Background

Painful diabetic neuropathy is an important therapeutic challenge as the efficacy of analgesic drugs in this setting is still unsatisfactory. Monotherapy with available treatments is often not sufficient and a combination of drugs is necessary. Trazodone (TRZ) is a compound with a multi-modal mechanism of action, being a serotonin-2 antagonist/reuptake inhibitor developed and approved for the treatment of depression in several countries. Previous clinical trials suggest a possible beneficial effect of low doses of trazodone for the treatment of patients affected by painful diabetic neuropathy.

Objective

This phase II study was designed to collect data on the efficacy and safety of low doses of TRZ combined with gabapentin after 8 weeks of treatment in patients affected by painful diabetic neuropathy.

Methods

This was a randomized, double-blind, placebo-controlled, multi-center, international, prospective study. Male and female diabetic patients aged 18–75 years and affected by painful diabetic neuropathy were eligible for enrollment. Subjects were randomized (1:1:1 ratio) to TRZ30 (10 mg three times daily for 8 weeks) or TRZ60 (20 mg three times daily for 8 weeks) or placebo. Gabapentin as background therapy was administered in open-label conditions to all patients. The primary endpoint was the change from baseline of the Brief Pain Inventory Short Form item 5 to week 8. Secondary endpoints included the other Brief Pain Inventory Short Form items, and the assessment of anxiety, sleep, quality of life, patient’s improvement, and safety.

Results

One hundred and forty-one patients were included in the intention-to-treat population: 43 allocated to the TRZ30 group, 50 to the TRZ60 group, and 48 to the placebo group. After 8 weeks, the mean changes of Brief Pain Inventory Short Form item 5 from baseline were − 3.1, − 2.6, and − 2.5 in the TRZ30, TRZ60, and placebo groups, respectively. No statistically significant differences between groups were seen. Nevertheless, a better trend was observed for TRZ30 vs placebo (95% confidence interval − 1.30, 0.15; p = 0.1179), on top of the background effect of gabapentin administered to all study groups. 62.8% of patients achieved a ≥ 50% reduction in the TRZ30 group, 54% in the TRZ60 group, and 45.8% in the placebo group. At the same time, a statistically significant improvement was observed in Brief Pain Inventory Short Form item 6 for TRZ30 vs placebo (95% confidence interval − 1.54, − 0.07; p = 0.0314). No serious adverse event occurred during the trial and the most frequent treatment-emergent adverse events involved nervous system, QT prolongation, and gastrointestinal disorders.

Conclusions

All treatment groups showed a clinically meaningful pain improvement; nevertheless, patients in the TRZ30 treatment group reported better efficacy outcomes. This finding suggests that low doses of TRZ could be useful for treating painful diabetic neuropathy, and support further adequately powered confirmatory trials investigating the efficacy of TRZ.

Clinical Trial Registration

NCT03202979, date of registration: 29/06/2017.

中文翻译：

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低剂量曲唑酮对受疼痛性糖尿病神经病变影响并接受加巴喷丁治疗的患者的疗效和安全性：一项随机对照试验研究。

背景

疼痛性糖尿病神经病变是一项重要的治疗挑战，因为镇痛药物在这种情况下的疗效仍然不能令人满意。现有疗法的单一疗法通常是不够的，需要联合用药。Trazodone (TRZ) 是一种具有多模式作用机制的化合物，是一种 serotonin-2 拮抗剂/再摄取抑制剂，已在多个国家开发并批准用于治疗抑郁症。先前的临床试验表明，低剂量曲唑酮可能对治疗受疼痛性糖尿病神经病变影响的患者产生有益作用。

客观的

这项 II 期研究旨在收集低剂量 TRZ 联合加巴喷丁治疗疼痛性糖尿病神经病变患者 8 周后的疗效和安全性数据。

方法

这是一项随机、双盲、安慰剂对照、多中心、国际、前瞻性研究。年龄在 18-75 岁且受疼痛性糖尿病神经病变影响的男性和女性糖尿病患者有资格入组。受试者被随机分配（1:1:1 比例）至 TRZ30（10 毫克，每天 3 次，持续 8 周）或 TRZ60（20 毫克，每天 3 次，持续 8 周）或安慰剂。加巴喷丁作为背景疗法在开放标签条件下给予所有患者。主要终点是从第 5 周简短疼痛量表简表项目的基线到第 8 周的变化。次要终点包括其他简明疼痛量表简表项目，以及对焦虑、睡眠、生活质量、患者改善和安全性的评估.

结果

意向治疗人群包括 141 名患者：43 名分配到 TRZ30 组，50 名分配到 TRZ60 组，48 名分配到安慰剂组。8 周后，在 TRZ30、TRZ60 和安慰剂组中，Brief Pain Inventory Short Form 项目 5 相对于基线的平均变化分别为 - 3.1、- 2.6 和 - 2.5。组间未见统计学显着差异。然而，TRZ30 与安慰剂相比，观察到了更好的趋势（95% 置信区间 - 1.30, 0.15；p = 0.1179)，在加巴喷丁对所有研究组的背景影响之上。62.8% 的患者在 TRZ30 组、TRZ60 组和安慰剂组中分别达到 ≥ 50%、54% 和 45.8%。同时，在 TRZ30 与安慰剂的简要疼痛量表简表第 6 项中观察到统计学显着改善（95% 置信区间 - 1.54, - 0.07；p  = 0.0314）。试验期间未发生严重不良事件，最常见的治疗中出现的不良事件涉及神经系统、QT 间期延长和胃肠道疾病。

结论

所有治疗组均表现出有临床意义的疼痛改善；尽管如此，TRZ30 治疗组的患者报告了更好的疗效结果。这一发现表明低剂量的 TRZ 可用于治疗疼痛性糖尿病神经病变，并支持进一步研究 TRZ 功效的充分验证性试验。

临床试验注册

NCT03202979，注册日期：29/06/2017。