The history and rationale of the development of new drugs for migraine treatment

Kowacs, Pedro André; Rocha- Filho, Pedro Augusto Sampaio; Peres, Mário Fernando Prieto; Edvinsson, Lars

doi:10.1055/s-0043-1777723

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View and Review • Arq. Neuro-Psiquiatr. 81 (12) • Dec 2023 • https://doi.org/10.1055/s-0043-1777723 copy

The history and rationale of the development of new drugs for migraine treatment

A história e os fundamentos do desenvolvimento de novos medicamentos para o tratamento da migrânea

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

Migraine is one of the most prevalent and disabling diseases in the world. Migraine attack treatments and prophylactic treatments of this disease are essential to lessen its individual, social, and economic impact. This is a narrative review of the main drugs used for treating migraine, as well as the experimental models and the theoretical frameworks that led to their development. Ergot derivatives, triptans, non-steroid anti-inflammatory drugs, tricyclic antidepressants, beta-blockers, flunarizine, valproic acid, topiramate, onabotulinumtoxin A, ditans, monoclonal antibodies against CGRP and its receptor, and gepants are discussed. Possible therapeutic targets for the development of new drugs that are under development are also addressed. Many of the drugs currently in use for treating migraine were developed for the treatment of other diseases, but have proven effective for the treatment of migraine, expanding knowledge about the disease. With a better understanding of the pathophysiology of migraine, new drugs have been and continue to be developed specifically for the treatment of this disease.

Keywords
Headache; Migraine Disorders; Drug Development; Therapeutics; Pathophysiology

Drug	Dose (mg) and route of administration	Tmax (h)	T1/2 (h)	Headache free at 2 hours (%)	Therapeutic gain (%)	NNT	Headache relief at 2 hours (%)	Therapeutic gain* (%)	NNT*
Placebo		–	–	10.6	–	–	26.7	–	–
Sumatriptan	6 SC	0.17	2	36.6	26	3.8	75.7	49	2
	25 PO			24.9	14.3	6.9	44.2	17.5	5.7
	50 PO	1.5	1.8	27.7	17.1	5.8	49.7	23%	4.3
	100 PO	1.5	2	32.1	21.5	4.6	53.4	26.7	3.7
	20 IN	1.5	1.8	21.2	10.6	9.4	52.6	25.9	3.8
Zolmitriptan	1.25 PO			21	10.4	9.6	44	17.3	5.7
	2.5 PO	1.5	2.3 - 2.6 ᵃ	27.1	16.5	6	50	23.3	4.2
	5 PO	1.5	3	31	20.4	4.9	51.4	24.7	4
Naratriptan	2.5 PO	2	5.5	17.5	6.9	14.4	44.5	17.8	5.6
Rizatriptan	5 PO			27.5	16.9	5.9	51.2	24.5	4
	10 PO	1	2	36.6	20	5	57.1	30.4	3.2
	20 PO			50.1	39.5	2,5	64.2	37.5	2.6
Eletriptan	20 PO			28.5	17.9	5.5	52.5	25.8	3.8
	40 PO	1.8	–	39.2	28.6	3.4	60.4	33.7	2.9
	80 PO	1.4	6.3	48	37.4	2,6	66.2	39.5	2.5
Almotriptan	6,25 PO			18.5	7.9	12.6	43.3	16.6	6
	12.5 PO	2.5	3.1	24.5	13.9	7.1	48.3	21.6	4.6
	25 PO	2.7	3.6	32.4	21.8	4.5	50.6	23.9	4.1
Frovatriptan	1.25 PO			12.6	2	50	27.3	0.6	16.6
	2.5 PO	3	25.7	34.7	24.1	4.1	42.4	15.7	6.3
	5 PO	5	29.7	35.2	24.6	4	40.3	13.6	7.4

Dose	50mg, 100mg
Maximum dose tested for migraine	400 mg
Administration route	oral
Tmax	1.8h
T1/2	5.7h
Binding to proteins	55%–60%
Metabolism	hepatic and extrahepatic (ketone reduction)
Therapeutic gain for headache response	17% (50mg) and 38.1% (100mg)
Therapeutic gain for headache free at 2 hours	14.05%
NNT for episodic migraine	15, 10 and 7 (50mg, 100mg e 200mg, respectively)
Most common side effects	dizziness, fatigue, vertigo, somnolence, paresthesia, nausea and heaviness

Drug	Erenumab 70mg / 140mg	Galcanezumab 120mgᵃ	Fremanezumab 225mg / 675mg^b	Eptinezumab 100mg / 300mg^b
Class	IgG2	IgG4	IgG2Δa	IgG1
Humanization	fully humanized	fully humanized	fully humanized	genetically humanized
Administration route	S.C.	S.C.	S.C.	I.V.
Tmax (h)	6	5	5	1-3
T1/2 (days)	≅28	≅27	≅32	≅27
Binding	CGRP receptor	CGRP ligand	CGRP ligand	CGRP ligand
Therapeutic gain for episodic migraine	10.5 / 19.1	23	19.8 / 16.5	12.4 / 18.9
NNT for episodic migraine	9.5 / 5.2	4.3	5 / 6	8 / 5.3
episodic migraine responders (%)	8 / 8.6	12	9.6	–
Therapeutic gain for chronic migraine ^R	17 / 18	12.2	11.3 / 8.8	18.3 / 22.1
NNT for chronic migraine ^R	5.8 / 5.5	8.1	8.8 / 11.3	5.4 / 4.5
chronic migraine responders (%)	2.7 / 4.3	0.4	1.5	–

	Rimegepant	Ubrogepant	Atogepant	Zavegepant
Dose	75mg	50mg 100mg	10mg 30mg 60mg	5mg 10mg 20mg
Administration route	PO	PO	PO	IN
Tmax (hours)	1.5	1.5	2	0.25
T1/2 (hours)	11	5 - 7	11	6.55
Therapeutic gain for migraine attacks: headache free^z at 2 hours	10%	16.6%	–	5mg: 4.1% 10mg: 7% 20mg: 7.6%
NNT for migraine attacks: headache free^z at 2 hours	10	6	-	5mg: 24.3 10mg: 10 20mg: 13
Therapeutic gain for migraine prophylaxis ≥ 50% reduction episodic migraine	8%	–	10mg: 26.6% 30mg: 29.7% 60mg 31.8%	–
NNT for episodic migraine prophylaxis	12.5	–	10mg: 3.7 30mg: 3.3 60mg: 3.1	–

	Amitriptyline	Propranolol	Flunarizine	Valproate	Topiramate
Dose	25-150 mg /day	20-240mg /day	5-10mg/day	250-1000mg /day	50-200mg /day
Administration route	oral	oral	oral	oral, i.v.	oral
T 1/2	25 h	8 h	18 d	13-19 h	25 - 33 h
Binding to serum proteins	95%	90%	99%	90	9 - 17%
Pharmacodynamics	Inhibits the membrane pump mechanism responsible for the re-uptake norepinephrine and serotonin.	Leads to vasoconstriction, inhibits angiogenic factors, inducts apoptosis of endothelial cells, and down regulates the renin-angiotensin-aldosterone system.	Inhibits the influx of extracellular calcium through membrane pores by physically plugging the channel. Also decreases intracellular calcium.	Blocks sodium channels increasing gamma- aminobutyric-acid levels in the brain and decreasing hyper- excitability of nerve cells, via Kv7.2 channel and AKAP5.	Acts on GABAa, NMDA, AMPA/kainate receptors and on ion channels (Na + , K + , Ca + +.
Metabolism / Excretion	Demethylation (CYP2C19, CYP3A4), hydroxylation (CYP2D6) and glucuronidation. CYP1A2 and CYP2C9 are also involved. Elimination is through the urine.	Oxidation to α-naphthoxylactic acid, ring oxidation to 4'-hydroxypropranolol, or glucuronidation to propranolol glucuronide. N-desisopropylated to become N-desisopropyl propranolol.	N-dealkylation and hydroxylation	Glucuronidation (30-50%) mitochondrial β-oxidation (40%). Oxidation (15-20%), hydroxylation, and dehydrogenation leading to hydroxyls, ketones, carboxyls, a lactone metabolite, double bonds, and combinations	Hydroxylation, hydrolysis and glucuronidation (15%); renal excretion (85%).
TG for EpMig	34.5%	44%	43%	47%	23.5%
NNT for EpMig	2.8	2.2	2.3	2.1	4.2
TG for ChMig	–	–	–	*	6.6%
NNT for ChMig	–	–	–	*	15.1%
Most common side effects	Heart rate variability, arrhythmias and block, prolong QTc interval, blurred vision, dry mouth, urinary retention, glaucoma, confusion, sedation, increased appetite, weight gain, decreased seizure threshold, liver dysfunction, bone frailty, bone marrow suppression, mania.	Bradycardia, abdominal pain, nausea, erectile dysfunction, and wheezing, bronchospasms, drowsiness, fatigue, cold extremities, allergic reactions, insulin resistance, hallucinations.	Drowsiness, weight gain, headache, depression, gastric pain, nausea, dry mouth, insomnia, rash, dyskinesia, akathisia and parkinsonism.	Hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, Hypersensitivity reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity.	Paresthesia, fatigue, nausea, anorexia, dizziness, diarrhea, difficulty in memory, difficulty with concentration, somnolence, acute myopia and glaucoma, crystalluria and/ or nephrolithiasis.

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[1] Address for correspondence Pedro André Kowacs (email: pkowacs@gmail.com)