Danish Headache Center and Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
JAMA Neurol. 2018 Oct 1;75(10):1187-1197. doi: 10.1001/jamaneurol.2018.1675.
Signaling molecule calcitonin gene-related peptide (CGRP) induces migraine attacks and anti-CGRP medications abort and prevent migraine attacks. Whether CGRP provokes cluster headache attacks is unknown.
To determine whether CGRP induces cluster headache attacks in episodic cluster headache in active phase, episodic cluster headache in remission phase, and chronic cluster headache.
DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled, 2-way crossover study set at the Danish Headache Center, Rigshospitalet Glostrup, in Denmark. Analyses were intent to treat. Inclusion took place from December 2015 to April 2017. Inclusion criteria were diagnosis of episodic/chronic cluster headache, patients aged 18 to 65 years, and safe contraception in women. Exclusion criteria were a history of other primary headache (except episodic tension-type headache <5 days/mo), individuals who were pregnant or nursing; cardiovascular, cerebrovascular, or psychiatric disease; and drug misuse.
Thirty-seven patients with cluster headaches received intravenous infusion of 1.5 μg/min of CGRP or placebo over 20 minutes on 2 study days.
Difference in incidence of cluster headache-like attacks, difference in area under the curve (AUC) for headache intensity scores (0 to 90 minutes), and difference in time to peak headache between CGRP and placebo in the 3 groups.
Of 91 patients assessed for eligibility, 32 patients (35.2%) were included in the analysis. The mean (SD) age was 36 (10.7) years (range, 19-60 years), and the mean weight was 78 kg (range, 53-100 kg). Twenty-seven men (84.4%) completed the study. Calcitonin gene-related peptide induced cluster headache attacks in 8 of 9 patients in the active phase (mean, 89%; 95% CI, 63-100) compared with 1 of 9 in the placebo group (mean, 11%; 95% CI, 0-37) (P = .05). In the remission phase, no patients with episodic cluster headaches reported attacks after CGRP or placebo. Calcitonin gene-related peptide-induced attacks occurred in 7 of 14 patients with chronic cluster headaches (mean, 50%; 95% CI, 20-80) compared with none after placebo (P = .02). In patients with episodic active phase, the mean AUC from 0 to 90 minutes for CGRP was 1.903 (95% CI, 0.842-2.965), and the mean AUC from 0 to 90 minutes for the placebo group was 0.343 (95% CI, 0-0.867) (P = .04). In patients with chronic cluster headache, the mean AUC from 0 to 90 minutes for CGRP was 1.214 (95% CI, 0.395-2.033), and the mean AUC from 0 to 90 minutes for the placebo group was 0.036 (95% CI, 0-0.114) (P = .01). In the remission phase, the mean AUC from 0 to 90 minutes for CGRP was 0.187 (95% CI, 0-0.571), and the mean AUC from 0 to 90 minutes for placebo was 0.019 (95% CI, 0-0.062) (P > .99).
Calcitonin gene-related peptide provokes cluster headache attacks in active-phase episodic cluster headache and chronic cluster headache but not in remission-phase episodic cluster headache. These results suggest anti-CGRP drugs may be effective in cluster headache management.
ClinicalTrials.gov (NCT02466334).
重要性：信号分子降钙素基因相关肽（CGRP）可引发偏头痛发作，而抗 CGRP 药物可终止和预防偏头痛发作。CGRP 是否引发丛集性头痛发作尚不清楚。
目的：确定 CGRP 在发作性丛集性头痛的活动期、缓解期和慢性丛集性头痛中是否引发丛集性头痛发作。
设计、设置和参与者：这是一项在丹麦哥本哈根的丹麦头痛中心进行的、随机、双盲、安慰剂对照、2 向交叉研究。分析采用意向治疗。纳入时间为 2015 年 12 月至 2017 年 4 月。纳入标准为诊断为发作性/慢性丛集性头痛、年龄 18 至 65 岁、女性安全避孕。排除标准为其他原发性头痛（除了发作性紧张型头痛<5 天/月）、妊娠或哺乳期、心血管疾病、脑血管疾病或精神疾病；以及药物滥用。
干预措施：37 名丛集性头痛患者在 2 个研究日接受静脉输注 1.5μg/min 的 CGRP 或安慰剂，持续 20 分钟。
主要结果和测量：CGRP 和安慰剂组在 3 组中的丛集性头痛样发作发生率差异、头痛强度评分（0 至 90 分钟）的曲线下面积（AUC）差异和头痛峰值时间差异。
结果：在 91 名符合条件的患者中，32 名患者（35.2%）纳入分析。平均（SD）年龄为 36（10.7）岁（范围，19-60 岁），平均体重为 78 公斤（范围，53-100 公斤）。27 名男性（84.4%）完成了研究。CGRP 在 9 名活动期丛集性头痛患者中诱发了 8 名（平均，89%；95%CI，63-100）头痛发作，而安慰剂组中仅有 1 名（平均，11%；95%CI，0-37）（P=0.05）。在缓解期，没有发作性丛集性头痛患者在接受 CGRP 或安慰剂后报告发作。CGRP 诱导的发作发生在 14 名慢性丛集性头痛患者中的 7 名（平均，50%；95%CI，20-80），而安慰剂组中无发作（P=0.02）。在发作性活动期患者中，CGRP 组 0 至 90 分钟的 AUC 为 1.903（95%CI，0.842-2.965），安慰剂组为 0.343（95%CI，0-0.867）（P=0.04）。在慢性丛集性头痛患者中，CGRP 组 0 至 90 分钟的 AUC 为 1.214（95%CI，0.395-2.033），安慰剂组为 0.036（95%CI，0-0.114）（P=0.01）。在缓解期，CGRP 组 0 至 90 分钟的 AUC 为 0.187（95%CI，0-0.571），安慰剂组为 0.019（95%CI，0-0.062）（P>.99）。
结论和相关性：CGRP 可引发活动期发作性丛集性头痛和慢性丛集性头痛发作，但不会引发缓解期发作性丛集性头痛发作。这些结果表明抗 CGRP 药物可能对丛集性头痛的管理有效。
试验注册：ClinicalTrials.gov（NCT02466334）。
