Top

Published in:

Open Access 01-12-2022 | Central Nervous System Trauma | Research

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury

Authors: Håkan Ashina, Afrim Iljazi, Haidar M. Al-Khazali, Thien Phu Do, Anna K. Eigenbrodt, Eigil L. Larsen, Amalie M. Andersen, Kevin J. Hansen, Karoline B. Bräuner, Basit Ali Chaudhry, Casper E. Christensen, Faisal Mohammad Amin, Henrik W. Schytz

Published in: The Journal of Headache and Pain | Issue 1/2022

Abstract

Objective

To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine.

Methods

A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period.

Results

A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5–43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20–60), and the median peak headache intensity was 6 (IQR, 5–8) on the 11-point numeric rating scale.

Conclusion

Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.

Ashina H, Eigenbrodt AK, Seifert T, Sinclair AJ, Scher AI, Schytz HW, Lee MJ, de Icco R, Finkel AG, Ashina M (2021) Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment. Lancet Neurol 20(6):460–469. https://doi.org/10.1016/S1474-4422(21)00094-6CrossRefPubMed

Lieba-Samal D, Platzer P, Seidel S, Klaschterka P, Knopf A, Wober C (2011) Characteristics of acute posttraumatic headache following mild head injury. Cephalalgia 31(16):1618–1626. https://doi.org/10.1177/0333102411428954CrossRefPubMed

Lucas S, Hoffman JM, Bell KR, Dikmen S (2014) A prospective study of prevalence and characterization of headache following mild traumatic brain injury. Cephalalgia 34(2):93–102. https://doi.org/10.1177/0333102413499645CrossRefPubMed

van der Naalt J, Timmerman ME, de Koning ME, van der Horn HJ, Scheenen ME, Jacobs B et al (2017) Early predictors of outcome after mild traumatic brain injury (UPFRONT): an observational cohort study. Lancet Neurol 16(7):532–540. https://doi.org/10.1016/S1474-4422(17)30117-5CrossRefPubMed

Voormolen DC, Haagsma JA, Polinder S, Maas AIR, Steyerberg EW, Vuleković P, Sewalt CA, Gravesteijn BY, Covic A, Andelic N, Plass AM, von Steinbuechel N (2019) Post-Concussion Symptoms in Complicated vs. Uncomplicated Mild Traumatic Brain Injury Patients at Three and Six Months Post-Injury: Results from the CENTER-TBI Study. J Clin Med 8(11):1921. https://doi.org/10.3390/jcm8111921CrossRefPubMedCentral

Ingebrigtsen T, Waterloo K, Marup-Jensen S, Attner E, Romner B (1998) Quantification of post-concussion symptoms 3 months after minor head injury in 100 consecutive patients. J Neurol 245(9):609–612. https://doi.org/10.1007/s004150050254CrossRefPubMed

Xu H, Pi H, Ma L, Su X, Wang J (2016) Incidence of Headache After Traumatic Brain Injury in China: A Large Prospective Study. World Neurosurg 88:289–296. https://doi.org/10.1016/j.wneu.2015.12.028CrossRefPubMed

Ashina H, Iljazi A, Al-Khazali HM, Ashina S, Jensen RH, Amin FM et al (2020) Persistent post-traumatic headache attributed to mild traumatic brain injury: deep phenotyping and treatment patterns. Cephalalgia 40(6):554–564. https://doi.org/10.1177/0333102420909865CrossRefPubMed

Ashina H, Porreca F, Anderson T, Amin FM, Ashina M, Schytz HW, Dodick DW (2019) Post-traumatic headache: epidemiology and pathophysiological insights. Nat Rev Neurol 15(10):607–617. https://doi.org/10.1038/s41582-019-0243-8CrossRefPubMed

10.

Ashina H, Dodick DW (2022) Post-traumatic Headache: Pharmacologic Management and Targeting CGRP Signaling. Curr Neurol Neurosci Rep 22(2):105–111. https://doi.org/10.1007/s11910-022-01175-wCrossRefPubMed

11.

Ashina H, Iljazi A, Al-Khazali HM, Christensen CE, Amin FM, Ashina M et al (2020) Hypersensitivity to Calcitonin Gene-Related Peptide in Post-Traumatic Headache. Ann Neurol 88(6):1220–1228. https://doi.org/10.1002/ana.25915CrossRefPubMed

12.

Ashina H, Moskowitz MA (2021) Shared biological foundations of post-traumatic headache and migraine. Headache 61(3):558–559. https://doi.org/10.1111/head.14084CrossRefPubMed

13.

Headache Classification Committee of the International Headache Society (IHS) (2018) The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38(1):1–211

14.

Iljazi A, Ashina H, Zhuang ZA, Lopez Lopez C, Snellman J, Ashina M, Schytz HW (2021) Hypersensitivity to calcitonin gene-related peptide in chronic migraine. Cephalalgia 41(6):701–710. https://doi.org/10.1177/0333102420981666CrossRefPubMed

15.

Younis S, Christensen CE, Toft NM, Søborg T, Amin FM, Hougaard A, Ashina M (2019) Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil. Cephalalgia 39(14):1776–1788. https://doi.org/10.1177/0333102419882474CrossRefPubMed

16.

Vollesen ALH, Snoer A, Beske RP, Guo S, Hoffmann J, Jensen RH, Ashina M (2018) Effect of Infusion of Calcitonin Gene-Related Peptide on Cluster Headache Attacks: A Randomized Clinical Trial. JAMA Neurol 75(10):1187–1197. https://doi.org/10.1001/jamaneurol.2018.1675CrossRefPubMedPubMedCentral

17.

Ashina M (2020) Migraine. N Engl J Med 383(19):1866–1876. https://doi.org/10.1056/NEJMra1915327CrossRefPubMed

18.

Ashina M, Hansen JM, Do TP, Melo-Carrillo A, Burstein R, Moskowitz MA (2019) Migraine and the trigeminovascular system-40 years and counting. Lancet Neurol 18(8):795–804. https://doi.org/10.1016/S1474-4422(19)30185-1CrossRefPubMedPubMedCentral

19.

Iyengar S, Johnson KW, Ossipov MH, Aurora SK (2019) CGRP and the Trigeminal System in Migraine. Headache 59(5):659–681. https://doi.org/10.1111/head.13529CrossRefPubMedPubMedCentral

20.

Iyengar S, Ossipov MH, Johnson KW (2017) The role of calcitonin gene-related peptide in peripheral and central pain mechanisms including migraine. Pain 158(4):543–559. https://doi.org/10.1097/j.pain.0000000000000831CrossRefPubMedPubMedCentral

21.

Kopruszinski CM, Turnes JM, Swiokla J, Weinstein TJ, Schwedt TJ, Dodick DW, Anderson T, Navratilova E, Porreca F (2021) CGRP monoclonal antibody prevents the loss of diffuse noxious inhibitory controls (DNIC) in a mouse model of post-traumatic headache. Cephalalgia 41(6):749–759. https://doi.org/10.1177/0333102420981688CrossRefPubMed

22.

Navratilova E, Rau J, Oyarzo J, Tien J, Mackenzie K, Stratton J, Remeniuk B, Schwedt T, Anderson T, Dodick D, Porreca F (2019) CGRP-dependent and independent mechanisms of acute and persistent post-traumatic headache following mild traumatic brain injury in mice. Cephalalgia 39(14):1762–1775. https://doi.org/10.1177/0333102419877662CrossRefPubMed

23.

Bree D, Levy D (2018) Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 38(2):246–258. https://doi.org/10.1177/0333102416681571CrossRefPubMed

24.

Daiutolo BV, Tyburski A, Clark SW, Elliott MB (2016) Trigeminal Pain Molecules, Allodynia, and Photosensitivity Are Pharmacologically and Genetically Modulated in a Model of Traumatic Brain Injury. J Neurotrauma 33(8):748–760. https://doi.org/10.1089/neu.2015.4087CrossRefPubMedPubMedCentral

25.

Ashina M, Terwindt GM, Al-Karagholi MA, de Boer I, Lee MJ, Hay DL, Schulte LH, Hadjikhani N, Sinclair AJ, Ashina H, Schwedt TJ, Goadsby PJ (2021) Migraine: disease characterisation, biomarkers, and precision medicine. Lancet 397(10283):1496–1504. https://doi.org/10.1016/S0140-6736(20)32162-0CrossRefPubMed

26.

Al-Karagholi MA, Hansen JM, Guo S, Olesen J, Ashina M (2019) Opening of ATP-sensitive potassium channels causes migraine attacks: a new target for the treatment of migraine. Brain 142(9):2644–2654. https://doi.org/10.1093/brain/awz199CrossRefPubMed

27.

Al-Karagholi MA, Ghanizada H, Waldorff Nielsen CA, Skandarioon C, Snellman J, Lopez-Lopez C, Hansen JM, Ashina M (2021) Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine. Pain 162(10):2512–2520. doi: https://doi.org/10.1097/j.pain.0000000000002238CrossRefPubMed

28.

Hansen JM, Hauge AW, Olesen J, Ashina M (2010) Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30(10):1179–1186. https://doi.org/10.1177/0333102410368444CrossRefPubMed

29.

Schytz HW, Birk S, Wienecke T, Kruuse C, Olesen J, Ashina M (2009) PACAP38 induces migraine-like attacks in patients with migraine without aura. Brain 132(Pt 1):16–25. https://doi.org/10.1093/brain/awn307CrossRefPubMed

30.

Ghanizada H, Al-Karagholi MA, Arngrim N, Olesen J, Ashina M (2020) PACAP27 induces migraine-like attacks in migraine patients. Cephalalgia 40(1):57–67. https://doi.org/10.1177/0333102419864507CrossRefPubMed

31.

Ghanizada H, Al-Karagholi MA, Walker CS, Arngrim N, Rees T, Petersen J, Siow A, Mørch-Rasmussen M, Tan S, O’Carroll SJ, Harris P, Skovgaard LT, Jørgensen NR, Brimble M, Waite JS, Rea BJ, Sowers LP, Russo AF, Hay DL, Ashina M (2021) Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients. Ann Neurol 89(6):1157–1171. https://doi.org/10.1002/ana.26072CrossRefPubMedPubMedCentral

32.

Ghanizada H, Al-Karagholi MA, Arngrim N, Mørch-Rasmussen M, Walker CS, Hay DL, Ashina M (2021) Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study. Neurology 96(20):e2488–e2499. https://doi.org/10.1212/WNL.0000000000011930CrossRefPubMed

33.

Guo S, Olesen J, Ashina M (2014) Phosphodiesterase 3 inhibitor cilostazol induces migraine-like attacks via cyclic AMP increase. Brain 137(Pt 11):2951–2959. https://doi.org/10.1093/brain/awu244CrossRefPubMed

34.

Christensen CE, Younis S, Lindberg U, de Koning P, Tolnai D, Paulson OB, Larsson HBW, Amin FM, Ashina M (2021) Intradural artery dilation during experimentally induced migraine attacks. Pain 162(1):176–183. https://doi.org/10.1097/j.pain.0000000000002008CrossRefPubMed

35.

Ferrari MD, Goadsby PJ, Burstein R, Kurth T, Ayata C, Charles A, Ashina M, van den Maagdenberg AMJM, Dodick DW (2022) Migraine. Nat Rev Dis Primers 8(1):2. https://doi.org/10.1038/s41572-021-00328-4CrossRefPubMed

36.

Melo-Carrillo A, Strassman AM, Nir RR, Schain AJ, Noseda R, Stratton J, Burstein R (2017) Fremanezumab-A Humanized Monoclonal Anti-CGRP Antibody-Inhibits Thinly Myelinated (Aδ) But Not Unmyelinated (C) Meningeal Nociceptors. J Neurosci 37(44):10587–10596. https://doi.org/10.1523/JNEUROSCI.2211-17.2017CrossRefPubMedPubMedCentral

37.

Noseda R, Schain AJ, Melo-Carrillo A, Tien J, Stratton J, Mai F, Strassman AM, Burstein R (2020) Fluorescently-labeled fremanezumab is distributed to sensory and autonomic ganglia and the dura but not to the brain of rats with uncompromised blood brain barrier. Cephalalgia 40(3):229–240. https://doi.org/10.1177/0333102419896760CrossRefPubMed

38.

De Logu F, Nassini R, Hegron A, Landini L, Jensen DD, Latorre R, Ding J, Marini M, Souza Monteiro de Araujo D, Ramírez-Garcia P, Whittaker M, Retamal J, Titiz M, Innocenti A, Davis TP, Veldhuis N, Schmidt BL, Bunnett NW, Geppetti P (2022) Schwann cell endosome CGRP signals elicit periorbital mechanical allodynia in mice. Nat Commun 13(1):646. doi: https://doi.org/10.1038/s41467-022-28204-zCrossRefPubMedPubMedCentral

39.

Ashina H, Iljazi A, Al-Khazali HM, Eigenbrodt AK, Larsen EL, Andersen AM, Hansen KJ, Bräuner KB, Mørch-Jessen T, Chaudhry B, Antic S, Christensen CE, Ashina M, Amin FM, Schytz HW (2020) Efficacy, tolerability, and safety of erenumab for the preventive treatment of persistent post-traumatic headache attributed to mild traumatic brain injury: an open-label study. J Headache Pain 21(1):62. https://doi.org/10.1186/s10194-020-01136-zCrossRefPubMedPubMedCentral

40.

Amin FM, Hougaard A, Schytz HW, Asghar MS, Lundholm E, Parvaiz AI, de Koning PJ, Andersen MR, Larsson HB, Fahrenkrug J, Olesen J, Ashina M (2014) Investigation of the pathophysiological mechanisms of migraine attacks induced by pituitary adenylate cyclase-activating polypeptide-38. Brain 137(Pt 3):779–794. https://doi.org/10.1093/brain/awt369CrossRefPubMed

41.

Benemei S, Labastida-Ramírez A, Abramova E, Brunelli N, Caronna E, Diana P, Gapeshin R, Hofacker MD, Maestrini I, Pías EM, Mikulenka P, Tikhonova O, Martelletti P, MaassenVanDenBrink A, European Headache Federation School of Advanced Studies (EHF-SAS) (2020) Persistent post-traumatic headache: a migrainous loop or not? The preclinical evidence. J Headache Pain 14(1):90. doi: https://doi.org/10.1186/s10194-020-01135-0CrossRef

42.

Labastida-Ramírez A, Benemei S, Albanese M, D’Amico A, Grillo G, Grosu O, Ertem DH, Mecklenburg J, Fedorova EP, Řehulka P, di Cola FS, Lopez JT, Vashchenko N, MaassenVanDenBrink A, Martelletti P(2020) ; Persistent post-traumatic headache: a migrainous loop or not? The clinical evidence. J Headache Pain. 2020 May 24;21(1):55. doi: https://doi.org/10.1186/s10194-020-01122-5

Title: CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury
Authors: Håkan Ashina
Afrim Iljazi
Haidar M. Al-Khazali
Thien Phu Do
Anna K. Eigenbrodt
Eigil L. Larsen
Amalie M. Andersen
Kevin J. Hansen
Karoline B. Bräuner
Basit Ali Chaudhry
Casper E. Christensen
Faisal Mohammad Amin
Henrik W. Schytz
Publication date: 01-12-2022
Publisher: Springer Milan
Keywords: Central Nervous System Trauma
Migraine
Traumatic Brain Injuries
Tension Headache
Headache
Published in: The Journal of Headache and Pain / Issue 1/2022
Print ISSN: 1129-2369
Electronic ISSN: 1129-2377
DOI: https://doi.org/10.1186/s10194-022-01499-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury

Abstract

Objective

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2022

Pre-attack and pre-episode symptoms in cluster headache: a multicenter cross-sectional study of 327 Chinese patients

Altered functional connectivity of the right caudate nucleus in chronic migraine: a resting-state fMRI study

Expression of vasopressin and its receptors in migraine-related regions in CNS and the trigeminal system: influence of sex

Longitudinal changes in functional connectivity and pain-induced brain activations in patients with migraine: a functional MRI study pre- and post- treatment with Erenumab

Headache, anosmia, ageusia and other neurological symptoms in COVID-19: a cross-sectional study

Two-year effectiveness of erenumab in resistant chronic migraine: a prospective real-world analysis