DHE in the pharmacotherapy of migraine: potential for a larger role

Despite a large array of currently marketed, frequently effective drugs for the acute treatment of migraine headache, comprising various classes and formulations, predictably reliable treatment for most headache types is often lacking. Dihydroergotamine mesylate (DHE) is a comparatively safe and effective therapy for migraine headache that could potentially be used for a broader range of headache types than occurs at present. The features of DHE supporting this assertion include (1) effectiveness in terminating severe, long-lasting headaches, (2) rapid onset of action, (3) very low rates of headache recurrence, (4) minimal risk of medication-overuse headache, and (5) in the nasal spray formulation, suitability for outpatients (especially patients who are very nauseated or vomiting, potentially obviating the need for an office or hospital visit for acute care). Conditions or circumstances for which there are data supporting the expanded use of DHE include menstrual migraine, migraine with central sensitization and cutaneous allodynia, medication-overuse headache, migraine recurrence, and status migrainosus. The introduction of the intranasal formulation of DHE provides both pharmacologic and patient-convenience advantages for use in migraine therapy. This article reviews the rationale for the use of DHE in these common, often difficult-to-treat migraine forms.     

Home Administration of Intramuscular DHE for the Treatment of Acute Migraine Headache

SYNOPSIS
Dihydroergotamine (DHE) has been used for the treatment of acute migraine headache for almost 50 years. Previous studies have emphasized use in emergency room, inpatient, or office settings. Twenty-nine patients with migraine headache who had failed to obtain relief with conventional therapy were trained to self-administer intramuscular DHE. The patients administered 0.5 mg DHE and 100 mg trimethobenzamide at the onset of their headache and an additional O.5mg DHE if satisfactory headache relief was not obtained. Twenty patients were successfully contacted and interviewed. Forty-five percent of the patients had at least 50% relief of headache and continued to use the protocol. Eighty-two percent of patients who initially had at least 50% headache relief continued to use the drug, whereas none of the patients who initially had less than 10% relief continued the protocol. Sixty-one percent of patients whose headaches precluded continuation of activity had at least 50% response to initial treatment, whereas only 29% whose headaches were less severe had this response. Initial response to therapy was predictive of continued use of the treatment protocol and patients who described more severe headache had a higher response to the initial treatment. Thus, home administration of I.M. DHE offers an additional treatment regimen for patients with migraine headache.     

Headache currents commentary

What Happens to the Old Headache Medicines? Rapoport AM, MD Old headache medicines never die; they either fade away or come back in disguise. The disguise is often a new route of administration, which may work better, faster, more completely, with fewer adverse events, and/or have certain other advantages. The clinical aspects of 3 of the oldest headache medicines (ergotamine tartrate, dihydroergotamine, and methysergide) will be discussed here. Sumatriptan will then be discussed as the prototype of the newest category of acute care therapy (triptans) for migraine. It will be compared with the older medications, and the new forms being developed will be briefly discussed. Diclofenac potassium for oral solution will be mentioned as the newest drug approved for migraine by the Food and Drug Administration and a possible alternative to triptans in patients with frequent headaches or those with contraindications to vasoconstrictors. Dihydroergotamine, Ergotamine, Methysergide and Sumatriptan – Basic Science in Relation to Migraine Treatment Dahlöf C, Maassen Van Den Brink A. The 5‐hydroxytryptamine (5‐HT) receptor family mediates the effects of several drugs highly effective in migraine primarily by activating 5‐HT_1B, 5‐HT_1D, and 5‐HT_1F receptors. Ergotamine, dihydroergotamine and methysergide, as well as the “triptan” sumatriptan, are all agonists for these receptors. The receptor profile and degree of selectivity of these 4 drugs differ, which is reflected by their side effects that limit their use in the acute and prophylactic treatment of migraine. The acute antimigraine efficacy of these remedies is very much dependent on the formulation used where, in general, parenteral formulations are more effective in relieving the symptoms of a migraine attack.     

Butalbital in the treatment of headache: history, pharmacology, and efficacy

Analgesics containing butalbital compounded with aspirin, acetaminophen, and/or caffeine are widely used for the treatment of migraine and tension-type headache. The butalbital-containing compounds are efficacious in placebo-controlled trials among patients with episodic tension-type headaches. Despite their frequent clinical use for migraine, they have not been studied in placebo-controlled trials among patients with migraine. Barbiturates can produce intoxication, hangover, tolerance, dependence, and toxicity. Butalbital can result in intoxication that is clinically indistinguishable from that produced by alcohol. Butalbital-containing analgesics can produce drug-induced headache in addition to tolerance and dependence. Higher doses can produce withdrawal syndromes after discontinuation. Butalbital-containing analgesics may be effective as backup medications or when other medications are ineffective or cannot be used. Because of concerns about overuse, medication-overuse headache, and withdrawal, their use should be limited and carefully monitored.     

Management of Pediatric Migraine Headache in the Emergency Room and Infusion Center

Migraine is a common disorder that starts at an early age and takes a variable pattern from intermittent to chronic headache with several exacerbations throughout a lifetime. Children and adolescents are significantly affected. If an acute headache is not aborted by outpatient migraine therapy, it often causes severe disability, preventing the child from attending school and social events. Treating the acute severe headache aggressively helps prevent prolonged disability as well as possible chronification. Multiple medications are available, mostly for the outpatient management of an attack and include the use of over‐the‐counter anti‐inflammatory medications as well as prescribed medications in the triptan group. These therapies do sometime fail and the exacerbation can last from days to weeks. If the headache lasts 72 hours or longer it will fall in the category of status migrainosus. Status migrainosus is described as a severe disabling headache lasting 72 hours or more by the ICHD3 criteria. Disability is a major issue in children and adolescents and aggressive acute measures are to be taken to control it as soon as possible. Early aggressive intravenous therapy can be very effective in breaking the attack and allowing the child to be quickly back to normal functioning. This article reviews what is available for the treatment of pediatric primary headaches in the emergency room.     

Pharmacology of Dihydroergotamine and Evidence for Efficacy and Safety in Migraine

Dihydroergotamine mesylate (DHE), an ergot alkaloid, has been extensively utilized and studied in the treatment of episodic and chronic migraine. This article reviews the pharmacokinetics, pharmacodynamics, and clinical efficacy and safety of DHE, particularly in comparison to ergotamine tartrate (ET), a similar ergot alkaloid with a long history of use in the treatment of migraine. Structural differences between these 2 compounds account for clinically important distinctions in their pharmacokinetic, pharmacodynamic, and adverse event profiles. DHE is a significantly less potent arterioconstrictor than is ET, which makes it a potentially much safer drug. In addition, DHE is associated with a markedly lower incidence of medication-withdrawal headache, nausea, and vomiting than is ET. The safety and efficacy data presented here are derived from clinical trials and case series involving DHE administered by intravenous infusion, intramuscular or subcutaneous injection, or intranasal spray.     

Migraine pain location: a tertiary care study of 1283 migraineurs

OBJECTIVES: This study of headache location in migraine was performed (1) to document the location of pain in a large group of migraine patients and (2) to assess the impact of different types of migraine, gender, aura, and headache features on the location of the headache. BACKGROUND: The literature documenting the location of the pain of acute attack of migraine is sparse. METHODS: A total of 1283 migraine patients (ICHD, 2004, 1.1, 1.2, 1.5.1, and 1.6) were evaluated at the 1st visit. Headache location and character were graded on a scale of 0 to 3 with 0 being none and 3 the most. Triggers were graded on a frequency scale of 0 to 3; 0 = none; 1 = less than 1/3 of time; 2 = between 1/3 and 2/3 of time; 3 = greater than 2/3 of time. Other headache features and medication responsiveness, were also recorded. Patients were stratified by migraine type and headache frequency. Combined and isolated locations, and the impact of age, gender, headache frequency, migraine types, and aura were addressed. Unremitting headache was excluded. RESULTS: Migraine patients reported that the highest location frequencies were in the eyes (67.1%), temporal (58.0%), and frontal (55.9%). The lowest were diffusely (17.5%) and vertex (24.1%). The intermediate were in the occipital (39.8%) and neck areas (39.7%). Other migraine types were remarkably similar. Hemi-cranial location was present in 66.6% of patients, 71.2% in episodic migraine and 61.4% in chronic migraine, 67.2% in females and 63.2% in males, 59.7% in migraine without aura and 68.9% in migraine with aura 100% of the time. Headaches were reported on the right side in 27.3%, left side 24.3%, both sides 23.7%, either side 15.0%, and in the middle of the head in 4.6% of cases. Significant differences in headache location were seen only within migraine and not other migraine types. Headache location was not correlated with lifetime duration of migraine, prodrome, response to triptan, intensity, time to peak of headache, recurrence frequency, and time to recurrence. CONCLUSIONS: This study provides a detailed documentation of headache location in a large cohort of patients. The commonest locations are the orbital, frontal, and temporal areas and least common sites being diffuse and the vertex. A single location is infrequent. Hemi-cranial location is present in two thirds of subjects and a quarter each are on the left side, right side, and both sides. The locations of the headache are very similar in different migraine types, but there are some differences. Under age 21 and older patients tended to show some differences in location and side. Location differences are seen with gender, headache frequency, and aura. Location shows many correlations with triggers and headache features.     

Inpatient Treatment of Status Migraine With Dihydroergotamine in Children and Adolescents

Objective.— To assess the effectiveness of aggressive therapy of status migraine in children and adolescents.
Background.— Inpatient management of pediatric status migraine and intractable headache is limited because of a lack of studies and guidelines. Adult treatment is often based on anecdotal experience, although a few controlled studies have been reported. Added to that is the discomfort of general pediatricians and neurologists in using available effective treatments in pediatric patients (such as dihydroergotamine: DHE).
Methods.— Charts of all patients admitted to the neurology service, at Cincinnati Children's Hospital Medical Center—Department of Neurology, for inpatient treatment for intractable headache/status migraine over a 6-week period were reviewed. Demographics, evaluation, diagnosis, and treatment used were tabulated. Data on the effectiveness of the treatments provided were evaluated. Thirty-two total consecutive charts were retrospectively reviewed during that period.
Results.— Upon discharge, 74.4% of the patients were headache-free. The mean severity of the pain upon discharge was 1.02 ± 2.22 (using the 0-10 pain scale).
Conclusion.— From our review, DHE is very effective in treating and aborting an episode of status migraine and should be offered to children and adolescent patients who have failed their usual abortive therapy to prevent further severe disability that mainly affects their schooling and social activities.     

The Hospital Management of Severe Migrainous Headache

In a two year period, 47 patients with migraine were hospitalized for the management of severe headache; 18 had acute migraine (duration less than 72 hours), 17 had status migrainosus (duration by definition more than 72 hours), and 12 had chronic daily headaches qualitatively of a migraine type. Treatment in all comprised cessation of all previous medication, plus one of the following: intravenous DHE, intravenous lidocaine, a combination of lidocaine + DHE, or subcutaneous sumatriptan. Improvement from DHE, lidocaine, or both was slow and often incomplete. Sumatriptan was not used in patients with chronic daily headaches; in the 8 cases of acute migraine or status migrainosus in which it was used, improvement was rapid and complete in seven.     

Does the Addition of Dexamethasone to Standard Therapy for Acute Migraine Headache Decrease the Incidence of Recurrent Headache for Patients Treated in the Emergency Department? A Meta‐analysis and Systematic Review of the Literature

Objectives: Neurogenic inflammation is thought to play a role in the development and perpetuation of migraine headache. The emergency department (ED) administration of dexamethasone in addition to standard antimigraine therapy has been used to decrease the incidence of recurrent headaches at 24 to 72 hours following evaluation. This systematic review details the completed trials that have evaluated the use of dexamethasone in this role. Methods: The authors searched MEDLINE, EMBASE, CINAHL, LILACS, recent emergency medicine scientific abstracts, and several prepublication trial registries for potential investigations related to the research question. The authors included studies that incorporated randomized, double‐blind, placebo‐controlled methodology and that were performed in the ED. A fixed‐effects and random‐effects model was used to obtain summary risk ratios (RRs) and 95% confidence intervals (CIs) for the self‐reported outcome of moderate or severe headache on follow‐up evaluation. Results: A pooled analysis of seven trials involving 742 patients suggests a modest but significant benefit when dexamethasone is added to standard antimigraine therapy to reduce the rate of patients with moderate or severe headache on 24‐ to 72‐hour follow‐up evaluation (RR = 0.87, 95% CI = 0.80 to 0.95; absolute risk reduction = 9.7%). The treatment of 1,000 patients with acute migraine headache using dexamethasone in addition to standard antimigraine therapy would be expected to prevent 97 patients from experiencing the outcome of moderate or severe headache at 24 to 72 hours after ED evaluation. The sensitivity analysis yielded similar results with sequential trial elimination, indicating that no single trial was responsible for the overall result. Adverse effects related to the administration of a single dose of dexamethasone were infrequent, mild, and transient. Conclusions: These results suggest that dexamethasone is efficacious in preventing headache recurrence and safe when added to standard treatment for the management of acute migraine headache in the ED.     

Physical treatments for headache: a structured review

BACKGROUND: Primary headache disorders, especially migraine, are commonly accompanied by neck pain or other symptoms. Because of this, physical therapy (PT) and other physical treatments are often prescribed. This review updates and synthesizes published clinical trial evidence, systematic reviews, and case series regarding the efficacy of selected physical modalities in the treatment of primary headache disorders. METHODS: The National Library of Medicine (MEDLINE), The Cochrane Library, and other sources of information were searched through June 2004 to identify clinical studies, systematic reviews, case series, or other information published in English that assessed the treatment of headache or migraine with chiropractic, osteopathic, PT, or massage interventions. RESULTS: PT is more effective than massage therapy or acupuncture for the treatment of TTH and appears to be most beneficial for patients with a high frequency of headache episodes. PT is most effective for the treatment of migraine when combined with other treatments such as thermal biofeedback, relaxation training, and exercise. Chiropractic manipulation demonstrated a trend toward benefit in the treatment of TTH, but evidence is weak. Chiropractic manipulation is probably more effective in the treatment of tension-type headache (TTH) than it is in the treatment of migraine. Evidence is lacking regarding the efficacy of these treatments in reducing headache frequency, intensity, duration, and disability in many commonly encountered clinical situations. Many of the published case series and controlled studies are of low quality. CONCLUSIONS AND RECOMMENDATIONS: Further studies of improved quality are necessary to more firmly establish the place of physical modalities in the treatment of primary headache disorders. With the exception of high velocity chiropractic manipulation of the neck, the treatments are unlikely to be physically dangerous, although the financial costs and lost treatment opportunity by prescribing potentially ineffective treatment may not be insignificant. In the absence of clear evidence regarding their role in treatment, physicians and patients are advised to make cautious and individualized judgments about the utility of physical treatments for headache management; in most cases, the use of these modalities should complement rather than supplant better-validated forms of therapy.     

Rescue therapy for acute migraine, part 3: opioids, NSAIDs, steroids, and post-discharge medications

Objective.— The final section of this 3‐part review analyzes published reports involving the acute treatment of migraine with opioids, non‐steroidal anti‐inflammatory drugs (NSAIDs), and steroids in the emergency department (ED), urgent care, and headache clinic settings, as well as post‐discharge medications. In the Conclusion, there is a general discussion of all the therapies presented in the 3 sections. Method.— Using the terms (“migraine” AND “emergency”) AND (“therapy” OR “treatment”), the author searched MEDLINE for reports from ED and urgent care settings that involved all routes of medication delivery. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.— Seventy‐five reports were identified that compared the efficacy and safety of multiple acute migraine medications for rescue. Of the medications reviewed in Part 3, opioids, NSAIDs, and steroids all demonstrated some effectiveness. When used alone, nalbuphine and metamizole were superior to placebo. NSAIDs were inferior to the combination of metoclopramide and diphenhydramine. Meperidine was arguably equivalent when compared with ketorolac and dihydroergotamine (DHE) but was inferior to chlorpromazine and equivalent to the other dopamine antagonists. Steroids afford some protection against headache recurrence after the patient leaves the treatment center. Conclusions.— All 3 opioids most frequently studied – meperidine, tramadol, and nalbuphine – were superior to placebo in relieving migraine pain, although meperidine combined with promethazine was not. Opioid side effects included dizziness, sedation, and nausea. With ketorolac being the most frequently studied drug in the class, NSAIDs were generally well tolerated, and they may provide benefit even when given late in the migraine attack. The rate of headache recurrence within 24‐72 hours after discharge from the ED can be greater than 50%. Corticosteroids can be useful in reducing headache recurrence after discharge. As discussed in Parts 1, 2, and 3, there are effective medications for provider‐administered “rescue” in all the classes discussed. Prochlorperazine and metoclopramide are the most frequently studied of the anti‐migraine medications in the emergent setting, and their effectiveness is superior to placebo. Prochlorperazine is superior or equivalent to all other classes of medications in migraine pain relief. Although there are fewer studies involving sumatriptan and DHE, relatively “migraine‐specific” medications, they appear to be equivalent to the dopamine antagonists for migraine pain relief. Lack of comparisons with placebo and the frequent use of combinations of medications in treatment arms complicate the comparison of single agents to one another. When used alone, prochlorperazine, promethazine, metoclopramide, nalbuphine, and metamizole were superior to placebo. Droperidol and prochlorperazine were superior or equal in efficacy to all other treatments, although they also are more likely to produce side effects that are difficult for a patient to tolerate (especially 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 only paired comparisons were considered. The overall percentage of patients with pain relief after taking sumatriptan was equivalent to that observed with droperidol or prochlorperazine. (Headache 2012;52:467‐482)     

Rizatriptan (MAXALT) for the Acute Treatment of Migraine and Migraine Recurrence. A Placebo-Controlled, Outpatient Study

Rizatriptan is a novel 5-HT_1B/1D agonist which is rapidly absorbed after oral administration. The efficacy and tolerability of oral rizatriptan (5 mg and 10 mg) were examined in this multicenter, double-blind, outpatient study of 1473 migraineurs which featured randomized, placebo-controlled treatment of migraine recurrences. On experiencing moderate or severe migraine headaches, patients rated headache severity prior to dosing and at 30-minute intervals for 2 hours after dosing. Onset of effect was seen as early as 30 minutes after dosing with rizatriptan 10 mg. At 2 hours postdose, the percentage of patients with pain relief was significantly higher after rizatriptan 5 mg (62%) or 10 mg (71%) compared with placebo (35%). Complete relief was also significantly higher after rizatriptan 5 mg (33%) and 10 mg (42%) compared with placebo (10%). In patients experiencing headache recurrence after initial benefit, further relief was obtained in 71% with rizatriptan 5 mg (placebo 54%) and in 82% with rizatriptan 10 mg (placebo 44%). Complete relief of recurrent headache was obtained in 36% with rizatriptan 5 mg, 49% with rizatriptan 10 mg, and 15% with placebo ( P <0.05). The most common drug-related adverse experiences were dizziness, somnolence, asthenia/fatigue, and nausea (the incidences of which were low and dose related). There was no increase in the incidence of adverse experiences after use of up to three doses of rizatriptan within 24 hours. We conclude that both doses of rizatriptan are effective and well tolerated in the acute treatment of migraine and migraine recurrence, with the l0-mg dose preferred as it is more effective with a faster onset of action.     

History of the use of ergotamine and dihydroergotamine in migraine from 1906 and onward

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.     

IHS Criteria for Migraine and Tension-Type Headache in Children and Adolescents

We investigated the influence of age on the IHS criteria for migraine and tension-type headache in 437 consecutive children and adolescents and found the following age-associated statistically significant differences: migraine duration, occurrence of migraine aura, and bilateral location of tension-type headache were more often fulfilled by adolescents, whereas aggravation of headache by physical activity (in migrainous disorder) and photophobia (in migraine with aura) were more often fulfilled by children, Accordingly, there are only a few, differences concerning the fulfillment of the IHS criteria for migraine and tension-type headache in children and adolescents. Independent of age, the intensity of headache and the presence or absence of nausea are most important for differentiating the two major types of idiopathic headache. The sensitivity of the IHS criteria for migraine could be increased by reducing the minimum duration of migraine and by allowing the diagnosis of migraine when severe headache is associated with nausea, even though the criteria of location, quality, and aggravation by physical activity are not fulfilled.     

Rescue therapy for acute migraine, part 1: triptans, dihydroergotamine, and magnesium

Objective.— To review and analyze published reports on the acute treatment of migraine headache with triptans, dihydroergotamine (DHE), and magnesium in emergency department, urgent care, and headache clinic settings. Methods.— MEDLINE was searched using the terms “migraine” and “emergency,” and “therapy” or “treatment.” Reports from emergency department and urgent care settings that involved all routes of medication delivery were included. Reports from headache clinic settings were included only if medications were delivered by a parenteral route. Results.— Acute rescue treatment studies involving the triptans were available for injectable and nasal sumatriptan, as well as rizatriptan. Effectiveness varied widely, even when the pain‐free and pain‐relief statistics were evaluated separately. As these medications are known to work best early in the migraine, part of this variability may be attributed to the timing of triptan administration. Multiple studies compared triptans with anti‐emetics, dopamine antagonists, and non‐steroidal anti‐inflammatory drugs. The overall percentage of patients with pain relief after taking sumatriptan was roughly equivalent to that recorded with droperidol and prochlorperazine. Sumatriptan was equivalent to DHE when only paired comparisons were performed. While the data extracted suggest that magnesium may be effective in treating all symptoms in patients experiencing migraine with aura across all migraine patients, its effectiveness seems to be limited to treating only photophobia and phonophobia. Conclusions.— Although there are relatively few studies involving health‐care provider‐administered triptans or DHE for acute rescue, they appear to be equivalent to the dopamine antagonists for migraine pain relief. The relatively rare inclusion of a placebo arm and the frequent use of combination medications in active treatment arms complicate the comparison of single agents with each other.     

Chiari-associated exertional,cough, and sneeze headache responsive to medical therapy

Benign exertional headache is coded as a separate entity within the International Headache Society's classification system, but the pathophysiological mechanisms underlying this clinical headache subtype are unknown and possibly are similar to those generating migraine. Coexistence of migraine and benign exertional headache in the same patient is not unusual, and antimigraine pharmacologic treatments are often effective in both headache types. Regardless, optimal management mandates that the clinician exclude any intracranial or systemic disease that could mimic "primary" exertional headache. The same holds for primary headaches induced by coughing or sneezing; congenital malformations or neoplasms, particularly within the posterior fossa, are not rare in these patients. The neurologic examination may not be sufficiently sensitive to detect the offending lesion. We describe a patient with migraine without aura and exertional secondary headache due to Chiari malformation type I whose headaches responded to treatment with propranolol and indomethacin.