Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack : Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack: a Cross-over, Randomized Controlled Study

This is an interventional, randomized, crossover and double-blind placebo-controlled study. The enrolled subjects will participate in two study sessions (V1 and V2, respectively) placed at least one week apart.A first screening visit (V0) is planned, during which the clinical-demographic data will be collected, the patients will undergo a complete neurological and objective examination, and an ECG will be performed to exclude major cardiac pathologies. Patients who meet the inclusion / exclusion criteria will continue with the subsequent study sessions (V1 and V2). During V1 and V2 the subjects must be in the inter-critical phase of the disease, i.e. free from headache and in the absence of analgesic drugs in the previous 48 hours.First study session (V1):At baseline (T0), disease assessment scales (MIDAS, HIT-6, ASC-12, MSQ, BDI, STAI) will be administered, and the first electrophysiological test session (nociceptive blink reflex -nBR) will be performed along with the first blood sample from a peripheral venous catheter positioned in the antecubital vein.At the end of the baseline evaluation, the subjects will be randomized into two groups to receive, during the first of the two sessions, NTG (0.5 μg / kg / min intravenous in 20 minutes) or placebo (intravenous saline in 20 minutes) via infusion pump.The subjects will then be monitored in hospital for 4 hours following the NTG infusion (hospital phase) and then discharged with the indication to keep a headache diary for a further 8 hours (12 hours of overall observation). At the end of the 4 hours of hospital observation, the investigator or the patient may decide to extend the observation period based on the possible occurrence of adverse effects or in any case as required.Starting from the infusion, the onset of headache and associated characteristics (nausea, vomiting, photophobia, phonophobia, location of pain, quality of pain, aggravation with cough, intensity) will be evaluated every ten minutes, as well as the presence of other symptoms or adverse events. The vital parameters (blood pressure, heart rate) will be monitored every 5 minutes during the infusion, then every 10 minutes for the entire duration of the in-hospital observation. Additional vital sign measurements will be performed based on clinical need or trend.After 2 hours (T1) and 4 hours (T2) from the end of the NTG / placebo infusion, the electrophysiological evaluations and blood samples will be repeated, and the assessment scale for allodynia (ASC-12) will be administered.In subjects in which the induced migraine attack will appear within the hospital observation phase (4 hours), sumatriptan 6 mg will be administered subcutaneously. 1 hour after the administration of sumatriptan, the electrophysiological evaluation of the nBR and blood sampling after (TS) will be repeated.Second study session (V2):Patients will return to the center for the second session (V2) of the study at least one week after the first session. The second session will completely mirror the first, patients will receive placebo (intravenous saline in 20 minutes) or NTG (0.5 μg / kg / min intravenous in 20 minutes) in cross-over according to the randomization list.It is specified that, for female subjects, a urine pregnancy test will be carried out before each study session.The patient will be informed that headache may arise during the test, but no information will be shared on the possible course after NTG / placebo to avoid breaking the blind.NBR registration procedure:The R2 response of nBR will be evaluated using a planar concentric electrode (Bionen, Florence, Italy), placed 10 mm above the emergence of the supraorbital nerve. For each subject, the preferential side of pain localization of migraine crises will be chosen, alternatively the right side will be used. Stimulation parameters: single monopolar stimulation, duration 0.3 ms, band filter: 3 Hz to 3 kHz, recording frequency: 2.5 kHz, analysis time: 200ms, sensitivity: 100 mV.The surface electromyographic recording (CED Powerlab 1401, Cambridge Electronic Design) will be carried out at the level of the orbicularis oculi muscle through a pair of surface electrodes, the reference electrode on the side of the eye, the recording electrode on the midpoint of the lower eyelid. A progressive increase in the stimulation intensity (0.3 mA at a time) will be used to evaluate the reflex threshold (RT = reflex threshold), defined as a stably present response to at least 3 stimulations. To assess the habituation of nBR, 26 consecutive stimuli will be administered at different stimulus frequencies, according to a random order (0.2, 0.3, 0.5 Hz), with a stimulation intensity equal to 1.8 times the RT. Of these stimulations, the first will be removed from the analysis to eliminate the startle response. The 25 electromyographic recordings will be collected in 5 blocks, and the values of the area under the amplitude curve (AUC, ms * mV) will be calculated for each block. The percentage change in the AUC of the last block, compared to the first, represents the "habituation index" (HI) value.Biochemical panel:Plasma levels of pro and anti inflammatory cytokines (TNF-alpha, IL-1beta, IL-6, IL-4, IL-10) through a latest generation ELISA analysisPlasma levels of quinolinic acid, through mass spectrometry;Plasma levels of CGRP, PACAP, VIP through commercially available ELISA kits.Gene expression of the cytokines mentioned above and specific microRNAs (mir-155, mir-382, mir-34a, mir-30a) and MALAT1 through RT-PCR method..

Medienart:	Klinische Studie

Erscheinungsjahr:	2023
Erschienen:	2023

Enthalten in:	ClinicalTrials.gov - (2023) vom: 08. Feb. Zur Gesamtaufnahme - year:2023

Sprache:	Englisch

Links:	Volltext [kostenfrei]

Themen:	610 Migraine Disorders Recruitment Status: Recruiting Study Type: Interventional

Anmerkungen:	Source: Link to the current ClinicalTrials.gov record., First posted: February 8, 2023, Last downloaded: ClinicalTrials.gov processed this data on February 15, 2023, Last updated: February 15, 2023

Study ID:

NCT05718310 NTG_nBR

Veröffentlichungen zur Studie:

Burstein R, Noseda R, Borsook D. Migraine: multiple processes, complex pathophysiology. J Neurosci. 2015 Apr 29;35(17):6619-29. doi: 10.1523/JNEUROSCI.0373-15.2015. Bohotin V, Fumal A, Vandenheede M, Gerard P, Bohotin C, Maertens de Noordhout A, Schoenen J. Effects of repetitive transcranial magnetic stimulation on visual evoked potentials in migraine. Brain. 2002 Apr;125(Pt 4):912-22. doi: 10.1093/brain/awf081. Di Clemente L, Coppola G, Magis D, Fumal A, De Pasqua V, Schoenen J. Nociceptive blink reflex and visual evoked potential habituations are correlated in migraine. Headache. 2005 Nov-Dec;45(10):1388-93. doi: 10.1111/j.1526-4610.2005.00271.x. Coppola G, Di Lorenzo C, Schoenen J, Pierelli F. Habituation and sensitization in primary headaches. J Headache Pain. 2013 Jul 30;14(1):65. doi: 10.1186/1129-2377-14-65. Di Clemente L, Coppola G, Magis D, Gerardy PY, Fumal A, De Pasqua V, Di Piero V, Schoenen J. Nitroglycerin sensitises in healthy subjects CNS structures involved in migraine pathophysiology: evidence from a study of nociceptive blink reflexes and visual evoked potentials. Pain. 2009 Jul;144(1-2):156-61. doi: 10.1016/j.pain.2009.04.018. Epub 2009 May 19. Ashina M, Hansen JM, A Dunga BO, Olesen J. Human models of migraine - short-term pain for long-term gain. Nat Rev Neurol. 2017 Dec;13(12):713-724. doi: 10.1038/nrneurol.2017.137. Epub 2017 Oct 6. De Icco R, Perrotta A, Grillo V, Cosentino G, Sances G, Sandrini G, Tassorelli C. Experimentally induced spinal nociceptive sensitization increases with migraine frequency: a single-blind controlled study. Pain. 2020 Feb;161(2):429-438. doi: 10.1097/j.pain.0000000000001726. Sances G, Tassorelli C, Pucci E, Ghiotto N, Sandrini G, Nappi G. Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia. 2004 Feb;24(2):110-9. doi: 10.1111/j.1468-2982.2004.00639.x. De Icco R, Greco R, Demartini C, Vergobbi P, Zanaboni A, Tumelero E, Reggiani A, Realini N, Sances G, Grillo V, Allena M, Tassorelli C. Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks. Pain. 2021 Sep 1;162(9):2376-2385. doi: 10.1097/j.pain.0000000000002223. Karsan N, Perez-Rodriguez A, Nagaraj K, Bose PR, Goadsby PJ. The migraine postdrome: Spontaneous and triggered phenotypes. Cephalalgia. 2021 May;41(6):721-730. doi: 10.1177/0333102420975401. Epub 2021 Jan 10. Demartini C, Greco R, Zanaboni AM, Sances G, De Icco R, Borsook D, Tassorelli C. Nitroglycerin as a comparative experimental model of migraine pain: From animal to human and back. Prog Neurobiol. 2019 Jun;177:15-32. doi: 10.1016/j.pneurobio.2019.02.002. Epub 2019 Feb 13.

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PPN (Katalog-ID):	CTG008930317