Journal of Pre-Clinical and Clinical Research, 2018, Vol 12, No 4, 149-157 REVIEW PAPER www.jpccr.eu Dihydroergotamine (DHE) – Is there a place for its use? Agnieszka Piechal1, Kamilla Blecharz-Klin1, Dagmara Mirowska-Guzel1 1 Medical University of Warsaw, Poland Piechal A, Blecharz-Klin K, Mirowska-Guzel D. Dihydroergotamine (DHE) – Is there a place for its use? J Pre-Clin Clin Res. 2018; 12(4): 149–157. doi: 10.26444/jpccr/99878 Abstract Nowadays, dihydroergotamine (DHE) is sporadically used as a vasoconstrictor in the treatment of acute migraine. The importance of this drug in medicine has significantly decreased in the recent years. Limitations on the use of dihydroergotamine are due to the high toxicity and increased the risk of severe adverse events after prolonged theraphy. The Committee for Medicinal Products for Human Use of the European Medicines Agency recommends limiting the use of drugs that contain ergotamine derivatives due to the potential risk of ischemic vascular events, fibrosis and ergotism. However, ergot alcaloids preparations are not recommended for use in the prophylaxis of migraine pain, although it is still a good alternative for people with status migrainosus, migraine recurrence or chronic daily headache that do not respond to the classical theraphy. In clinical practice, DHE can be used as a rescue medication to treat migraine attacks involving aura or without aura, as well as for the acute treatment of cluster headache episodes. The effectiveness of DHE in alleviating migraine headache was assessed in multiple clinical studies. This review describes the pharmacodynamic and pharmacokinetic properties of DHE in an expanded view and its role in modern therapy based on available clinical trials. Most clinical data confirm that the drug is still an important element of contemporary migraine therapy, especially in cases when conventional medicine fails. Key words dihydroergotamine, migraine, efficacy, safety INTRODUCTION development of migraine pain. Furthermore, the drug has a strong affinity for other types of receptors, e.g. adrenergic a a a a a Migraine is estimated to affect 18% of women and 6% of men, ( 1A, 1B, 2A, 2B, 2C) and dopaminergic (D2L, D3, D4). causing their quality of life to deteriorate and generating Studies indicate that DHE also limits ATP-mediated considerable costs for the healthcare system. Vasodilation sensitization of trigeminal ganglion neurons and inhibits the of the extracranial blood vessels is considered to play a key expression of P2X3 membrane receptor, which is important role in the pathophysiology of migraine headaches. For some for peripheral pain responses and plays a significant role people with migraine who do not respond to the classical in migraine pathology [9]. Additionally, DHE decreases analgesics, therapy with dihydroergotamine (DHE) is a good activation of the trigeminal nucleus caudalis by inhibiting alternative, particularly for people with status migrainosus, the release of prostaglandins from glia [10, 11]. migraine recurrence, chronic daily headache, or those who In the past, DHE was also recommended for treating suffer from medication-overuse headache (MOH). DHE can dementia, including Alzheimer’s disease, because it inhibits be used to treat migraine attacks involving aura or without binding of amyloid-β oligomers on ephrin type-B receptor aura, as well as for the acute treatment of cluster headache 2, but this type of treatment is currently less practiced [12]. episodes [1, 2, 3]. Pharmacokinetics of DHE. The pharmacokinetic parameters Dihydroegrgotamine (DHE) pharmocodynamics. DHE is characteristic of DHE can vary depending on the route of occasionally used as a rescue medication for acute migraine administration (Tab. 1). According to Silberstein and Kori [13], headache and as first-line therapy in the treatment of drug- who presented an overview of the pharmacokinetic properties resistant migraine headaches. The therapeutic effect of DHE of various DHE formulations, the peak concentration occurs comprises vasoconstriction of the carotid artery beds via 6 minutes after intravenous administration, 34 minutes after modulation of the serotonergic system. This mechanism is intramuscular administration, 56 minutes after intranasal based mostly on the drug bonding with 5-HT1Dα and 5-HT1Dβ administration, and 12 minutes after oral inhalation, whereas serotonin receptors, as well as with 5-HT1A, 5-HT2A, 5-HT1B, after oral administration it occurs after 75 minutes. Due 5-HT2C, 5-HT1E, 5-HT1F, and 5-HT4 serotonin receptors [4, 5, to the high first-pass effect, the bioavailability of the drug 6, 7, 8]. As an agonist, DHE stimulates serotonin receptors after oral administration is low (~1%, total bioavailability of located in the intracranial blood vessels, including those on DHE and its active metabolites does not exceed 6–8%); thus, arterio-venous anastomoses, leading to vasoconstriction. the preferred routes of administration are intravenous and Simultaneously, activation of these receptors on sensory intramuscular (bioavailability close to 100%). DHE can also nerve endings of the trigeminal system inhibits the release be used subcutaneously, intramuscular, intranasally or via of pro-inflammatory neuropeptides, such as calcitonin oral inhalation [14, 15, 16, 17, 18]. Oral inhalation of DHE gene-related peptide (CGRP), which plays a key role in the (MAP0004) allows therapeutic concentrations to be achieved in a short time (~10 minutes) and causes fewer adverse Adress for correspondence: Kamilla Blecharz-Klin, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw,, Poland effects than intravenous administration due to the selective E-mail: [email protected] influence of the drug, when thus administered, on 5-HT1B Received: 11 October 2018; Acceptewd: 20 November 2018 and 5-HTD receptors [19, 20]. DHE intended for intranasal 150 Journal of Pre-Clinical and Clinical Research, 2018, Vol 12, No 4 Agnieszka Piechal, Kamilla Blecharz-Klin, Dagmara Mirowska-Guzel. Dihydroergotamine (DHE) – Is there a place for its use? administration is also well tolerated by patients, and such study, 35% had a very good response and 18% a good response drug administration is convenient and non-invasive. to the treatment. However, 35% of the patients stopped using The drug binds well to serum proteins (93%) and the DHE due to cumbersome adverse effects [31]. volume of distribution in adult patients is 800 L [21]. The One possibility for migraine therapy is using orally inhaled most important enzyme for hepatic metabolism of DHE DHE, which is better tolerated by the patients. Good efficacy is CYP3A4. The main DHE metabolite is 8’hydroxy- was noted regarding both acute migraine symptoms (e.g., dihydroergotamine (8’OH-DHE), which also has vasodilatory pain, phonophobia, and photophobia) and allodynia (Tab. properties. Other active metabolites include 8’,10’-dihydroxy- 3). However, there is no scientific basis on which to claim dihydroergotamine (8’10’OH-DHE) and dihydrolysergic acid that orally inhaled DHE demonstrates the same efficacy as amide (DH-LSA) [4, 22]. intravenously administered DHE. Studies show that Cmax DHE is eliminated by the liver in the bile and excreted in is much lower with oral inhalation than with intravenous faeces (clearance 1.5 L/min). Only 6–7% of DHE is excreted administration. At the same time, the vasodilatory effect is unchanged in the urine. The 1/2T for the drug is 10–13 h [23]. diminished and binding of 5-HT2B receptors limited, which In addition, the drug slowly dissociates from bonds with the minimizes fibrotic complications. Other adverse effects, such receptor which causes a longer pharmacological effect than as nausea, also occur less often. Yet, there are no discernible the concentration of the drug in blood plasma would suggest. effects on asthma and pulmonary arterial systemic pressure. The prolonged effect on blood vessels is also related to active Taking into account all of these factors, one can maintain that metabolites, which have vasodilatory properties similar to this route of administration is useful in specific situations, the original compound. such as morning migraine, migraine with quick time to onset, prolonged migraine, status migrainous, and menstrually DIHYDROERGOTAMINE IN THE TREATMENRT OF related migraine [32]. MIGRAINE. The use of DHE is sometimes recommended for According to FDA recommendations, a contraindication the treatment of acute migraine pain in the case of resistance for triptans and DHE is basilar and haemiplegic migraine to other drugs. Studies have shown that DHE is effective in due to the potential risk of ischemic vascular events. For the case of menstrual migraines, migraines with cutaneous this reason, patients with this type of migraine were not allodynia, migraine recurrence, status migrainosus, and included in the clinical studies designed to assess the efficacy headaches caused by using other drugs. DHE should be of intravenously administered DHE. However, in 2016, the given to patients in emergency situations, preferably for a results of a study evaluating the efficacy and safety of abortive short period of time. Currently, DHE preparations are not treatment was published concerning this group of patients recommended for use in the prophylaxis of migraine pain, [33]. The study included 67 patients with basilar migraine and as prolonged use of the drug significantly increases the risk 13 patients with haemiplegic migraine. The risk of occurrence of severe adverse events. The current