Tolerability and efficacy of duloxetine for the prevention of persistent musculoskeletal pain after trauma and injury: a pilot three-group randomized controlled trial
度洛西汀预防创伤后持续性肌肉骨骼疼痛的耐受性和有效性：先导性三组随机对照试验
Introduction：
Chronic pain is highly prevalent among U.S. adults and is associated with significant personal, societal, and economic costs. The chronic low back being the most prevalent overall. Chronic musculoskeletal pain (MSP) can develop after everyday events such as motor vehicle collisions (MVCs) and lower-back strains. More than half of those with moderate or severe acute MSP transitioned to chronic MSP.
慢性疼痛在美国成年人中非常普遍，并与巨大的个人、社会和经济成本有关。慢性腰背是最常见的一种。慢性肌肉骨骼疼痛(MSP)可在日常事件(如机动车碰撞(MVC)和下背部拉伤)后发展。超过一半的中或重度急性MSP患者过渡到慢性MSP。
We investigated duloxetine as a potential therapeutic option for the prevention of persistent MSP. In this proof-of-concept study, we report on the tolerability and preliminary efficacy of a 2-week course of duloxetine initiated in the ED among adults presenting with acute MSP after trauma or injury
我们研究了度洛西汀作为预防持久性MSP的潜在治疗方案。在这项概念验证研究中，我们报告了在急诊室开始的为期两周的度洛西汀疗程在创伤或损伤后出现急性MSP的成年人中的耐受性和初步疗效。
Methods
1. Trial design：a prospective, randomized, double-blind, placebo-controlled clinical trial with 3 study arms.
2. Inclusion and exclusion criteria，Randomization, allocation, and blinding，statistical analysis————Reference text
3. Study procedures:During the ED visit, participants completed survey questions from validated questionnaires regarding somatic and psychological symptoms([SF-36], [CES-D],[RPQ]), pain and pain-related symptoms (NRS), general health and medication history, drug use (DAST-10), and a demographics questionnaire.Such attributes are predictive of development of persistent and chronic MSP and may influence pain outcomes. In addition, the Peritraumatic Distress Inventory was used to measure participants’ perception of PTS because stress is often implicated in pain outcomes.To increase adherence to the protocol, participants were asked to download the Medisafe application onto their smartphone for daily prompts to take study medication.After discharge and receipt of the study medication, participants received follow-up assessments via internet-based surveys and phone to monitor for AEs and evaluate outcome measures. Six weeks after their initial ED visit, each participant returned to the study site for an in-person follow-up interview and pill count.
在急诊科访问期间，参与者完成了关于躯体和心理症状的验证问卷中的调查问题（[SF-36]、流行病学研究中心抑郁量表 [CES-D] 和脑震荡后症状问卷[RPQ]）、疼痛和疼痛相关症状（NRS）、一般健康和用药史、药物使用 (DAST-10) 和人口统计学问卷。这些属性可预测持续性和慢性 MSP 的发展并且可能会影响疼痛结果。此外，由于压力通常与疼痛结果有关，因此还使用围外伤痛苦清单来衡量参与者对 PTS 的看法。为了提高对协议的遵守，参与者被要求将 Medisafe 应用程序下载到他们的智能手机上每日提示服用研究药物。在出院和接受研究药物治疗后，参与者通过基于互联网的调查和电话接受后续评估，以监测不良事件并评估结果措施。在初次就诊ED六周后，每个参与者都返回研究地点进行面对面的后续访谈和药片计数。
4. Tolerability assessments(耐受性评估)
The primary aim of the proposed study was to assess the tolerability of duloxetine in patients with acute MSP. Tolerability was assessed by (1) the proportion of participants in each treatment arm reporting adverse side effects and (2) the proportion of participants who dropped out because of side effects in the first 21 days of study assessments. Duloxetine was considered acceptable if the dropout rate differed by ≤25% in duloxetine arms vs the control arm and if the rate of AEs in the duloxetine treatment arms was ≤25%. These metrics were chosen based on differences observed in numerous clinical trials of opioids and duloxetine conducted in patients with MSP.
拟议研究的主要目的是评估度洛西汀在急性MSP患者中的耐受性。耐受性由(1)每个治疗分支中报告不良副作用的参与者的比例和(2)在研究评估的前21天因副作用而退出的参与者的比例来评估。如果度洛西汀组与对照组的脱落率相差≤25%，并且度洛西汀治疗组的不良反应发生率为≤25%，则度洛西汀被认为是可以接受的。这些指标是根据在MSP患者中进行的大量阿片类药物和度洛西汀临床试验中观察到的差异来选择的
Secondary outcomes of interest included the potential efficacy of duloxetine for improving persistent pain outcomes in patients with acute MSP indicated by examining whether duloxetine reduced self-reported MSP over the 6-week study period.
次要结果包括度洛西汀改善急性MSP患者持续性疼痛结果的潜在疗效，通过检查度洛西汀是否在 6 周的研究期间降低了自我报告的 MSP。
Results
In this randomized, double-blind, placebo-controlled study, eligible participants (n 5 78) were randomized to 2 weeks of a daily dose of one of the following: placebo (n 5 27), 30 mg duloxetine (n 5 24), or 60 mg duloxetine (n 5 27). In both intervention groups, duloxetine was well tolerated and there were no serious adverse events. There was a statistically significant difference in pain over time for the 60 mg vs placebo group (P 5 0.03) but not for the 30 mg vs placebo group (P 5 0.51).
在这项随机、双盲、安慰剂对照研究中，符合条件的参与者 (n = 5 = 78) 被随机分配接受以下药物之一的每日剂量 2 周：安慰剂 (n = 5 = 27)、30 mg 度洛西汀 (n = 5 = 24) ，或 60 毫克度洛西汀 (n = 5 27)。在两个干预组中，度洛西汀的耐受性都很好，没有出现严重的不良事件。60 毫克与安慰剂组相比，随着时间的推移，疼痛在统计学上有显着差异 (P = 0.03)，但 30 毫克与安慰剂组相比则无差异 (P = 0.51)。
Conclusion
Duloxetine was generally well tolerated in patients with acute MSP after MVC and other injuries. This pilot study also provides some preliminary evidence that duloxetine might be particularly efficacious among individuals with acute pain after traumatic stress exposure/MVC and may also reduce psychological symptoms in such patients. These data are consistent with the substantial role of stress systems in the development of chronic pain after traumatic stress, and further study of pain and psychological symptoms is warranted in individuals with specific types of trauma exposures such as MVC.
MVC 和其他损伤后的急性 MSP 患者对度洛西汀的耐受性普遍良好。这项初步研究还提供了一些初步证据，表明度洛西汀可能对创伤性应激暴露/MVC 后急性疼痛的个体特别有效，并且还可以减轻此类患者的心理症状。这些数据与应激系统在创伤应激后慢性疼痛发展中的重要作用一致，并且有必要对具有特定类型创伤暴露（如 MVC）的个体进行疼痛和心理症状的进一步研究。
主要结果：
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1. Participant characteristics.
The most common inciting mechanisms for pain were minor nonMVC injuries such as muscle strains (52.6%), followed by MVCs (37.2%) and falls (10.3%). Across all 3 treatment groups, there were no significant sociodemographic differences except for highest level of education (P＜0.05). The most common region of reported pain was in the back (88.5%), followed by neck (51.3%), shoulders (42.6%), and extremities (37.7%).
最常见的疼痛诱发机制是轻微的非 MVC 损伤，例如肌肉拉伤 (52.6%)，其次是 MVCs (37.2%) 和跌倒 (10.3%)。在所有 3 个治疗组中，除了最高教育水平外，没有显着的社会人口统计学差异（P＜0.05）。报告疼痛最常见的部位是背部 (88.5%)，其次是颈部 (51.3%)、肩部 (42.6%) 和四肢 (37.7%)。
2. Tolerability
Across all 3 treatment groups, no participants dropped out because of adverse side effects and there were no serious adverse events recorded. Twenty-one unique participants reported AEs: 5 (19.2%) in the placebo group, 8 (33.3%) in the 30 mg duloxetine group, and 8 (30.8%) in the 60 mg duloxetine group (P 5 0.49). Across all groups, the most reported AEs were diarrhea and nausea. One participant in each of the placebo and 30 mg duloxetine groups reported diarrhea, whereas 4/26 (15.4%) of participants in the 60 mg experienced the symptom.
在所有 3 个治疗组中，没有参与者因副作用而退出，也没有记录到严重的不良事件。21 名独特的参与者报告了 AE：安慰剂组 5 起 (19.2%)，30 mg 度洛西汀组 8 起 (33.3%)，60 mg 度洛西汀组 8 起 (30.8%) (P = 5 0.49)。在所有组中，报告最多的 AE 是腹泻和恶心。安慰剂组和 30 毫克度洛西汀组各有一名参与者报告了腹泻，而 60 毫克度洛西汀组中有 4/26 (15.4%) 的参与者出现了腹泻症状。
Dropout rates during the 14-day dosing period were 7.7%, 12.5%, and 23.1% in the placebo, duloxetine 30 mg, and duloxetine 60 mg groups, respectively (P 5 0.49).
在 14 天给药期间，安慰剂组、度洛西汀 30 mg 组和度洛西汀 60 mg 组的脱落率分别为 7.7%、12.5% 和 23.1% (P= 0.49)。
3. Pain efficacy
The mean axial pain score at 6 weeks after trauma was highest in the placebo group (NRS=4.5) vs 30 mg duloxetine group (NRS=3.3) and 60 mg duloxetine group (NRS=3.2).
安慰剂组 (NRS=4.5) 与 30 mg 度洛西汀组 (NRS= 3.3) 和 60 mg 度洛西汀组 (NRS= 3.2) 相比，创伤后 6 周的平均轴向疼痛评分最高。
Of the 29 participants who presented to the ED after an MVC, at 6 weeks, 71.4% in the placebo group reported moderate or severe axial pain, 66.7% in the 30 mg duloxetine group reported moderate or severe pain, and 25.0% in the 60 mg duloxetine group reported moderate or severe pain (Table 2). The percentage of participants reporting widespread pain was 10.5% in the placebo group, 6.3% in the 30 mg duloxetine group, and 0.0% in the 60 mg duloxetine group.
在 MVC 后 6 周时到急诊室就诊的 29 名参与者中，安慰剂组 71.4% 的人报告中度或重度轴向疼痛，30 mg 度洛西汀组 66.7% 的人报告中度或重度疼痛，60 mg 组 25.0% 的人报告中度或重度疼痛mg 度洛西汀组报告中度或重度疼痛（表 2）。报告广泛性疼痛的参与者百分比在安慰剂组中为 10.5%，在 30 mg 度洛西汀组中为 6.3%，在 60 mg 度洛西汀组中为 0.0%。
A linear mixed-effects model with 2 splines (with a break at 14 days) provided the best fit for pain intensity scores among the entire sample (Table 3). After controlling for age, sex, and race, there was a significant difference in pain over time for the 60 mg duloxetine vs placebo group (β=-0.08, P=0.02) across the whole sample during the follow-up period (days 14-42), but not for the 30 mg duloxetine vs placebo group (β=-0.03, P=0.43).
两条样条线的线性混合效应模型(在14天时断裂)在整个样本中提供了最适合疼痛强度评分的模型(表3)。在控制了年龄、性别和种族后，在整个样本的随访期(第14-42天)中，服用60毫克度洛西汀的患者与安慰剂组的疼痛随时间的变化有显著差异(β=-0.08, P=0.02)，而服用30 mg度洛西汀的患者与安慰剂组的疼痛程度无显著差异(β=-0.03, P=0.43)。
度洛西汀预防创伤后持续性肌肉骨骼疼痛的耐受性和有效性：先导性三组随机对照试验.pdf
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