Harvard Medical School, Boston, MA 02115, USA.
Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
Brain. 2024 Apr 4;147(4):1312-1320. doi: 10.1093/brain/awad367.
Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38), known for its role in migraine pathogenesis, has been identified as a novel drug target. Given the clinical parallels between post-traumatic headache (PTH) and migraine, we explored the possible role of PACAP-38 in the pathogenesis of PTH. To this end, we conducted a randomized, double-blind, placebo-controlled, two-way crossover trial involving adult participants diagnosed with persistent PTH resulting from mild traumatic brain injury. Participants were randomly assigned to receive a 20-min continuous intravenous infusion of either PACAP-38 (10 pmol/kg/min) or placebo (isotonic saline) on two separate experimental days, with a 1-week washout period in between. The primary outcome was the difference in incidence of migraine-like headache between PACAP-38 and placebo during a 12-h observational period post-infusion. The secondary outcome was the difference in the area under the curve (AUC) for baseline-corrected median headache intensity scores during the same 12-h observational period. Of 49 individuals assessed for eligibility, 21 were enrolled and completed the trial. The participants had a mean age of 35.2 years, and 16 (76%) were female. Most [19 of 21 (90%)] had a migraine-like phenotype. During the 12-h observational period, 20 of 21 (95%) participants developed migraine-like headache after intravenous infusion of PACAP-38, compared with two (10%) participants after placebo (P < 0.001). Furthermore, the baseline-corrected AUC values for median headache intensity scores during the 12-h observational period was higher after PACAP-38 than placebo (P < 0.001). These compelling results demonstrate that PACAP-38 is potent inducer of migraine-like headache in people with persistent PTH. Thus, targeting PACAP-38 signalling might be a promising avenue for the treatment of PTH.
垂体腺苷酸环化酶激活肽-38（PACAP-38）因其在偏头痛发病机制中的作用而被确定为一种新的药物靶点。鉴于创伤后头痛（PTH）和偏头痛之间存在临床相似性，我们探讨了 PACAP-38 在 PTH 发病机制中的可能作用。为此，我们进行了一项随机、双盲、安慰剂对照、双向交叉试验，纳入了被诊断为轻度创伤性脑损伤后持续 PTH 的成年参与者。参与者被随机分配在两天的实验日中接受持续 20 分钟的静脉内输注 PACAP-38（10pmol/kg/min）或安慰剂（等渗盐水），中间有一周的洗脱期。主要结局是在输注后 12 小时观察期间，PACAP-38 与安慰剂之间偏头痛样头痛的发生率差异。次要结局是同一 12 小时观察期间，基线校正中位数头痛强度评分的曲线下面积（AUC）差异。在评估合格性的 49 人中，有 21 人入组并完成了试验。参与者的平均年龄为 35.2 岁，16 人（76%）为女性。大多数[21 人中有 19 人（90%）]有偏头痛样表型。在 12 小时观察期间，21 名参与者中有 20 名（95%）在静脉输注 PACAP-38 后出现偏头痛样头痛，而 2 名（10%）参与者在输注安慰剂后出现偏头痛样头痛（P<0.001）。此外，在 12 小时观察期间，PACAP-38 后基线校正中位数头痛强度评分的 AUC 值高于安慰剂（P<0.001）。这些有力的结果表明，PACAP-38 是持续性 PTH 患者偏头痛样头痛的有力诱导剂。因此，靶向 PACAP-38 信号可能是治疗 PTH 的一种有前途的方法。
