Habituation of the Nociceptive Blink Reflex in Experimentally Induced Migraine Attack: a Cross-over, Randomized Controlled Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 22
- 试验地点
- 2
- 主要终点
- Difference in the habituation index between the experimental and control group
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Basic Science
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
研究组 & 干预措施
Nitroglycerin
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.
干预措施: Nitroglycerin (Drug)
Saline
250 ml of sodium chloride 0.9% will be administered intravenously in 20 minutes via an infusion pump.
干预措施: Saline (Drug)
结局指标
主要结局
Difference in the habituation index between the experimental and control group
时间窗: 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
次要结局
- 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))
- Difference in the CGRP 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 CGRP expression 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 VIP expression 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 quinolinic acid panel 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 quinolinic acid panel expression between 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 PACAP 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 VIP 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 PACAP expression 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 epigenetic panel expression 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 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 epigenetic panel expression between the experimental and control group(Change from baseline (T0) to 2 hours after infusion (T1) to 4 hours after infusion (T2))