There has been growing interest in determining the possible immune consequences of opioid administration for the management of postoperative pain. We studied the effects of morphine and tramadol on pain and immune function during the postoperative period in 30 patients undergoing abdominal surgery for uterine carcinoma. Phytohemoagglutinin-induced T lymphocyte proliferation and natural killer cell activity were evaluated immediately before and after surgery, and 2 h after the acute administration of either 10 mg of morphine IM or 100 mg tramadol IM for pain. In all patients, phytohemagglutinin-induced lymphoproliferation was significantly depressed by surgical stress. However, in the morphine-treated group, proliferative values remained lower than basal levels for 2 h after treatment, whereas in tramadol-administered patients proliferative values returned to basal levels. Natural killer cell activity was not significantly affected by surgery nor by morphine administration, whereas tramadol significantly enhanced the activity of natural killer cells. Both drugs produced a comparable reduction in postoperative pain. We conclude that, as previously observed in the experimental animal, tramadol and morphine, when administered in analgesic doses, induce different immune effects. Recent studies suggest that opioids can have an adverse impact on the immune system. Because surgical stress also induces immune dysfunction, the search for analgesic drugs devoid of immunosuppressive effects is of import. This study compared the effects on immune responses of morphine and of the atypical opioid analgesic, tramadol, given for postoperative pain to gynecological cancer patients. Tramadol and morphine showed comparable analgesic activity; however, tramadol, in contrast to morphine, induced an improvement of postoperative immunosuppression and, therefore, may be preferred to morphine for the treatment of postoperative pain.

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 μ-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.

This review provides an overview of the immunological effects of commonly used analgesic opioid drugs with particular emphasis on human studies, with the final aim to highlight their potential clinical relevance. The immunomodulatory effects of morphine have been characterized in animal and human studies. Morphine decreases the effectiveness of several functions of both natural and acquired immunity, interfering with important intracellular pathways involved in immune regulation. Mainly from animal studies, however, it has emerged that not all opioids induce the same immunosuppressive effects and evaluating each opioid's profile is important for appropriate analgesic selection. The potent opioid fentanyl also exerts a relevant immunosuppression, while the partial agonist buprenorphine appears to have a more favourable immune profile. The impact of the opioid-mediated immune effects could be particularly dangerous in selective vulnerable populations, such as the elderly or immunocompromised patients. The impact of opioid drug treatment on immunity may be a new safety concern for the physician. Although many advances have been made in understanding the effects of opioid drugs on immune responses, their relevance is not completely clear. The scientific community must be aware that it is about time to perform well designed clinical studies in order to assess the importance of opioid-induced immune suppression.

Suppression of the immune system has been constantly reported in the last years as a classical side effect of opioid drugs. Most of the studies on the immunological properties of opioids refer to morphine. Although morphine remains the “reference molecule,” other semisynthetic and synthetic opioids are frequently used in the clinical practice. The primary objective of this review is to analyze the available literature on the immunomodulating properties of opioid drugs different from morphine in preclinical models and in the human. A search strategy was conducted in PubMed, Embase, and the Cochrane databases using the terms “immunosuppression,” “immune system,” “opioids,” “Natural killer cells,” “cytokines,” and “lymphocytes.” The results achieved concerning the effects of fentanyl, methadone, oxycodone, buprenorphine, remifentanil, tramadol, and tapentadol on immune responses in animal studies, in healthy volunteers and in patients are reported. With some limitations due to the different methods used to measure immune system parameters, the large range of opioid doses and the relatively scarce number of participants in the available studies, we conclude that it is not correct to generalize immunosuppression as a common side effect of all opioid molecules.