Emergency Department and Mobile Intensive Care Unit, Grenoble Alpes University Hospital, Grenoble, France.
HP2 Laboratory, INSERM U1042, University Grenoble Alpes, Grenoble, France.
PLoS Med. 2019 Jul 16;16(7):e1002849. doi: 10.1371/journal.pmed.1002849. eCollection 2019 Jul.
Intravenous morphine (IVM) is the most common strong analgesic used in trauma, but is associated with a clear time limitation related to the need to obtain an access route. The intranasal (IN) route provides easy administration with a fast peak action time due to high vascularization and the absence of first-pass metabolism. We aimed to determine whether IN sufentanil (INS) for patients presenting to an emergency department with acute severe traumatic pain results in a reduction in pain intensity non-inferior to IVM.
In a prospective, randomized, multicenter non-inferiority trial conducted in the emergency departments of 6 hospitals across France, patients were randomized 1:1 to INS titration (0.3 μg/kg and additional doses of 0.15 μg/kg at 10 minutes and 20 minutes if numerical pain rating scale [NRS] > 3) and intravenous placebo, or to IVM (0.1 mg/kg and additional doses of 0.05 mg/kg at 10 minutes and 20 minutes if NRS > 3) and IN placebo. Patients, clinical staff, and research staff were blinded to the treatment allocation. The primary endpoint was the total decrease on NRS at 30 minutes after first administration. The prespecified non-inferiority margin was -1.3 on the NRS. The primary outcome was analyzed per protocol. Adverse events were prospectively recorded during 4 hours. Among the 194 patients enrolled in the emergency department cohort between November 4, 2013, and April 10, 2016, 157 were randomized, and the protocol was correctly administered in 136 (69 IVM group, 67 INS group, per protocol population, 76% men, median age 40 [IQR 29 to 54] years). The mean difference between NRS at first administration and NRS at 30 minutes was -4.1 (97.5% CI -4.6 to -3.6) in the IVM group and -5.2 (97.5% CI -5.7 to -4.6) in the INS group. Non-inferiority was demonstrated (p < 0.001 with 1-sided mean-equivalence t test), as the lower 97.5% confidence interval of 0.29 (97.5% CI 0.29 to 1.93) was above the prespecified margin of -1.3. INS was superior to IVM (intention to treat analysis: p = 0.034), but without a clinically significant difference in mean NRS between groups. Six severe adverse events were observed in the INS group and 2 in the IVM group (number needed to harm: 17), including an apparent imbalance for hypoxemia (3 in the INS group versus 1 in the IVM group) and for bradypnea (2 in the INS group versus 0 in the IVM group). The main limitation of the study was that the choice of concomitant analgesics, when they were used, was left to the discretion of the physician in charge, and co-analgesia was more often used in the IVM group. Moreover, the size of the study did not allow us to conclude with certainty about the safety of INS in emergency settings.
We confirm the non-inferiority of INS compared to IVM for pain reduction at 30 minutes after administration in patients with severe traumatic pain presenting to an emergency department. The IN route, with no need to obtain a venous route, may allow early and effective analgesia in emergency settings and in difficult situations. Confirmation of the safety profile of INS will require further larger studies.
ClinicalTrials.gov NCT02095366. EudraCT 2013-001665-16.
静脉注射吗啡（IVM）是创伤中最常用的强力镇痛药，但由于需要获得入路，其使用时间受到明显限制。鼻内（IN）途径由于高血管化和不存在首过代谢，给药方便，起效迅速。我们旨在确定对于因急性严重创伤疼痛而就诊于急诊科的患者，IN 舒芬太尼（INS）是否可使疼痛强度降低，非劣效于 IVM。
在法国 6 家医院急诊科进行的一项前瞻性、随机、多中心非劣效性试验中，患者按 1:1 随机分为 INS 滴定组（0.3μg/kg，10 分钟和 20 分钟时如果数字疼痛评分量表[NRS] > 3，则额外给予 0.15μg/kg）和静脉安慰剂组，或 IVM（0.1mg/kg，10 分钟和 20 分钟时如果 NRS > 3，则额外给予 0.05mg/kg）和 IN 安慰剂组。患者、临床人员和研究人员对治疗分配均不知情。主要终点为首次给药后 30 分钟时 NRS 的总下降值。预设的非劣效性边界为 NRS 上的-1.3。主要结局按方案进行分析。在 4 小时内前瞻性记录不良事件。2013 年 11 月 4 日至 2016 年 4 月 10 日期间，在急诊科队列中纳入的 194 例患者中，157 例被随机分组，136 例（方案人群中 69 例 IVM 组，67 例 INS 组，76%为男性，中位年龄 40[IQR 29 至 54]岁）正确给予了方案。IVM 组首次给药时的 NRS 与 30 分钟时的 NRS 之间的平均差值为-4.1（97.5%CI-4.6 至-3.6），INS 组为-5.2（97.5%CI-5.7 至-4.6）。证明了非劣效性（单侧均值等效 t 检验的 p<0.001），因为 0.29（97.5%CI 0.29 至 1.93）的下限 97.5%置信区间高于预设的-1.3 边界。INS 优于 IVM（意向治疗分析：p=0.034），但两组间的平均 NRS 差异无临床意义。INS 组观察到 6 例严重不良事件，IVM 组 2 例（需要治疗的人数：17），包括低氧血症（INS 组 3 例，IVM 组 1 例）和呼吸过缓（INS 组 2 例，IVM 组 0 例）的明显失衡。该研究的主要局限性是当使用时，伴随镇痛药物的选择留给主管医生决定，并且在 IVM 组中更常使用合并镇痛。此外，该研究的规模不足以确定 INS 在急诊环境中的安全性。
我们证实与 IVM 相比，INS 在急诊科因严重创伤疼痛而就诊的患者中，在给药后 30 分钟时可降低疼痛强度，具有非劣效性。IN 途径无需获得静脉途径，可能允许在急诊环境和困难情况下早期和有效镇痛。需要进一步的更大规模研究来证实 INS 的安全性概况。
ClinicalTrials.gov NCT02095366。EudraCT 2013-001665-16。
