MigraineNCT05718310
Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack
A study testing Nitroglycerin and Saline in people with Migraine and Migraine Disorders, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 2 sites in Italy.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 65 years
- Conditions the study is for
- Migraine, Migraine Disorders, Pain
- What is being tested?
- Nitroglycerin and Saline
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 22 participants
- Where
- 2 sitesItaly
- Study dates
- 1 Nov 2022to Dec 2024
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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;
Show all 10Show fewer
- 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.
Trial locations and contacts
2 sites in 1 country.
Italy2 sites, 2 recruiting
- Recruiting
Headache Science & Neurorehabilitation Center
Pavia, 27100
Roberto De Icco, MD, 0382380387, roberto.deicco@mondino.it
Michele Corrado, MD, 0039 0382 380387, michele.corrado01@universitadipavia.it
- Recruiting
IRCCS Mondino Foundation
Pavia, 27100
Roberto De Icco, MD, 0039 0382 380425, roberto.deicco@mondino.it
Cinzia Fattore, MD, 0039 0382 380385, cinzia.fattore@mondino.it
About this study
Official title: Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack: a Cross-over, Randomized Controlled Study
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).
Read more
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.
Read the detailed description
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 analysis
- Plasma 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.
- Conditions
- Migraine, Migraine Disorders, Pain
- Being tested
- Nitroglycerin, Saline
- Medical subject headings
- Migraine Disorders, Pain
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
NitroglycerinDrug
Also called NTG
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
SalineDrug
Also called Isotonic saline, 0.9% NaCl
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
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: Drug: Nitroglycerin |
| Saline | Placebo comparator | 250 ml of sodium chloride 0.9% will be administered intravenously in 20 minutes via an infusion pump. Receives: Drug: Saline |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 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
A secondary outcome is the difference of the habituation index in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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
A secondary outcome is to assess the difference of the nociceptive blink reflex threshold between the NTG exposed group and the placebo group across the main timepoints
Measured: 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
A secondary outcome is to assess the difference of the nociceptive blink reflex threshold in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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
A secondary outcome is the difference of TNF-alpha, IL-1beta, IL-6, IL-4, IL-10 plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: 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
A secondary outcome is the difference of TNF-alpha, IL-1beta, IL-6, IL-4, IL-10 plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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 quinolinic acid panel expression between the experimental and control group
A secondary outcome is the difference of quinolinic acid plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the quinolinic acid panel expression between in the experimental group treated with sumatriptan
A secondary outcome is the difference of quinolinic acid plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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 CGRP expression between the experimental and control group
A secondary outcome is the difference of CGRP plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the PACAP expression between the experimental and control group
A secondary outcome is the difference of PACAP plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the VIP expression between the experimental and control group
A secondary outcome is the difference of VIP plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the CGRP expression in the experimental group treated with sumatriptan
A secondary outcome is the difference of CGRP plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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 PACAP expression in the experimental group treated with sumatriptan
A secondary outcome is the difference of PACAP plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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 VIP expression in the experimental group treated with sumatriptan
A secondary outcome is the difference of VIP plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: 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 epigenetic panel expression between the experimental and control group
A secondary outcome is the difference of mir-155, mir-382, mir-34a, mir-30a, MALAT1 plasma levels between the NTG exposed group and the placebo group across the main timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the epigenetic panel expression in the experimental group treated with sumatriptan
A secondary outcome is the difference of mir-155, mir-382, mir-34a, mir-30a, MALAT1 plasma levels in patients exposed to NTG who will develop headache with migraine features during the in-hospital observation period, and will be subsequently treated with sumatriptan, as compared to the remaining timepoints
Measured: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2) to 1 hour after sumatriptan injection (TS)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Feb 2023
- Study start1 Nov 2022
- Primary completionDec 2024 (estimated)
- Study completionDec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (11)Papers the sponsor has linked to this study.
- Other trials for MigraineStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 22 participants (estimated)
Sponsor and investigators
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" Foundation
- Sponsor type
- University, hospital or other
- Collaborators
- University of Pavia
- Responsible party
- Sponsor
- Investigators
- Roberto De Icco, MD, Principal investigator, IRCCS, Mondino Foundation
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05718310
- Sponsor's protocol ID
- NTG_nBR
- Status last verified
- Jan 2023
- First submitted
- 19 Jan 2023
- Last updated
- 8 Feb 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
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.
PubMed 25926442Bohotin 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.
PubMed 11912123Di 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.
PubMed 16324171Coppola 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.
PubMed 23899115Di 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.
PubMed 19457613Ashina 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.
PubMed 28984313De 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.
PubMed 31633594Sances 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.
PubMed 14728706De 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.
PubMed 33587406Karsan 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.
PubMed 33423506Demartini 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.
PubMed 30771365
Study at a glance
From the registry record, last updated by the sponsor on 8 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack: a Cross-over, Randomized Controlled Study
- ClinicalTrials.gov ID
- NCT05718310
- Acronym / sponsor ID
- NTG_nBR
- Conditions
- Migraine, Migraine Disorders, Pain
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 22 participants (estimated)
- Lead sponsor
- IRCCS National Neurological Institute "C. Mondino" FoundationUniversity, hospital or other
- Collaborators
- University of Pavia
- Study start
- 1 Nov 2022 (actual)
- Primary completion
- Dec 2024 (estimated)
- Study completion
- Dec 2024 (estimated)
- First posted
- 8 Feb 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 analysis
- Plasma 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.
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Nitroglycerin | Active comparator | Drug: NitroglycerinNitroglycerin 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. |
| Saline | Placebo comparator | Drug: Saline250 ml of sodium chloride 0.9% will be administered intravenously in 20 minutes via an infusion pump. |
Who may qualify
- Ages
- 18 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (10 listed)
- 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;
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| NitroglycerinAlso: NTG25 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 | Drug | Nitroglycerin |
| SalineAlso: Isotonic saline, 0.9% NaCl25 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 | Drug | Saline |
Primary outcome
Difference in the habituation index between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
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
15 secondary outcomes
Difference in the habituation index in the experimental group treated with sumatriptan
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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 quinolinic acid panel expression between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the quinolinic acid panel expression between in the experimental group treated with sumatriptan
Time frame: 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 CGRP expression between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the PACAP expression between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the VIP expression between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the CGRP expression in the experimental group treated with sumatriptan
Time frame: 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 PACAP expression in the experimental group treated with sumatriptan
Time frame: 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 VIP expression in the experimental group treated with sumatriptan
Time frame: 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 epigenetic panel expression between the experimental and control group
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)
Difference in the epigenetic panel expression in the experimental group treated with sumatriptan
Time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2) to 1 hour after sumatriptan injection (TS)
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Feb 2023.
- Background: PubMed 25926442Burstein 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.
- Background: PubMed 11912123Bohotin 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.
- Background: PubMed 16324171Di 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.
- Background: PubMed 23899115Coppola 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.
- Background: PubMed 19457613Di 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.
- Background: PubMed 28984313Ashina 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.
- Background: PubMed 31633594De 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.
- Background: PubMed 14728706Sances 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.
- Background: PubMed 33587406De 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.
- Background: PubMed 33423506Karsan 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.
- Background: PubMed 30771365Demartini 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Roberto De Icco, MD principal investigator
IRCCS, Mondino Foundation
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Nitroglycerin and Saline in people with Migraine and Migraine Disorders, run by IRCCS National Neurological Institute "C. Mondino" Foundation at 2 sites in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Roberto De Icco, MD (0039 0382 380425, roberto.deicco@mondino.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Difference in the habituation index between the experimental and control group (time frame: Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05718310, which also lists 11 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Feb 2023.