School of Medical Sciences (Neuroscience) and the Brain and Mind Centre, The University of Sydney, New South Wales, Australia.
Behav Pharmacol. 2021 Sep 1;32(6):479-486. doi: 10.1097/FBP.0000000000000642.
Many people with chronic pain escalate their opioid dosage to counteract tolerance effects. A treatment regimen consisting of placebos admixed with opioids has been suggested as a possible therapeutic option that could reduce the harm of long-term opioid use. However, the analgesic efficacy of such a regimen requires further investigation before widespread adoption. We have recently reported that a 4-day pharmacological conditioning procedure, which paired morphine (6 mg/kg) with contextual cues, elicited placebo analgesia in subpopulations of male (35%) and female (25%) rats with sciatic nerve chronic constriction injury (CCI). Here, we investigated how an escalating morphine dosage during conditioning affects the incidence and strength of placebo analgesia. Forty-four male, Sprague-Dawley rats received CCI. Thirty-eight (86%) rats developed strong cold allodynia by day 6 post-surgery, as measured by hind paw withdrawal (HPW) behaviour on a 5°C cold plate (120 s). In this experiment, pharmacological conditioning consisted of an escalating morphine dose over 4 days (8/9/10/12 mg/kg). This dosing regimen produced strong reductions in HPW behaviour and counteracted the effects of morphine tolerance during conditioning. However, none of the rats given the placebo treatment (n = 12) demonstrated reductions in HPW behaviour when morphine was substituted for saline (i.e. placebo analgesia), but instead showed a strong behavioural response (rearing). These results demonstrate that a high, escalating dose of morphine failed to produce conditioned placebo analgesia in rats with CCI. It is possible that admixing placebos with opioids may be similarly ineffective in chronic pain patients when the opioids regimen is high or escalating.
许多慢性疼痛患者会增加阿片类药物的剂量以对抗耐受效应。有人提出，将安慰剂与阿片类药物混合使用的治疗方案可能是一种减少长期使用阿片类药物危害的治疗选择。然而，这种方案的镇痛效果需要进一步研究，然后才能广泛采用。我们最近报道，4 天的药理学预处理程序，即将吗啡（6mg/kg）与环境线索配对，可以在慢性坐骨神经缩窄损伤（CCI）的雄性（35%）和雌性（25%）大鼠亚群中引发安慰剂镇痛。在这里，我们研究了在预处理过程中增加吗啡剂量如何影响安慰剂镇痛的发生率和强度。44 只雄性 Sprague-Dawley 大鼠接受了 CCI。38 只（86%）大鼠在手术后第 6 天出现了强烈的冷感觉过敏，通过后腿撤回（HPW）行为在 5°C 冷板上测量（120s）。在这个实验中，药理学预处理包括 4 天内逐渐增加吗啡剂量（8/9/10/12mg/kg）。这种给药方案产生了强烈的 HPW 行为减少，并在预处理过程中对抗了吗啡耐受的影响。然而，给予安慰剂治疗的 12 只大鼠（n=12）中的任何一只在吗啡被盐水替代时（即安慰剂镇痛）都没有表现出 HPW 行为的减少，而是表现出强烈的行为反应（后肢站立）。这些结果表明，在 CCI 大鼠中，高剂量、递增的吗啡未能产生条件性安慰剂镇痛。当阿片类药物剂量较高或递增时，将安慰剂与阿片类药物混合使用可能对慢性疼痛患者同样无效。
