Centre for Human Drug Research, Leiden, The Netherlands.
Leiden University Medical Centre, Leiden, The Netherlands.
Eur J Pain. 2019 May;23(5):874-883. doi: 10.1002/ejp.1353. Epub 2019 Feb 1.
Pain models are commonly used in drug development to demonstrate analgesic activity in healthy subjects and should therefore not cause long-term adverse effects. The ultraviolet B (UVB) model is a model for inflammatory pain in which three times the minimal erythema dose (3MED) is typically applied to induce sensitization. Based on reports of long-lasting postinflammatory hyperpigmentation (PIH) associated with 3MED, it was decided to investigate the prevalence of PIH among subjects who were previously exposed to 3MED at our research centre. In addition, re-evaluation of the UVB inflammation model using a reduced exposure paradigm (2MED) was performed in healthy subjects.
In the first study, all 142 subjects previously exposed to 3MED UVB were invited for a clinical evaluation of PIH. In the second study, 18 healthy subjects were exposed to 2MED UVB, and heat pain detection threshold (PDT) and PIH were evaluated.
In total, 78 of the 142 subjects responded. The prevalence of PIH among responders was 53.8%. In the second study, we found a significant and stable difference in PDT between UVB-exposed and control skin 3 hr after irradiation; 13 hr post-irradiation, the least squares mean estimate of the difference in PDT ranged from -2.6°C to -4.5°C (p < 0.0001). Finally, the prevalence of PIH was lower in the 2MED group compared to the 3MED group.
The 3MED model is associated with a relatively high prevalence of long-lasting PIH. In contrast, 2MED exposure produces stable hyperalgesia and has a lower risk of PIH and is therefore recommended for modelling inflammatory pain.
Postinflammatory hyperpigmentation is an unwanted long-term side effect associated with the UVB inflammation model using the 3× minimal erythema dose (3MED) paradigm. In contrast, using a 2MED paradigm results in hyperalgesia that is stable for 36 hr and has a lower risk of inducing postinflammatory hyperpigmentation.
在药物开发中，疼痛模型常用于在健康受试者中证明镇痛活性，因此不应引起长期不良反应。紫外线 B（UVB）模型是一种炎症性疼痛模型，通常应用三倍最小红斑剂量（3MED）来诱导致敏。基于 3MED 相关的长期炎症后色素沉着过度（PIH）的报告，决定调查先前在我们的研究中心接受 3MED 照射的受试者中 PIH 的患病率。此外，在健康受试者中使用减少暴露范式（2MED）重新评估 UVB 炎症模型。
在第一项研究中，邀请所有先前接受过 3MED UVB 照射的 142 名受试者进行 PIH 的临床评估。在第二项研究中，18 名健康受试者接受 2MED UVB 照射，评估热痛觉检测阈值（PDT）和 PIH。
共有 142 名受试者中的 78 名作出回应。应答者中 PIH 的患病率为 53.8%。在第二项研究中，我们发现照射后 3 小时，UVB 暴露皮肤和对照皮肤的 PDT 存在显著且稳定的差异；照射后 13 小时，PDT 差值的最小二乘均值估计值范围为-2.6°C 至-4.5°C（p<0.0001）。最后，与 3MED 组相比，2MED 组的 PIH 患病率较低。
3MED 模型与长期存在的 PIH 发生率较高相关。相比之下，2MED 暴露会产生稳定的痛觉过敏，且 PIH 的风险较低，因此建议用于模拟炎症性疼痛。
炎症后色素沉着过度是与使用 3×最小红斑剂量（3MED）范式的 UVB 炎症模型相关的一种不期望的长期副作用。相比之下，使用 2MED 范式会导致持续 36 小时的痛觉过敏，且 PIH 的风险较低。
