Effect of Opioids on Survival in Patients with Cancer

Abstract

Opioids are commonly used for pain management in patients with cancer. They have a range of unwanted effects, including some that potentially influence cancer growth. This article reviews the data assessing the effects of opioids on survival in patients with cancer. Many studies assessing this show an association between opioids and decreased survival. This effect is present even at very low doses of opioids. These studies do not assess causality, so it is not known if it is a direct effect of opioids on survival. As the control groups are not matched to the opioid group it might be that opioids are being used to control pain and patients receiving opioids have more aggressive cancers and it is the underlying cancer which is causing the decreased survival. Furthermore, although some studies allude to different opioids having different effects on survival, often all opioids are pooled in analysis. Future work needs to try to ascertain causality and differentiate between different opioids, pain, and cancer-mediated effects on survival in specific cancer types. Until then, opioids should continue to be used in patients with cancer as part of measures to optimise comfort and quality of life.

Keywords: cancer; immune; neoplasms; oncology; opioid; pain; palliative care; survival.

Figure 1

Peripheral and central mechanisms of opioid-induced immune suppression. Opioids can have direct effects on immune cells which express appropriate receptors such as the mu opioid receptor (MOR) and Toll-like receptor-4 (TLR-4); although there are differences between opioids [6,21,23,24]. Opioids can also have centrally mediated immunosuppressive effects [26,27]. Immediate central effects of opioids include enhancement of periaqueductal gray (PAG) activity. This in turn causes activation of the sympathetic nervous system (SNS). By innervating lymphoid organs, activation of the SNS leads to the release of biological amines which decreases cytotoxicity of NK cells and splenic lymphocyte proliferation [26]. In rodent models, morphine has acute effects via D1 dopamine receptors in the nucleus accumbens shell, which leads to an increase in the release of neuropeptide Y (NPY), this then reduces splenic NK cell cytotoxicity [27]. Chronic opioid administration increases activity in the hypothalamic pituitary adrenal (HPA) axis leading to glucocorticoid production, decreasing cytotoxicity of NK cells [26]. Reproduced with permission by Boland, J.W. et al. Br. J. Cancer 2014, 111, 866–873. [22].

Figure 2

Triangulation of the effects of opioids on pain, immunity and cancer. Cancer can cause pain, by nociceptive, neuropathic, and inflammatory mechanisms, partly caused by the immune response to cancer [1,2,53]. It is this pain state that necessitates opioid use [1,2,49]. Pain is potentially immunosuppressive which might worsen cancer outcomes in some cancer types [44,51,52]. By reducing pain, opioids might have beneficial effects on immune function, the cancer and potentially survival [44,51,52]. However, some opioids suppress immune function, which might decrease anti-tumour immunity and promote cancer growth [6]. Furthermore, there are non-immune effects of opioids on cancer cell regulation [17,18,19,20,28]. Opioids can also act directly on the MOR on cancer and non-cancer cells of the tumour microenvironment [28,30]. Together, these multiple effects converge to influence cancer growth and survival [11,12,54]. The balance of these effects is critical and might be dependent on the immune properties of the opioid used and the cancer type [6,15]. Many of the aforementioned effects are bidirectional (depicted by double arrowed lines in the figure). The immune system, via microglia and cytokines, influences the pain state [55]. Activated immune cells can also produce endogenous opioids, as well as morphine [56]. The immune system and the cancer are constantly influencing each other, with processes such as immunoediting and immunosculpting [57]. The aforementioned interactions lead to either cancer cell destruction or growth. How the cancer progresses influences survival. Green arrows depict a beneficial effect, red arrows depict a detrimental effect of opioids on the immune system, cancer development and survival. Question marks are used to highlight uncertainly of the net balance of effects, which might vary depending on the opioid. Adapted with permission from Boland, J.W. et al. Br. J. Pharmacol. 2018, 175, 2726–2736. [15]; Boland, J.W. et al. Br. J. Cancer 2014, 111, 866–873 [22]; Eur. J. Clin. Pharmacol. 2020, 76, 393–402. [12].