High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.
High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design.
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DOI：
10.1371/journal.pone.0242169
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发表时间：
2020
期刊：
影响因子：
3.7
通讯作者：
Werner MU
中科院分区：
文献类型：
--
作者：
Springborg AD;Jensen EK;Kreilgaard M;Petersen MA;Papathanasiou T;Lund TM;Taylor BK;Werner MU
严重的慢性术后疼痛在手术人群中患病率为4-10%。潜在的伤害机制尚未被很好地描述。在炎症损伤的晚期消退阶段，高剂量μ-阿片受体逆激动剂恢复对伤害性刺激的超敏反应。这种对潜在疼痛敏化的揭示在啮齿动物中是一致的发现，而只在有限数量的人类志愿者中观察到。潜在致敏可能是慢性术后疼痛的潜在触发点。本试验的目的是详细检查损伤引起的继发性痛觉过敏和纳洛酮引起的潜在致敏的揭露之间的关系。健康志愿者（n = 80）接受皮肤热损伤（47°C, 420 s, 12.5 cm2）。损伤后1小时评估基线继发性痛觉过敏区域。采用强化入组设计，选取上四分位数（“高致敏者”[n = 20]）和下四分位数（“低致敏者”[n = 20]）继发性痛觉过敏区域大小的受试者进行进一步研究。在连续4个实验阶段（第1 - 4阶段），受试者在两个阶段（第1和第3阶段）接受皮肤热损伤，并在168 h后（第2和第4阶段）进行三步靶控静脉输注纳洛酮（3.25 mg/kg）或生理盐水。在注射前和注射过程中对继发性痛觉过敏区域进行评估。简单的单变量统计显示，纳洛酮和安慰剂治疗组继发性痛觉过敏区域无显著差异（P = 0.215），高致敏者和低致敏者之间无显著差异（P = 0.757）。在混合效应模型中，与安慰剂相比，纳洛酮对“高致敏剂”的继发痛觉过敏区域明显更大（P < 0.001），但对“低致敏剂”的继发痛觉过敏区域则没有（P = 0.651）。虽然我们不能明确证明纳洛酮诱导的热损伤性痛觉过敏的恢复，但在临床手术后疼痛模型的进一步研究是有必要的。
Severe chronic postsurgical pain has a prevalence of 4–10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile (‘high-sensitizers’ [n = 20]) and the lower quartile (‘low-sensitizers’ [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between ‘high-sensitizers’ and ‘low-sensitizers’ (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for ‘high-sensitizers’ (P < 0.001), but not ‘low-sensitizers’ (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.
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影响因子：
2.1
作者：
Brennum, J;Kaiser, F;Dahl, JB
通讯作者：
Dahl, JB
影响因子：
2.9
作者：
COHEN, MR;COHEN, RM;MURPHY, DL
通讯作者：
MURPHY, DL
影响因子：
8.3
作者：
ADAMS, HP;OLINGER, CP;HOLLERN, R
通讯作者：
HOLLERN, R
影响因子：
2.5
作者：
Dowling, Jonathonm;Isbister, Geoffrey K.;Graudins, Andis
通讯作者：
Graudins, Andis
影响因子：
8.8
作者：
BARSAN, WG;OLINGER, CP;MARLER, J
通讯作者：
MARLER, J