Aetna considers parenteral administration of dihydroergotamine (DHE) medically necessary for the treatment of intractable migraine or cluster headache. Prolonged multi-day administration of DHE is considered medically necessary when both of the following conditions are met:

1. Member has intractable cluster headache or severe migraine headache (i.e., status migrainosus, chronic daily headache, transformed migraine, rebound headache); and

2. Headache is refractory to maximum outpatient anti-migraine therapy.

Aetna considers parenteral DHE experimental and investigational for all other types of headache.

See also CPB 011 - Electrical Stimulation for Pain, CPB 113 - Botulinum Toxin, CPB 132 - Biofeedback, CPB 172 - Hyperbaric Oxygen Therapy (HBOT), and CPB 388 - Complementary and Alternative Medicine.

Migraine is a paroxysmal disorder with attacks of headache, nausea, vomiting, photo- and phonophobia and malaise. Cluster headaches occur as a severe, sudden headache typified by constant, unilateral pain around the eye, with onset usually within 2-3 hours of falling asleep. Pharmacologic symptomatic treatment is aimed at reversing, aborting, or reducing pain and the accompanying symptoms of an attack, and to optimize the patient's ability to function normally.

Most attacks of mild migraine and cluster headache can be effectively treated by anti-emetics followed by analgesics such as aspirin, acetaminophen or non-steroidal anti-inflammatory drugs (NSAIDs). Moderate to severe attacks are successfully treated utilizing combinations of ergotamine tartrate (ET), dihydroergotamine (DHE), and sumatriptan (Imitrex) with anti-emetics, simple analgesics, NSAIDs, and/or opiates. For severe migraine headaches, alternative medications include intravenous administration of neuroleptics such as chlorpromazine (Thorazine) and prochlorperazine (Compazine), occasionally corticosteroids such as prednisone, hydrocortisone, dexamethasone, and methylprednisone, and lastly parenteral narcotic analgesics such as meperidine and the nasal spray butorphanol tartrate (Stadol NS). Moreover, corticosteroid therapy may also be indicated in patients with status migrainosus.

Subcutaneous, intramuscular, and intravenous DHE can be safely administered in the office, clinic, or emergency room setting at any time during a migraine attack, including the aura. Intravenous administration provides rapid peak plasma levels and is the most effective form when a rapid effect is desired or for patients with intractable severe headache (status migrainosus, transformed migraine, rebound headache) and cluster headache. One of the most appropriate indications for intravenous DHE is status migrainosus. Another important indication of repetitive intravenous DHE administration is a transformed migraine type of chronic daily headache with or without analgesic overuse. Intramuscular administration is effective for moderate to severe migraine with or without nausea and vomiting in the outpatient setting. Patients can even be taught to self-administer DHE intramuscularly, thus avoiding emergency room or doctor visits.

For unresponsive patients with severe or ultra-severe attacks, 5-10 mg prochlorperazine may be given IV in the emergency room, followed immediately by 0.75 mg DHE IV given over 3 minutes. If there is no relief in 30 minutes, another 0.5 mg of DHE IV may be given. Overall clinical efficacy of DHE is highly satisfactory with a reported 90% of the attacks aborted when the drug was given intravenously. Occasionally, intravenous fluids and repeated injections of intravenous DHE for about 24 to 72 hours may be necessary to relieve uncontrollable pain. Hospitalization may be necessary for such prolonged multi-day administration, but only after maximal treatment in the outpatient setting fails to abort the headache. Various protocols are available for the use of repetitive injections of DHE. In all of them, an initial test dose of 0.33 mg of DHE plus 5 mg of metoclopramide or prochlorperazine is given, followed by 0.50 mg of DHE with either of the two anti-emetics every 6 hours for 48 to 72 hours. Such therapy allows a break in the headache cycle sufficiently long enough to facilitate the patient's transition to prophylactic therapy.

According to the FDA-approved product labeling, DHE-45 administration is contraindicated in any of the following patients:

1. Persons with previously known hypersensitivity to ergot alkaloids; or
2. Persons having conditions predisposing to vasospastic reactions such as known peripheral arterial disease, coronary artery disease (in particular, unstable or Prinzmetal's vasospastic angina), sepsis, vascular surgery, uncontrolled hypertension, and severely impaired hepatic or renal function; or
3. Pregnant women, as DHE possesses oxytocic properties; or
4. Nursing mothers; or
5. Persons on vasoconstrictors because the combination may result in extreme elevation of blood pressure; or
6. Persons with hemiplegic or basilar migraine.

Fisher et al (2007) evaluated the effectiveness and tolerability of DHE nasal spray for the treatment of headache that is refractory to triptans. Patients who failed previous treatments with one or more triptan formulations were considered refractory to triptan treatment and were included in the study. Headache severity was assessed by the patient at the center using a visual analog scale (VAS) of 1 to 10 (10 being most severe) at baseline and 4 weeks after initiating DHE. The responses to DHE were assessed and categorized as complete response (headache symptoms resolved), partial response (greater than or equal to 50 % reduction in VAS), or unresponsive (less than 50 % reduction in VAS). Four weeks after DHE use, any adverse event (AE) that occurred during DHE use was reported by the patient at the center. The effectiveness of DHE was determined by headache severity reductions. Tolerability was assessed in terms of AE frequency. A total of 97 patients met the study criteria: 13 patients were lost to follow-up; 33 patients (34.0 %) reported a complete response to DHE treatment, 13 (13.4 %) experienced a partial response, and 38 (39.2 %) were unresponsive. Seven of 97 patients (7.2 %) reported AEs (e.g., nasal congestion, dysphoria) while using DHE. The authors noted that this retrospective chart review included patients who failed triptan therapy for treatment of headaches. They reported that 47 % of patients experienced partial to complete response to DHE treatment. Study limitations included the retrospective design, the small sample size, and the use of patient recollection to evaluate the effectiveness and tolerability of DHE. They stated that randomized, double-blind, controlled studies are needed to ascertain the clinical value of this approach. This is in agreement with the findings of a pilot study by Weintraub (2006) who reported that repetitive intra-nasal DHEmay be a safe and effective therapy for refractory headaches. However, interpretation of these results is limited by the open-label, uncontrolled design and the small number of patients. The author stated that development of a double-blind, placebo-controlled study to further evaluate this treatment regimen is warranted.