Mannes Andrew J, Heiss John D, Berger Ann, Alewine Christine C, Butman John A, Hughes Marybeth S, Rabbee Nusrat, Hayes Christina, Williams Tracy S, Sapio Matthew R, Iadarola Michael J
Department of Perioperative Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
NEJM Evid. 2025 Jun;4(6):EVIDoa2400423. doi: 10.1056/EVIDoa2400423. Epub 2025 May 27.
A substantial number of patients with advanced cancer suffer from refractory pain despite comprehensive medical management. In this article, we evaluate a nonopioid analgesic, resiniferatoxin (RTX), a potent agonist of the transient receptor potential vanilloid 1 (TRPV1) ion channel, which selectively interrupts nociceptive activity transmitted by a subpopulation of dorsal root ganglion neurons.
In this interim analysis of a first-in-human, open-label, Phase 1 study, 19 patients with refractory cancer pain localized to the abdomen and/or lower extremities received one dose of intrathecal RTX. The primary outcome was safety. Secondary outcomes were efficacy assessed over the course of the study using a numerical rating scale measuring the "worst pain" over a 24-hour period. This is a 0 to 10 scale where 0 is "no pain" and 10 is the "worst pain imaginable." Opioid consumption was measured as morphine equivalents used to control pain.
Over 188 days after RTX injection, a total of 213 treatment-emergent adverse events (AEs) were reported among 19 patients treated, including 37 serious adverse events in 14 patients. Nine deaths occurred an average of 70 days after treatment (range from 11 to 140 days). Many of these events, including death, are consistent with the course of advanced cancer. At least one AE occurred in all 19 patients. Three patients experienced loss of heat sensitivity in the dermatomes exposed to RTX (grades I and II). Seven patients experienced urinary retention lasting more than 24 hours (three were grade III). Five patients had AEs related to a transient increase in the electrocardiographic QT interval that resolved within 24 hours (grades I and II). The only grade IV AE was an unstageable decubitus ulcer. RTX was associated with decreased "worst" pain intensity by 38% (pretreatment 8.4±0.4 vs. posttreatment 5.2±0.6) and reduced opioid consumption by 57% measured at posttreatment day 15.
Intrathecal RTX is a single-administration, opioid-sparing analgesic in patients with intractable cancer pain. There were expected and unexpected AEs of various grades with an encouraging initial impact on pain. (Funded by the Intramural Research Program of the National Institutes of Health Clinical Center and others; ClinicalTrials.gov number, NCT00804154).
尽管进行了全面的药物治疗，但仍有相当数量的晚期癌症患者遭受难治性疼痛。在本文中，我们评估了一种非阿片类镇痛药——树脂毒素（RTX），它是瞬时受体电位香草酸亚型1（TRPV1）离子通道的强效激动剂，可选择性地阻断背根神经节神经元亚群传递的伤害性活动。
在这项首次人体开放标签1期研究的中期分析中，19例腹部和/或下肢难治性癌痛患者接受了一剂鞘内注射RTX。主要结局是安全性。次要结局是在研究过程中使用数字评分量表评估疗效，该量表测量24小时内的“最严重疼痛”。这是一个0至10的量表，其中0表示“无疼痛”，10表示“难以想象的最严重疼痛”。阿片类药物的消耗量以用于控制疼痛的吗啡当量来衡量。
在RTX注射后的188天内，19例接受治疗的患者共报告了213例治疗中出现的不良事件（AE），其中14例患者出现了37例严重不良事件。9例患者在治疗后平均70天（11至140天）死亡。许多这些事件，包括死亡，都与晚期癌症的病程一致。所有19例患者均至少出现了1次AE。3例患者在暴露于RTX的皮节中出现热敏感性丧失（I级和II级）。7例患者出现持续超过24小时的尿潴留（3例为III级）。5例患者出现与心电图QT间期短暂延长相关的AE，这些AE在24小时内缓解（I级和II级）。唯一的IV级AE是1例无法分期的褥疮溃疡。RTX使“最严重”疼痛强度降低了38%（治疗前8.4±0.4 vs. 治疗后5.2±0.6），并使治疗后第15天测量的阿片类药物消耗量降低了57%。
鞘内注射RTX是一种用于治疗顽固性癌痛患者的单次给药、节省阿片类药物的镇痛药。出现了各种等级的预期和意外AE，对疼痛产生了令人鼓舞的初步影响。（由美国国立卫生研究院临床中心的内部研究项目及其他机构资助；ClinicalTrials.gov编号，NCT00804154）
