Secondary Logo

Opioids and cancer: friend or foe?

Wigmore, Timothy; Farquhar-Smith, Paul

Current Opinion in Supportive and Palliative Care: June 2016 - Volume 10 - Issue 2 - p 109–118
doi: 10.1097/SPC.0000000000000208
PAIN: CANCER: Edited by Anthony H. Dickenson and Paul Farquhar-Smith
Free
Editor's Choice

Purpose of review Most cancer patients experience pain and many will require opioids. However, the effects of opioids on cancer progression, metastasis, and recurrence is increasingly being questioned. There is evidence that opioids affect immune system function, angiogenesis, apoptosis, and invasion in a potentially deleterious manner. This review will examine the preclinical and clinical evidence.

Recent findings Recent clinical data have struggled to find robust evidence that opioids promote cancer progression. Although most study has involved morphine, differential effects of other opioids on immune function and cancer are revealing a more complex picture.

Summary Although there is a biologically plausible story, evidence for the action of opioids on cancer is mixed. Indeed, it may even be that in the chronic setting morphine has a beneficial effect on outcome in certain cancer types. This review critically examines and evaluates the evidence for the action of opioids on the processes involved in cancer progression. In the light of the uncertainty of opioid effect on cancer, any decision making should be tempered by knowing that stress and pain undoubtedly contribute to cancer progression.

The Royal Marsden NHS Foundation Trust, London, UK.

Correspondence to Paul Farquhar-Smith, The Royal Marsden NHS Foundation Trust, London, UK. Tel: +44 0207 352 8171 ex 2727; fax: +44 0207 808 2726; e-mail: Paul.farquhar-smith@rmh.nhs.uk

Back to Top | Article Outline

INTRODUCTION

Pain prevalence rates in cancer patients are high [1]. Many will require opioids for their pain during their treatment pathway and opioids remain the most effective form of pain relief. However, the effect of opioids on cancer progression, metastases, and recurrence is increasingly being questioned. Opioid receptors are expressed on cells out with the nervous system, and they are present on cancer cells. In animal models, stimulation of these receptors can result in cancer cell stimulation. However, the story is complex. Opioid receptors are present on many cells that make up the milieu in which cancer cells exist in vivo. Opioid-induced immunomodulation can reduce CD8+ and natural killer (NK) cells facilitating tumour immunoevasion, cause changes in proinflammatory cytokines, and promote angiogenesis. However, some actions on the immune system may not promote tumour development, and are effectively anticancer and equally may not actually be opioid receptor-mediated. Furthermore, the ability of opioids to negate or minimise the highly deleterious effect of pain and stress on cancer progression needs to be borne in mind.

Box 1

Box 1

Back to Top | Article Outline

Opioids and the immune system

Morphine and other opioids have been shown to have a variety of effects on the immune system and to understand their impact on cancer, we must understand normal interactions between immune and tumour cells (Fig. 1).

FIGURE 1

FIGURE 1

Back to Top | Article Outline

Cancer immunoediting

From Paul Erlich's ‘magic bullets’ to the immunosurveillance theories of Burnet and Thomas, the immune system plays a pivotal role in cancer control. More recent iterations have incorporated the role of the adaptive and innate immunities in policing cancer. There is a balance of mechanisms that are both tumour suppressive and promoting which has being coined ‘cancer immunoediting’ [3].

Cancer cells have undergone genetic changes that release them from normal apoptotic control. These differences are potentially identifiable as nonself by the immune system. However, not all cancer cells express these immunogenic nonself ‘transplantation rejection antigens’ and several distinct mechanisms contribute to the failure of immune-mediated cancer suppression.

  1. Vascular endothelial cells within tumours may not express the requisite adhesion molecules for cytotoxic lymphocytes (CTLs) and similar cell function [4].
  2. Other immune regulatory systems designed to temper overzealous auto-immune activity (e.g. regulatory T cells, Tregs) are often increased in cancer, can interfere with anticancer immune processes (e.g. T-cell immunity) and may be associated with a poorer prognosis [5]. The biology of Tregs exhibits dichotomy since they promote tumour growth by suppression of antitumour immunity yet by reducing procancer inflammatory stress may hinder tumourgenesis [6].
  3. Tumour cells can be immunosuppressive through release of soluble factors and by expression of moieties on cell surfaces such as transforming growth factor-β (TGF-β) [7] which may contribute to poor outcomes [8].
  4. Activation of proinflammatory immune systems can be involved in oncogenesis [9], and chronic inflammation (e.g. from tobacco smoke) is associated with 20% of all cancers. Chronic inflammation promotes oncogenic mutations, increases cellular growth, and stimulates angiogenesis [6]. In contrast to the cytolytic anticancer actions of CD8+ cells, a subpopulation of CD8+ cells promotes tumourgenesis, and is implicated in chronic inflammation-induced cancers [10]. Acute inflammation may in itself be actively anticancer and forms the basis of some therapies.
  5. Immunoediting: Removal by the immune system of the most immunogenic tumour cells leaves (less immunogenic) ‘edited’ cells. These are less likely to be detected and removed by subsequent immunosurveillance [3]. ‘Edited’ cells subsequently implanted into immunocompetent mice have been shown to be more likely to result in tumour growth than the ‘unedited’ cells that were still immunogenically ‘visible’ to tumour surveillance systems [11].

Three phases of immunoediting have been described [12].

Back to Top | Article Outline

Elimination

Innate immunity can be activated by early tumour cell ligand expression, which activates a tumour-targeting adaptive immune response. Although innate systems can remove certain early tumour cells, typically both innate and adaptive (including the propagation and expansion of CD4+ and CD8+ T cells) are required. NK cells are an integral part of the tumour ligand-activated innate response.

Back to Top | Article Outline

Equilibrium

Tumour cells that escape elimination are ‘kept in check’ by the adaptive immune system but retain the potential to develop into tumours if the equilibrium is unbalanced. The pivotal role of the adaptive system is highlighted by the development of latent tumours after immune system compromise (e.g. reduction of CD4+ and CD8+ cells) [13,14].

Back to Top | Article Outline

Escape

Escape from equilibrium is likely to be achieved by immunoevasive cells. Cancer immunosuppression may be mediated by diminution of antigen expression/processing and abetted by the editing-driven selection of immunologically ‘invisible’ cells. Local microenvironment changes by suppressive cytokines [e.g. vascular endothelial growth factor (VEGF) and TGF-β] and recruitment of inhibitory cell systems (Tregs) are also implicated [12]. However, it is not simply the presence or absence of CTLs but a complex interplay of infiltrating CD8+, NK cells and tumour-associated macrophages that determines whether escape is likely [15].

Back to Top | Article Outline

OPIOID RECEPTORS

There are three distinct classical opioid receptors: mu opioid receptor (MOR) (μ), kappa opioid receptor (KOR) (κ), and delta opioid receptor (DOR) (δ). These G protein coupled receptors are expressed widely in the central nervous system (CNS), especially in areas germane to pain [16]. However, there may also be expression on many elements of the immune system [17], (although this concept has been questioned) [18▪▪]. A fourth receptor, the opioid receptor-like (ORL-1 or nociceptin opioid receptor) receptor has been identified [19]. Nociceptin (or orphanin FQ) is the endogenous ligand and opioid receptor-like-1 may be preferentially expressed on immune cells [20].

There is evidence for opioid receptor involvement in cancer progression and outcome. MOR over expression is observed in certain cancer cell lines and polymorphism of the MOR (A118G exhibits reduced receptor response to opioid binding) is associated with decreased breast cancer mortality [21▪▪].

Many actions of opioids are mediated through nonclassical receptors (demonstrated by lack of reversal by classical opioid receptor antagonists) and may contribute to opioid actions.

Back to Top | Article Outline

EFFECTS OF OPIOIDS ON KEY IMMUNE CELLS INVOLVED IN ANTITUMOUR IMMUNE EFFECTS

Although there are exceptions, organized CTLs play a major role in tumour control [22]. Morphine inhibits activation of CTLs, especially CD4+CD8+ cells [23]. Both immature and mature/differentiated T cells are reduced significantly by morphine treatment (including cytotoxic CD8+ cells) in part mediated by a morphine-induced increase in corticosteroids [24]. Poorly controlled pain and other stressors contributing to rises in endogenous corticosteroids makes the opioid effect difficult to separate out.

Further evidence for opioid-mediated, cancer promoting actions on CTLs is supported by antagonism of MOR and DOR decreasing mammary cancer progression and increasing NK cell activation [25]. However, in-vitro morphine can increase CTL function, especially CD8+ cells, and modulate a potential anticancer effect [26].

Human data are similarly conflicted. Low-dose intrathecal morphine can inhibit NK cell activity [27]. However, blood from chronic morphine users showed no difference in NK cytolytic activity compared with opioid-naïve controls [28▪] and in some models morphine can ‘increase’ cytolytic activity in NK cells [29].

The mast cell is the conductor of the immunosurveillance microenvironment, causing context dependent pro and anticancer actions [30]. Morphine is suppressive of mast cells and reduces function in some models of inflammation [31]. However, morphine can activate mast cells [32▪] and raise histamine by a non-MOR-mediated action [33].

Back to Top | Article Outline

OPIOID MODULATION OF CYTOKINES AND CHEMOKINES

Chronic morphine increases TGFβ resulting in a reduction of IL-2 and IFNγ mediated by MOR [34]. IL-2 is especially important in the maturation and differentiation of CD4+CD8+ cells and NK cell activity, and therefore this anti-inflammatory action could result in cancer promotion. However, TGFβ can be proinflammatory [35]. Morphine can also stimulate proinflammatory cytokines, while reducing anti-inflammatory ones (IL-10) [36]. MOR activation increases some chemokines [chemokine ligand receptor 5 (CCL5) and chemokine (C-X-C motif) receptor 4] via increased TGFβ synthesis [37]. CCL5 is proinflammatory, promoting T-cell chemotaxis and stimulating NK cell cytotoxicity [38].

Other opioid-mediated actions, such as ‘reduction’ of the proinflammatory IL-1, IL-6, and TNFα, are influenced by different opioid receptor types. This anti-inflammatory action is KOR mediated [39].

Microglia are part of the immune system of the CNS and morphine activates microglia via the Toll-like receptor 4 (‘the endogenous danger signal’ receptor), which results in release of proinflammatory cytokines [40].

Anti-inflammatory actions can promote cancer by reducing immunosurveillance but inflammatory changes may be necessary steps in cancer development. Both pro and anti-inflammation morphine actions can potentially have inhibitory and stimulatory effects on cancer progression.

Back to Top | Article Outline

EFFECTS OF OPIOIDS ON ANGIOGENESIS, MIGRATION/INVASION, METASTASIS, AND APOPTOSIS

Evidence of opioid effects on tumour growth, angiogenesis, migration, and metastasis is inconsistent and contradictory. Interpretation of the studies is influenced by timing and dosage. Angiogenesis is only a prerequisite for continued growth when the tumour mass reaches approximately 1 × 106 cells [41]. Conclusions drawn from studies where early growth differences were observed should be interpreted with caution.

Differences in morphine dosage also have a significant impact. Very high doses of morphine are cytotoxic [42] and the clinical relevance of those utilized in studies needs to be assured.

Back to Top | Article Outline

ANGIOGENESIS

Tumour-induced proliferation of endothelial cells is mediated by upregulation of angiogenic growth factors (VEGF). This upregulation occurs as a result of localized hypoxia in the tumour microenvironment [via Hypoxia Inducible Factor 1α (HIF1α)], but also directly by proto-oncogenes (e.g. the ras family).

Opioids can enhance tumour-induced angiogenesis. Morphine stimulates the VEGF receptor through MOR. Singleton found that morphine, [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin (DAMGO) (MOR agonist) and VEGF all stimulated proliferation and migration of human microvascular cells. The MOR receptor antagonism prevented this effect as did VEGF tyrosine kinase inhibition [43]. Gupta showed in human endothelial cells, morphine activates mitogen-activated protein kinase/extracellular signal regulated kinase phosphorylation to produce cell proliferation via a nitric oxide-dependent pathway, analogous to that activated by VEGF [42]. This is opioid receptor-mediated, but was also observed with DOR and KOR agonists. Morphine-treated mice also showed accelerated breast tumour growth associated with increased vascularization [42]. Coadministration of naloxone with morphine-inhibited tumour growth but did not inhibit the angiogenic effect, suggesting a possible separate naloxone-specific antitumour effect. As above, Gupta's group also found that concentrations (much higher than clinical) were cytotoxic to endothelial cells [42] (Fig. 2).

FIGURE 2

FIGURE 2

More recently, mice with invasive breast carcinoma receiving morphine over 7 weeks showed a marked increase in angiogenesis. This study demonstrated an increase in cytokine release, substance P and mast-cell activation, which may have increased growth and angiogenesis [32▪].

Although this evidence supports the concept of morphine-induced angiogenesis, the literature is not consistent. Koodie found that morphine administered in clinically relevant plasma concentrations to the Lewis Lung carcinoma model, resulted in an inhibition of angiogenesis by reduction of HIF1α. This effect was opioid receptor dependent [44].

Moreover, data also suggest different opioid receptor effects. KOR agonists inhibit angiogenesis by suppressing VEGF expression in human endothelial cells. Furthermore, KOR knockout mice with melanoma or lung cancer showed enhanced angiogenesis relative to wild-type mice, whereas the wild-type showed enhanced KOR expression (but nor MOR or DOR), suggesting that KOR could play a role as an antiangiogenic mediator in tumours [45▪].

Back to Top | Article Outline

MIGRATION/INVASION AND METASTASIS

Data concerning the effect of opioids on tumour cell migration and proliferation are also conflicting. Although Harimaya [46] found that morphine decreased metastasis of colon cancer cells by decreasing migration and adhesion, a study involving three cancer cell types (including colonic) found no opioid effect [47]. By contrast, in a further study, morphine promoted cell migration and proliferation of breast adenocarcinoma cells via a nonopioid receptor dependent action [48]. Additionally, antagonism at peripheral MOR resulted in cancer cell inhibition in human nonsmall-cell lung cancer (NSCLC) lines [49].

A crucial step in the migration of cancer cells is degradation of the extracellular matrix by urokinases and matrix metalloproteinases (MMPs) which facilitate passage through the basement membrane, a sine qua non of metastasis. Urokinase plasminogen activator and its receptor are raised in many cancers [50–52] and morphine augments its secretion [53–55]. Raised MMP levels are associated with advanced tumour stage and presence of metastasis [56]. Interestingly, morphine has been found to decrease MMP2 and MMP9 levels in breast cancer cells via a nonopioid receptor pathway and in another study decreased MMP9 and increased the endogenous MMP inhibitor tissue inhibitor of metalloproteinase 1 (TIMP-1) [57▪]. This raises the possibility that morphine can be antimetastatic through a nonopioid receptor-mediated inhibition of extracellular matrix degradation.

Back to Top | Article Outline

APOPTOSIS

Cancer-mediated inhibition of apoptosis (programmed cell death) is key to tumour survival. Evidence suggests that opioids enhance apoptosis implying a possible additional antitumour action to that suggested above. Opioid receptor-mediated apoptosis has been demonstrated in breast cancer cells [58] and in small cell lung cancer cells via DOR and KOR [59]. Morphine (via MORs)-induced expression of Fas (a transmembrane receptor of the tumour necrosis factor family) in immune cells priming them for Fas ligand-mediated apoptosis [60]. Furthermore, proliferation of prostate cancer cells was inhibited in a dose-dependent manner by etorphine (a nonselective opioid agonist) and morphine and antagonized in some cases by a nonselective opioid antagonist, indicating both opioid receptor and nonopioid receptor dependent pathways on apoptosis promotion [61].

However, different opioid concentrations induce differential actions in apoptosis. Hayashi's group observed a DOR-mediated protection of phaeochromocytoma cells against cell death in femtomolar to picomolar concentrations but was cytotoxic via MOR-induced Fas-ligand activation at higher concentrations [62]. In another study, use of clinically relevant concentrations of morphine-induced apoptosis in different cancer cells [63]. Supratherapeutic doses were cytotoxic. Similarly, Tegeder [64] reported therapeutic concentrations of morphine inhibited breast cancer cell progression but higher doses were cytotoxic via an opioid receptor-independent pathway. In some models, morphine may actually promote cell proliferation or have a much reduced proapoptotic effect (including reducing the effects of coadministered proapoptotic chemotherapeutic agents) [65,66].

Back to Top | Article Outline

STRESS AND CANCER PROGRESSION

Surgical stress has a profound influence on the immune system increasing potential for metastasis [67] and cancer progression [68]. Indeed stress of multiple causes has been shown to do the same, putatively mediated by immunological inhibition [69]. Increases in stress hormones with consequent stimulation of many procancer mediators (including VEGF) are in part responsible for these observations [70]. In addition, glucocorticoids are profoundly immunosuppressive to both the innate and adaptive systems. However, effects on the hypothalamic–pituitary–adrenal (HPA) axis are notoriously difficult to study because of numerous potential modulators of glucocorticoid production [71].

The indirect action of opioids on the immune system via the HPA axis is also dogged with conflicting evidence and sensitivity to differences in opioid dose and chronicity [72]. Acute exposure to high-dose opioid (morphine 2 mg/kg) in rats was shown to increase adenocorticotrophic hormone (ACTH) yet 0.5 mg/kg had no effect [73].

In contrast, in humans a single dose of oral morphine decreased ACTH and cortisol [74]. Longer term administration of a wide range of morphine doses (30–240 mg for 1–12 weeks) reduced the elevated ACTH and cortisol levels in pain patients [75]. Here, opioids are protective against the glucocorticoid-mediated immunosuppressive effect. However, complexities of HPA axis function, such as diurnal variation, makes these observations difficult to assess.

Back to Top | Article Outline

COMPARISON WITH NONMORPHINE OPIOIDS

Most research into immunological action of opioids has focused on morphine. However, comparative studies have suggested that certain opioids may be less immunoactive with less potential adverse affects on cancer immunosurveillance. Sacerdote looked at the action of several opioids on NK cell activity and IL-2 production and found morphine but not oxycodone had a powerful immunosuppressive effect. The MOR and KOR agonist nalorphine was strongly immunosuppressive but only mildly antinociceptive [76]. The antinociceptive effect was reduced by a KOR antagonist independently of the immunosuppressive action [76].

Tramadol significantly reduced lung metastasis in a rat model by reversing surgery-induced NK cell inhibition as well as stimulating NK cell activity in nonoperated animals [77]. Morphine and fentanyl stimulated the HPA axis, reduced NK cell activity and enhanced metastasis in unoperated rats, yet buprenorphine did not. Buprenorphine also reduced the surgical stress-induced suppression of NK cell activity and ameliorated the resulting increase in lung metastasis of an NK cell-sensitive tumour [78]. Unlike fentanyl, buprenorphine had no effect after acute administration on several splenic cellular immune processes, including NK cell activity and IL-2 production [79]. In the same study, administration of fentanyl or buprenorphine chronically (7 days) was not associated with immunosuppression. Such tolerance suggests that the immunomodulation of perioperative ‘acute’ opioid administration may be fundamentally different to chronic opioids. However, a buprenorphine-MOR-mediated and dose-dependent immunosuppression (including reduced NK cell activity) has been reported [80].

Notably, remifentanil, a rapid onset/offset opioid used in the intraoperative setting, seems also to have little effect on immune function [81].

Back to Top | Article Outline

CLINICAL EVIDENCE

Despite the wealth of, albeit conflicting, data in preclinical models, there are relatively few clinical studies on the effect of opioids on cancer growth, recurrence or survival. A multitude of contributory factors, especially pain per se, makes elucidation of the specific action of opioids difficult.

Reduction of total opioid use associated with intrathecal morphine was compared with comprehensive medical management in patients with refractory cancer pain [82▪▪]. The reduction in total opioid dose appeared to correlate with an increased cancer survival. After breast cancer surgery, paravertebral rather than morphine analgesia, was associated with significantly reduced cancer recurrence [83].

Also looking at the effect of chronic opioids, 113 nonsurgical, advanced prostate cancer patients demonstrated increased opioid requirements that were associated with worse progression-free survival and worse overall survival [84] although more aggressive disease could have resulted in greater pain and increased opioid needs.

Although increased VEGF is implicated in morphine procancer action, reduction of morphine use through the use of a paravertebral block had no effect on VEGF [85]. Patients who had a local anaesthetic epidural infusion for prostate cancer surgery experienced a 57% reduction in biochemical cancer recurrence compared with an opioid-using group [86] yet in a methodologically similar retrospective analysis after the same surgical intervention, no difference was found [87]. Hiller and colleagues [88] found that ‘effective’ epidural analgesia in patients undergoing oesphago-gastrectomy also had a survival benefit and decreased time to recurrence of gastro-oesophageal cancer. Another retrospective analysis in 1642 patients having radical prostatectomy detected increased cancer progression and decreased survival associated with not having neuraxial blockade [89▪]. It is difficult to conclude that this effect was related to a reduction in opioid consumption as the patient in the epidural group still received significant doses of intravenous morphine (mean 20 mg compared with 40 mg in the patients without epidural).

A meta-analysis of colorectal cancer patients comparing epidural to a general anaesthetic alone for perioperative pain management showed a significant improvement in overall survival associated with an epidural but no effect on recurrence-free survival [90]. The authors could not conclude that the epidural influenced the control of cancer. Similarly, a retrospective analysis of over 42 000 patients having surgery for nonmetastatic colorectal cancer identified a link between epidural and improved survival but no effect on recurrence [91].

Several other retrospective perioperative studies failed to show a survival benefit using opioid sparing, neuraxial/regional techniques after lung cancer surgery [92] surgery for colorectal cancer [93] or ovarian cancer [94] or brachytherapy treatment [95].

Similarly, there was no protective effect of reduction of morphine from regional blockade after radial open prostatectomy [96]. One ‘prospective’ study examined 503 patients who had major abdominal surgery for cancer (MASTER trial) and failed to show any influence of epidural on survival even though the epidural group received a median of 0 mg morphine compared with 107 mg in the controls [97▪].

Recently two meta-analyses have been published reviewing most (but not all) of the literature for the effect of neuraxial blockade on mixed cancer surgery and specifically surgery for colonic carcinoma [98▪▪,99▪]. Pei [98▪▪] suggested that there may be a benefit for neuraxial blockade for surgery for prostate cancer but there was no evidence for such a link with colonic cancer. Only two of the total of 10 studies included were prospective [98▪▪]. Vogelaar [99▪] concluded from analysis of only colonic cancer surgery that overall survival was improved by having an epidural. However, results were mixed and there was no effect on disease-free survival [99▪].

Clinical evidence concerning nonmorphine opioids. The action of morphine and tramadol on NK cell activity was investigated postoperatively in 30 patients with uterine cancer 2 h after a single i.m. dose of opioid [100]. Both drugs were equipotent for analgesia, but while neither morphine nor surgery affected NK cell activity, tramadol was associated with a significant increase in NK cell activity. Of note, surgical stress profoundly reduced immunological competence. In 150 patients using different patient-controlled analgesia opioids, morphine, and fentanyl reduced surgery-induced nuclear factor kappa B (NF-κB) activation but tramadol did not. Morphine also reduced IL-2 yet tramadol was associated with increased IL-2 production [101]. The opposing actions of fentanyl in vitro and in vivo and underlines the hazards of extrapolation of in-vitro results to clinical scenarios.

Multifactorial perioperative techniques to achieve optimal analgesia and resultant ‘opioid sparing’ may offer long-term benefits for cancer patients [102]. However, most of the data is retrospective and confounded by wide variations in practice and the difficulties of providing adequate controls. It would be erroneous to extrapolate and assume similar effects for opioids chronically administered for cancer pain.

Back to Top | Article Outline

CONCLUSION

There is sufficient in vitro and animal model work to make a biologically plausible case for a detrimental effect of opioids on cancer progression. It is likely this is mediated through immunosuppression and potentiation of angiogenesis. However, there is huge variability within the evidence. Opioid dosage, chronicity of administration and the specific opioid can influence outcome, and different cancers exhibit differential responses to opioids. In-vitro studies cannot factor the effects of the complex environment that cancer cells exist, thus excluding the modulating effects of the interactions that occur in vivo. Moreover, other confounders include the inseparability of the actions of stress and morphine. Opioid receptor polymorphism may also be important in explaining differential responses in animal and humans. Alternate genotypes of the MOR may lead research into peripheral opioid receptor antagonists as a cancer treatment [21▪▪,103].

Clinical evidence is sparse but there are some retrospective data that suggest perioperative opioid sparing may lead to better long-term cancer outcomes. However, high-quality studies are needed in the perioperative environment, and in the use of opioids for chronic cancer-related pain. Research into these two areas is surely now mandatory.

High rates of pain prevalence in cancer patients and the absence of effective alternative nonopioid regimens in many cases leaves us in a conundrum. Abandoning a highly effective analgesic without a replacement is both inhumane and likely to be self defeating given the very significant adverse influence of pain and stress on cancer progression.

Back to Top | Article Outline

Acknowledgements

None.

Back to Top | Article Outline

Financial support and sponsorship

None.

Back to Top | Article Outline

Conflicts of interest

T.W. and P.F.S. wrote and edited the review. There was no other assistance. P.F.S. has received payment for consultancy and educational work for Pfizer, Grunenthal, and Astellas. There are no conflicts of interest.

Back to Top | Article Outline

REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
Back to Top | Article Outline

REFERENCES

1. Van Den Beuken-Van Everdingen MHJ, De Rijke JM, Kessels AG, et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18:1437–1449.
2. Dunn GP, Koebel CM, Schreiber RD. Interferons, Immunity and Cancer Immunoediting. Nature Reviews Immunology 2006; 6:836–848.
3. Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive immunity to cancer. Annu Rev Immunol 2011; 29:235–271.
4. Griffioen AW. Antiangiogenesis: making the tumour vulnerable to the immune system. Cancer Immunol Immunother 2008; 57:1553–1558.
5. Curiel TJ, Coukos G, Zou L, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 2004; 10:942–949.
6. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell 2010; 140:883–899.
7. Croci DO, Salatino M. Tumor immune escape mechanisms that operate during metastasis. Curr Pharm Biotechnol 2011; 12:1923–1936.
8. Tong CC, Kao J, Sikora AG. Recognizing and reversing the immunosuppressive tumor microenvironment of head and neck cancer. Immunol Res 2012; 54:266–274.
9. Karin M, Cao Y, Greten FR, Li ZW. NF-kappaB in cancer: from innocent bystander to major culprit. Nat Rev Cancer 2002; 2:301–310.
10. Roberts SJ, Ng BY, Filler RB, et al. Characterizing tumor-promoting T cells in chemically induced cutaneous carcinogenesis. Proc Natl Acad Sci USA 2007; 104:6770–6775.
11. Shankaran V, Ikeda H, Bruce AT, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature 2001; 410:1107–1111.
12. Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity's roles in cancer suppression and promotion. Science 2011; 331:1565–1570.
13. Koebel CM, Vermi W, Swann JB, et al. Adaptive immunity maintains occult cancer in an equilibrium state. Nature 2007; 450:903–907.
14. Veroux M, Puliatti C, Fiamingo P, et al. Early de novo malignancies after kidney transplantation. Transplant Proc 2004; 36:718–720.
15. Camus M, Tosolini M, Mlecnik B, et al. Coordination of intratumoral immune reaction and human colorectal cancer recurrence. Cancer Res 2009; 69:2685–2693.
16. Vallejo R, de Leon-Casasola O, Benyamin R. Opioid therapy and immunosuppression: a review. Am J Ther 2004; 11:354–365.
17. Bidlack JM, Khimich M, Parkhill AL, et al. Opioid receptors and signaling on cells from the immune system. J Neuroimmune Pharmacol 2006; 1:260–269.
18▪▪. Al-Hashimi M, Scott SW, Thompson JP, Lambert DG. Opioids and immune modulation: more questions than answers. Br J Anaesth 2013; 111:80–88.

Excellent review of the complexities of the effect of opioids on immune modulation.

19. Lambert DG. The nociceptin/orphanin FQ receptor: a target with broad therapeutic potential. Nat Rev Drug Discov 2008; 7:694–710.
20. Peluso J, LaForge KS, Matthes HW, et al. Distribution of nociceptin/orphanin FQ receptor transcript in human central nervous system and immune cells. J Neuroimmunol 1998; 81:184–192.
21▪▪. Bortsov AV, Millikan RC, Belfer I, et al. M-Opioid receptor gene A11G polymorphism predicts survival in patients with breast cancer. Anesthesiology 2012; 116:896–902.

Key reference in the emerging importance of opioid receptor polymorphisms and cancer.

22. Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 2003; 348:203–213.
23. Scott M, Carr DJ. Morphine suppresses the alloantigen-driven CTL response in a dose-dependent and naltrexone reversible manner. J Pharmacol Exp Ther 1996; 278:980–988.
24. Zhang EY, Xiong J, Parker BL, et al. Depletion and recovery of lymphoid subsets following morphine administration. Br J Pharmacol 2011; 164:1829–1844.
25. Sarkar DK, Sengupta A, Zhang C, et al. Opioid antagonist prevents μ- and δ-opioid receptor dimerization to facilitate ability of agonist to control ethanol-altered natural killer cell functions and mammary tumor growth. J Biol Chem 2012; 287:16734–16747.
26. Fuggetta MP, Di Francesco P, Falchetti R, et al. Effect of morphine on cell-mediated immune responses of human lymphocytes against allogeneic malignant cells. J Exp Clin Cancer Res 2005; 24:255–263.
27. Yokota T, Uehara K, Nomoto Y. Intrathecal morphine suppresses NK cell activity following abdominal surgery. Can J Anaesth 2000; 47:303–308.
28▪. Tabellini G, Borsani E, Benassi M, et al. Effects of opioid therapy on human natural killer cells. Int Immunopharmacol 2014; 18:169–174.

Study that found no effect of chronic morphine on activity of NK cells highlighting the importance of chronicity on opioid-induced immunomodulation.

29. Borman A, Ciepielewski Z, Wrona D, et al. Small doses of morphine can enhance NK cell cytotoxicity in pigs. Int Immunopharmacol 2009; 9:277–283.
30. Khazaie K, Blatner NR, Khan MW, et al. The significant role of mast cells in cancer. Cancer Metastasis Rev 2011; 30:45–60.
31. Madera-Salcedo IK, Cruz SL, Gonzalez-Espinosa C. Morphine decreases early peritoneal innate immunity responses in Swiss-Webster and C57BL6/J mice through the inhibition of mast cell TNF-α release. J Neuroimmunol 2011; 232:101–107.
32▪. Nguyen J, Luk K, Vang D, et al. Morphine stimulates cancer progression and mast cell activation and impairs survival in transgenic mice with breast cancer. Br J Anaesth 2014; 113 (Supp 1):i4–i13.

Evidence for a procancer effect of morphine mediated in part by mast cell activation and release of cytokines that also may relate to paradoxically increased pain.

33. Blunk JA, Schmelz M, Zeck S, et al. Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 2004; 98:364–370.
34. Finley MJ, Happel CM, Kaminsky DE, Rogers TJ. Opioid and nociceptin receptors regulate cytokine and cytokine receptor expression. Cell Immunol 2008; 252:146–154.
35. Happel C, Steele AD, Finley MJ, et al. DAMGO-induced expression of chemokines and chemokine receptors: the role of TGF-beta1. Leukoc Biol 2008; 83:956–963.
36. Messmer D, Hatsukari I, Hitosugi N, et al. Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation. Mol Med 2006; 12:284–290.
37. Happel C, Steele AD, Finley MJ, et al. DAMGO-induced expression of chemokines and chemokine receptors: the role of TGF-beta1. Leukoc Biol 2008; 83:956–963.
38. Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol 2010; 341:37–58.
39. Belkowski SM, Alicea C, Eisenstein TK, et al. Inhibition of interleukin-1 and tumor necrosis factor-alpha synthesis following treatment of macrophages with the kappa opioid agonist U50, 488H. J Pharmacol Exp Ther 1995; 273:1491–1496.
40. Watkins LR, Hutchinson MR, Rice KC, Maier SF. The ‘toll’ of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci 2009; 30:581–591.
41. Lodish H, Berk A, Zipursky SL, et al. Molecular cell biology. 4th edNew York, NY: W. H. Freeman; 2000; Section 24.1, Tumor Cells and the Onset of Cancer.
42. Gupta K, Kshirsagar S, Chang L, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth. Cancer Research 2002; 62:4491–4498.
43. Singleton PA, Lingen MW, Fekete MJ, et al. Methylnaltrexone inhibits opioid and VEGF-induced angiogenesis: role of receptor transactivation. Microvascular research 2006; 72:3–11.
44. Koodie L, Ramakrishnan S, Roy S. Morphine suppresses tumor angiogenesis through a HIF-1α/p38MAPK pathway. Am J Pathol 2010; 177:984–997.
45▪. Yamamizu, Kohei, Sadayoshi Furuta, et al. к Opioids inhibit tumor angiogenesis by suppressing VEGF signaling. Sci Rep 2013; 3:3213.

Potentially anticancer effect mediated by κ opioid receptor distinct from previously described morphine procancer effects on angiogenesis.

46. Harimaya Y, Koizumi K, Andoh T, et al. Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells. Cancer Lett 2002; 187:121–127.
47. Zagon IS, Rahn KA, McLaughlin PJ. Opioids and migration, chemotaxis, invasion, and adhesion of human cancer cells. Neuropeptides 2007; 41:441–452.
48. Ecimovic P, Murray D, Doran P, et al. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene. Br J Anaesth 2011; 107:916.
49. Lennon FE, Mirzapoiazova T, Mambetsariev B, et al. Overexpression of the μ-opioid receptor in human nonsmall cell lung cancer promotes Akt and mTOR activation, tumor growth, and metastasis. Anesthesiology 2012; 116:857.
50. Pedersen H, Brünner N, Francis D, et al. Prognostic impact of urokinase, urokinase receptor, and type 1 plasminogen activator inhibitor in squamous and large cell lung cancer tissue. Cancer Res 1994; 54:4671–4675.
51. 1998; Sier CF, Stephens R, Bizik J, et al. Cancer Res. 58:1843–1849.
52. Stephens RW, Nielsen HJ, Christensen IJ, et al. Plasma urokinase receptor levels in patients with colorectal cancer: relationship to prognosis. J Natl Cancer Inst 1999; 91:869–874.
53. Gach K, Szemraj J, Fichna J, et al. The influence of opioids on urokinase plasminogen activator on protein and mRNA level in MCF-7 breast cancer cell line. Chem Biol Drug Des 2009; 74:390–396.
54. Nylund G, Pettersson A, Bengtsson C, et al. Functional expression of μ-opioid receptors in the human colon cancer cell line, HT-29, and their localization in human colon. Dig Dis Sci 2008; 53:461–466.
55. Gach K, Wyrębska A, Szemraj J, Janecka A. The influence of opioid peptides on matrix metalloproteinase-9 and urokinase plasminogen activator expression in three cancer cell lines. Mol Biol 2012; 46:796–801.
56. Lynch CC, Matrisian LM. Matrix metalloproteinases in tumor-host cell communication. Differentiation 2002; 70:561–573.
57▪. Afsharimani B, Baran J, Watanabe S, et al. Morphine and breast tumor metastasis: the role of matrix-degrading enzymes. Clin Exp Metastasis 2014; 31:149–158.

Evidence of reduction of matrix metalloproteinases by morphine that potentially could reduce metastasis that requires these enzymes to degrade basement membranes and invade.

58. Maneckjee R, Biswas R, Vonderhaar BK. Binding of opioids to human MCF-7 breast cancer cells and their effects on growth. Cancer Res 1990; 50:2234–2238.
59. Manackjee R, Minna D. Opioids induce while nicotine suppresses apoptosis in human lung cancer cells. Cell Growth differ 1994; 5:1033–1040.
60. Yin D, Mufson RA, Wang R, Shi Y. Fas-mediated cell death promoted by opioids. Nature 1999; 397:218–1218.
61. Kampa M, Bakogeorgou E, Hatzoglou A, et al. Opioid alkaloids and casomorphin peptides decrease the proliferation of prostatic cancer cell lines (LNCaP, PC3 and DU145) through a partial interaction with opioid receptors. Eur J Pharmacol 1997; 335:255–265.
62. Hayashi T, Tsao LI, Su TP. Antiapoptotic and cytotoxic properties of delta opioid peptide [D-Ala2, D-Leu5] enkephalin in PC12 cells. Synapse 2002; 43:86–94.
63. Hatsukari I, Hitosugi N, Ohno R, et al. Induction of apoptosis by morphine in human tumor cell lines in vitro. Anticancer Res 2007; 27:857–864.
64. Tegeder I, Grösch S, Schmidtko A, et al. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation. Cancer Res 2003; 63:1846.
65. Zagon IS, McLaughlin PJ. Opioids and the apoptotic pathway in human cancer cells. Neuropeptides 2003; 37:79–88.
66. Lin X, Li Q, Wang YJ, et al. Morphine inhibits doxorubicin-induced reactive oxygen species generation and nuclear factor kappaB transcriptional activation in neuroblastoma SH-SY5Y cells. Biochem J 2007; 406:215–221.
67. Ben-Eliyahu S. The price of anticancer intervention. Does surgery promote metastasis? Lancet Oncol 2002; 3:578–579.
68. Page GG, Blakely WP, Ben-Eliyahu S. Evidence that postoperative pain is a mediator of the tumor-promoting effects of surgery in rats. Pain 2001; 90:191–199.
69. Reiche EM, Nunes SO, Morimoto HK. Stress, depression, the immune system, and cancer. Lancet Oncol 2004; 5:617–625.
70. Yang EV, Kim SJ, Donovan EL, et al. Norepinephrine upregulates VEGF, IL-8, and IL-6 expression in human melanoma tumor cell lines: implications for stress-related enhancement of tumor progression. Brain Behav Immun 2009; 23:267–275.
71. Franchimont D. Overview of the actions of glucocorticoids on the immune response: a good model to characterize new pathways of immunosuppression for new treatment strategies. Ann N Y Acad Sci 2004; 1024:124–137.
72. Vuong C, Van Uum SH, O’Dell LE, et al. The effects of opioids and opioid analogs on animal and human endocrine systems. Endocr Rev 2010; 31:98–132.
73. El Daly ES. Influence of acute and chronic morphine or stadol on the secretion of adrenocorticotrophin and its hypothalamic releasing hormone in the rat. Life Sci 1996; 59:1881–1890.
74. Allolio B, Schulte HM, Deuss U, et al. Effect of oral morphine and naloxone on pituitary-adrenal response in man induced by human corticotropin-releasing hormone.). Acta Endocrinol (Copenh) 1987; 114:509–514.
75. Palm S, Moenig H, Maier C. Effects of oral treatment with sustained release morphine tablets on hypothalamic-pituitary-adrenal axis. Methods Find Exp Clin Pharmacol 1997; 19:269–273.
76. Sacerdote P, Manfredi B, Mantegazza P, Panerai AE. Antinociceptive and immunosuppressive effects of opioid drugs: a structure-related activity study. Br J Pharmacol 1997; 121:834–840.
77. Gaspani L, Bianchi M, Limiroli E, et al. The analgesic drug tramadol prevents the effect of surgery on natural killer cell activity and metastatic colonization in rats. J Neuroimmunol 2002; 129:18–24.
78. Franchi S, Panerai AE, Sacerdote P. Buprenorphine ameliorates the effect of surgery on hypothalamus-pituitary-adrenal axis, natural killer cell activity and metastatic colonization in rats in comparison with morphine or fentanyl treatment. Brain Behav Immun 2007; 21:767–774.
79. Martucci C, Panerai AE, Sacerdote P. Chronic fentanyl or buprenorphine infusion in the mouse: similar analgesic profile but different effects on immune responses. Pain 2004; 110:385–392.
80. Carrigan KA, Saurer TB, Ijames SG, Lysle DT. Buprenorphine produces naltrexone reversible alterations of immune status. Int Immunopharmacol 2004; 4:419–428.
81. Cronin AJ, Aucutt-Walter NM, Budinetz T, et al. Low-dose remifentanil infusion does not impair natural killer cell function in healthy volunteers. Br J Anaesth 2003; 91:805–809.
82▪▪. Smith TJ, Coyne PJ, Staats PS, et al. An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM). Ann Oncol 2005; 16:825–833.

Early and pivotal study demonstrating the possible link between opioid sparing and increased cancer survival.

83. Exadaktylos AK, Buggy DJ, Moriarty DC, et al. Can anesthetic technique for primary breast cancer surgery affect recurrence or metastasis? Anesthesiology 2006; 105:660–664.
84. Zylla D, Gourley BL, Vang D, et al. Opioid requirement, opioid receptor expression, and clinical outcomes in patients with advanced prostate cancer. Cancer 2013; 119:4103–4110.
85. O’Riain SC, Buggy DJ, Kerin MJ, et al. Inhibition of the stress response to breast cancer surgery by regional anesthesia and analgesia does not affect vascular endothelial growth factor and prostaglandin E2. Anesth Analg 2005; 100:244–249.
86. Biki B, Mascha E, Moriarty DC, et al. Anesthetic technique for radical prostatectomy surgery affects cancer recurrence: a retrospective analysis. Anesthesiology 2008; 109:180–187.
87. Tsui BC, Rashiq S, Schopflocher D, et al. Epidural anesthesia and cancer recurrence rates after radical prostatectomy. Can J Anaesth 2010; 57:107–112.
88. Hiller JG, Hacking MB, Link EK, et al. Perioperative epidural analgesia reduces cancer recurrence after gastro-oesophageal surgery. Acta Anaesthesiologica Scandinavica 2014; 58:281–290.
89▪. Scavonetto F, Yeoh TY, Umbreit EC, et al. Association between neuraxial analgesia, cancer progression, and mortality after radical prostatectomy: a large, retrospective matched cohort study. Br J Anaesth 2014; 113 (Suppl 1):i95–102.

Large retrospective trial that give some evidence for the cancer sparing effect of epidural analgesia for prostate surgery.

90. Chen WK, Miao CH. The effect of anesthetic technique on survival in human cancers: a meta-analysis of retrospective and prospective studies. PLoS One 2013; 8:e56540.
91. Cummings KC, Xu F, Cummings LC, Cooper GS. A comparison of epidural analgesia and traditional pain management effects on survival and cancer recurrence after colectomy: a population-based study. Anesthesiology 2012; 116:797–806.
92. Cata JP, Gottumukkala V, Thakar D, et al. Effects of postoperative epidural analgesia on recurrence-free and overall survival in patients with nonsmall cell lung cancer. J Clin Anesth 2014; 26:3–17.
93. Gottschalk A, Ford JG, Regelin CC, et al. Association between epidural analgesia and cancer recurrence after colorectal cancer surgery. Anesthesiology 2010; 113:27–34.
94. Lacassie HJ, Cartagena J, Brañes J, et al. The relationship between neuraxial anesthesia and advanced ovarian cancer-related outcomes in the Chilean population. Anesth Analg 2013; 117:653–660.
95. Ismail H, Ho KM, Narayan K, Kondalsamy-Chennakesavan S. Effect of neuraxial anaesthesia on tumour progression in cervical cancer patients treated with brachytherapy: a retrospective cohort study. Br J Anaesth 2010; 105:145–149.
96. Wuethrich PY, Thalmann GN, Studer UE, Burkhard FC. Epidural analgesia during open radical prostatectomy does not improve long-term cancer-related outcome: a retrospective study in patients with advanced prostate cancer. PLoS One 2013; 8:e72873.
97▪. Myles PS, Peyton P, Silbert B, et al. ANZCA Trials Group Investigators. Perioperative epidural analgesia for major abdominal surgery for cancer and recurrence-free survival: randomised trial. BMJ 2011; 342:d1491.

One of the few prospective trials investigating epidural anaesthesia and cancer progression, which found no evidence of a link.

98▪▪. Pei L, Tan G, Wang L, et al. Comparison of combined general-epidural anaesthesia with general anaesthesia effects on survival and cancer recurrence: a meta-analysis of retrospective and prospective studies. PLos One 2014; 9:e114667.

Largest and most up-to-date meta-analysis of the effect of neuraxial blockade on cancer progression after surgery.

99▪. Vogelaar FJ, Abegg R, van der Linden FC, et al. Epidural anaesthesia associated with better survival in colon cancer. Int J Colorectal Dis 2015; 30:1103–1107.

Important meta-analysis of epidural anaesthesia and cancer survival/recurrence in patients having surgery for colonic cancer.

100. Sacerdote P, Bianchi M, Gaspani L, et al. The effects of tramadol and morphine on immune responses and pain after surgery in cancer patients. Anesth Analg 2000; 90:1411–1414.
101. Liu Z, Gao F, Tian Y. Effects of morphine, fentanyl and tramadol on human immune response. J Huazhong Univ Sci Technolog Med Sci 2006; 26:478–481.
102. Dahl JB, Mathiesen O, Kehlet H. An expert opinion on postoperative pain management, with special reference to new developments. Expert Opin Pharmacother 2010; 11:2549–2570.
103. Shigeta Y, Kasai S, Han W, et al. Association of morphine-induced antinociception with variations in the 5′ flanking and 3′ untranslated regions of the μ opioid receptor gene in 10 inbred mouse strains. Pharmacogenetics and genomics 2008; 18:927–936.
Keywords:

angiogenesis; apoptosis; immunomodulation; morphine; outcomes

Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.