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Perioperative Immunosuppression and Risk of Cancer Progression: the Impact of Opioids on Pain Management

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Perioperative Immunosuppression and Risk of Cancer Progression: the Impact of Opioids on Pain Management Hindawi Pain Research and Management Volume 2018, Article ID 9293704, 8 pages https://doi.org/10.1155/2018/9293704 Review Article Perioperative Immunosuppression and Risk of Cancer Progression: The Impact of Opioids on Pain Management Renata Zaja˛czkowska ,1 Wojciech Leppert,2 Joanna Mika ,3 Magdalena Kocot-Ke˛pska,4 Jarosław Woron´ ,1 Anna Wrzosek ,1 and Jerzy Wordliczek 1 1Department of Interdisciplinary Intensive Care, Jagiellonian University Medical College, Krako´w, Poland 2Department of Palliative Medicine, Poznan University of Medical Sciences, Poznan, Poland 3Department of Pain Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krak´ow, Poland 4Department of Pain Research and Treatment, Jagiellonian University Medical College, Krako´w, Poland Correspondence should be addressed to Anna Wrzosek; [email protected] Received 24 May 2018; Revised 5 August 2018; Accepted 19 August 2018; Published 19 September 2018 Academic Editor: Massimiliano Valeriani Copyright © 2018 Renata Zaja˛czkowska et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Opioids comprise an important group of drugs used in cancer pain pharmacotherapy. In recent years, more and more studies have emerged indicating the potentially immunosuppressive effects of opioid analgesics and their serious consequences, including the risk of cancer progression. -e identification of these risks has prompted a search for other effective, and most importantly, safer methods of perioperative analgesic management. Regional analgesia techniques, which allow for a significant reduction in opioid dosing and thus diminish the risk of immunosuppression associated with these drugs, seem to offer substantial hope in this respect. A number of studies available in the literature assess the effects of regional analgesia techniques on cancer progression; however, it is often difficult to interpret their results owing to several perioperative factors (such as surgical trauma, inadequate pain and stress relief, and hypothermia) which are also attributed immunosuppressive effects and tend to be implicated in increased risk of cancer progression. Further research is needed to verify the available data on both the potential adverse effects of opioids and the possible protective effects of regional analgesia techniques on cancer patients. 1. Introduction achieved: pain was experienced by 39.3% of patients after radical cancer treatment, by 55% of patients during cancer Cancer pain poses a serious clinical and epidemiological treatment, and by 66.4% at the advanced stage of cancer problem. It may be the first symptom of the disease, occurs treatment. 38% of patients experienced moderate to severe during its diagnosis and treatment, and accompanies pa- pain (NRS > 5) [2]. tients at the advanced stages of the disease. It is estimated Apart from the unimaginable suffering and the hu- that, regardless of the stage, at least one-half of cancer manitarian aspect of the problem, the consequences of in- patients experience pain, but their proportion is significantly sufficiently treated pain, both acute and chronic, can also be higher as the disease progresses. -e World Health Orga- disastrous from a purely medical point of view. -is is nisation (WHO) reports that over 5.5 million patients particularly important in cancer patients as more and more worldwide do not receive or receive inadequate treatment data indicate a correlation between severe pain and in- for cancer-related pain. -e above data, due to the lack of creased risk of cancer progression and a shorter time to the worldwide registers, are based on epidemiological estimates appearance of metastatic lesions [3]. Research shows that [1]. A meta-analysis published in 2016, which included 117 ineffective pain and stress treatment adversely affects the reports of pain in cancer patients, showed that the goal of body’s defence systems, including cellular immunity and the effective pain management still remains far from being functioning of the natural killer (NK) cells. Andersen et al. 2 Pain Research and Management demonstrated that the stress associated with the diagnosis Owing to the steadily increasing use of opioids, their and surgical treatment of breast cancer in women impaired potential side effects are being studied in more depth. In their immune cell response, including NK cell toxicity and recent years, a number of studies have suggested immu- T-cell responses. Stress levels significantly predicted lower nosuppressive effects of opioid analgesics and their potential NK cell lysis, diminished response of NK cells to serious consequences, including an increased risk of cancer recombinant interferon gamma, and decreased proliferative progression in patients treated with these drugs [3]. response of peripheral blood lymphocytes to plant lectins Classically, three opioid receptor types (µ, σ, and κ) have and to a monoclonal antibody directed against the T-cell been identified on the central and peripheral nervous system receptor [4]. neurons. Moreover, based on the analysis of mRNA, re- Experimental and clinical studies demonstrate the im- ceptor protein, or opioid binding capacity of cells or their portance of effective pain management also in terms of opioid response, it has been confirmed that opioid receptors cancer progression. Page et al. found a longer time interval to are also present on other cells, including cancer cells [7]. lung metastasis in a group of experimental animals (rats in Interestingly, it has been shown that, by influencing the the experimental model of breast adenocarcinoma) with proliferation and apoptosis processes, opioids can regulate effective analgesia (intrathecal or systemic opioids) com- the growth and activity of a number of cells, including the pared with a group of animals not subject to analgesic cancer cells [8]. -is may result in an increased risk of cancer treatment [5]. Lillemoe et al. in their randomised prospective progression. However, the test results are ambiguous as they study (RCT), which included a group of patients with ad- depend on the type of cell tested, the dosage, the time of vanced pancreatic cancer, concluded that alcohol-induced administration, and the type of opioid used. -e question visceral neurolysis (neurolytic splanchnicectomy) per- remains whether the direct effect of opioids on cancer cells formed in one of the two groups of patients provided not observed in experimental studies translates into comparable only pain relief but also longer survival time, compared with effects in vivo and how opioids ultimately affect the immune the group of patients given saline instead of alcohol. -ere system status of cancer patients. was no improvement in overall survival (OS) compared with the control group of patients who underwent the same 3. Potential Mechanisms of Opioid- procedure but who did not experience pain prior to its Induced Immunosuppression onset [6]. Opioids are being used by the anaesthesiologists not only -e immune system plays a key role in cancer defence. Its to treat acute pain in the perioperative period but also to important components include NK (natural killer cells), control chronic cancer pain. Studies conducted over the T cells, mast cells, macrophages and mediators, including recent years have given results indicating the potentially cytokines (interleukins and chemokines). It turns out that immunosuppressive effects of opioids and their serious acute and chronic administration of exogenous opioids consequences, including the risk of cancer progression. -is affects both the cellular and humoral components of the is a very important and complex problem both in peri- immune response. Exogenous opioids affect several of the operative period and in chronic pain treatment course. components of the immune system, including lymphocyte Morphine has immunosuppressant properties which can proliferation, their phagocytic activity, NK cell activity, promote cancer, but on the other hand suppressing of pain cytokine expression, and antibody production [9]. Several alleviates the surgical stress and thus might be protective mechanisms responsible for immunosuppression associated against tumour metastases. with the use of opioids in cancer patients have been iden- tified. -ey can be divided into central and peripheral ones 2. Opioids and Their Receptors and are schematically presented in Figure 1. -e importance of central mechanisms is demonstrated Pharmacotherapy constitutes the basic pain treatment by the fact that opioids that easily penetrate the blood-brain method in cancer patients. For moderate to severe pain in barrier have a stronger immunosuppressive effect compared cancer patients, the mainstay of the therapy is opioid an- with those that do not pass through it—the latter demon- algesics (weak or strong ones, depending on pain severity). strates this effect only after central administration [10]. -ese drugs exert their clinical effects by influencing indi- Moreover, it turned out that MOP knockout mice did not vidual opioid receptors, which are currently classified into show any immune-modulating effect after central admin- three groups: MOP (µ, mu), DOP (σ, delta), and KOP (κ, istration of morphine in experimental studies. -is confirms kappa). Opioids can also affect other receptors, especially the view that central immune modulatory effects of opioids NOPs (nonclassical nociceptin/orphanin FQ receptor, are
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