257
Views
1
CrossRef citations to date
0
Altmetric
Review

Emerging experimental drugs in clinical trials for migraine: observations and key talking points

, , , & ORCID Icon
Pages 761-771 | Received 26 Apr 2023, Accepted 30 Aug 2023, Published online: 08 Sep 2023

References

  • Stovner LJ, Hagen K, Linde M, et al. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022 Apr 12;23(1):34. doi: 10.1186/s10194-022-01402-2
  • Vos T, Abajobir AA, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990–2016: a systematic analysis for the global burden of disease study 2016. Lancet. 2017;390(10100):1211–1259. doi: 10.1016/S0140-6736(17)32154-2
  • Hepp Z, Bloudek LM, Varon SF. Systematic review of migraine prophylaxis adherence and persistence. J Managed Care Pharm. 2014;20(1):22–33. doi: 10.18553/jmcp.2014.20.1.22
  • Cohen F, Yuan H, Depoy EMG, et al. The arrival of anti-CGRP monoclonal antibodies in migraine. Neurotherapeutics. 2022;19(3):922–930. doi: 10.1007/s13311-022-01230-x
  • Overeem LH, Raffaelli B, Mecklenburg J, et al. Indirect comparison of topiramate and monoclonal antibodies against CGRP or its receptor for the prophylaxis of episodic migraine: a systematic review with meta-analysis. CNS Drugs. 2021 Aug;35(8):805–820. doi: 10.1007/s40263-021-00834-9
  • Varnado OJ, Manjelievskaia J, Ye W, et al. Treatment patterns for calcitonin gene-related peptide monoclonal antibodies including Galcanezumab versus conventional preventive treatments for migraine: a retrospective US claims study. Patient Prefer Adherence. 2022;16:821–839. doi: 10.2147/PPA.S346660
  • Edvinsson L, Haanes KA, Warfvinge K, et al. CGRP as the target of new migraine therapies—successful translation from bench to clinic. Nat Rev Neurol. 2018 Jun;14(6):338–350. doi: 10.1038/s41582-018-0003-1
  • Raffaelli B, Fitzek M, Overeem LH, et al. Clinical evaluation of super-responders vs. non-responders to CGRP(-receptor) monoclonal antibodies: a real-world experience. J Headache Pain. 2023 Feb 27;24(1):16. doi: 10.1186/s10194-023-01552-x
  • Young NP, Philpot LM, Vierkant RA, et al. Episodic and chronic migraine in primary Care. Headache. 2019 Jul;59(7):1042–1051. doi: 10.1111/head.13543
  • Wattiez AS, Sowers LP, Russo AF. Calcitonin gene-related peptide (CGRP): role in migraine pathophysiology and therapeutic targeting. Expert Opin Ther Targets. 2020 Feb;24(2):91–100. doi: 10.1080/14728222.2020.1724285
  • Ray JC, Kapoor M, Stark RJ, et al. Calcitonin gene related peptide in migraine: current therapeutics, future implications and potential off-target effects. J Neurol Neurosurg Psychiatry. 2021;92(12):1325–1334. doi: 10.1136/jnnp-2020-324674
  • Shah T, Bedrin K, Tinsley A. Calcitonin gene relating peptide inhibitors in combination for migraine treatment: a mini-review. Front Pain Res. 2023;4:1130239. doi: 10.3389/fpain.2023.1130239
  • Russell FA, King R, Smillie SJ, et al. Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev. 2014 Oct;94(4):1099–1142. doi: 10.1152/physrev.00034.2013
  • Messlinger K. The big CGRP flood - sources, sinks and signalling sites in the trigeminovascular system. J Headache Pain. 2018 Mar 12;19(1):22.
  • Iyengar S, Johnson KW, Ossipov MH, et al. CGRP and the trigeminal system in migraine. Headache. 2019;59(5):659–681. doi: 10.1111/head.13529
  • Poyner DR, Sexton PM, Marshall I, et al. International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors. Pharmacol Rev. 2002 Jun;54(2):233–246. doi: 10.1124/pr.54.2.233
  • Altamura C, Cevoli S, Brunelli N, et al. When should we consider chronic patients as non-responders to monoclonal antibodies targeting the CGRP pathway? J Neurol. 2022 Feb;269(2):1032–1034. doi: 10.1007/s00415-021-10772-7
  • Salvatore CA, Mallee JJ, Bell IM, et al. Identification and pharmacological characterization of domains involved in binding of CGRP receptor antagonists to the calcitonin-like receptor. Biochemistry. 2006 Feb 14;45(6):1881–1887. doi: 10.1021/bi052044w
  • Negro A, Martelletti P. Gepants for the treatment of migraine. Expert Opin Investig Drugs. 2019 Jun;28(6):555–567. doi: 10.1080/13543784.2019.1618830
  • Moreno-Ajona D, Villar-Martínez MD, Goadsby PJ. New generation gepants: migraine acute and preventive medications. J Clin Med. 2022 Mar 16;11(6):1656. doi: 10.3390/jcm11061656
  • Marcus R, Goadsby PJ, Dodick D, et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia. 2014;34(2):114–125. doi: 10.1177/0333102413500727
  • Croop R, Madonia J, Stock DA, et al. Zavegepant nasal spray for the acute treatment of migraine: a phase 2/3 double-blind, randomized, placebo-controlled, dose-ranging trial. Headache. 2022 Oct;62(9):1153–1163. doi: 10.1111/head.14389
  • Min YW, Lee JH, Min BH, et al. Clinical predictors for migraine in patients presenting with nausea and/or vomiting. J Neurogastroenterol Motil. 2013 Oct;19(4):516–520. doi: 10.5056/jnm.2013.19.4.516
  • Dhillon S. Zavegepant: first approval. Drugs. 2023 Jun;83(9):825–831. doi: 10.1007/s40265-023-01885-6
  • Zebenholzer K, Gall W, Wöber C. Use and overuse of triptans in Austria – a survey based on nationwide healthcare claims data. J Headache Pain. 2018 May 18;19(1):34.
  • Diener HC, Dodick D, Evers S, et al. Pathophysiology, prevention, and treatment of medication overuse headache. Lancet Neurol. 2019 Sep;18(9):891–902. doi: 10.1016/S1474-4422(19)30146-2
  • Lipton RB, Croop R, Stock DA, et al. Safety, tolerability, and efficacy of zavegepant 10 mg nasal spray for the acute treatment of migraine in the USA: a phase 3, double-blind, randomised, placebo-controlled multicentre trial. Lancet Neurol. 2023 Mar;22(3):209–217. doi: 10.1016/S1474-4422(22)00517-8
  • Negro A, Koverech A, Martelletti P. Serotonin receptor agonists in the acute treatment of migraine: a review on their therapeutic potential. J Pain Res. 2018;11:515–526. doi: 10.2147/JPR.S132833
  • Eigenbrodt AK, Ashina H, Khan S, et al. Diagnosis and management of migraine in ten steps. Nat Rev Neurol. 2021;17(8):501–514. doi: 10.1038/s41582-021-00509-5
  • Pero A, Pace A, Dhamoon MS. Triptan medication use among patients with migraine with contraindications in the US. Headache. 2022 Jul;62(7):883–889. doi: 10.1111/head.14327
  • Chu MK, Buse DC, Bigal ME, et al. Factors associated with triptan use in episodic migraine: results from the American migraine prevalence and prevention study. Headache. 2012 Feb;52(2):213–223. doi: 10.1111/j.1526-4610.2011.02032.x
  • Razzaque Z, Pickard JD, Ma QP, et al. 5-HT1B-receptors and vascular reactivity in human isolated blood vessels: assessment of the potential craniovascular selectivity of sumatriptan. Br J Clin Pharmacol. 2002 Mar;53(3):266–274. doi: 10.1046/j.0306-5251.2001.01536.x
  • Krege JH, Lipton RB, Baygani SK, et al. Lasmiditan for patients with migraine and contraindications to triptans: a post hoc analysis. Pain Ther. 2022 Jun;11(2):701–712. doi: 10.1007/s40122-022-00388-8
  • Tepper SJ. Safety and rational use of the triptans. Med Clin North Am. 2001 Jul;85(4):959–970. doi: 10.1016/S0025-7125(05)70353-9
  • Roberto G, Raschi E, Piccinni C, et al. Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine: systematic review of observational studies. Cephalalgia. 2015 Feb;35(2):118–131. doi: 10.1177/0333102414550416
  • Dodick DW, Shewale AS, Lipton RB, et al. Migraine patients with cardiovascular disease and contraindications: an analysis of real-world claims data. J Prim Care Commun Health. 2020;11:215013272096368. doi: 10.1177/2150132720963680
  • Li Y, Cao GY, Jing WZ, et al. Global trends and regional differences in incidence and mortality of cardiovascular disease, 1990−2019: findings from 2019 global burden of disease study. Eur J Prev Cardiol. 2023 Feb 14;30(3):276–286. doi: 10.1093/eurjpc/zwac285
  • Lamb YN. Lasmiditan: first approval. Drugs. 2019 Dec;79(18):1989–1996. doi: 10.1007/s40265-019-01225-7
  • Beauchene JK, Levien TL. Lasmiditan: acute migraine treatment without vasoconstriction. A review. J Pharm Technol. 2021 Oct;37(5):244–253. doi: 10.1177/87551225211024630
  • Lo Castro F, Guerzoni S, Pellesi L. Safety and risk of medication overuse Headache in lasmiditan and second-generation gepants: a rapid review. Drug Healthc Patient Saf. 2021;13:233–240. doi: 10.2147/DHPS.S304373
  • Ashina M, Reuter U, Smith T, et al. Randomized, controlled trial of lasmiditan over four migraine attacks: findings from the CENTURION study. Cephalalgia. 2021 Mar;41(3):294–304. doi: 10.1177/0333102421989232
  • Cowan R, Cohen JM, Rosenman E, et al. Physician and patient preferences for dosing options in migraine prevention. J Headache Pain. 2019 May 09;20(1):50. doi: 10.1186/s10194-019-0998-8
  • Seng EK, Rains JA, Nicholson RA, et al. Improving medication adherence in migraine treatment. Curr Pain Headache Rep. 2015 Jun 04;19(6):24. doi: 10.1007/s11916-015-0498-8
  • Tassorelli C, Bragg S, Krege JH, et al. Safety findings from CENTURION, a phase 3 consistency study of lasmiditan for the acute treatment of migraine. J Headache Pain. 2021 Nov 6;22(1):132. doi: 10.1186/s10194-021-01343-2
  • Pearlman EM, Wilbraham D, Dennehy EB, et al. Effects of lasmiditan on simulated driving performance: results of two randomized, blinded, crossover studies with placebo and active controls. Hum Psychopharmacol. 2020 Sep;35(5):e2732. doi: 10.1002/hup.2732
  • Pradhan AA, Bertels Z, Akerman S. Targeted nitric oxide synthase inhibitors for migraine. Neurotherapeutics. 2018 Apr;15(2):391–401. doi: 10.1007/s13311-018-0614-7
  • Zhou L, Zhu DY. Neuronal nitric oxide synthase: structure, subcellular localization, regulation, and clinical implications. Nitric Oxide. 2009 Jun;20(4):223–230. doi: 10.1016/j.niox.2009.03.001
  • Moncada S, Higgs EA. The discovery of nitric oxide and its role in vascular biology. Br J Pharmacol. 2006 Jan;1(Suppl S1):S193–201. doi: 10.1038/sj.bjp.0706458
  • Brenman JE, Chao DS, Gee SH, et al. Interaction of nitric oxide synthase with the Postsynaptic Density protein PSD-95 and α1-syntrophin mediated by PDZ domains. Cell. 1996 Mar 8;84(5):757–767. doi: 10.1016/S0092-8674(00)81053-3
  • Garthwaite J, Charles SL, Chess-Williams R. Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain. Nature. 1988 Nov 24;336(6197):385–388. doi: 10.1038/336385a0
  • Bryan NS, Bian K, Murad F. Discovery of the nitric oxide signaling pathway and targets for drug development. Front Biosci. Landmark Ed 2009 Jan 1;14(14):1–18. doi: 10.2741/3228
  • Chachlaki K, Garthwaite J, Prevot V. The gentle art of saying NO: how nitric oxide gets things done in the hypothalamus. Nat Rev Endocrinol. 2017 Sep;13(9):521–535. doi: 10.1038/nrendo.2017.69
  • Francis SH, Busch JL, Corbin JD, et al. cGMP-dependent protein kinases and cGMP phosphodiesterases in nitric oxide and cGMP action. Pharmacol Rev. 2010 Sep;62(3):525–563. doi: 10.1124/pr.110.002907
  • Kruuse C, Thomsen LL, Birk S, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 2003 Jan;126(1):241–247. doi: 10.1093/brain/awg009
  • Kruuse C, Thomsen LL, Jacobsen TB, et al. The phosphodiesterase 5 inhibitor sildenafil has no effect on cerebral blood flow or blood velocity, but nevertheless induces headache in healthy subjects. J Cereb Blood Flow Metab. 2002 Sep;22(9):1124–1131. doi: 10.1097/00004647-200209000-00010
  • Onderwater GLJ, Dool J, Ferrari MD, et al. Premonitory symptoms in glyceryl trinitrate triggered migraine attacks: a case-control study. Pain. 2020 Sep 1;161(9):2058–2067. doi: 10.1097/j.pain.0000000000001894
  • Bellamy J, Bowen EJ, Russo AF, et al. Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons. Eur J Neurosci. 2006;23(8):2057–2066. doi: 10.1111/j.1460-9568.2006.04742.x
  • Hougaard A, Hauge AW, Guo S, et al. The nitric oxide synthase inhibitor and serotonin-receptor agonist NXN-188 during the aura phase of migraine with aura: a randomized, double-blind, placebo-controlled cross-over study. Scand J Pain. 2013;4(1):48–52. doi: 10.1016/j.sjpain.2012.08.002
  • Spahn V, Stein C. Targeting delta opioid receptors for pain treatment: drugs in phase I and II clinical development. Expert Opin Investig Drugs. 2017 Feb;26(2):155–160. doi: 10.1080/13543784.2017.1275562
  • Tepper SJ. Opioids should not be used in migraine. Headache. 2012 May;52(Suppl 1):30–34. doi: 10.1111/j.1526-4610.2012.02140.x
  • Lipton RB, Buse DC, Friedman BW, et al. Characterizing opioid use in a US population with migraine. Neurology. 2020;95(5):e457–e468. doi: 10.1212/WNL.0000000000009324
  • Moye LS, Siegersma K, Dripps I, et al. Delta opioid receptor regulation of calcitonin gene–related peptide dynamics in the trigeminal complex. Pain. 2021 Aug 1;162(8):2297–2308. doi: 10.1097/j.pain.0000000000002235
  • Pradhan AA, Befort K, Nozaki C, et al. The delta opioid receptor: an evolving target for the treatment of brain disorders. Trends Pharmacol Sci. 2011 Oct;32(10):581–590. doi: 10.1016/j.tips.2011.06.008
  • Pradhan AA, Smith ML, Zyuzin J, et al. δ-opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice. Br J Pharmacol. 2014 May;171(9):2375–2384. doi: 10.1111/bph.12591
  • Chung PC, Boehrer A, Stephan A, et al. Delta opioid receptors expressed in forebrain GABAergic neurons are responsible for SNC80-induced seizures. Behav Brain Res. 2015 Feb 1;278:429–434. doi: 10.1016/j.bbr.2014.10.029
  • Hirabayashi T, Nakamachi T, Shioda S. Discovery of PACAP and its receptors in the brain. J Headache Pain. 2018 Apr 4;19(1):28. doi: 10.1186/s10194-018-0855-1
  • Vaudry D, Falluel-Morel A, Bourgault S, et al. Pituitary adenylate cyclase-activating polypeptide and its receptors: 20 years after the discovery. Pharmacol Rev. 2009 Sep;61(3):283–357. doi: 10.1124/pr.109.001370
  • Ashina H, Guo S, Vollesen ALH, et al. PACAP38 in human models of primary headaches. J Headache Pain. 2017 Nov 23;18(1):110. doi: 10.1186/s10194-017-0821-3
  • Chan KY, Baun M, de Vries R, et al. Pharmacological characterization of VIP and PACAP receptors in the human meningeal and coronary artery. Cephalalgia. 2011 Jan;31(2):181–189. doi: 10.1177/0333102410375624
  • Guo S, Ernstsen C, Hay-Schmidt A, et al. PACAP signaling is not involved in GTN- and levcromakalim-induced hypersensitivity in mouse models of migraine. J Headache Pain. 2022 Dec 5;23(1):155. doi: 10.1186/s10194-022-01523-8
  • Ernstsen C, Christensen SL, Rasmussen RH, et al. The PACAP pathway is independent of CGRP in mouse models of migraine: possible new drug target? Brain. 2022 Jul 29;145(7):2450–2460. doi: 10.1093/brain/awac040
  • Guo S, Vollesen AL, Hansen YB, et al. Part II: biochemical changes after pituitary adenylate cyclase-activating polypeptide-38 infusion in migraine patients. Cephalalgia. 2017 Feb;37(2):136–147. doi: 10.1177/0333102416639517
  • Tuka B, Helyes Z, Markovics A, et al. Alterations in PACAP-38-like immunoreactivity in the plasma during ictal and interictal periods of migraine patients. Cephalalgia. 2013 Oct;33(13):1085–1095. doi: 10.1177/0333102413483931
  • Lundbeck announces positive phase II proof of concept results with Lu AG09222 in migraine prevention [Press Release] [Internet]. [cited 2023 Apr 19]. Available from: https://news.cision.com/h–lundbeck-a-s/r/lundbeck-announces-positive-phase-ii-proof-of-concept-results-with-lu-ag09222-in-migraine-prevention,c3754245
  • Ashina M, Dolezil D, Bonner JH, et al. A phase 2, randomized, double-blind, placebo-controlled trial of AMG 301, a pituitary adenylate cyclase-activating polypeptide PAC1 receptor monoclonal antibody for migraine prevention. Cephalalgia. 2021 Jan;41(1):33–44. doi: 10.1177/0333102420970889
  • de Lecea L, Sutcliffe JG. The hypocretins/orexins: novel hypothalamic neuropeptides involved in different physiological systems. Cell Mol Life Sci. 1999 Oct 30;56(5–6):473–480. doi: 10.1007/s000180050446
  • Strother LC, Srikiatkhachorn A, Supronsinchai W. Targeted orexin and hypothalamic neuropeptides for migraine. Neurotherapeutics. 2018 Apr;15(2):377–390. doi: 10.1007/s13311-017-0602-3
  • Kiyashchenko LI, Mileykovskiy BY, Maidment N, et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci. 2002 Jul 1;22(13):5282–5286. doi: 10.1523/JNEUROSCI.22-13-05282.2002
  • Villano I, La Marra M, Di Maio G, et al. Physiological role of orexinergic system for Health. Int J Environ Res Public Health. 2022 Jul 8;19(14):8353. doi: 10.3390/ijerph19148353
  • Chieffi S, Carotenuto M, Monda V, et al. Orexin system: the key for a healthy Life [review]. Front Physiol. 2017 May 31;8.
  • Kang X, Tang H, Liu Y, et al. Research progress on the mechanism of orexin in pain regulation in different brain regions. Open Life Sci. 2021;16(1):46–52. doi: 10.1515/biol-2021-0001
  • Tiseo C, Vacca A, Felbush A, et al. Migraine and sleep disorders: a systematic review. J Headache Pain. 2020 Oct 27;21(1):126. doi: 10.1186/s10194-020-01192-5
  • Sarchielli P, Rainero I, Coppola F, et al. Involvement of corticotrophin-releasing factor and orexin-A in chronic migraine and medication-overuse headache: findings from cerebrospinal fluid. Cephalalgia. 2008 Jul;28(7):714–722. doi: 10.1111/j.1468-2982.2008.01566.x
  • Ostroukhova I, Rudko O, Tretiakov A, et al. Migraine and orexin. J Neurol Stroke. 2021;11(2):37–39. doi: 10.15406/jnsk.2021.11.00452
  • Razavi BM, Hosseinzadeh H. A review of the role of orexin system in pain modulation. Biomed Pharmacother. 2017 Jun 01;90:187–193. doi: 10.1016/j.biopha.2017.03.053.
  • Mobarakeh JI, Takahashi K, Sakurada S, et al. Enhanced antinociception by intracerebroventricularly and intrathecally-administered orexin a and B (hypocretin-1 and -2) in mice. Peptides. 2005 May 01;26(5):767–777. doi: 10.1016/j.peptides.2005.01.001
  • Cady RJ, Denson JE, Sullivan LQ, et al. Dual orexin receptor antagonist 12 inhibits expression of proteins in neurons and glia implicated in peripheral and central sensitization. Neuroscience. 2014 Jun 6;269:79–92. doi: 10.1016/j.neuroscience.2014.03.043
  • Hoffmann J, Supronsinchai W, Akerman S, et al. Evidence for orexinergic mechanisms in migraine. Neurobiol Dis. 2015 Feb;74:137–143.
  • Chabi A, Zhang Y, Jackson S, et al. Randomized controlled trial of the orexin receptor antagonist filorexant for migraine prophylaxis. Cephalalgia. 2015 Apr;35(5):379–388. doi: 10.1177/0333102414544979
  • Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm (Vienna). 2014 Aug;121(8):799–817. doi: 10.1007/s00702-014-1180-8
  • Reiner A, Levitz J. Glutamatergic signaling in the central nervous system: ionotropic and metabotropic receptors in concert. Neuron. 2018 Jun 27;98(6):1080–1098. doi: 10.1016/j.neuron.2018.05.018
  • Bathel A, Schweizer L, Stude P, et al. Increased thalamic glutamate/glutamine levels in migraineurs. J Headache Pain. 2018 Jul 17;19(1):55. doi: 10.1186/s10194-018-0885-8
  • Sarchielli P, Di Filippo M, Nardi K, et al. Sensitization, glutamate, and the link between migraine and fibromyalgia. Curr Pain Headache Rep. 2007 Oct 01;11(5):343–351. doi: 10.1007/s11916-007-0216-2
  • Liu XJ, Salter MW. Glutamate receptor phosphorylation and trafficking in pain plasticity in spinal cord dorsal horn. Eur J Neurosci. 2010 Jul;32(2):278–289. doi: 10.1111/j.1460-9568.2010.07351.x
  • Niu Y, Zeng X, Zhao L, et al. Metabotropic glutamate receptor 5 regulates synaptic plasticity in a chronic migraine rat model through the PKC/NR2B signal. J Headache Pain. 2020 Dec 04;21(1):139. doi: 10.1186/s10194-020-01206-2
  • Lujan R, Nusser Z, Roberts JD, et al. Perisynaptic location of metabotropic glutamate receptors mGlur1 and mGlur5 on dendrites and dendritic spines in the rat hippocampus. Eur J Neurosci. 1996 Jul;8(7):1488–1500. doi: 10.1111/j.1460-9568.1996.tb01611.x
  • Hoffmann J, Charles A. Glutamate and its receptors as therapeutic targets for migraine. Neurotherapeutics. 2018 Apr;15(2):361–370. doi: 10.1007/s13311-018-0616-5
  • Wang H, Zhuo M. Group I metabotropic glutamate receptor-mediated gene transcription and implications for synaptic plasticity and diseases [review]. Front Pharmacol. 2012 Nov 01;3. doi: 10.3389/fphar.2012.00189.
  • Vincent K, Cornea VM, Jong YI, et al. Intracellular mGlur5 plays a critical role in neuropathic pain. Nat Commun. 2016 Feb 3;7(1):10604. doi: 10.1038/ncomms10604
  • Wang WW, Zhang XR, Zhang ZR, et al. Effects of mGlur5 antagonists on Parkinson’s patients with L-Dopa-induced dyskinesia: a systematic review and meta-analysis of randomized controlled trials. Front Aging Neurosci. 2018;10:262. doi: 10.3389/fnagi.2018.00262
  • Razeghi Jahromi S, Ghorbani Z, Martelletti P, et al. Association of diet and headache. J Headache Pain. 2019 Nov 14;20(1):106. doi: 10.1186/s10194-019-1057-1
  • Gross EC, Klement RJ, Schoenen J, et al. Potential Protective mechanisms of ketone bodies in migraine prevention. Nutrients. 2019 Apr 10;11(4):811. doi: 10.3390/nu11040811
  • Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014 Jan;25(1):42–52. doi: 10.1016/j.tem.2013.09.002
  • Lovati C, d’Alessandro CM, Ventura SD, et al. Ketogenic diet in refractory migraine: possible efficacy and role of ketone bodies-a pilot experience. Neurol Sci. 2022 Nov;43(11):6479–6485. doi: 10.1007/s10072-022-06311-5
  • Bongiovanni D, Benedetto C, Corvisieri S, et al. Effectiveness of ketogenic diet in treatment of patients with refractory chronic migraine. Neurol Sci. 2021 Sep;42(9):3865–3870. doi: 10.1007/s10072-021-05078-5
  • McDonald TJW, Cervenka MC. Lessons learned from recent clinical trials of ketogenic diet therapies in adults. Curr Opin Clin Nutr Metab Care. 2019 Nov;22(6):418–424. doi: 10.1097/MCO.0000000000000596
  • Vandenberghe C, St-Pierre V, Pierotti T, et al. Tricaprylin alone increases plasma ketone response more than coconut oil or other medium-chain triglycerides: an acute crossover study in healthy adults. Curr Dev Nutr. 2017 Apr;1(4):e000257. doi: 10.3945/cdn.116.000257
  • DCH CJ, Schofield GM, Williden M, et al. The effect of medium chain triglycerides on time to nutritional ketosis and symptoms of keto-induction in healthy adults: a randomised controlled clinical trial. J Nutr Metab. 2018;2018:2630565. doi: 10.1155/2018/2630565
  • Schell JC, Rutter J. The long and winding road to the mitochondrial pyruvate carrier. Cancer Metab. 2013 Jan 23;1(1):6.
  • Moreno-Ajona D, Pérez-Rodríguez A, Goadsby PJ. Gepants, calcitonin-gene-related peptide receptor antagonists: what could be their role in migraine treatment? Curr Opin Neurol. 2020 Jun;33(3):309–315. doi: 10.1097/WCO.0000000000000806
  • Polavieja P, Belger M, Venkata SK, et al. Relative efficacy of lasmiditan versus rimegepant and ubrogepant as acute treatments for migraine: network meta-analysis findings. J Headache Pain. 2022 Jul 06;23(1):76. doi: 10.1186/s10194-022-01440-w
  • Singh A, Gupta D, Singh A. Ditans vs gepants: a systematic review and indirect network meta-analysis for comparative analysis of efficacy and safety. Neurol India. 2021 Mar;69(7):S43–s50. doi: 10.4103/0028-3886.315991

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.