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.     

Efficacy and tolerability of prochlorperazine buccal tablets in treatment of acute migraine

OBJECTIVES: To study the efficacy and tolerability of prochlorperazine (PCZ) management of acute migraine. DESIGN AND METHODS: A double blind comparative study was conducted to assess the efficacy of buccal PCZ 3 mg compared with oral ergotamine tartarate 1 mg plus caffeine 100 mg (ERG) or placebo (buccal or oral) for treatment of acute migraine. In all, 114 episodes of acute migraine were evaluated. Patients graded symptoms on a four-point scale before and up to 4 hours after treatment. The primary efficacy parameters included headache resolution within 2 hours (grade 3 or 2 to grade 0) and alleviation of other accompanying symptoms of migraine. The supplementary endpoints included improvement in quality of life (QOL). RESULTS: The percentage of patients reporting resolution of headache (to grade 0) was 51.4% for buccal PCZ and 21.7% for buccal placebo, 23.1% for oral ERG and 28.6% for oral placebo, headache tended to recur in both the placebo and ERG groups after initial improvement. Buccal PCZ was well tolerated; no signs of local irritation were evident, and patients found the formulation easy to use. Mild but transient sedation and drowsiness were observed in 41%. CONCLUSIONS: In the present study, PCZ 3 mg via the buccal route produced faster improvement and greater efficacy than placebo (oral as well as buccal) or oral ERG. The global QOL score 2 hours after treatment scores was higher in the PCZ group. Buccal PCZ may represent a particularly effective alternative for acute migraine treatment.     

Ergotamine and dihydroergotamine: a review

The ergot alkaloids were the first specific antimigraine therapy available. However, with the advent of the triptans, their use in the treatment of migraine has declined and their role has become less clear. This review discusses the pharmacology, efficacy, and safety of the ergots. In randomized clinical trials, oral ergotamine was found to be superior to placebo, but inferior to 100 mg of oral sumatriptan. In contrast, rectal ergotamine was found to have higher efficacy (73% headache relief) than rectal sumatriptan (63% headache relief). Intranasal dihydroergotamine was found to be superior to placebo, but less effective than subcutaneous and intranasal sumatriptan. Ergotamine is still widely used in some countries for the treatment of severe migraine attacks. It is generally regarded as a safe and useful drug if prescribed for infrequent use, in the correct dose, and in the absence of contraindications; however, safer and more effective options do exist in the triptans. In patients with status migrainous and patients with frequent headache recurrence, ergotamine is still probably useful.     

Revisiting the Role of Ergots in the Treatment of Migraine and Headache

(Headache 2010;50:1353‐1361) The harmful side effects of the ergots described by early civilizations have been overcome with efficacious treatment for headaches including migraine, cluster, and chronic daily headache. Use of ergots contributed to initial theories of migraine pathogenesis and provided the substrate for development of the triptans. Triptans are very efficacious for many migraineurs, and since their widespread use, use of ergots has significantly declined. Unfortunately, there remain many migraineurs who benefit little from triptans, yet respond very well to ergots. Discoveries in migraine pathophysiology have given us better understanding of the complex processes involved, although there remain many unknown factors in migraine treatment. Additional, unrecognized therapeutic targets may exist throughout the neuronal connections of the brainstem, cortex, and cerebral vasculature. Ergots interact with a broader spectrum of receptors than triptans. This lack of receptor specificity explains potential ergot side effects, but may also account for efficacy. The role of ergots in headache should be revisited, especially in view of newer ergot formulations with improved tolerability and side effect profiles, such as orally inhaled dihydroergotamine. Redefining where in the headache treatment spectrum ergots belong and deciding when they may be the optimal choice of treatment is necessary.     

Placebo-controlled clinical trials with ergotamine in the acute treatment of migraine

Although oral ergotamine alone or in combination with caffeine is widely used for the acute treatment of migraine, there is little evidence that it is significantly more effective than placebo. There are no placebo-controlled data to support the use of aerosol or suppository formulations. In addition, the recommended doses of ergotamine cannot be justified. Each formulation of ergotamine now should be tested in clinical studies performed according to the IHS criteria for trial design and in migraine patients fulfilling the diagnostic criteria of the IHS. Until these clinical data are available, no dear recommendations can be given for the use of ergotamine in the acute treatment of migraine.     

Naproxen Sodium Versus Ergotamine Tartrate in the Treatment of Acute Migraine Attacks

A double-blind parallel study compared the efficacy and safety of naproxen sodium (NPX) and ergotamine tartrate (ERG) as abortive therapy for acute headache in 79 patients with classical or common migraine. The design study was of the double-blind design. Forty-two patients completed the study. Discontinuation of treatment was generally due to lack of efficacy or adverse reactions. NPX was significantly better than ERG in the overall efficacy of treatment rated by the patients (p less than 004). NPX was comparable to ERG in reducing the severity and duration of the headache and its associated symptoms. In classical migraine, NPX was better than ERG in alleviating the severity of headache. Patients in the NPX group tended to use less rescue medication. There was no significant difference in the frequency of side-effects reported by the patients under NPX or ERG. This study demonstrates that NPX is as safe as ERG, and somewhat more effective in acute migraine attacks (although the difference is not statistically significant) and that migrainous patients tend to prefer NPX to ERG in treating their acute migraine headaches.     

Reduced serotonin vascular sensitivity in ergotamine abusers

The action of ergotamine on the 5-hydroxytryptamine (5-HT) venous sensitivity was studied in ergotamine abuser and non-abuser migraine patients. Ergotamine abusers showed reduced 5-HT hand vein contraction during abuse, compared to seven days after ergotamine withdrawal. In non-ergotamine users, the 5-HT venoconstriction was not significantly modified 12 h after a single intramuscular ergotamine (0.25 mg) administration. Even the administration of ergotamine locally into the vein did not change the venospasm of 5-HT given acutely in the same vein. Therefore, it seems that the 5-HT antagonism does not contribute to the therapeutic effect of ergotamine during the migraine attack. Moreover, the reduced 5-HT responsiveness during ergotamine abuse may possibly be compatible with the chronic headache present in some abusers, the withdrawal headache attacks and the abuse itself.     

Comparison of pharmacodynamic effects and plasma levels of oral and rectal ergotamine

Plasma levels and the vasoconstrictive effect of 1 mg ergotamine tartrate given as tablets or suppositories were compared. In a crossover study, eight male volunteers received tablets or suppositories containing ergotamine in a drug combination (Anervan) and, as a control, suppositories without ergotamine. Blood sampling and measurement of toe-arm systolic gradients with a strain-gauge technique were done for up to 6 h and again after 24 h and 48 h. Only 29 of 160 blood samples contained detectable (greater than 0.1 ng/ml) amounts of ergotamine, and kinetic comparison could not be performed. Only ergotamine-containing suppositories caused a significant (p less than 0.008) decrease in toe-arm systolic gradient which was significantly different (p less than 0.003) from the effects of ergotamine tablets and control suppositories. Rectal ergotamine is thus more biologically active, for the factor used, than oral ergotamine. We suggest that a rectal dose of 1 mg ergotamine tartrate should be tried as the initial dose in the treatment of migraine attacks.     

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.     

What Happens to the Old Headache Medicines?

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.     

Ergotamine abuse. Do patients benefit from withdrawal?

A follow-up study of 40 patients (migraine 39, cluster headache 1) previously treated for ergotamine abuse was conducted. Their statements regarding ergotamine intake were checked using butalbital (contained in the suppositories abused by 90% of the patients) as a tracer, and later by contact with the family doctor. Eleven patients abused ergotamine again during a median observation time of 21 months. Nineteen patients had more than a 50% reduction in headache days after withdrawal and half of the patients were relieved of other symptoms of ergotamine toxicity. Even with a failure rate of approximately 25% it is concluded that efforts to withdraw after abuse of ergotamine are worthwhile.     

Long-term outcome of patients with headache and drug abuse after inpatient withdrawal: five-year follow-up

Thirty-eight patients with "chronic daily" headache and ergotamine and/or analgesics abuse according to the criteria proposed by the international Headache Society were re-investigated 5 years after inpatient drug withdrawal. At the end of the observation period, 19 patients (50.0%) had their headaches on only 8 days per month or less, 18 patients (47.4%) were free of symptoms or had only mild headaches. A close correlation was found between the frequency of headache and the duration of drug abuse, as well as between the intensity of headache and the number of tablets taken per month. Frequency and intensity of headache had changed within the first 2 years after withdrawal, but remained stable afterwards. Fifteen patients (39.5%) reported on recurrent drug abuse. Patients with migraine showed a tendency towards a better prognosis compared to patients with tension-type headache or with combined migraine and tension-type headache. The results of this study highlight the long-term efficacy of inpatient drug withdrawal in patients with headache and ergotamine and/or analgesics abuse.     

The early use of ergotamine in migraine. Edward Woakes' report of 1868, its theoretical and practical background and its international reception

Although ergot had been used in obstetrics for several centuries, it was proposed for the treatment of migraine only in the 19th century. The British ENT-surgeon Edward Woakes (1837-1912) recommended ergot as a vasoconstricting agent for migraine and other neurogenic conditions associated with vasodilatation in 1868. He subscribed to the theory of vasodilatation by sympathetic deficit, presented in the early 1850s by Brown-Séquard and Claude Bernard. Du Bois-Reymond proposed vasoconstriction by sympathetic overactivity as the cause of migraine in 1860; Brown-Séquard opposed this in favour of vasodilatation. Vasodilatation due to sympathetic deficit in migraine was again supported by M?llendorf, with clinical evidence, in 1867. Woakes' paper of 1868 introduced ergot as a vasoconstrictor for the same condition. Reception abroad was prompt. A German version appeared in 1869, and Eulenburg cited Woakes in his textbook of 1871. Eulenburg presented the use of ergot for migraine as a routine measure in the second edition of his textbook in 1878, and in a paper published in 1883. The method was internationally accepted, but it became really popular only after the isolation of pure ergotamine in 1918, resulting in the first reliable compounds with stable properties and predictable effects. Contrary to Woakes' theory, in the early 20th century ergot was used for migraine because of its well-documented adrenolytic properties, as migraine was by then again believed to be a sympathotonic and vasospastic condition.     

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 Caused by a Sphenoid Mucocele but Presenting as an Ergotamine-Induced Headache

In a 65-year-old woman, symptomatic headache caused by a mucocele of the sphenoid sinus led to ergotamine abuse and subsequent ergotamine-induced headache. Since there were no neurological symptoms initially and the patient previously suffered from migraine, the mucocele was not recognized. Only after unsuccessful drug withdrawal therapy and an MRI, was the correct diagnosis made. Surgical removal of the mucocele led to complete relief of headache within 3 weeks. We conclude that ergotamine-induced headache can develop on the basis of symptomatic headache. In spite of the effectiveness of ergotamine tartrate, an MRI should be performed if focal neurological symptoms occur.     

Comparison Between Venoconstrictor Effects of Sumatriptan and Ergotamine in Migraine Patients

SYNOPSIS
The vasoconstrictor activity of sumatriptan and ergotamine were compared by injecting these drugs in the hand vein of migraine subjects. We used the "venotest method", which permits the evaluation of the venoconstrictor effect of small doses of drugs, acting locally in the hand vein.
Sumatriptan injected at increasing doses in the hand vein provoked contraction only at high doses (500 μg): venoconstriction lasted 5–15 minutes and was similar in intensity and duration to that induced by 0.5-1 μg of 5-hydroxytryptamine (5-HT). Likewise, ergotamine induced contraction only at a dose of 50 μg: this venoconstrictor effect was long lasting (at least I hour). Ergotamine-induced hand vein contraction, almost completely inhibited by ketanserin, seems mediated at least in part by 5-HT ₂ receptors, like the one induced by 5-HT and sumatriptan, already observed in a previous study.
Clinical doses of ergotamine (0.25 mg intramuscular) and of sumatriptan (6 mg subcutaneous) do not provoke hand vein contraction for at least I hour: this could be due to a low activity of these drugs on the 5-HT ₂ vein receptors or a technique that is unsuitable to detect the vasoconstrictor effect of drugs given by the systemic route.
The long lasting venoconstrictor effect of ergotamine may be due to a slow dissociation from receptor sites. The short vasoconstriction induced by sumatriptan could account for the recurrence of headache in many sumatriptan-treated migraine subjects.     

Cellular adaptation in migraineurs with chronic daily headache

Ergotamine and analgesic misuse are now recognized as causes of chronic daily headache and the condition responds well to drug withdrawal with reduced headache frequency. In this study, we have investigated whether medication misuse is associated with an alteration in membrane transduction which is sensitive to drug withdrawal. This was carried out by assay of the thrombin-stimulated generation of inositol phosphates in platelets from 12 migraine patients with chronic daily headache and analgesic misuse, 7 migraine patients with chronic daily headache and ergotamine misuse and 7 control subjects. After drug withdrawal, a significant decrease in headache frequency was seen at one month in both patient groups. Withdrawal of analgesics produced a significant decrease in thrombin-stimulated inositol phosphate production at one month; this was further decreased a month later with a reduction in B_max of 60% and no significant change in K_D. A similar pattern was obtained in ergot misuse patients, with the K_D value decreasing by 56% one month after drug withdrawal. These results provide evidence of an adaptation in transduction with misuse of analgesics and ergotamine which correlates with headache frequency.     

Practice and Economics Cost Considerations in Headache Treatment Part 2: Acute Migraine Treatment

Today's physician has many useful medication options available for acute migraine treatment. There is a wide cost range among these drugs and today's health care environment demands that cost be factored into the decision process. Effective migraine abortive treatment decreases the costs of repeat dosing and disability. Early use of migraine abortive medication can increase its rapidity of action and effectiveness. Adjunctive medication such as metoclopramide ($0.10) is inexpensive and may improve the effectiveness of the primary abortive medication.
Over-the-counter medications such as aspirin ($0.02/325 mg), Excadrin· ($0.09/tablet), ibuprofen ($0.04/200 mg), or naproxen sodium ($0.09/220 mg) are inexpensive and effective. "Triple therapy" combining metoclopramide, a nonsteroidal ant-inflammatory agent, and an ergotamine preparation may improve tolerance and effectiveness of the ergot. Locally compounded dihydroergotamine nasal spray is inexpensive ($0.78/1 mg spray). The cost of using oral sumatriptan can be almost halved by prescribing half of a 50-mg tablet.
Emergency department services are expensive. Huge cost savings occur through self-controlled administration of oral, rectal, or even intramuscular narcotic medications. Oral narcotic agents such as hydromorphone ($0.42/4 mg) and meperidine ($0.92/200 mg) are generally used in inadequate doses to be effective for severe migraine. Guidelines are given for more effective use of these agents.
Sophisticated comparative studies are needed to evaluate, not only the direct costs of medications, but all costs of treatment of an acute migraine attack, as well as Indirect costs to the patient, family, and society.