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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 6  |  Issue : 1  |  Page : 11-14

The ditans, a new class for acute migraine: Minireview


Department of Neurology; Department of Medicine, Federal University of Santa Maria, Santa Maria, Rio Grande do Sul, Brazil

Date of Submission18-Nov-2019
Date of Decision31-Dec-2019
Date of Acceptance21-Feb-2020
Date of Web Publication20-Jul-2020

Correspondence Address:
Jamir Pitton Rissardo
Rua Roraima, Santa Maria, Rio Grande do Sul
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrsm.jcrsm_45_19

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  Abstract 


Lasmiditan (LDT), a new drug, was approved by the Food and Drug Administration in October 2019 for acute migraines with or without aura. LDT belongs to a new class of drugs “-ditans,” in which the mechanism is different from the triptans since it does not show vasoactive effects. The “-ditans” are more likely to be involved with the trigeminal system without causing vasoconstriction because of its low affinity for 5-HT1B receptors and highly selective 5-HT1F receptor agonist. The LDT probably decreases the neurogenic inflammation of the dura by lowering plasma protein extravasation and inhibits or suppresses neuronal firing in the trigeminal nucleus caudalis. Moreover, 5HT1F agonists have shown to decrease c-fos activity within the trigeminal nucleus, which reduces the level of synaptic activation. The onset of action of LDT is fast, which shows rapid absorption with good oral bioavailability. The peak plasma occurs within 2 h and the distribution is half associated with proteins. The LDT metabolism is hepatic but also nonhepatic by noncytochromes P450.

Keywords: 5-HT1F receptor agonist, lasmiditan, migraine, trigeminal ganglion, trigeminal nucleus caudalis


How to cite this article:
Rissardo JP, Fornari Caprara AL. The ditans, a new class for acute migraine: Minireview. J Curr Res Sci Med 2020;6:11-4

How to cite this URL:
Rissardo JP, Fornari Caprara AL. The ditans, a new class for acute migraine: Minireview. J Curr Res Sci Med [serial online] 2020 [cited 2020 Aug 11];6:11-4. Available from: http://www.jcrsmed.org/text.asp?2020/6/1/11/290252




  Brief Historical Background Top


Millions of people suffer from a migraine all over the world, with an estimated prevalence of about 15%, and it is the second most common reported cause of headache. Migraine can be functionally disabling and significantly impair the activities of daily living of the patient and all their surroundings.[1] Usually, migraine is episodically associated with other symptoms such as sensitivity to light, sound, or movement; nausea; and vomiting, but around at least 2% of the world population is found to be suffering from chronic migraines. In this context, management could be divided into prophylactic and abortive.[2]

In the literature, we can find three main hypotheses to explain migraine. First, the vascular theory, which suggested that migraine headache is caused by meningeal vessel dilatation; this theory can be supported by the mechanism proposed by the triptan drugs and by the visual aura, which some authors believed to be of vascular origin.[3] Second, the cortical spreading depression that was thought when epileptic patients with headache were studied, and there was evidence in electrodiagnostic studies of some current during the patient headache.[3],[4] Third, a more recent theory, which sometimes intermingles with the second, is the neuronal process involving activation and sensitization of the trigeminal nociceptors and the trigeminocervical complex.[5] In this context, based on the third theory, new drugs are being developed and one of these new therapeutic options is the “DITAN” class.

The treatment of migraine begins as early as BC 2500, in which Egyptian papyrus described banding a clay crocodile to the head of the individual with migraine. Herein, we would like to discuss the treatment of acute migraines.[6] In the 1930s, Graham and Wolff during chemical studies developed an ergot derivative, which later in animal studies showed to relieve migraines.[7] In other studies, it was observed that ergot in the peripheral vascular system leads to vasoconstriction, so it was proposed that migraines are due to vasodilation and the tart is given to vasoconstrict the vessels leading to relief of the symptoms. However, the majority of this tart had severe side effects in the cardiovascular circulation causing severe complications such as stroke, acute myocardial infarction, and distal limb ischemia.[8] Almost 50 years later, Humphrey at GlaxoSmithKline searching a drug with selective vasoconstriction for the extracranial circulation and a lesser number of adverse events developed the triptans.[9] The first clinically available triptan was sumatriptan, which has been marketed since 1991.

During animal studies on chronic pain, the presence of calcitonin gene-related peptide (CGRP) was noted.[10] Later, this peptide was observed in the trigeminal system, which is believed to be present in the vascular smooth muscle; to be more specific, many studies have shown that the CGRP neurotransmitter is released into the circulation during migraine attack, and its level remains elevated in patients suffering from chronic migraine.[11] Thus, drugs blocking the CGRP receptors have been developed for the treatment of migraine. One of these medications is erenumab, which was approved by the Food and Drug Administration (FDA) in May 2018 for migraine prophylaxis and episodic migraine. Other drugs of this class that have been studied or pending approval by the FDA for acute migraine treatment include rimegepant and ubrogepant.[12]

Based on the second–third theories, efforts have been made to develop new medications for acute migraine treatments targeting the trigeminal pathways while avoiding the vascular theory (5HT1B and 5HT1D receptors). The 5HT1F receptors are a potential target in this new trend and are providing promising preliminary results.


  Summary of the Established Principles Top


Lasmiditan (LDT), also known as COL-144 and LY573144, is the first drug of the “DITANS” family and has highly selective for 5HT1F receptors.[13]

The LDT replaces the indole group of triptans by a pyridine-piperidine scaffold, which provides to the structure high affinity for the 5HT1F receptors.[14] In a comparative analysis between these two drug classes, it is interesting to observe the binding affinity to 5HT receptors. The binding affinities of LDT at human 5HT receptors (receptor [Ki]) include 1A (1053 ± 134 nM); 1B (1043 ± 124 nM); 1D (1357 ± 156 nM); 1F (2.21 ± 0.22 nM); 2A (>5 μM); 2B (>2 μM); 2C (>3 μM); 6 (>4 μM); and 7 (>3 μM).[15] When we analyze, for example, the sumatriptan pKi, the results are 1A (6.4); 1B (7.8); 1D (8.5); 1F (7.9); 2A (<5); 2B (6.9); 2C (<5); 6 (<5.5); and 7 (5.9).[16]

The exact mechanism of action is unknown.[14] However, in some studies, it was observed that the agonist activity in the 5HT1F receptor leads to a decrease of the plasma protein extravasation inhibiting the neurogenic inflammation of the dura, and eventually, suppressing neuronal firing within the trigeminal nucleus caudalis.[15] In addition, LDT can decrease c-fos activity within the trigeminal nucleus [Figure 1].[15],[16],[17],[18]
Figure 1: Schematic diagram of the mechanism of action of lasmiditan. Lasmiditan is an agonism of 5HT1F receptor (coupled to the Gi protein and mediates inhibitory neurotransmission), which inhibits adenylate cyclase decreasing the cyclic adenosine monophosphate and consequently the protein kinase A action. This general decrease of phosphorylation causes: (1) reduction of the cyclic adenosine monophosphate response element-binding activity and possibly resulting in low levels of c-Fos; (2) reduction of histamine release, which does not change the vascular permeability decreasing the dural plasma protein extravasation (3) reduction of calcitonin gene-related peptide release

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  Current State of the Art Top


In October 2019, LDT was approved by the FDA for acute migraine with or without aura. The approval comes after the results of three clinical trials, which were two double-blind, placebo-controlled, randomized controlled trials (SAMURAI and SPARTAN) and one prospective, randomized, open-label study to assess the long-term safety and efficacy of LDT (GLADIATOR) [Table 1].[19],[20],[21],[22],[23] We included in [Table 1] the results from the COL MIG-202, which was a second Phase II clinical trial that evaluated the safety and efficacy of oral LDT in acute migraine.[14]
Table 1: Summary of COL MIG-202, SAMURAI, SPARTAN, and GLADIATOR

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The commercially available LDT doses are 50 or 100 mg; a single dose of 50, 100, or 200 mg is recommended.[22] It is noteworthy that the second dose of LDT showed some evidence of efficacy when taken for headache recurrence. However, there was no clear benefit of a second dose of LDT for rescue treatment. When the second dose of LDT is needed, the studies showed that the administration should be in more than 24 h due to the drug's mechanism of action. Furthermore, the safety in subjects that have more than four attacks per month was not established.[13]

The onset of action of LDT is fast, which shows rapid absorption with good oral bioavailability. The peak plasma occurs within 2 h and the distribution is half associated with proteins. The LDT metabolism is hepatic but also nonhepatic by noncytochromes P450.[22] This drug has interactions with commonly used migraine drugs such as amitriptyline and eletriptan because LDT is believed to increase the effects of P-glycoprotein (MDR1) efflux transporter. When used with propranolol, a significant reduction of the heart rate can be observed. Other medications that also need to monitor closely when used together of LDT include apixaban, amiodarone, ciprofloxacin, and pantoprazole. There is also a risk of serotonin syndrome with coadministration of selective serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors.[13],[14],[22],[23]

Dizziness is the only adverse effect that occurs in more than 10% of the population.[14] 1%–10% population will have paresthesia, sedation, fatigue, nausea, vomiting, and muscle weakness.[20] It is worth mentioning that FDA published a warning that the user not drive or operate machines for at least 8 h after taking the medication, which significantly affects an important portion of the economically active population.[24]


  Highlight of Future Directions Top


We believe that the development and approval of this new drug provided new insight into the mechanism and management of migraine. However, the complaints about the side effects of this drug are quite similar to the older classes, so new discoveries are still needed with oral drugs for the acute treatment of migraine with, for example, less sedation and maintenance of the efficacy.

An interesting point of discussion after the efficacy of the agonism of serotonin 5HT1F is that probably there is more than one explanation for migraines or the hypothesis converges to a common pathway. For example, triptans, anticonvulsants, and LDT even though have different pharmacodynamics, pharmacokinetics, and mechanism of actions, probably they converge to the same end pathway; which could be a point for research since appears that something is missing between the pathways, or another explanation could be that triptans act in vascular, antiepileptic drugs in the cortical depression and LDT in the protein extravasation, but their actions in their respective pathways block the development of the episodic migraine; thus, it is like the three pathways that are needed for the development of migraine, as a result with the missing of one (due to the triptan, anticonvulsant, or LDT action) pathway the migraine did not occur.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Adams AM, Serrano D, Buse DC, Reed ML, Marske V, Fanning KM, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia 2015;35:563-78.  Back to cited text no. 1
    
2.
Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: A qualitative systematic review. Headache 2016;56:49-70.  Back to cited text no. 2
    
3.
Parsons AA, Strijbos PJ. The neuronal versus vascular hypothesis of migraine and cortical spreading depression. Curr Opin Pharmacol 2003;3:73-7.  Back to cited text no. 3
    
4.
Charles A. Migraine is not primarily a vascular disorder. Cephalalgia 2012;32:431-2.  Back to cited text no. 4
    
5.
May A, Schulte LH. Chronic migraine: Risk factors, mechanisms and treatment. Nat Rev Neurol 2016;12:455-64.  Back to cited text no. 5
    
6.
Popko L. Some notes on papyrus Ebers, ancient Egyptian treatments of migraine, and a crocodile on the patient's head. Bull History Med 2018;92:352-66.  Back to cited text no. 6
    
7.
Graham JR, Wolff HG. Mechanism of migraine headache and action of ergotamine tartrate. Arch Neurol Psychiatry 1938;39:737-63.  Back to cited text no. 7
    
8.
Arulmozhi DK, Veeranjaneyulu A, Bodhankar SL. Migraine: Current concepts and emerging therapies. Vascul Pharmacol 2005;43:176-87.  Back to cited text no. 8
    
9.
Humphrey PP. The discovery and development of the triptans, a major therapeutic breakthrough. Headache 2008;48:685-7.  Back to cited text no. 9
    
10.
Maggi CA. Tachykinins and calcitonin gene-related peptide (CGRP) as co-transmitters released from peripheral endings of sensory nerves. Prog Neurobiol 1995;45:1-98.  Back to cited text no. 10
    
11.
Edvinsson L, Jansen Olesen I, Kingman TA, McCulloch J, Uddman R. Modification of vasoconstrictor responses in cerebral blood vessels by lesioning of the trigeminal nerve: Possible involvement of CGRP. Cephalalgia 1995;15:373-83.  Back to cited text no. 11
    
12.
Rissardo JP, Caprara AL. Anticalcitonin gene-related peptide monoclonal antibodies: An overview. APIK J Int Med 2020;8:33-4.  Back to cited text no. 12
  [Full text]  
13.
Loo LS, Plato BM, Turner IM, Case MG, Raskin J, Dowsett SA, et al. Effect of a rescue or recurrence dose of lasmiditan on efficacy and safety in the acute treatment of migraine: Findings from the Phase 3 trials (SAMURAI and SPARTAN). BMC Neurol 2019;19:191.  Back to cited text no. 13
    
14.
Brashier D, Maggo S, Gill S, Angrish P, Singh A, Rawat D. Lasmiditan: New drug for acute migraine. Int J Basic Clin Pharmacol 2019;8:372.  Back to cited text no. 14
    
15.
Nelson DL, Phebus LA, Johnson KW, Wainscott DB, Cohen ML, Calligaro DO, et al. Preclinical pharmacological profile of the selective 5-HT1F receptor agonist lasmiditan. Cephalalgia 2010;30:1159-69.  Back to cited text no. 15
    
16.
Rubio-Beltrán E, Labastida-Ramírez A, Villalón CM, Maassen Van Den Brink A. Is selective 5-HT (1F) receptor agonism an entity apart from that of the triptans in antimigraine therapy? Pharmacol Ther 2018;186:88-97.  Back to cited text no. 16
    
17.
Worm J, Falkenberg K, Olesen J. Histamine and migraine revisited: Mechanisms and possible drug targets. J Headache Pain 2019;20:30.  Back to cited text no. 17
    
18.
Claesson-Welsh L. Vascular permeability – The essentials. Ups J Med Sci 2015;120:135-43.  Back to cited text no. 18
    
19.
Oswald JC, Schuster NM. Lasmiditan for the treatment of acute migraine: A review and potential role in clinical practice. J Pain Res 2018;11:2221-7.  Back to cited text no. 19
    
20.
Kuca B, Silberstein SD, Wietecha L, Berg PH, Dozier G, Lipton RB, et al. Lasmiditan is an effective acute treatment for migraine: A Phase 3 randomized study. Neurology 2018;91:e2222-32.  Back to cited text no. 20
    
21.
Goadsby PJ, Wietecha LA, Dennehy EB, Kuca B, Case MG, Aurora SK, et al. Phase 3 randomized, placebo-controlled, double-blind study of lasmiditan for acute treatment of migraine. Brain 2019;142:1894-904.  Back to cited text no. 21
    
22.
Krege JH, Rizzoli PB, Liffick E, Doty EG, Dowsett SA, Wang J, et al. Safety findings from Phase 3 lasmiditan studies for acute treatment of migraine: Results from SAMURAI and SPARTAN. Cephalalgia 2019;39:957-66.  Back to cited text no. 22
    
23.
Brandes JL, Klise S, Krege JH, Case M, Khanna R, Vasudeva R, et al. Interim results of a prospective, randomized, open-label, Phase 3 study of the long-term safety and efficacy of lasmiditan for acute treatment of migraine (the GLADIATOR study). Cephalalgia 2019;39:1343-57.  Back to cited text no. 23
    
24.
SPARTAN. Three Doses of Lasmiditan (50 mg, 100 mg and 200 mg) Compared to Placebo in the Acute Treatment of Migraine (SPARTAN) 2019. Available from: https://clinicaltrials.gov/ct2/show/NCT02605174. [Last accessed on 2019 Dec 31].  Back to cited text no. 24
    


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