Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack

NCT05718310 | Unknown

• 1 other identifier: NTG_nBR
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 2

Brief Summary

People with migraine typically show impaired responsivity to visual, auditory and pain stimuli (Burstein et al, 2015). The electrophysiological study of the nociceptive blink reflex (nBR) is widely adopted for the instrumental evaluation of trigeminal afferent function. Migraine sufferers characteristically show deficits in the habituation to repeated stimulations of various sensory modalities, in the interictal phase of the disease (Bohotin et al, 2002; Di Clemente et al, 2005). It has been described how the habituation / sensitization pattern presents a characteristic pattern over the course of the migraine cycle. Past evidence suggests that the habituation deficit may turn towards a normalization of the pattern near the acute migraine attack (Coppola et al, 2013; Katsarava et al, 2003). However, the study of the spontaneous attack shows various limits and difficulties, mainly due to the impossibility of predicting the onset of the next attack and of standardizing the experimental conditions. The use of human models of migraine allows us to overcome these obstacles. Di Clemente et al. (2009) evaluated the electrophysiological changes in nBR after administration of nitroglycerin (NTG) in healthy subjects. The authors described a modification of trigeminal circuits and cortical responses (visual evoked potentials) after NTG. However, NTG administration does not induce migraine attack in healthy subjects, therefore this model cannot be directly translated to migraine pathology (Ashina et al. 2017). Our group has previously used the human model of migraine based on the administration of NTG to study central and spinal level sensitization through the nociceptive avoidance reflex in the lower limb (RIII) (De Icco et al. 2020). The results of the previous study deepened our understanding of the central mechanisms of sensitization. The investigation of the nBR allows to study the modulation of the caudal trigeminal complex (TCC). In the present study we therefore intend to evaluate, under well-controlled experimental conditions, the modulation of the trigeminal caudal complex during an experimentally induced migraine attack. The study will allow us to confirm or not the normalization of habituation described in the acute phase through the adoption of a solid cross-over and placebo-controlled study design.

Conditions

Migraine; Migraine Disorders; Pain

Outcome Measures

Primary Outcomes (1)

• Difference in the habituation index between the experimental and control group

  The primary outcome is to assess the difference of the habituation index between the NTG exposed group and the placebo group across the main timepoints

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)

Secondary Outcomes (15)

• Difference in the habituation index in the experimental group treated with sumatriptan

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2) to 1 hour after sumatriptan injection (TS)

• Difference in the nociceptive blink reflex threshold between the experimental and control group

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)

• Difference in the nociceptive blink reflex threshold in the experimental group treated with sumatriptan

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2) to 1 hour after sumatriptan injection (TS)

• Difference in the inflammatory cytokines expression between the experimental and control group

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)

• Difference in the inflammatory cytokines expression in the in the experimental group treated with sumatriptan

  Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2) to 1 hour after sumatriptan injection (TS)

Study Arms (2)

Nitroglycerin

ACTIVE COMPARATOR

Nitroglycerin diluted in 250 ml of sodium chloride 0.9% will be administered once via an infusion pump intravenously, at a dose of 0.5 μg/kg/min in 20 minutes.

Drug: Nitroglycerin

Saline

PLACEBO COMPARATOR

250 ml of sodium chloride 0.9% will be administered intravenously in 20 minutes via an infusion pump.

Drug: Saline

Interventions

Nitroglycerin DRUG

25 migraine patients without aura of both genders are randomized to receive a 20-minutes infusion of NTG and/or sterile saline on two days, with at least one week in between

Also known as: NTG

Nitroglycerin

Saline DRUG

25 migraine patients without aura of both genders are randomized to receive a 20-minutes infusion of NTG and/or sterile saline on two days, with at least one week in between

Also known as: Isotonic saline, 0.9% NaCl

Saline

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of "1.1 Migraine without aura", according to ICHD-3 criteria, with a history of disease of at least one year;
• Frequency between 3 and 14 migraine days per month;
• Have completed a prospective headache diary for at least 1 month to confirm diagnosis and frequency.

You may not qualify if:

• Current or previous diagnosis of other forms of primary or secondary headache according to ICHD-3 criteria; it will be possible to enroll patients diagnosed with "2.1 Sporadic episodic tension-type headache", according to ICHD-3 criteria;
• Other conditions causing chronic pain;
• Significant cardiovascular disorders;
• History of other neurological or psychiatric disorders that may affect the study assessments;
• Contraindications or intolerance to the administration of Sumatriptan or NTG;
• Use of more than 1 preventive drug for the treatment of migraine, according to national guidelines;
• Change in the dosage of prevention treatment for migraine in the last month;
• Women in current or planned pregnancy, and breastfeeding;
• Chronic use of active ingredients with analgesic or sedative action (steroids, opioids, anti-inflammatories, paracetamol) or in any case capable of modifying the pain threshold (for example tricyclic antidepressants or serotonin reuptake inhibitors);
• Use of phosphodiesterase inhibitors.

Sponsors & Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation: lead
• University of Pavia: collaborator

Study Sites (2)

Headache Science & Neurorehabilitation Center

Pavia, 27100, Italy

RECRUITING

IRCCS Mondino Foundation

Pavia, 27100, Italy

RECRUITING

Related Publications (11)

• 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.

  PMID: 25926442 BACKGROUND

• 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.

  PMID: 11912123 BACKGROUND

• 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.

  PMID: 16324171 BACKGROUND

• 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.

  PMID: 23899115 BACKGROUND

• 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.

  PMID: 19457613 BACKGROUND

• 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.

  PMID: 28984313 BACKGROUND

• 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.

  PMID: 31633594 BACKGROUND

• 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.

  PMID: 14728706 BACKGROUND

• 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.

  PMID: 33587406 BACKGROUND

• 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.

  PMID: 33423506 BACKGROUND

• 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.

  PMID: 30771365 BACKGROUND

MeSH Terms

Conditions

Migraine Disorders; Pain

Interventions

Nitroglycerin; Sodium Chloride; Saline Solution

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Nitro Compounds; Organic Chemicals; Chlorides; Hydrochloric Acid; Chlorine Compounds; Inorganic Chemicals; Sodium Compounds; Crystalloid Solutions; Isotonic Solutions; Solutions; Pharmaceutical Preparations

Study Officials

• Roberto De Icco, MD

  IRCCS, Mondino Foundation

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Roberto De Icco, MD

CONTACT

0039 0382 380425; roberto.deicco@mondino.it

Cinzia Fattore, MD

CONTACT

0382380385; cinzia.fattore@mondino.it

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 19, 2023
• First Posted: February 8, 2023
• Study Start: November 1, 2022
• Primary Completion: December 1, 2024
• Study Completion: December 1, 2024
• Last Updated: February 8, 2023

Record last verified: 2023-01

Data Sharing

• IPD Sharing: Will not share

Locations

IT (2)