Sacerdote Paola
Department of Pharmacology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy.
Palliat Med. 2006;20 Suppl 1:s9-15.
Opioid compounds such as morphine produce powerful analgesia that is effective in treating various types of pain. In addition to their therapeutic efficacy, opioids can produce several well known adverse events, and, as has recently been recognized, can interfere with the immune response. The immunomodulatory activities of morphine have been characterized in animal and human studies. Morphine can decrease the effectiveness of several functions of both natural and adaptive immunity, and significantly reduces cellular immunity. Indeed, in animal studies morphine is consistently associated with increased morbidity and mortality due to infection and worsening of cancer. However, from several animal studies it emerges that not all opioids induce the same immunosuppressive effects, and evaluating each opioid's profile is important for appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine has been shown in rats not to affect cellular immune responses, while a statistically significant inhibition of the immune response was observed with morphine. In mouse studies, chronic administration of buprenorphine led to immune parameters important for antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer (NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In contrast, levels of these immune markers were significantly reduced when the potent micro-agonist fentanyl was administered, but recovered after longer periods as tolerance developed. Because the intrinsic immunosuppressive activity varies between individual opioids, predicting the outcome on immunity can be difficult. To study this, the effects of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by experimental surgery were examined in rats. Treating animals immediately after surgery with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was ameliorated, although not completely. In contrast, fentanyl did not prevent immunosuppression induced by surgery. Overall, from several animal studies it emerges that buprenorphine has the more favourable profile, being a potent analgesic devoid of intrinsic immunosuppressive activity.
阿片类化合物如吗啡能产生强大的镇痛作用，对治疗各种类型的疼痛均有效。除了具有治疗功效外，阿片类药物还会引发一些众所周知的不良事件，并且，正如最近所认识到的，它们还会干扰免疫反应。吗啡的免疫调节活性已在动物和人体研究中得到表征。吗啡会降低天然免疫和适应性免疫的多种功能的有效性，并显著降低细胞免疫。事实上，在动物研究中，吗啡一直与因感染导致的发病率和死亡率增加以及癌症病情恶化相关。然而，从多项动物研究中可以看出，并非所有阿片类药物都会产生相同的免疫抑制作用，评估每种阿片类药物的特性对于合理选择镇痛药很重要。丁丙诺啡是一种强效阿片类药物，常用于治疗慢性疼痛。在大鼠中，急性脑室内注射丁丙诺啡已被证明不会影响细胞免疫反应，而注射吗啡则观察到有统计学意义的免疫反应抑制。在小鼠研究中，长期给予丁丙诺啡不会影响对抗菌反应或抗肿瘤监测很重要的免疫参数（淋巴细胞增殖、自然杀伤（NK）淋巴细胞活性、细胞因子产生、淋巴细胞数量）。相比之下，当给予强效微阿片激动剂芬太尼时，这些免疫标志物的水平会显著降低，但随着耐受性的发展，较长时间后会恢复。由于不同阿片类药物的内在免疫抑制活性不同，预测其对免疫的影响可能会很困难。为了研究这一点，在大鼠中检查了吗啡、芬太尼和丁丙诺啡对实验性手术所致NK淋巴细胞活性降低的影响。术后立即用等效镇痛剂量的吗啡和丁丙诺啡治疗动物，可显著减轻手术诱导的免疫抑制。然而，丁丙诺啡可使NK淋巴细胞活性恢复到术前水平，而在吗啡治疗的大鼠中，NK淋巴细胞活性有所改善，但未完全恢复。相比之下，芬太尼并不能预防手术诱导的免疫抑制。总体而言，从多项动物研究中可以看出，丁丙诺啡具有更有利的特性，它是一种强效镇痛药，没有内在的免疫抑制活性。
