Safety, tolerability, and dose limiting toxicity of lacosamide in patients with painful chronic pancreatitis

摘要：背景：慢性腹痛是慢性腹痛的标志症状。 胰腺炎(CP)，50%-80%的患者寻求医疗服务以控制疼痛。虽然有几个 管理选择可能是可用的，结果往往令人失望，阿片类药物 仍然是治疗的支柱。阿片诱导性痛觉过敏(OIH)可能会发生，这是一种现象 导致剂量增加，部分原因似乎是阿片类药物对疼痛的影响- 相关的电压门控钠通道。乳糖胺阻断和稳定这些通道 并可抑制OIH的作用。这可能会改善疼痛控制，减少 阿片类药物的使用。在神经病理性疼痛的临床前和临床试验中，乳糖胺降低了疼痛评分 并得到了很好的容忍。然而，没有数据评估乳糖胺在CP中的使用 病人。目的：1.评价阿司匹林的安全性、耐受性和剂量限制毒性 疑似和明确疼痛CP患者的乳糖胺对阿片类药物的治疗；2.评估 在这些受试者的阿片类药物治疗中加入乳糖胺的先导性研究的可行性。 作为一项探索性目标，我们将评估在阿片类药物治疗中加入乳糖胺的疗效。 CP所致腹痛的治疗。方法：这是一项第一阶段试验，利用贝叶斯方法 最佳间隔(Boin)设计以求出最大耐受剂量(MTD)。目标剂量- MTD的极限毒性(DLT)率为ɸ=0.3，最大样本量为24。给定 样本量小，预计研究周期相对较短，并有可能在 几个临床中心，预计所有数据将在研究的36个月内积累 入会仪式。意义：这项研究将产生关于安全性、毒性和 乳糖胺在慢性前列腺炎患者中的剂量限制性毒性。预计乳糖胺将证明 要安全，耐受性好。这项初步研究的结果将支持下一阶段的工作 在阿片类药物治疗的基础上加用乳糖胺缓解腹痛的2项试验 来自CP。

ABSTRACT: Background: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50-80% of patients seeking medical attention for pain control. While several management options are potentially available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia (OIH) may occur, a phenomenon resulting in dose escalation, and appears to be due in part to the effect of opioids on pain- associated voltage-gated sodium channels. Lacosamide blocks and stabilizes these channels and may inhibit the effects of OIH. This may result in improved pain control with a decrease in opioid use. In pre-clinical and clinical trials with neuropathic pain, lacosamide reduced pain scores and was well tolerated. There are no data, however, evaluating the use of lacosamide in CP patients. Aims: 1. To evaluate the safety, tolerability and dose-limiting toxicity of adding lacosamide to opioid therapy in subjects with suspected and definite painful CP; 2. To assess the feasibility of performance of a pilot study adding lacosamide to opioid therapy in these subjects. As an exploratory aim, we will assess the efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP. Methods: This is a Phase 1 trial, utilizing the Bayesian optimal interval (BOIN) design to find the Maximum Tolerated Dose (MTD). The target dose- limiting toxicity (DLT) rate for the MTD is ɸ = 0.3 and the maximum sample size is 24. Given the small sample size, anticipated relatively short study period and potential for patient recruitment at several clinical centers, it is anticipated that all data will be accrued within 36 months of study initiation. Significance: This study will generate new knowledge regarding the safety, toxicity and dose-limiting toxicity of lacosamide in CP patients. It is anticipated that lacosamide will prove to be safe and well-tolerated. The results of this pilot study will then support proceeding with a phase 2 trial assessing the efficacy of lacosamide added to opioid therapy to alleviate abdominal pain from CP.