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Am Fam Physician. 2000;61(1):180-186

Two new intranasal migraine medications, sumatriptan and dihydroergotamine mesylate, may offer specific advantages for patients who are seeking alternatives to various oral or parenteral migraine abortive therapies. Placebo-controlled clinical studies demonstrate that both intranasal forms are effective in relieving migraine headache pain, but published clinical trial information comparing these two intranasal medications with current abortive therapies is lacking. Both agents are generally well tolerated by patients, with the exception of mild, local adverse reactions of the nose and throat.

Migraine headaches are fairly common in the general population: 17.6 percent of women and 5.7 percent of men have one or more migraine headaches per year.1 Because of the episodic nature of migraine attacks, treatment options that rapidly and effectively minimize pain are needed. Although non-pharmacologic interventions play a role in headache management, most migraine patients seek relief with medication. Approximately 95 percent of patients with severe migraine take some medication (prescription or over-the-counter) for their headaches.2 A survey of patients with migraine indicated that they desire a medication that provides quick, sustained pain relief and also decreases the likelihood of recurrence.3

Although injectable sumatriptan (Imitrex Statdose) appears to be effective in aborting migraine attacks, many patients are reluctant to self-administer an injection.46 Oral medication for the acute treatment of migraine is the most convenient route of administration but is often impractical because of the high association of nausea and vomiting with migraine attacks. Up to 92 percent of patients have experienced nausea during a migraine attack, and 50 to 68 percent also have vomited.3,7 In addition, the absorption of oral medications may be delayed or diminished because of the high prevalence of gastroparesis during the attack.810

The recently approved intranasal forms of dihydroergotamine mesylate (Migranal) and sumatriptan (Imitrex) may help alleviate some of the aforementioned problems. The intranasal route of administration is less invasive than self-administration of an injection and offers the advantage of bypassing the need for gastric absorption.

This article reviews these two intranasal forms of migraine medications and their role in the treatment of acute migraine.

Dihydroergotamine Nasal Spray

Dihydroergotamine (DHE) has been used in the parenteral form for the treatment of acute migraine for many years. The intranasal form is labeled by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine headaches.


DHE is a derivative of ergotamine and exhibits more selective vasoconstriction than the parent compound. It binds to a number of receptor sites in the body, including serotonin, adrenergic and dopaminergic receptors. One postulated mechanism of action is its vasoconstrictive effects on intracranial vessels. Another possible action is inhibition of the release of inflammatory peptide mediators from trigeminal system nerve endings that may be involved in generating migraine pain.11


The mean bioavailability of intranasal DHE is approximately one third that of intravenous DHE. Systemic absorption after intranasal administration varies among patients, depending on different absorption rates and self-administration techniques. On average, maximum plasma concentration is achieved in 45 minutes (range of 30 to 60 minutes). The primary excretory route for DHE is via the bile in the feces, with an average elimination half-life of 10 hours.11


Table 1 reviews the efficacy of DHE nasal spray in comparison with other migraine treatments.1117 Headache “relief” or “response” in migraine studies is typically defined as a reduction in headache severity (as reported by patients) from moderate or severe to mild or absent pain.

DrugRouteHeadache response rate (%) Adverse reactions (%)
At 2 hours post-doseAt 4 hours post-doseTaste disturbanceParesthesia, burning sensationChest pain, chest tightness
DHE (Migranal), 2 mg11 Nasal30 to 6147 to 7082
Placebo20 to 2322 to 3512
Sumatriptan (Imitrex nasal), 5 mg12 Nasal45 to 4919 to 240.4
Sumatriptan, 20 mgNasal55 to 6425 to 361.4
Placebo25 to 360 to 20.1
Sumatriptan (Imitrex), 25 mg13 Oral5265 to 7036
Sumatriptan, 50 mgOral50 to 6168 to 7856
Sumatriptan, 100 mgOral56 to 6271 to 7938
Placebo17 to 2719 to 3824
Sumatriptan (Imitrex Statdose), 6 mg14 Injectable81 to 827.54.5
Placebo31 to 390.31.4
Naratriptan (Amerge), 1 mg15 Oral4250 to 5412
Naratriptan, 2.5 mgOral45 to 5160 to 6624
Placebo3127 to 34< 12
Rizatriptan (Maxalt), 5 mg16 Oral60 to 633< 2
Rizatriptan, 10 mgOral67 to 7743
Placebo23 to 40< 21
Zolmitriptan (Zomig), 2.5 mg17 Oral62 to 657373
Zolmitriptan, 5 mgOral59 to 677794
Placebo16 to 444021

Of the four placebo-controlled trials involving intranasal DHE,11,1820 only one19 demonstrated a statistically significant difference in response rates between DHE and placebo at the two-hour post-dose period. At four hours post-dose, three of the four trials11,18,19 demonstrated statistically significant effects in favor of the DHE-treated patients. Benefits in the DHE-treated patients were also achieved for the following secondary end points: decrease in severity of nausea,18,19 decrease in rates of photophobia and phonophobia,19 and fewer escape medications needed during the 24-hour post-dose period.19 The number of vomiting episodes did not differ significantly between patients receiving placebo and patients receiving intranasal DHE in any of the studies.

In one study,19 a low incidence of recurrent headache pain within 24 hours after initial response to intranasal DHE was reported; only 14 percent of patients had a recurrence of headache pain after initial response. This low recurrence rate may be due in part to the long half-life of DHE.


During the major clinical trials for intranasal DHE, the most common side effects were related to local reactions of the medication in the nasal passage (rhinitis, application site reactions) and an altered sense of taste. During the study period, 26 of 1,796 patients (1.4 percent) discontinued the active medication because of adverse reactions. The most common reasons for discontinuation were rhinitis, dizziness and facial edema.11


Because of its vasoconstrictive effects, DHE nasal spray should not be taken by patients with known ischemic heart disease or coronary vasospasm. Patients should be evaluated for cardiac risk factors before starting therapy. Other known contraindications include pregnancy (category X) and lactation, uncontrolled hypertension, peripheral arterial obstructive disease, recent history of vascular surgery, severe hepatic or renal disease, ongoing hemiplegic or basilar migraine, and known hypersensitivity to ergot alkaloids. The drug should not be taken within 24 hours of administration of other vasoconstrictive medications such as serotonin agonists, other ergotamine-containing medications or methysergide.


DHE intranasal spray is currently manufactured and dispensed to patients in a customized administration kit containing four glass ampules per tray. The medication is stored in glass ampules to maintain stability. The glass ampule should be opened and the sprayer device assembled and primed as directed. Each spray is equal to 0.5 mg. Patients should administer one spray into each nostril, wait 15 minutes and repeat the sequence to deliver the total recommended dose of 2 mg. Patients should be instructed not to tilt the head back or inhale through the nose during administration of the medication. Any unused medication in an open ampule should be discarded after eight hours. Safety information regarding the use of more than 3 mg per 24 hours or 4 mg (two doses) per seven days is unavailable.

The manufacturer of DHE nasal spray, Novartis, is in the process of obtaining approval from the FDA for a new type of storage bottle that will not require patients to break the glass ampule.

Sumatriptan Nasal Spray

Sumatriptan has been available in injectable and oral forms in the United States since 1992 and 1995, respectively. The intranasal form of sumatriptan is FDA-labeled for the acute treatment of migraine with or without aura.


Sumatriptan is a serotonin agonist with primary activity at the vascular 5-HT1 receptor subtype (5-HT1d). The resultant effect of sumatriptan on the serotonin system leads to vasoconstriction and effects on inflammatory peptide release similar to that of DHE.12


The bioavailability for the intranasal route of administration for sumatriptan has been calculated to be 17 percent of that for the subcutaneous route. Sumatriptan reaches maximum plasma concentration in 60 to 90 minutes when administered intranasally. It is metabolized by a monoamine oxidase enzyme system to an inactive compound, with only 3 percent of the parent drug excreted by the kidneys. The average elimination half-life is approximately two hours.12


Table 11117 summarizes the efficacy data of placebo-controlled trials for sumatriptan nasal spray.12 Headache pain at two hours post-dose decreased significantly in all five clinical trials using the 20-mg dose when compared to placebo.12 In addition, the 5-mg dose had a statistically significant effect in reducing headache pain, compared with placebo in two trials using this dose.12 In both of these trials, however, the patients receiving the 20-mg dose achieved better headache relief than patients receiving the 5-mg dose (P <0.05). The sumatriptan-treated patients also had a lower incidence of migraine-associated symptoms (such as nausea, vomiting, phonophobia and photophobia), when compared with the placebo-treated patients.21,22


The intranasal form of sumatriptan is generally well tolerated, with mild, local reactions reported as the most common events during the clinical trials. One of the most frequently reported complaints was the bitter taste of the medication. In the placebo-controlled trials, nearly 25 percent of patients complained about the bitter taste when using the 20-mg spray (versus 1.7 percent of placebo-treated patients). Of the 3,653 clinical trial patients, 0.4 percent withdrew because of adverse reactions.12


Because of its vasoconstrictive properties, sumatriptan should be avoided in patients with known coronary artery disease or Prinzmetal's variant angina. Patients at risk for coronary artery disease should undergo a cardiac evaluation before taking the product. When therapy is initiated in this high-risk group, the first dose should be administered in a physician's office to allow assessment for possible adverse outcomes.

Intranasal sumatriptan should not be taken within 24 hours of other ergotamines or ergotamine-like drugs. Patients currently taking monoamine oxidase inhibitors (MAOIs) should avoid the use of sumatriptan. A two-week washout period should elapse between discontinuation of the MAOI and initiation of sumatriptan. It is also contraindicated in patients with hemiplegic or basilar migraine, uncontrolled hypertension or history of allergic reactions to sumatriptan or its components.

Sumatriptan is listed as a pregnancy category C medication. If sumatriptan is prescribed during pregnancy, health professionals should contact the Glaxo Pregnancy Registry to track the outcomes (telephone: 800-336-2176).


Sumatriptan is available in 5-mg and 20-mg, single-use, preprimed spray devices. Patients should be instructed to administer one spray into one nostril. If a rescue dosage is required, patients should wait at least two hours before administering another. The total dosage of sumatriptan administered per 24 hours should not exceed 40 mg.

Because the 20-mg strength fared better in clinical trials, it is generally recommended that treatment be initiated at this strength. The 5-mg strength may be prescribed for those patients who may be more sensitive to the medication's effects and who are likely to experience more adverse reactions with the higher dose.


It is difficult to directly compare these new intranasal medications with the current abortive regimens in terms of overall efficacy. The efficacy data provided in Tables 11117 and 24,19,2126 (headache response rates and headache recurrence rates) are derived from results of clinical trials. In general, trial data comparing abortive agents is lacking; therefore, additional published data are needed to assess the most effective treatment for acute migraine.

DrugRoute24-hour recurrence rate (%)Half-life (hours)
DHE (Migranal), 2 mg19 Nasal1410
Sumatriptan (Imitrex nasal), 5 mg22 Nasal342
Sumatriptan, 20 mg21,22 Nasal32 to 34
Sumatriptan (Imitrex), 100 mg23 Oral22 to 25
Sumatriptan (Imitrex Statdose), 6 mg4 Injectable38
Naratriptan (Amerge), 1 mg24,25 Oral33 to 396
Naratriptan, 2.5 mg24,25 Oral27 to 28
Rizatriptan (Maxalt), 5 mg and 10 mg*Oral30 to 452 to 3
Zolmitriptan (Zomig), 2.5 mg26 Oral372
Zolmitriptan, 5 mg26 Oral32

For physicians, new abortive medications and routes of administration have allowed more patients to be effectively treated. The range of options may seem wide but can be narrowed by tailoring the medication to each patient based on the migraine pattern, previous responses to medications and individual preferences. A thorough review of all the available abortive medications is not included here, but a previous manuscript has addressed prescribing information for most of the available abortive regimens.27


The intranasal forms of migraine medications are reasonable options for patients with acute migraine. The relatively quick absorption into the bloodstream enables a rapid headache response. Patient acceptance for this route of administration, in comparison with other routes, will need to be addressed when selecting which treatment to use. Patients who have migraine attacks of variable severity may prefer to have two or three dosage forms available for personal use, depending on the rate of pain escalation, associated symptoms and whether or not they are at home.

The costs of the newer drugs (Table 31117 ) may be a factor in the selection of an appropriate dosage form. Injectable sumatriptan is the most expensive form of triptan currently available. The acquisition costs for intranasal sumatriptan and DHE are comparable. Although many insurance companies are limiting access to these newer migraine medications, pharmacoeconomic studies may reveal overall cost-effectiveness.28

DrugAvailability (how supplied)Initial dose per attackInterval time (hours) for repeated doseMaximum dose per 24 hoursCost per initial dose*
DHE nasal spray (Migranal)11 4 mg per ampule (4 ampules per tray)2 mgNR3 mg$17
Sumatriptan nasal (Imitrex Nasal)12 5 mg, 20 mg (box of 6)5, 10 or 20 mg240 mg19
Sumatriptan tablets (Imitrex)13 25 mg, 50 mg (blister pack of 9 tablets)25, 50 or 100 mg2200 mg15
Sumatriptan injection (Imitrex Statdose)14 6-mg syringes (box of 2)6 mg112 mg45
Naratriptan tablets (Amerge)15 1 mg, 2.5 mg (blister pack of 9 tablets)1 or 2.5 mg45 mg15
Rizatriptan tablets (Maxalt)16 5 mg, 10 mg (blister pack of 6 tablets)5 or 10 mg210 mg14
Zolmitriptan (Zomig)17 2.5 mg, 5 mg (blister pack of 6 tablets: 2.5 mg; blister pack of 3 tablets: 5 mg)1.25, 2.5 or 5 mg210 mg14 to 15

When comparing sumatriptan nasal spray with DHE nasal spray, some factors should be considered. The sumatriptan device is less cumbersome to use than the DHE nasal spray. Once the new sprayer formulation for DHE is FDA-labeled for this indication, this advantage will no longer be of major importance. An advantage of the DHE nasal spray is the longer serum half-life, resulting in fewer recurrent headaches than with sumatriptan.

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