Tumor Proliferation and Apoptosis

The ability of opioids to modulate tumor growth in both perioperative and nonsurgical settings has been of great interest to scientists and clinicians. The mechanisms underlying the role of opioids in regulating tumor cell growth are complex. In practice, cancer patients often receive high opioid doses; therefore the relationship between opioid dose and tumor proliferation has significant clinical ramifications. The literature reports a range of plasma concentrations of opioids commonly consumed for cancer pain in the surgical setting ( Table 12.1 ).

Opioids exert their effects on both malignant and nonmalignant cells, with the ability to influence proliferation and apoptotic pathways, thereby modulating tumor growth. ^. The effects of morphine on tumor growth in vitro and in vivo have been extensively reviewed, and these reviews highlight that the results are inconsistent. These discrepancies can be partially explained by the differences in cell types and the concentrations of opioids used.

It is known that opioids have both pro- ^, and antiproliferative ^, effects on tumor cells. In vitro studies testing the effect of various opioids on cancer cell survival and/or proliferation have been reviewed previously. It has been proposed that at higher opioid concentrations, tumor cell growth is inhibited, whereas at lower concentrations the inverse is true. The literature further suggests the potential involvement of various opioid receptors in tumor cell growth ( Table 12.2 ). It has been reported that stimulation of the κ-opioid receptor induces apoptosis of CNE2 human epithelial cancer cells via a phospholipase C-mediated pathway. Over the years, several studies have shown the presence of μ-opioid receptors (MORs) in various cancer types and have investigated their roles in promoting cell proliferation, adhesion, migration, and tumorigenesis. A recent study found that MOR expression is positively associated with hepatocarcinoma (HCC) progression, and MOR silencing decreased HCC tumorigenesis in vitro and in vivo, significantly extending the survival of tumor-bearing mice. A triple-negative breast cancer mouse model treated with morphine and naloxone showed that over 30 days, naloxone was able to prevent the morphine-induced increase in tumor volume.

It has been proposed that instead of MOR involvement, opioid growth factor receptors (OGFR) may be involved in control of tumor proliferation. Research has shown that exogenous morphine reduced the growth of H1975 human adenocarcinoma cells that overexpressed OGFR but not MOR. This antiproliferative effect of morphine was attenuated upon OGFR knockdown, suggesting a potential underlying morphine-OGFR binding mechanism. Current research in the field has found that methionine enkephalin upregulated OGFR expression and significantly inhibited the growth of human gastric cancer cell lines (SG7901 and HGC27). This induced G0/G1 cell cycle arrest and caspase-dependent apoptosis, suggesting the application of methionine enkephalin as a potential anticancer drug for the treatment of gastric cancers.

Tumor Cell Invasion, Migration, and Metastasis

The spread of a tumor from its primary site to a distant organ accounts for approximately 90% of all cancer-related deaths. During the metastatic process, disruptions in the cell matrix and cell-cell adhesion are of upmost importance. Epithelial-mesenchymal transition (EMT) is a key step in converting cancer cells into a migratory population that is capable of systemic metastasis. A number of factors are involved in cancer cell metastasis, including invasion/extravasation through the basement membrane and extracellular matrix via the secretion of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP) production, and increased vascular basement membrane permeability.

Various studies have shown that morphine can both increase ^, and decrease ^, the invasion of cancer cells through the vascular basement membrane. Morphine also increases vascular permeability (i.e., decreases endothelial barrier function). A more recent study has found that morphine promoted, whereas naloxone and nalmefene (MOR antagonists) suppressed migration and invasion in various hepatocellular carcinoma cell lines and in mouse models. Morphine has also been reported to increase ^, or decrease uPA secretion by cancer cells.

Earlier studies showed that morphine inhibits adhesion and migration of colon 26-L5 carcinoma cells to the extracellular matrix and invasion into basement membrane matrigel, inhibiting the production of both MMP-2 and MMP-9. Naloxone did not attenuate the inhibitory effects of morphine on MMP production from tumor cells, suggesting that morphine may inhibit cell adhesion and enzymatic degradation of the extracellular matrix via nonopioid receptor mechanisms.

Several mechanisms have been proposed to explain the inhibitory effects of morphine on MMP production. The involvement of a MOR-independent, nitric oxide synthase-dependent mechanism has been suggested ; morphine has been shown to decrease both endothelial oxide synthase (NOS) mRNA and nitric oxide secretion in MCF-7 cells. In a coculture of breast cancer cells and macrophages or endothelial cells, morphine reduced the levels of MMP-9, while increasing the levels of its endogenous inhibitor, TIMP-1; this was not observed in cells grown individually. It has been suggested that morphine may exert its antitumor effects via modulation of paracrine communication between cancer and nonmalignant cells. Morphine prevented the increase in IL-4-induced MMP-9 by inhibiting the conversion of macrophages to an M2 phenotype via an opioid receptor-mediated mechanism. A more recent study found that when compared with serum from saline-treated controls, serum from morphine-treated mice (10 mg/kg for 3 days) reduced the chemotaxis of breast cancer and endothelial cells and reduced cancer cell invasion. This was also associated with a decrease in MMP-9 and an increase in TIMP-1 and TIMP3/4 levels. Inhibition of MMP-9 abolished the reduction in chemotactic attraction, indicating that MMP9 reduction in the serum of morphine-treated mice may mediate the decrease in chemoattraction.

The effect of opioids on migration can further be seen in noncancer models where remifentanil was shown to increase the migration of C2C12 cells (mouse pluripotent mesenchymal cell line), significantly increasing osteoblast differentiation. It has previously been shown that morphine can induce microglial migration via an interaction between the MOR and ionotropic P2 × 4 purinergic receptors, dependent on PI3K/Akt pathway activation. This occurred in vitro at a low (100 nM) concentration of morphine and is proposed to have implications in morphine-induced side effects such as tolerance or hyperalgesia.

Immunosuppression

The immune system plays a vital role in the defense against cancer. However, exogenous opioids have been reported to influence key aspects of the immune system, including lymphocyte proliferation, natural killer cell and phagocytic activity, expression of important cytokines, and antibody production. The inhibitory effect of opioids on the immune system has attracted great interest from researchers and clinicians especially because of its potential consequences for postsurgical outcomes. The surgical process is often accompanied by pain and surgical stress, known triggers for the release of mast cells, neutrophils, macrophages, eosinophils, monocytes, and most importantly, natural killer cells. Opioids have been identified to influence this cascade via two main mechanisms: (1) peripheral and (2) central. Opioids can directly act on immune cells (e.g., B and T lymphocytes) through the MOR, which can inhibit NK cell migration, or indirectly via nonopioid receptors such as Toll-like receptor 4. Centrally, acute morphine administration activates periaqueductal gray (PAG), which in turn activates the CNS to induce lymphoid organs, i.e., the spleen, to trigger the release of biological amines, suppressing NK cell activity and lymphocyte proliferation in the spleen. Following surgery, some patients take opioids long-term, which stimulates the HPA axis to produce glucocorticoids, thereby decreasing NK cell activity.

Opioids can act directly on immune cells and have been reported to exert a number of effects on macrophages. Morphine reduces the proliferation of macrophage progenitor cells, their recruitment, Fc gamma receptor (Fcg R)-mediated phagocytosis, and the release of nitric oxide. Recent literature suggests that morphine may exert its antitumor effect in the tumor microenvironment by modulating the paracrine communication between nonmalignant and cancer cells and modulates tumor aggressiveness by influencing M2 polarization and the production of macrophage proteases within the tumor environment. Results from the same laboratory have further shown that morphine can prevent proangiogenic interactions between macrophages and breast cancer cells in the tumor microenvironment.

To place these mechanisms in the context of cancer surgery, it is important to acknowledge that: (1) in the context of pain, which itself is immunosuppressive, opioids are protective due to the analgesia they provide, (2) in response to surgical stress the body itself can trigger the release of endogenous opioids, and (3) the level of immunosuppression may vary greatly between opioids ( Table 12.3 ).

Remifentanil, an opioid analgesic used intraoperatively, has been shown to significantly reduce neutrophil migration and cell adhesion molecule expression in vitro when compared to fentanyl. Remifentanil inhibited lipopolysaccharide (LPS)-induced activation of human neutrophils and decreased the expression of various proinflammatory factors. No effect, however, was seen with the structurally related opioids, including sufentanil, alfentanil, fentanyl, delta, or kappa receptor antagonists. A more recent study conducted in 40 gynecological laparotomy patients found that at 2 h postincision when compared with oxycodone or nonopioid analgesia, morphine significantly downregulated the expression of various genes in CD4+, CD8+, and NK cells; increased IL-6 concentration; and suppressed NK cell activity. A number of studies have found that following incubation of blood from gastric or blood cancer patients with opioids ex vivo, fentanyl increased the number of regulatory T cells. ^,

In contrast, the administration of tramadol (20 and 40 mg/kg) before and after laparotomy prevented surgery-induced NK cell suppression in rat models. Oxycodone has been shown to increase the generation of reactive oxygen intermediates and nitric oxide by macrophages in mice, while also increasing the release of IL-6, TNF-α, and TNF-β. In this study oxycodone did not influence the humoral immune response, whereas morphine suppressed and buprenorphine enhanced B-cell activation. Buprenorphine has been shown to reduce corticosterone levels, with no effect on immune parameters such as CD4+ and CD8+ or NK cell activity. In the context of surgery-induced immunosuppression, it was found that when compared to fentanyl or morphine, buprenorphine ameliorated the effects of surgery on the HPA axis, NK cell activity, and metastatic colonization in rats.

Opioids are commonly administered in the perioperative period; hence their immunosuppressive profile and ability to influence cancer outcomes are of clinical importance. While opioids such as morphine, remifentanil, fentanyl, and methadone are proposed to be highly immunosuppressive, the literature suggests nonimmunosuppressive and immunoprotective roles for buprenorphine and tramadol, respectively.

Inflammation

The inflammatory response plays a key role in various stages of tumor development, including initiation, tumor growth, invasion, and metastasis. Opioids have been shown to modulate the inflammatory response via regulating the expression of key inflammatory cytokines and their receptors and mediating the release of endogenous opioids (i.e., β-endorphin) from immune cells at the site of inflammation. Morphine significantly enhanced the release of neuropeptide substance P (SP) from mast cells in a transgenic sickle mouse model. Similarly, morphine was shown to promote mast cell activation and degranulation in a murine breast cancer model while also increasing the expression of inflammatory cytokines and neuropeptide SP release. A more recent study showed that morphine increased CD11b+ cells and microglia at the site of injury in vivo, exacerbating the inflammatory response; pretreatment with minocycline (an antibiotic with antiinflammatory properties), however, reduced this effect, aiding functional recovery.

In contrast, several studies have suggested an inhibitory effect of opioids on the production of key inflammatory markers. Morphine decreases inflammation-induced angiogenesis and inhibits the early recruitment of phagocytes to an inflammatory signal, with a significant reduction in monocyte chemoattractant protein-1 (MCP-1). Morphine also attenuated peripheral inflammation in a rat model of chronic antigen-induced arthritis (AIA). Interestingly, opposing roles of opioid receptors have been reported, whereby the activation of the kappa (κ) opioid receptor (KOR) induces an antiinflammatory response, while MOR activation favors a proinflammatory response. ^,

Angiogenesis

The formation of new blood vessels plays an integral role in tumor development and progression. Angiogenesis is required for primary tumors or metastases to grow beyond a critical size. Localized tumor growth is often characterized by hypoxia, which upregulates the expression of hypoxia inducible factor (HIF) and stimulates the secretion of vascular endothelial growth factor (VEGF), a key player in the formation of new blood vessels that promotes tumor growth. The current literature suggests that morphine can have both stimulatory ^, and inhibitory ^, effects on angiogenesis.

At clinically relevant (analgesic) concentrations, morphine significantly reduced angiogenesis and tumor growth in a Lewis lung carcinoma mouse model. This inhibitory effect was mediated through a hypoxia-induced p38 MAPK pathway. A simple chorioallantoic membrane model, evaluating the effects of codeine, morphine, and tramadol on angiogenesis at three different concentrations, concluded that morphine had an antiangiogenic effect at 1 and 10 µM, whereas tramadol and codeine only inhibited angiogenesis at high concentrations. In the context of opioids and angiogenesis, morphine significantly inhibited hypoxia-induced VEGF expression in rat cardiac myocytes, and coculture induced VEGF production by macrophages and cancer cells, which was significantly reversed by naloxone, suggesting potential opioid receptor involvement. ^,

In contrast, morphine increased tumor neovascularization in MCF-7 human breast cancer cells in vivo, induced the in vitro proliferation of human endothelial cells, and stimulated angiogenesis. The results of this study must be clinically translated with care, since mice and humans metabolize morphine differently, and hence mg/kg dosing in humans cannot necessarily be applied to a mouse model. Chronic morphine treatment not only stimulated angiogenesis but also increased prostaglandin E2 (PGE2) and cyclooxygenase (COX)-2 in a breast cancer mouse model, but this was successfully prevented by coadministration of celecoxib (a selective COX-2 inhibitor). A more recent study showed that δ-opioid receptor stimulation in breast cancer cells may lead to COX-2 expression and the PI3K/Akt-dependent activation of HIF-1α, which stimulates endothelial cell sprouting via paracrine activation of PGE2 receptors. While discrepancies exist in the literature, it is apparent that opioids may influence the angiogenic process in the perioperative period.

Opioids Versus Opioid-Sparing Analgesia/Anesthesia for Cancer Surgery

Surgical excision of primary tumors is an essential component of cancer therapy; however, the surgical process itself can trigger the metastatic process. The presence of circulating tumor cells following cancer surgery has been shown to be independently associated with an elevated risk of tumor recurrence and reduced disease-free survival in various cancer types. Most importantly, the current literature suggests that there are three perioperative-associated factors that impair cellular immunity: (1) surgical stress and tissue injury as a result of tumor resection, which may influence the risk of tumor metastasis through the release of angiogenic factors and suppression of NK cells ; (2) general anesthesia (GA), which has been shown to impair various immune functions; and (3) opioid analgesia, which has been shown to impair both cellular and humoral immunity in humans.

In the context of surgery, the focus of current research has shifted toward the use of opioid-sparing techniques such as RAA, NSAIDs, LA, and propofol, and elucidating whether this influences perioperative outcomes. Current prospective clinical studies predominantly compare regimens where opioids are present to different extents but are primarily not designed to study the effects of opioids on cancer outcomes. A number of publications have reviewed the influence of opioid-sparing techniques on oncological outcomes in which opioids are part of both interventions, ^{, ,} but there are only few ex vivo, in vivo, and clinical studies (in which opioids are only part of one regimen) ( Table 12.4 ) that have compared the influence of opioid-sparing techniques versus opioid analgesia on cancer outcomes.

Regional Anesthesia and Analgesia

Regional anesthesia and analgesia attenuate the immunosuppressive and potentially tumor-promoting effects of both opioids and GA by preventing the neuroendocrine stress response that results from surgical excision. The combination of RAA and GA decreases the amount of GA utilized during surgery as well as the need for subsequent postoperative opioid analgesia, obviating subsequent immune-related effects while providing adequate pain relief. Studies have shown that epidural anesthesia (EA) attenuates the stress response but not the inflammatory response. ^,

Several retrospective studies comparing the effect of PVA/EA + GA with GA + opioid analgesia have shown a reduced risk of cancer recurrence or increased overall survival (OS) following cancer surgery. However, it was unclear whether this beneficial effect was due to the reduced perioperative opioid requirements. While it is known that in the context of pain RAA is protective, the results from systematic reviews and meta-analyses in assessing the influence of perioperative RAA versus GA + opioid analgesia on cancer outcomes have reported a benefit on OS but not recurrence-free survival (RFS). ^, A recent article by the American Society of Regional Anesthesia and Pain Medicine (ASRA) and the European Society of Regional Anesthesia and Pain Therapy (ESRA) concluded that there is currently weak evidence to suggest that the use of regional anesthesia and analgesia may reduce metastasis or cancer recurrence. Findings from a Cochrane review further concluded that there is currently inadequate evidence supporting the benefits of regional anesthesia techniques on tumor recurrence. Results from a recently completed large randomized controlled trial comparing the use of opioids (morphine) + GA versus propofol + thoracic epidural or PVA/A for breast cancer surgery found no difference between the groups in terms of cancer-specific survival or overall quality of life despite the RAA group receiving half the amount of opioids compared with the GA group. This study was the first prospective randomized multicenter trial specifically designed to assess whether anesthesia and analgesia techniques could affect the long-term outcome of breast cancer surgery. It is important to acknowledge that in this study RAA was not compared to opioids alone; therefore, the study was not designed to determine the role of opioids.

NSAIDs

Inflammation plays a key role in tumor development. An in vivo study found that prostaglandin (PGE2) promotes the formation of liver metastases in mice via various mechanisms. The influence of NSAIDs on cancer has been proposed to be through the decreased synthesis of PGE2 as a result of COX inhibition. In a murine breast cancer model the COX-2 inhibitor celecoxib has been shown to prevent morphine-induced stimulation of tumor cell growth, angiogenesis, metastasis, PGE2, and COX-2. Several studies have reported that the combination of NSAIDs and opioids better preserves immune function in vitro and increases survival in vivo when compared with opioids alone. In the clinical setting a number of studies have associated NSAID use with improved RFS postcancer ­surgery. ^,

Local Anesthetics

Intravenous LA such as lidocaine, bupivacaine, and ropivacaine are commonly used as part of multimodal analgesia and are known to possess antiinflammatory properties. LA have been reported to exert a number of antitumor effects on various cancer cells in vitro such as the inhibition of epidermal growth factor receptor (EGFR) and EGF-induced proliferation of human tongue cancer cells, reduced metastatic progression, and demethylation of DNA in breast cancer cells while also reducing tumor cell proliferation, viability, and migration of prostate, ovarian, and breast cancer cells. Intraperitoneally injected lidocaine was further shown to suppress human hepatocellular carcinoma HepG2 xenograft tumor growth in vivo. Results from an ASRA/ESRA special article reported that there is strong evidence, arising from in vitro data, suggesting a protective effect of LA on cancer recurrence; however, there is a lack of preclinical and clinical studies to suggest a beneficial role in cancer surgery. In the context of pain, LA are likely to be ­protective; this requires validation by prospective clinical studies designed to compare the long-term oncological effects of opioids and LA on cancer surgery.

Propofol

Propofol, an intravenous anesthetic, is commonly used during cancer surgery and has been shown to affect malignant cancer cells via multiple mechanisms. A number of studies suggest that propofol exerts a stimulatory ^, effect on immune parameters and possesses antiinflammatory properties in vitro. In an ex vivo study, when compared with opioids + GA, PVA + propofol administered to breast cancer surgery patients altered the circulating cytokine profile, which may indicate an influence on perioperative cancer immunity. Several retrospective clinical studies have shown improved OS ^, with propofol-based anesthesia following colon and gastric cancer surgery, while reduced cancer recurrence ^, has been shown following breast and esophageal cancer surgery in other retrospective clinical studies. The long-term oncological effects of propofol have not been well established.

Clinical Trials Involving Opioids Versus Alternative Technique

As of 2019, there is one ongoing prospective randomized controlled trial (RCT) (listed at clinicaltrials.gov ) studying the influence of an opioid-sparing technique versus opioid + GA on cancer recurrence and survival ( Table 12.5 ).

Table 12.5

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