater headache relief (90% vs 56%; P = .04). One patient (5%) reported dysphoria with prochlorperazine, and four patients (25%) reported IV burning pain with magnesium. Frank et al[60] compared magnesium 2 g IV with placebo/normal saline IV. There was no difference in pain reduction (VAS) at 30 minutes (magnesium −16 vs placebo −15; P = .85). There were more side effects for magnesium (62% vs 29%, P = .03), most commonly flushing. Table 3 summarizes studies involving magnesium.

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