Ketamine to reduce postpartum depression and pain after cesarean delivery

氯胺酮可减轻产后抑郁和剖腹产后的疼痛

• 批准号: 10752797
• 负责人: Grace Lim
• 金额: $ 59.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10752797
• 关键词: Abdomen; Absence of pain sensation; Address; Advisory Committees; Affect; Birth; CD6 antigen; Cesarean section; Child; Clinical; Data; Deceleration; Depressed mood; Dimensions; Dose; Drug Kinetics; Future; Goals; Hemorrhage; Hour; Human Milk; Individual; Infant Care; Infusion procedures; Investigation; Ketamine; Knowledge; Lactation; Longterm Follow-up; Maternal Mortality; Maximum Tolerated Dose; Measures; Mental Depression; Mental Health; Minority; Modeling; Moods; Mothers; NMDA receptor antagonist; National Institute of Child Health and Human Development; Nausea; Neonatal; Observational Study; Operative Surgical Procedures; Opioid; Outcome; Pain; Pain management; Patients; Pharmaceutical Preparations; Pharmacodynamics; Plasma; Population; Postoperative Pain; Postpartum Depression; Postpartum Period; Postpartum Women; Predictive Factor; Pregnancy; Prevention; Preventive therapy; Publishing; Recovery; Reporting; Research; Risk; Safety; Sedation procedure; Serious Adverse Event; Site; Special Population; Suicide; Symptoms; Testing; Thinking; Vasoconstrictor Agents; Woman; Work; appropriate dose; concept mapping; depression model; depressive symptoms; design; diaries; drug disposition; dysphoria; effective therapy; expectation; experience; improved; individual variation; innovation; instrument; milk secretion; multimodality; new therapeutic target; non-opioid analgesic; novel; novel strategies; novel therapeutic intervention; open label; opioid use; pain outcome; pain reduction; pharmacokinetics and pharmacodynamics; postcesarean section; pregnant; prevent; prospective; randomized trial; secondary analysis; side effect; trial design

PROJECT SUMMARY (ABSTRACT) Postpartum depression (PPD) affects 28 million mothers worldwide in the first year after birth, risking suicide— a leading cause of maternal death globally—and placing children at risk for future mental health problems. Cesarean delivery (CD) is the most common major abdominal surgery in the world, and a lack of data on new pain treatments in pregnancy and lactation puts 1.2 million US women every year after CD at risk for poor pain control, depressed mood, and poor recovery. Despite high individual variability in pain after CD, current CD treatments ignore the multidimensionality of pain. NMDA receptor antagonists like ketamine are known to reduce postoperative pain and opioid use in non-obstetric surgical populations, and recently, ketamine has been recognized for its utility in treating depression. Although limited-use postpartum ketamine studies show no evidence of serious negative effects, ketamine has known and undesirable side effects (e.g., nausea, dysphoria) which can interfere with newborn care. Studies on pregnant/lactating women are limited by lack of data on optimal dose and long-term PPD and pain recovery outcomes. This knowledge gap precludes understanding how ketamine might reduce PPD and pain in this population. There is a critical need for better treatments to reduce PPD risk and pain after CD. To address these needs, we will identify ketamine’s tolerable dose, pharmacokinetics, and pharmacodynamics after CD so that future randomized trials using appropriately dosed ketamine in postpartum women can be conducted. Our long-term goal is to reduce the burden and impact of depression and pain in special populations. Our central hypothesis is that post-CD ketamine reduces PPD risk by reducing pain in multiple dimensions. Specific Aims: A1: Quantify tolerable dose of postpartum ketamine using MTD design. A2: Identify PK/PD of postpartum ketamine infusion in an open-label observational study. A3: Identify change points/trajectories of PPD symptoms to inform future postpartum ketamine trial outcomes. This proposal has the potential to change practice because preventive therapies for PPD are lacking, and the dearth of alternative non-opioid analgesia after CD has been a critical barrier to progress in postpartum pain recovery. Our approach is innovative because it employs novel theoretical concepts to postpartum multimodal pain management strategies. It addresses gaps in prior studies that used best-guess doses of ketamine, leading to variable results on efficacy and side effects. This work will identify new therapeutic strategies that reduce both PPD risk and postpartum pain. It will directly inform the next steps for a randomized trial on post-CD ketamine at a tolerable dose, for PPD and pain recovery outcomes.

项目概要（摘要） 产后抑郁症 (PPD) 影响着全球 2800 万母亲在出生后的第一年，她们面临着自杀的风险—— 是全球孕产妇死亡的主要原因，并使儿童面临未来出现心理健康问题的风险。 剖腹产（CD）是世界上最常见的腹部大手术，但缺乏新的数据 妊娠期和哺乳期的疼痛治疗每年使 120 万美国妇女在 CD 后面临疼痛加剧的风险 尽管 CD 后疼痛的个体差异很大，但当前的 CD 仍存在个体差异。 众所周知，治疗方法忽视了 NMDA 受体拮抗剂（如氯胺酮）的多维性。 减少非产科手术人群的术后疼痛和阿片类药物的使用，最近，氯胺酮已 尽管有限使用产后氯胺酮的研究表明，氯胺酮在治疗抑郁症方面的功效已得到认可。 没有证据表明存在严重的负面影响，氯胺酮有已知的不良副作用（例如恶心、 烦躁不安），这可能会干扰新生儿护理，对孕妇/哺乳期妇女的研究因缺乏而受到限制。 有关最佳剂量以及长期 PPD 和疼痛恢复结果的数据排除了这一知识差距。 了解氯胺酮如何减少该人群的 PPD 和疼痛 迫切需要更好的方法。 降低 PPD 风险和 CD 后疼痛的治疗方法 为了满足这些需求，我们将确定氯胺酮的耐受性。 CD 后的剂量、药代动力学和药效学，以便未来的随机试验适当使用 我们的长期目标是减轻产后妇女的负担和服用氯胺酮。 我们的中心假设是 CD 后氯胺酮会减少抑郁和疼痛对特殊人群的影响。 通过多维度减少疼痛来降低 PPD 风险 具体目标：A1：量化产后的耐受剂量。 使用 MTD 设计的氯胺酮：确定开放标签中产后氯胺酮输注的 PK/PD。 A3：确定 PPD 症状的变化点/轨迹，为未来的产后提供信息。 该提案有可能改变实践，因为预防性疗法。 缺乏 PPD，并且 CD 后缺乏替代性非阿片类镇痛已成为关键障碍 我们的方法是创新的，因为它采用了新颖的理论。 它解决了之前使用的研究中的空白。 这项工作将确定氯胺酮的最佳剂量，从而导致疗效和副作用的不同结果。 降低产后抑郁症风险和产后疼痛的新治疗策略将直接指导下一步。 一项关于 CD 后可耐受剂量氯胺酮的随机试验，用于 PPD 和疼痛恢复结果。