Review Article

The Mu Opioid Receptor: A New Target for Cancer Therapy?

Patrick A. Singleton, PhD1,2; Jonathan Moss, MD, PhD2; Daniel D. Karp, MD3,4; Johnique T. Atkins, PhD3;
and Filip Janku, MD, PhD3

Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as in the perioperative period. Several retrospective studies have suggested that opioid use might promote tumor progression and as a result negatively
impact survival in patients with advanced cancer; however, in the absence of appropriate prospective validation, any changes in recommendations for opioid use are not warranted. In this review, the authors present preclinical and clinical data that support their hypothesis
that the mu opioid receptor is a potential target for cancer therapy because of its plausible role in tumor progression. The authors also
propose the hypothesis that peripheral opioid antagonists such as methylnaltrexone, which reverses the peripheral effects of mu opioids
but maintains centrally mediated analgesia and is approved by the US Food and Drug Administration for the treatment of opioidC 2015 American Cancer Society.
induced constipation, can be used to target the mu opioid receptor. Cancer 2015;121:2681-8. V
KEYWORDS: cancer progression, methylnaltrexone, mu opioid receptor, opioids.

INTRODUCTION
Mu opioids are among the most widely used drugs for patients with cancer with both acute and chronic pain as well as during the perioperative period.1 Although there exists a family of opioid receptors (mu, kappa, delta, and nociception/orphanin FQ peptide), the G protein-coupled mu opioid receptor (MOR) is the therapeutic target for most clinically used
opioids, including morphine and fentanyl.2 The choice of anesthetic and its influence on cancer progression and outcome
has been extensively studied within the perioperative setting and there is increasing awareness by anesthesiologists of the
value of opioid-sparing techniques.3-7 Over the past decade, there has been evolving literature suggesting a relationship
between the MOR and cancer progression and recurrence extending to the management of chronic cancer pain. Preclinical data from several laboratories have suggested that mu opioids can promote cancer progression,8-10 but to the best of
our knowledge prospective human studies have been limited. The development and approval of methylnaltrexone
(MNTX), a peripherally restricted MOR antagonist, has allowed clinical studies to progress in this area.11 MNTX was
approved by the US Food and Drug Administration in 2008 to treat opioid-induced constipation (OIC) in patients with
advanced illness who are receiving palliative care and in whom response to laxatives is insufficient, and more recently to
treat OIC in patients with chronic nonmalignant pain. Because MNTX reverses the peripheral effects of mu opioids but
maintains centrally mediated analgesia, it can be given to patients receiving opioids. MNTX can be used to separate out
the peripheral from central effects of opioids both in the laboratory and in the clinical setting. Although to our knowledge
there are few preclinical studies demonstrating an effect of peripheral opiate antagonists on analgesia, clinical studies
regarding the approved agents naloxegol, alvimopan, and methylnaltrexone at normal therapeutic doses have not shown
an adverse effect on pain control or increased opioid use among patients with acute or chronic pain.
There are significant differences between the perioperative setting, in which opiate-naive individuals often are
exposed to high doses of opiates within a limited time frame, and chronic cancer, in which nearly one-half of patients
receive opiates for considerable periods of time.1 Aside from the differences in clinical time of exposure to mu opiates, it is
important to distinguish the effects of the MOR on tumorigenesis versus effects on tumor growth and metastasis. Very
recently, the relationship between opioid use and cancer progression has been demonstrated in patients with advanced
prostate cancer.12 Although there has yet to be any convincing prospective studies that would mandate a change in

Corresponding author: Filip Janku, MD, PhD, Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, 1400 Holcombe Blvd, Box 0455, Houston, TX 77030; Fax: (713) 745-2374; fjanku@mdanderson.org.
1
Section of Pulmonary and Critical Care, Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, Illinois; 2Department of Anesthesia and Critical Care, The University of Chicago, Chicago, Illinois; 3Division of Cancer Medicine, Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; 4Clinical Translational Research Center, The University of Texas MD Anderson Cancer Center, Houston,
Texas

DOI: 10.1002/cncr.29460, Received: February 11, 2015; Revised: April 3, 2015; Accepted: April 8, 2015, Published online June 4, 2015 in Wiley Online Library
(wileyonlinelibrary.com)

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Figure 1. Schematic diagram of a proposed mechanism of

methylnaltrexone (MNTX)s synergistic effects with mammalian
target of rapamycin (mTOR) inhibitors in blocking vascular endothelial growth factor (VEGF)-induced angiogenic events.
VEGF binding to VEGF receptors induces Src activation (tyrosine phosphorylation), Src-mediated phosphoinositide-3 (PI3)kinase/3-phosphoinositide-dependent protein kinase-1 (PDK1)
activation with consequent phospho-threonine (308) Akt phosphorylation, and mTOR complex 2 formation (mTOR/stressactivated protein kinase [SAPK] interacting protein 1 [SIN1]/
Rictor) with consequent phospho-serine (473) Akt phosphorylation. Activated (serine/threonine phosphorylated) Akt promotes mTOR complex 1 formation (mTOR/FKBP12/Raptor),
which is required for endothelial cell proliferation and migration. MNTX inhibits the mu opioid receptor (MOR) and promotes tyrosine phosphatase activity and Src inactivation.
Multiple mTOR inhibitors including temsirolimus bind to
FKBP12 and inhibit mTOR complex 2 formation. Therefore, the
synergistic effects of MNTX on mTOR inhibitors are achieved
through the inhibition of different components of a common
VEGF-induced angiogenic signaling pathway. MNTX can have
significant clinical usefulness by potentially lowering the therapeutic dose of temsirolimus in the treatment of various diseases requiring angiogenesis, including cancer.

practice,7 emerging literature involving epidemiologic,

cellular, and animal data suggests that mu opioids influence cancer progression and recurrence, and that antagonism of the MOR may have a therapeutic role. There also
appear to be effects mediated by the MOR, even in the absence of exogenous opiates.13,14
The purpose of the current study was to present evidence in favor of the involvement of MOR in tumor progression and as a potential target for opiate antagonists in
the treatment of cancer. We also present evidence that the
opiate antagonist MNTX is a potential cancer therapy for
patients receiving opioids due to its ability to separate the
peripheral from central nervous system effects.
Preclinical Studies

Although there have been scattered reports in the literature

regarding the effects of opiates and antagonists on tumor
2682

progression,15,16 considerable attention was brought to the

area after an initial study by Gupta et al8 demonstrated that
morphine, in clinically efficacious concentrations, stimulated angiogenesis in breast cancer xenografts. Based on our
anecdotal observations (Moss, personal oral communication, 2003) that several patients receiving the peripheral
MOR antagonist MNTX in compassionate use protocols
lived longer than expected, we initiated a series of laboratory
studies to examine a possible effect of the MOR on angiogenesis and tumor progression. Initial studies of human pulmonary and dermal cells demonstrated that mu opiates,
such as morphine and fentanyl, exhibited concentrationdependent effects on migration and proliferation. Morphine, at clinically relevant concentrations for perioperative
or palliative care, exhibited approximately 70% of the ability
of vascular endothelial growth factor (VEGF) to induce
angiogenesis and consequently increase migration and proliferation. These proangiogenic effects were blocked by
doses of MNTX that are effectively used to cause laxation
in a concentration-dependent fashion.9
To confirm these findings, the morphine-3glucuronide (M3G) derivative of morphine, which has no
analgesia, failed to demonstrate angiogenesis, whereas the
M6 metabolite, which is analgesic and has an age-related
dependency, was found to be angiogenic in a clinically relevant concentration-effect relationship.9 This study also
revealed that opioids induced reciprocal transactivation of
VEGF1 and VEGF2 receptors. We subsequently demonstrated a synergistic effect of MNTX with both 5fluorouracil (5-FU) and bevacizumab on the inhibition of
VEGF-induced angiogenesis and proliferation in vitro.17
We subsequently demonstrated that MNTX, in concentrations as low as 10 nmol, also inhibited Src in a
concentration-dependent fashion (Fig. 1).17 Src inhibition appeared to be specific to MNTX whereas naltrexone, the soluble tertiary opioid antagonist, did not exhibit
the same synergistic effect with 5-FU and bevacizumab.
While exploring how an insoluble drug such as MNTX
could affect angiogenesis, we discovered that the receptor
protein tyrosine phosphatase mu (RPTPmu) was the transporter for this signal; silencing the RPTPmu blocked
MNTX synergy with both 5-FU and bevacizumab.17 Subsequent studies have also demonstrated an important synergy of MNTX with mammalian target of rapamycin
(mTOR) antagonists in reducing angiogenesis (Fig. 1).18
Specifically, in vivo matrigel and cellular assays indicated
that MNTX acts synergistically with temsirolimus
through inhibition of various components of a common
pathway, resulting in reduced angiogenesis and
proliferation.
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The Mu Opioid Receptor in Cancer/Singleton et al

Figure 2. Graphic analysis of Lewis lung carcinoma tumor volume in wild-type and mu opioid receptor (MOR) knockout
mice (5 animals per condition; P<.001). C57BL/6 wild-type
and MOR knockout mice (MOR-/-) were injected with dualcolor labeled Lewis lung carcinoma cells (1 3 106) subcutaneously in the right flank. Adapted from Biji M, Lennon F, Siegler J, et al. The novel role of the mu opioid receptor in lung
cancer progression: a laboratory investigation. Anesth Analg.
2011;112:3.25

Figure 3. Graphic representation of the extent of Lewis lung

carcinoma (LLC) metastasis with or without continuous infusion of methylnaltrexone (MNTX) (5 mice per condition; P
=.018). LLC cells (1 3 106) were injected subcutaneously in
the right flank of mice. Adapted from Biji M, Lennon F, Siegler
J, et al. The novel role of the mu opioid receptor in lung cancer progression: a laboratory investigation. Anesth Analg.
2011;112:3.25

Other data have suggested that MOR agonists can

enhance the metastatic potential of a cancer by increasing
vascular permeability. In a study with human pulmonary
microvascular endothelial cells using measurement of
transendothelial electrical resistance, MOR agonists such
as morphine, at customary clinical doses, were found to
have a significant effect on cell-cell interaction and
increased vascular permeability.8,19 We demonstrated
that MNTX and other opiate antagonists provided barrier
protection against edemagenic agonists through inhibition of sphingosine-1-phosphate receptor 3 (S1PR3) activation19; maintenance of this barrier could play a role in
the prevention of metastases. Conversely, opioids can
help to facilitate the process of epithelial-mesenchymal
transition (EMT), which ultimately leads to increased
metastatic potential.20-23 It is interesting to note that in
an in vitro study using the non-small cell lung cancer
model (NSCLC), MOR was found to promote both
opioid-induced and growth factor-induced proliferation,
migration, and EMT, which could have been attenuated
by MNTX.24
Further studies have demonstrated that MNTX also
blocks epidermal growth factor-mediated epidermal
growth factor receptor signaling, which is crucial for
human lung cancer cell proliferation and migration.24 In
addition, NSCLC lines exhibited up to a 7-fold increase
in MOR expression compared with normal human bron-

chial epithelial cells.14 To understand whether this in vitro

finding extends to animals, MOR knockout mice were
examined using the Lewis lung carcinoma model and
demonstrated inhibition of tumor growth and metastasis
(Fig. 2).14,25 Furthermore, silencing the MOR in cancer
cells or treatment with MNTX inhibited metastatic invasion at doses as low as 10 nmol of MNTX.14 In addition,
MNTX infusion was found to inhibit human lung tumor
growth in mice by 2-fold (P =.009) (Fig. 3).25 To determine whether this effect was mediated by the immune system, a study was performed in T cell-deficient nude
mice.26 The results of this study indicated that the overexpression of the MOR in human NSCLC cells promoted
tumor growth in the nude mice, with a 2.5-fold increase
noted in tumor volume compared with controls and a 20fold difference in the rate of metastasis.13 Although the
immune system has been a major focus for the potential
role of anesthetic interventions in altering tumor recurrence after surgery,27 mu opioids have been shown to inhibit interleukin and natural killer cell activity and
plausibly enhance tumorigenicity.28-30 These studies in T
cell-deficient mice demonstrate that a direct effect on the
MOR is sufficient to explain the effects on tumor growth
and proliferation.
In clinically relevant doses, MOR antagonists were
found to reduce tumor growth in lung, head and neck,
and breast tumors.24,31,32 In a study of nude mice injected
with human squamous cell carcinoma of the head and

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TABLE 1. Preclinical Studies Involving the MOR and Cancer
Effects of Mu Opioids on Tumor Growth and Metastasis

1
2

Techniques

Findings

MCF-7 cell breast tumor xenografts in mice

Rats subjected to laparotomy using general anesthesia
alone or combined with either systemic morphine spinal block using bupivacaine with morphine after being
inoculated with lung adenocarcinoma cells, which
metastasize only to the lungs
Mice subjected to laparotomy using general anesthesia
alone or combined with a spinal block of bupivacaine
and morphine
Transgenic mice receiving human infiltrating ductal
breast carcinoma cells and morphine

Morphine stimulates angiogenesis (Gupta 20028)

General anesthesia alone increased lung tumor retention, but the addition of a spinal block reduced this
effect by 70%; spinal block also reduced the increase
in metastases (Bar-Yosef 200129)
General anesthesia alone increased the number of liver
metastases, but a spinal block significantly reduced
this increase (Wada 200730)
Morphine did not influence tumor development when
given before the onset of tumor appearance, but it
significantly promoted the progression of established
tumors and reduced survival (Nguyen 201435)

Effects of the Mu Opioid Receptor and

Cancer Progression
1

Wild-type and MOR-deficient mice were inoculated with B16

melanoma cells that secrete endogenous mu-opioid peptides

MOR-overexpressing lung cancer xenografts in nude mice

MOR-deficient mice demonstrated a marked reduction in tumor

growth and significantly higher infiltration of immune cells into
the tumors (Boehncke 201134)
Overexpression of MOR in cancer cells increased primary tumor
growth rates and lung metastases (Lennon 201424)

Antitumor Effects of Opiate Antagonists

1
2
3
4

S20Y neuroblastoma xenografts in mice treated with the opiate

antagonist naltrexone
Mice injected with MNTX and the expression of lung proteins
characterized
Mice injected with matrigel containing VEGF
LLC xenografts in both MOR knockout and wild-type mice
treated with and tumors treated with MNTX

Opiate antagonist has antineoplastic activity (Zagon &

McLaughlin 198315; Zagon & McLaughlin 198316)
MNTX was an effective barrier-protective agent against LPSinduced lung vascular permeability (Singleton 200719)
MNTX and mTOR inhibited angiogenesis in a synergistic fashion
(Singleton 201018)
MOR knockout mice do not develop significant tumors when
injected with LLC compared with wild-type controls. MNTX
attenuated primary LLC tumor growth and reduced lung metastasis (Mathew 201114)

Abbreviations: LLC, Lewis lung carcinoma; LPS, lipopolysaccharide; MNTX, methylnaltrexone; MOR, mu-opioid receptor, mTOR, mammalian target of rapamycin; VEGF, vascular endothelial growth factor.

neck, low-dose naltrexone (0.1 mg/kg) significantly

reduced tumor volume by up to 84%. This was accomplished without exogenous opioids, suggesting an effect of
endogenous opioids, or at least the opioid receptor, on tumor growth and proliferation.33 In malignant melanoma,
in vivo models using MOR knockout mice demonstrated
a marked reduction in tumor growth. Furthermore, the
expression of endogenous mu opioid peptides in tumor
samples from patients with melanoma positively correlated with more advanced disease stage, leading the
authors to suggest that peripheral MOR antagonists can
have clinical usefulness.34
Studies of transgenic mice receiving human infiltrating ductal breast carcinoma revealed that although mor2684

phine did not appear to affect tumor development when

given before the onset of tumor appearance, it significantly promoted progression of established tumors and
reduced survival.35,36 Although to the best of our knowledge no prospective clinical trials to prevent or treat
tumors have been reported to date, an analysis of clinical
trials leading to its approval to treat OIC in patients experiencing chronic pain revealed a marked improvement in
all-cause survival versus placebo (P =.0006). Although
these trials were not specifically designed to study a mortality endpoint and were not performed exclusively among
patients with cancer, subsequent analysis of phase 3 and
phase 4 clinical trials in patients with advanced cancer
revealed similar trends of decreased tumor progression in
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The Mu Opioid Receptor in Cancer/Singleton et al

Figure 4. Increased mu opioid receptor (MOR) expression in patients with metastatic lung cancer. Paraffin-embedded archived
biopsy samples from patients with non-small cell lung cancer were stained using MOR antibody and scored qualitatively by 2 independent pathologists using a 4-point scale. In human lung cancer and normal adjacent lung samples obtained from 34 patients
with lung cancer, MOR expression was found to be significantly increased in samples from patients with lung cancer compared
with adjacent control tissue (P =.0242). When the samples from patients with metastatic lung cancer were separated from those
of the cohort of the total number of patients with lung cancer, an approximately 2-fold increase in MOR expression was observed
(P =.0013). Adapted from Singleton PA, Mirzapoiazova T, Hasina R, Salgia R, Moss J. Increased mu-opioid receptor expression in
metastatic lung cancer. Br J Anaesthes. 2014;113(suppl 1):i103-i108.46

patients receiving MNTX.37 Pertinent preclinical studies

are listed in Table 1.8,14-16,18,19,24,29,30,34,35
Clinical Studies

Several retrospective observations have suggested that

opioids influence cancer progression in humans. A
randomized 3-arm clinical trial of 202 patients using either intrathecal drug delivery of morphine plus comprehensive clinical management that included systemic
morphine versus comprehensive clinical management
alone for the reduction of chronic pain (including cancerrelated pain) yielded interesting outcomes: 54% of
patients receiving palliative care who were treated with intrathecal opioids were alive at 180 days compared with
37% of patients receiving systemic opioids (P =.06).38
Although survival was not an endpoint of the study, the
finding of better survival rates among patients in the intrathecal group is consistent with deleterious effects of systemic opioids on tumor progression.
Recent investigations have focused on MOR polymorphisms, particularly A118G. This single-nucleotide
polymorphism leads to a change in the glycosylation site
in the extracellular terminus of the MOR.6,39 Although to
our knowledge the precise function of A118G is
unknown, it has been implicated in drug dependence.40
In a study of 2039 women with breast cancer who were of
different ethnicities, 5% to 24% of the women exhibited
the single-nucleotide polymorphism A118G in the MOR
gene, which is a mutation associated with increased resistance to opioids and prolonged survival.41 Specifically,
patients with A118G heterozygotes had better 10-year
survival compared with those with wild-type MOR
(91.3% vs 95.4% vs 82.4%; P 5 .0001).41 The use of
opioid analgesics was not measured. Similar results were
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observed in a Chinese study with 260 patients with esophageal squamous cell cancer and 291 controls. The patients
were overrepresented by wild-type MOR, whereas those
with A118G homozygotes had significantly less cancer on
multivariate analysis (odds ratio, 3.12; P 5 .001).42
Finally, as previously mentioned, increased b-endorphin
expression in human melanoma was correlated with
shorter progression-free survival (PFS).34
To our knowledge, there are limited populationbased data regarding whether opioids themselves can precipitate malignancy or influence tumor progression.7,43,44
A retrospective study examining 700 patients and 4000
patient-years compared the influence of methadone maintenance therapy versus chronic naltrexone therapy and
demonstrated no difference in the incidence of cancers45;
however, there were only 5 cancers diagnosed in the entire
patient population, suggesting that this study was underpowered to answer that question.
Another approach has been to examine MOR
expression in tumors. Several laboratories have demonstrated that the MOR is overexpressed in both malignant
lung and prostate tissue.12,46,47 In a small study of 34
patients with NSCLC, samples of adjacent nonmalignant
tissue revealed lower MOR expression on immunohistochemistry compared with tumor samples (P =.02). Furthermore, tumor samples from patients with lymph node
metastases had the highest MOR expression (P =.001)
(Fig. 4).46 A similar observation was reported from a study
with 480 patients with advanced prostate cancer, in which
greater opioid requirements were associated with shorter
PFS (hazard ratio [HR], 1.08; P<.001) and overall survival (OS) (HR, 1.07; P<.001).12 Of special clinical interest, every 5-mg/day increment in the opioid
requirement increased the risk of disease progression by
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TABLE 2. Clinical Studies Involving the MOR and Cancer
The Mu Opioid Receptor and Cancer Progression
No. of Patients

Techniques

Findings

2039

9385

A118G genotype of MOR associated with breast cancer-specific

mortality at 10 y (Bortsov 201241)
Significant association between this polymorphism and susceptibility to opioid dependence (Haerian & Haerian 201340)

551

593

34

Women with breast cancer underwent genotyping of

MOR and were followed to determine survival
Systematic review and meta-analysis examined whether
the A118G polymorphism of MOR is associated with
opioid dependence
Patients underwent MOR A118G genotyping and were
followed for the development of ESCC
Retrospective analysis of patients diagnosed with stage
IV prostate cancer and MOR activity analyzed in
biopsies
Association between MOR expression and metastasis in
archived biopsy samples from patients with lung cancer examined

239

Expression of MOR in ESCC evaluated

A118G polymorphism might be associated with an increased risk of

ESCC in a Chinese population (Wang 201342)
MOR expression and opioid requirement independently associated
with inferior PFS and OS (Zylla 201312)
MOR expression was significantly increased in cancer samples
compared with adjacent control tissue and a 2-fold increase in
MOR expression in samples from patients with metastatic disease (Singleton 201446)
MOR expression associated with lymph node metastasis, but not
OS (Zhang 201547)

Anesthetic Technique and Cancer Progression

1

4329

202

129

247

47,000

901

99

GA or local anesthesia used for the primary excision of

cutaneous melanoma
Randomized clinical trial of CMM vs IDDS plus CMM;
the main outcome measure was pain control combined with change in toxicity
Retrospective analysis of patients undergoing surgery
for breast cancer and given different forms of
anesthesia
Long-term survival studies after resection of colon cancer with GA with or without EA and analgesia
supplementation
Meta-analysis including 14 studies comparing GA with
EA and EA combined with GA
Retrospective analysis of patients with NSCLC who
underwent surgery and were administered varying
doses of opioids during surgery
Retrospective analysis of patients with NSCLC who
underwent surgery and were administered varying
doses of opioids during and after surgery

GA associated with a slight but not significant decrease in survival

rate; local anesthesia should be preferred (Schlagenhauff 200031)
IDDS improved clinical success in pain control, significantly relieved
common drug toxicities, and improved survival (Smith 200238)
Paravertebral anesthesia and analgesia combined with GA reduced
the risk of disease recurrence or metastasis during initial y of
follow-up compared with GA combined with postoperative morphine analgesia (Exadaktylos 200648)
Supplementation with EA associated with longer survival among
patients without metastases before 1.5 y; EA had no effect on
the survival of patients with metastases (Christopherson 200832)
Survival benefit in favor of EA compared with GA alone; significantly
positive association between EA and improved survival in CRC
(Chen 201349)
Intraoperative opioid use associated with decreased survival in
patients with stage I but not stage II to III NSCLC (Cata 201444)
Analysis suggests association between increased opioid doses during initial 96-h postoperative period and higher recurrence rate of
NSCLC within 5 y (Maher 201443)

Abbreviations: CMM, comprehensive medical management; CRC, colorectal cancer; ESCC, esophageal squamous cell carcinoma; EA, epidural anesthesia;
GA, general anesthesia; IDDS, intrathecal drug delivery systems; LLC, Lewis lung cancer; MOR, mu-opioid receptor; NSCLC, non-small cell lung cancer; OS,
overall survival; PFS, progression-free survival.

8% and the risk of death by 5%. In addition, higher

MOR expression was associated with shorter PFS (HR,
1.65; P <.001) and OS (HR, 1.55; P<.001). Furthermore, for every unit increase in MOR expression, the risk
of disease progression was increased by 65% and the risk
of death was increased by 55%.
The issue of opioid use perioperatively in cancer surgery has been increasingly recognized in the anesthesia literature over the past decade. A retrospective study of 129
patients with early-stage breast cancer who were undergoing surgery demonstrated a significant difference in 3year recurrence and metastasis-free survival, depending on
2686

whether the patient received a combined general anesthetic with paravertebral block or a general anesthetic that
included opioids (94% vs 77%; P 5 .012).48 Similarly, a
retrospective study of 225 patients with early-stage prostate cancer undergoing radical prostatectomy demonstrated that an epidural plus general anesthesia compared
with general anesthesia with opioids was associated with a
lower risk of disease recurrence (HR, 0.43; P 5 .012).12 A
recent meta-analysis summarized a large number of studies in the anesthesia literature addressing the issue of anesthetic technique and cancer.49 The results of this metaanalysis suggested that epidural anesthesia and/or
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The Mu Opioid Receptor in Cancer/Singleton et al

analgesia, compared with general anesthesia, might be

associated with improved OS in patients with cancer
undergoing surgical procedures (especially among
patients with colorectal cancer). Very recently, 2 retrospective studies in patients with early-stage NSCLC demonstrated that lung cancer recurrence is related to
perioperative opiate use.43,44 Clinical studies and outcomes are listed in Table 2.12,31,32,38,40-44,46-49
To the best of our knowledge, it is not completely
understood whether observation of an anesthetic effect on
tumors is related to sympathectomy, an effect of local anesthetics, or perhaps a decrease in the use of opioids. Prospective trials investigating whether there is an effect of the type
of anesthetic on surgical outcome in patients with breast,
colon, and lung cancer currently are underway.
Conclusions

There is emerging evidence that MOR expression and signaling plausibly plays a role in cancer progression by interacting
with angiogenesis, EMT, mTOR, Src, and other signaling
pathways. These findings have been substantiated by retrospective data suggesting worse outcomes in patients with cancer who are exposed to systemic opioids or those with high
levels of MOR expression. MNTX is a peripherally acting
MOR antagonist that is used for the treatment of refractory
OIC. Preclinical data have suggested that MOR inhibition
can reverse the adverse effect of MOR signaling on cancer
progression and further investigation in the clinical setting is
warranted. The first dose-finding study, which combines
MNTX with chemotherapy, is currently under way.
FUNDING SUPPORT
No specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURES

Drs. Singleton and Moss have the following patents pending through
the University of Chicago Technology Transfer Office: 11/905058;
14/061,331; 13/972,122; 14/292,816; Use of Opioid Antagonists in
Combination with mTOR Inhibitors; and 13/972,129. They have
the following patents that have been issued, also through the University of Chicago Technology Transfer Office: 11,379,010;
12,933,784/8,685,995; and 12,723,339. Dr. Moss is one of the
developers of methylnaltrexone (MNTX) and receives royalties from
the University of Chicago through Progenics Pharmaceuticals, to
whom MNTX was initially licensed. Dr. Moss is also a paid consultant for Salix Pharmaceuticals, which has worldwide sales rights to
MNTX, through Progenics Pharmaceuticals.

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