Gilron Ian, Bailey Joan M, Tu Dongsheng, Holden Ronald R, Jackson Alan C, Houlden Robyn L
Department of Anesthesiology, Queen's University, Kingston, ON, Canada.
Lancet. 2009 Oct 10;374(9697):1252-61. doi: 10.1016/S0140-6736(09)61081-3. Epub 2009 Sep 30.
Drugs for neuropathic pain have incomplete efficacy and dose-limiting side-effects when given as monotherapy. We assessed the efficacy and tolerability of combined nortriptyline and gabapentin compared with each drug given alone.
In this double-blind, double-dummy, crossover trial, patients with diabetic polyneuropathy or postherpetic neuralgia, and who had a daily pain score of at least 4 (scale 0-10), were enrolled and treated at one study site in Canada between Nov 5, 2004, and Dec 13, 2007. 56 patients were randomised in a 1:1:1 ratio with a balanced Latin square design to receive one of three sequences of daily oral gabapentin, nortriptyline, and their combination. In sequence, a different drug was given to each randomised group in three treatment periods. During each 6-week treatment period, drug doses were titrated towards maximum tolerated dose. The primary outcome was mean daily pain at maximum tolerated dose. Analysis was by intention to treat. This trial is registered, number ISRCTN73178636.
45 patients completed all three treatment periods; 47 patients completed at least two treatment periods and were analysed for the primary outcome. Mean daily pain (0-10; numerical rating scale) was 5.4 (95% CI 5.0 to 5.8) at baseline, and at maximum tolerated dose, pain was 3.2 (2.5 to 3.8) for gabapentin, 2.9 (2.4 to 3.4) for nortriptyline, and 2.3 (1.8 to 2.8) for combination treatment. Pain with combination treatment was significantly lower than with gabapentin (-0.9, 95% CI -1.4 to -0.3, p=0.001) or nortriptyline alone (-0.6, 95% CI -1.1 to -0.1, p=0.02). At maximum tolerated dose, the most common adverse event was dry mouth, which was significantly less frequent in patients on gabapentin than on nortriptyline (p<0.0001) or combination treatment (p<0.0001). No serious adverse events were recorded for any patients during the trial.
Combined gabapentin and nortriptyline seems to be more efficacious than either drug given alone for neuropathic pain, therefore we recommend use of this combination in patients who show a partial response to either drug given alone and seek additional pain relief. Future trials should compare other combinations to their respective monotherapies for treatment of such pain.
Canadian Institutes of Health Research.
用于治疗神经性疼痛的药物在单药治疗时疗效不完全且存在剂量限制的副作用。我们评估了联合使用去甲替林和加巴喷丁与单独使用每种药物相比的疗效和耐受性。
在这项双盲、双模拟、交叉试验中，2004年11月5日至2007年12月13日期间，在加拿大的一个研究地点招募并治疗了患有糖尿病性多发性神经病或带状疱疹后神经痛且每日疼痛评分至少为4分（0 - 10分制）的患者。56名患者按1:1:1的比例随机分组，采用平衡拉丁方设计，接受每日口服加巴喷丁、去甲替林及其联合用药三种方案中的一种。在三个治疗周期中，依次给每个随机分组的患者使用不同的药物。在每个为期6周的治疗周期内，将药物剂量滴定至最大耐受剂量。主要结局是最大耐受剂量时的每日平均疼痛程度。分析采用意向性分析。该试验已注册，注册号为ISRCTN73178636。
45名患者完成了所有三个治疗周期；47名患者完成了至少两个治疗周期，并对主要结局进行了分析。基线时每日平均疼痛程度（0 - 10分；数字评分量表）为5.4（95%CI 5.0至5.8），在最大耐受剂量时，加巴喷丁组疼痛程度为3.2（2.5至3.8），去甲替林组为2.9（2.4至3.4），联合治疗组为2.3（1.8至2.8）。联合治疗组的疼痛程度显著低于加巴喷丁组（差值为 -0.9，95%CI -1.4至 -0.3，p = 0.001）或单独使用去甲替林组（差值为 -0.6，95%CI -1.1至 -0.1，p = 0.02）。在最大耐受剂量时，最常见的不良事件是口干，加巴喷丁组患者口干的发生率显著低于去甲替林组（p < 0.0001）或联合治疗组（p < 0.0001）。试验期间未记录到任何患者发生严重不良事件。
联合使用加巴喷丁和去甲替林治疗神经性疼痛似乎比单独使用任何一种药物更有效，因此我们建议在对单独使用任何一种药物有部分反应且寻求进一步疼痛缓解的患者中使用这种联合治疗方案。未来的试验应比较其他联合治疗方案与各自单药治疗方案对这种疼痛的治疗效果。
加拿大卫生研究院。
