Opioids suppress both cell-mediated and humoral immunity [10
]. The mechanism is mediated by opioid receptors, sympathetic nervous system (SNS) and HPA. Morphine can directly activate µ3 opioid receptor on immune cell membrane and increase intracellular calcium level, then, constitutive nitric oxide synthase (cNOS) is activated, and nitric oxide(NO) is generated [11
], which may enhance the transcription of inhibitory kappa B alpha(I?Ba) and inhibit nuclear factor-?B(NF-?B) to bind with the representative DNA promoter region, as a result, Th1 cell activity is suppressed, and the expression of IFN-? and IL-2 is decreased [12
]. Moreover, opioids indirectly suppress immune function by inhibiting NK cells activity. Morphine activates SNS and HPA pathways, leading to the production of glucocorticoids and catecholamines, the former have negative effect on immunity, the latter activate adrenergic receptors on NK cell membrane, then, protein kinase A (PKA) is activated by cyclic adenosine monophosphate (cAMP). Activation of cAMP/PKA signaling pathway can ultimately affect the expression of genes and NK cell function by regulating the nuclear transcription factor.
Fentanyl, a synthetic µ-opioid receptor agonist, induces dose-dependent immunosuppressive effect in mice and humans [13
]. Animal studies have shown that continuous infusion of fentanly suppresses NK cell activity, lymph proliferation and cytokine production. Furthermore, in the rat model, fentanyl not only inhibits NK cell activity but also promotes cancer metastasis [15
Those results mentioned above show the immunosuppression of opioids in the absence of pain, while some animal studies suggest that perioperative opioid administration can attenuate surgery-induced immunosuppression by alleviating stress and pain. Perioperative systemic or intrathecal morphine administration not only significantly attenuated surgery-induced inhibition of NK cell activity but also decreased cancer metastasis [16
]. The previous results were contradictory, the reason may be, opioids per se exhibit the immunosuppressive effect in the absence of pain, but the immunosuppression caused by surgery is far greater than that of opioids. Opioids can effectively relieve pain and alleviate surgical stress, eventually improve perioperative immune function, which is impaired by surgery. Furthermore, the dosage of opioids reported in those studies was in the clinically related range.
Fortunately, not all the opioids share the immunosuppressive properties. Tramadol, a weak µ-opioid receptor agonist and reuptake inhibitor of norepinephrine and serotonin, does not suppress the immune function. On the contrary, it can increase NK cell activity and facilitate the production of IL-2, and can enhance the proliferation of spleen lymphocytes. In the rat model, tramadol could protect NK cell function and reduce the incidence of cancer metastasis [17
]. Moreover, the administration of tramadol 100mg after surgery could increase NK cell activity and promote the recovery of lymphocyte function in uterine cancer patients [18
]. The protective effect of tramadol
on immune function may be ascribed to its inhibition of 5-HT reuptake [19
Buprenorphine, the semi-synthetic partial µ-agonist, is a derivative of paramorphine that can be used to control moderate acute pain. Recent studies have found that buprenorphine has no inhibitory effect on immune function. Buprenorphine administered in the rat periaqueductal gray did not alter spleen NK cells, T lymphocytes or macrophages function, while morphine significantly inhibited all the cells function [20
]. In the animal studies, when using equianalgesic doses of fentanyl or morphine, only buprenorphine might protect immune function and reduce cancer metastasis induced by surgical stress [21
]. In humans, buprenorphine is commonly used to treat opioid addiction as a substitution, and the only available human study showed that buprenorphine was able to improve immune function. When buprenorphine is administered to relieve pain, it does not activate the HPA axis and the SNS [22