Schulte H, Graven-Nielsen T, Sollevi A, Jansson Y, Arendt-Nielsen L, Segerdahl M
Department of Anaesthesia and Intensive Care, Huddinge University Hospital, Stockholm, Sweden.
Acta Anaesthesiol Scand. 2003 Sep;47(8):1020-30. doi: 10.1034/j.1399-6576.2003.00204.x.
Muscle pain is a major clinical problem but the underlying mechanisms and its pharmacological modulation need further investigation. This study on 15 volunteers evaluates if two experimental muscle pain models are sensitive to micro -receptor agonists and to an N-methyl-D-aspartate (NMDA)-receptor antagonist.
In the left tibialis anterior, intramuscular electrical (IMES) pain thresholds were determined for single (SPTmuscle) and five (RPTmuscle) repeated stimuli. Also pain to suprathreshold stimulation at 150% of RPTmuscle, 10 s, was assessed on a visual analog scale (VAS) as AUCimes (area under the VAS curve). In the right TA muscle, pain intensity on infusion of 0.5 ml of hypertonic saline, 5% (AUCsaline) and pain distribution indicated as local and referred were evaluated. Pain variables were assessed before, during and after intravenous infusions of morphine (10 microg x kg-1 min-1, 10 min), alfentanil (target-controlled infusion, plasma concentration; 60 ng ml-1, 60 min) and ketamine (10 microg x kg-1 min-1, 60 min). All data were normalized to baseline pain values (before drug infusions were initiated) and compared with placebo (midazolam, 2 microg x kg-1 min-1, 10 min).
SPTmuscle increased (log mean values +/- SD, mA) with morphine (0.11 +/- 0.17, P < 0.05), alfentanil (0.28 +/- 0.24, P < 0.001) and ketamine (0.19 +/- 0.18, P < 0.01) as compared with placebo (-0.03 +/- 0.12). Alfentanil and ketamine also increased RPTmuscle (0.25 +/- 0.21, P < 0.01 and 0.21 +/- 0.19, P < 0.05, respectively) as compared with placebo (0.00 +/- 0.17). Pain to IMES (AUCimes) was reduced (median values [25th-75th percentiles], cm x s) by alfentanil and ketamine (-19.7 [-14.6 - -29.6] and-12.8 [-8.3 - -27.8], P < 0.05, respectively) vs. placebo (-0.8 [1.6 - -12.3]). Similar drug effects were seen when pain to infusion of hypertonic saline (AUCsaline) was assessed (alfentanil:-388 [-99 - -677] and ketamine:-326 [-227 - -573], P < 0.05 compared with placebo: 150 [449--240]). Ketamine also reduced the size of the local pain area (-58.4 [-21.2 - -176.1], < 0.05) as compared with placebo (-0.4 [70.6 - -13.4]). The frequency of referred pain was also lower when ketamine was given (3/13, P < 0.05) vs. placebo (9/14).
The study demonstrates that experimental muscle pain induced in humans by electrical stimulation and infusion of hypertonic saline is sensitive to pharmacological modulation similar to preclinical animal tests and clinical trials. The data suggest that these models can be valuable tools in analgesic drug development.
肌肉疼痛是一个主要的临床问题，但其潜在机制及其药物调节作用仍需进一步研究。本研究对15名志愿者进行评估，以确定两种实验性肌肉疼痛模型是否对微受体激动剂和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂敏感。
在左胫前肌，测定单次（SPTmuscle）和五次（RPTmuscle）重复刺激的肌肉内电刺激（IMES）疼痛阈值。同时，在视觉模拟量表（VAS）上评估RPTmuscle的150%、持续10秒的阈上刺激所引起的疼痛，并以AUCimes（VAS曲线下面积）表示。在右胫前肌，评估注入0.5 ml 5%高渗盐水时的疼痛强度（AUCsaline）以及局部和牵涉痛的疼痛分布情况。在静脉输注吗啡（10μg·kg⁻¹·min⁻¹，10分钟）、阿芬太尼（靶控输注，血浆浓度60 ng/ml，60分钟）和氯胺酮（10μg·kg⁻¹·min⁻¹，60分钟）之前、期间和之后评估疼痛变量。所有数据均相对于基线疼痛值（开始药物输注前）进行标准化，并与安慰剂（咪达唑仑，2μg·kg⁻¹·min⁻¹，10分钟）进行比较。
与安慰剂（-0.03±0.12）相比，吗啡（0.11±0.17，P<0.05）、阿芬太尼（0.28±0.24，P<0.001）和氯胺酮（0.19±0.18，P<0.01）使SPTmuscle升高（对数平均值±标准差，mA）。与安慰剂（0.00±0.17）相比，阿芬太尼和氯胺酮也使RPTmuscle升高（分别为0.25±0.21，P<0.01和0.21±0.19，P<0.05）。阿芬太尼和氯胺酮使IMES引起的疼痛（AUCimes）减轻（中位数[第25-75百分位数]，cm·s）（分别为-19.7[-14.6--29.6]和-12.8[-8.3--27.8]，P<0.05），而安慰剂为-0.8[1.6--12.3]。在评估高渗盐水输注引起的疼痛（AUCsaline）时也观察到类似的药物效果（阿芬太尼：-388[-99--677]，氯胺酮：-326[-227--573]，与安慰剂：150[449--240]相比，P<0.05）。与安慰剂（-0.4[70.6--13.4]）相比，氯胺酮还减小了局部疼痛区域的大小（-58.4[-21.2--176.1]，P<0.05）。给予氯胺酮时牵涉痛的发生率也低于安慰剂（3/13，P<0.05）（安慰剂为9/14）。
该研究表明，电刺激和注入高渗盐水在人体诱发的实验性肌肉疼痛对药物调节敏感，类似于临床前动物试验和临床试验。数据表明这些模型可能是镇痛药开发中有价值的工具。
