Centro de Dor, Departamento de Neurologia, Universidade de Sao Paulo, Sao Paulo, Brazil
Centro de Dor, Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil.
Oncologist. 2017 Oct;22(10):1154-e105. doi: 10.1634/theoncologist.2017-0235. Epub 2017 Jun 26.
Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo.
Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN.
Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m)+leucovorin(20 mg/m)/week for] 6 weeks+oxaliplatin(85 mg/m) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile.
One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]).
The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.
普瑞巴林是一种可以降低神经元过度兴奋、缓解神经病理性疼痛并在短短几天的滴定期后达到稳定血浆水平的药物。与安慰剂相比，在奥沙利铂输注期间使用普瑞巴林并不能降低慢性奥沙利铂相关神经病理性疼痛的发生率。
接受奥沙利铂（OXA）治疗的结直肠癌（CRC）患者会出现急性和慢性疼痛性奥沙利铂诱导的周围神经病变（OXAIPN）。急性和慢性 OXA 相关神经病变具有不同的病理生理基础，但都导致了一种共同的现象：伤害性神经元网络的中枢敏化（CS），导致躯体感觉系统的敏感性增加（痛觉过敏、感觉异常），这是慢性神经病理性疼痛的共同特征。因为 CS 与发生疼痛性 OXAIPN 的风险增加有关，我们假设在 OXA 输注期间预防性使用抗痛觉过敏药物普瑞巴林（已知可降低 CS）会降低慢性 OXAIPN 的发生率。
接受至少一个周期改良 FLOX [5-FU（500mg/m）+亚叶酸（20mg/m）/周 6 周+奥沙利铂（85mg/m）在第 1-3-5 周每 8 周]治疗的无疼痛、无化疗的 CRC 患者被随机（1:1）分为研究组。患者在每次 OXA 输注前 3 天和后 3 天接受普瑞巴林或安慰剂治疗，并随访长达 6 个月。在基线、化疗结束时和随访期后进行临床评估。主要终点是最后一次就诊时通过 Brief Pain Inventory（BPI）的视觉模拟量表（0-10）项评估的平均疼痛。次要终点是根据 Douleur Neuropathique-4（DN-4）、疼痛维度（简短形式 McGill 疼痛问卷 [MPQ]）、神经病理性疼痛症状量表（NPSI）和神经传导研究（NCS）变化以及副作用特征存在神经病理性疼痛。
199 名患者（57.0±10.7 岁，女性 98 名，男性 101 名）被随机分组。56 名患者的数据未纳入分析（因为他们未接受至少一个完整周期的改良 FLOX）。78 名普瑞巴林组和 65 名安慰剂组的患者数据被保留用于分析。在最后一次就诊时，普瑞巴林组的疼痛强度为 1.03（95%置信区间 [CI] = 0.79-1.26），安慰剂组为 0.85（95% CI = 0.64-1.06），但无统计学意义。BPI、MPQ、DN-4、NPSI 和 NCS 评分以及副作用特征和死亡率在两组之间没有差异。两组之间的生活质量（QoL）评分没有差异（安慰剂组为 76.9±23.1，普瑞巴林组为 79.4±20.6）。两组之间的情绪评分没有显著差异（安慰剂组为 9.7 [8.1-11.2]；普瑞巴林组为 6.8 [5.6-8.0]）。
在奥沙利铂输注期间预防性使用普瑞巴林是安全的，但不能降低与 OXAIPN 相关的慢性疼痛的发生率。
