Journal of Clinical Anesthesia (2016) 28, 3640

Editorial

Proposed mechanisms for association between opioid

usage and cancer recurrence after surgery,
1. Introduction
Cancer remains one of the most prevalent and burdensome diseases on the modern health care landscape.
Although significant success has been made toward effective
medical and surgical treatment, cancer pain management
presents a unique and continuing challenge. Recent epidemiological evidence has suggested that the selected anesthetic and analgesic management modalities for operative,
postoperative, and long-term pain control appear to be
associated with increased recurrence of certain malignancies
[18]. Several hypotheses to explain these clinical observations have been formulated and substantiated by basic
science research. However, a lack of well-designed,
prospective clinical trials precludes the dominance of one
hypothesis over the other. There also exists the possibility of
multiple near-simultaneous mechanisms being responsible
for the finding.
Amelioration of cancer pain is typically achieved through
the use of potent opioid analgesics. A 2007 review of pain
management suggested that concerns about opioid abuse
have led to the undertreatment of pain with opioid by
opioid-phobic physicians [9]. Numerous practice guidelines have been established that stress the importance of
individualized treatment of pain with both opioid and
nonopioid analgesics. Rigorous adherence to these guidelines can yield significant pain relief [1012]. With both
chronic and cancer-related pain, dose escalation typically
occurs in an effort to achieve a favorable balance of effective
analgesia and opioid-related adverse effects [13]. Opioid
analgesic use in cancer patients during the perioperative

Disclosures: This study was not associated with any grants, sponsors,
or funding (including National Institutes of Health, Wellcome Trust,
Howard Hughes Medical Institute, or departmental or institutional funding).
However, Dr White receives support for his academic activities from the
White Mountain Institute, The Sea Ranch, CA. This study has not been
published elsewhere and is not under consideration for publication in
another journal.

This manuscript has been read and approved by the 2 authors.

http://dx.doi.org/10.1016/j.jclinane.2015.05.010
0952-8180/ 2016 Elsevier Inc. All rights reserved.

period is largely based on their presurgical opioid requirement. However, this common practice may need to be
reexamined based on recent publications describing an
association between opioid usage and cancer recurrence after
excision of the primary tumor. We hypothesize that the
immediate use of opioids in the perioperative period could act
to suppress activity of natural killer cells (NK cells), whereas
the long-term use of opioids in patients who develop persistent
pain states may act to directly promote tumor growth.

2. Preliminary clinical studies examining the

effect of opioid analgesia on cancer recurrence
rates after surgery
Use of regional anesthesia decreases the requirement for
postoperative opioid analgesics [14]. For example, Irish
researchers found that surgery for breast cancer performed
with paravertebral blockade using only levobupivicaine was
associated with a 94% disease-free survival at both 24 and 36
months compared with 82% and 77% at the same time points
in a similar surgical patient population not receiving regional
anesthesia (P = .012) [2]. The use of paravertebral blocks for
breast surgery significantly reduced the opioid requirement
during the first 48 hours postoperatively [15]. Two years
later, the same Irish group of investigators reported that open
radical prostatectomies performed under combined epidural
and general anesthesia was associated with a 57% lower
recurrence risk compared with patients who had the same
surgery under general balanced anesthesia using opioids
for pain relief rather than the epidural block (P = .012) [3].
Epidural analgesic techniques are associated with a significant decrease in the perioperative opioid requirement in
patients undergoing radical prostatectomy procedures [16].
Other investigative groups have found a similar association
between opioid-sparing anesthetic techniques and diseasefree survival for a number of malignancies including non
small cell lung cancer (NSCLC), prostate adenocarcinoma,

Editorial
ovarian carcinoma, and colorectal adenocarcinoma [1,48].
In addition, the use of nonopioid analgesics, including
nonsteroidal anti-inflammatories drugs like ketorolac, for
treatment of chronic cancer pain has been associated with
improved cancer-free survival outcomes [17,18]. Although
the studied analgesic techniques have clear ramifications for
postoperative pain management, very few of these publications have clearly addressed differences in postoperative
opioid utilization. It should also be noted that several studies
have found incongruous results, including studies that have
even suggested a potential association between increased
morphine usage and decreased cancer recurrence [1921].
Surgery and anesthesia are the major traumatic elements
implicated in causing postoperative immunosuppression
[22]. The advent of minimally invasive surgical approaches
allows similar surgical outcomes with less overall tissue
trauma and results in a reduced need for postoperative opioid
analgesia [23]. Minimally invasive resection colon cancer
has been associated with increased disease-free survival
compared with traditional open approaches [24]. Furthermore, minimally invasive thoracoscopic surgery is associated with improved disease-free survival in lung cancer
patients when compared with conventional open thoracotomy procedures [25]. In addition, patients who underwent the
same minimally invasive thoracic surgery for NSCLC but
required larger amounts of opioid analgesics in the
postoperative period had a shorter disease-free survival
period [1]. Interestingly, neoplastic cell mobility and
circulating tumor burden are equivalent in patients undergoing minimally invasive surgical procedures [26,27].

3. Potential mechanisms for association

between opioid analgesics and cancer recurrences
after surgery
A leading hypothesis for the apparent association between
opioids and cancer recurrence rates is that chronic -opioid
receptor (MOR) agonism results in direct stimulation of
neoplastic cells and associated cellular pathways essential to
tumor cell growth and metastatic spread. Stimulation of
MORs has been found to promote the growth of existing
tumors but not the growth of new tumors in rodents [28].
-Opioid receptors have been identified on the cellular
surface of malignant tissue [29]. Although MORs are also
present in normal tissue, the density of MORs has been
found to be increased on malignant (vs normal) tissue and on
malignant tissue with clinical lymph node progression
compared with tissue without clinical lymph node invasion
[30]. Chronic MOR agonism with relatively high doses of
intravenous morphine (0.7-1.4 mg/[kg d]) in murine models
has been demonstrated to stimulate the growth-promoting
mitogen-activated protein kinases/extracellular signalregulated kinases signaling pathway and increases tumor
angiogenesis [31]. The clinical relevance of the studied dose

37
(namely, 336 mg daily of oral morphine in an 80-kg patient)
suggests that these findings are mostly pertinent within a
subset of patients on long-term opioid therapy. Furthermore,
MOR overexpression in murine models has been shown to
increase the activity of the survival-promoting mammalian
target of rapamycin pathways and to increase tumor burden
[29]. Stimulation of MORs has also been found to regulate
growth factorinduced EGF receptor signaling (Src, Gab-1,
PI3K, and STAT3 activation) that is crucial for consequent
malignant cell proliferation and migration [32].
Long-term infusion with the peripheral-acting MOR
antagonist methylnaltrexone (10 mg/[kg d]) reduced tumor
growth and decreased lung metastasis, indicating that a direct
opioid effect on tumor growth does exist in the setting of
chronic MOR agonism [33]. Athymic nude mouse models,
which lack adaptive immune cells such as B and T
lymphocytes but have normal or even increased numbers
of NK cells, have been used to study this important
phenomenon [29,34]. The introduction of malignant tissue
that was modified to overexpress MORs into nude mice
resulted in increased tumor development compared with
control malignant tissue [29]. A retrospective clinical study
correlated increased immunoreactivity of MORs on malignant tissue with both decreased disease-free survival and
increased opioid requirements [35]. However, this study did
not account for the likely possibility that more advanced
cancer states are responsible for both poorer outcomes and
increased pain levels and higher opioid requirements. A
similar study found that increased pain and increased opioid
requirements were independently associated with poor
outcomes in advanced stages of NSCLC [36]. However,
the results of this study are extremely difficult to apply to
specific clinical situations because of a lack of standardization of the chemotherapy; radiation; failure to account for the
location, invasiveness, or pathology of the tumors; nebulous
end points for assessing pain; and lack of distinction between
pain caused by chemotherapy and radiation therapy and pain
from the malignancy itself.
Another popular hypothesis is that immediate stimulation
of the central nervous system with MOR agonists causes
sympathetically mediated suppression of NK cell activity [37,38]. Preservation of competent nonspecific immune
surveillance in the postoperative period is important for
eliminating tumor cell emboli and preventing the progression
of embolic malignant cells into macroscopic distant
metastasis [39]. A continuation of this theory is that
analgesic techniques that allow for a decreased opioid
requirement both intraoperatively and in the early postoperative period (eg, regional local anesthetic nerve blocks)
preserve cell-mediated immunity. Local anesthetics can
favorably affect the postoperative inflammatory response,
and investigators have recently proposed that local anesthetics can exert a direct or indirect antimetastatic effect [40].
Natural killer cells are the first line of defense with respect to
nonspecific cellular immunity. The NK cells are large
circulating granular CD3 and CD56+ lymphocytes derived

38
from common lymphoid progenitor cells that mature in
extrathymic tissue [34]. Natural killer cells destroy their
targets (namely, viral-infected and tumor cells) by direct
contact in a non-major histocompatibility complex
dependent manner [41]. The primary mechanism responsible
for destruction of tumor cells involves direct contact with the
target cells and subsequent release of cytotoxic mediators,
which alter cellular membrane permeability and lead to
apoptosis. Effective surveillance during this early postoperative period is thought to be crucial in preventing tumor cell
emboli from developing into clinically relevant neoplasms.
Diminished NK cell function has been correlated with
increased occurrence of malignancies in humans [42]. In
addition, murine models with genetic total NK cell
elimination were associated with more rapid and aggressive
tumor growth and metastasis [39,43,44]. NK cells are
primarily responsible for elimination of malignancy in the
acute initial growth phase, whereas adaptive immunity is
primarily responsible for elimination of dormant established solid tumors due to poor homing mechanisms of NK
cells [39]. Data suggest that the role of opioids is more
pronounced in the early stages of a malignancy consistent
with the hypothesis that NK cells play a more critical role in
the acute (vs chronic) phase of surgical recovery after tumor
resection [45].
Opioid-specific immunomodulatory effects are complex
and not completely understood [4648]. The immediate
administration of fentanyl has been shown to decrease the
function of NK cells [17]. Opioid-mediated immunosuppression is thought to be due to alterations in the
hypothalamic-pituitary axis [49]. However, immediate
opioid administration will increase sympathetic outflow to
primary (thymus, spleen) and secondary (pyers patches,
lymph nodes) lymphoid tissues [49]. Secondary lymphoid
tissue is the site of maturation of NK cells [34]. Stimulation
of -adrenergic receptors is thought to suppress NK cell
activity, whereas stimulation of -adrenergic receptors is
thought to suppress B and T lymphocyte cell activity [50].
-Opioid receptor knockout mice do not exhibit opioidinduced suppression of NK cells [51]. Peripheral use of
N-methyl-morphine, which does not cross the blood-brain
barrier, also fails to inhibit NK cell activity, whereas direct
microinjection of morphine into the anterior hypothalamus
inhibits NK cell activity [52]. Similarly, direct microinjection
of morphine into the periaqueductal gray causes suppression
of NK cell function [53].
Natural killer cell cytotoxicity is also regulated by
proinflammatory and anti-inflammatory cytokines [54].
The acute phase inflammatory and immunological responses
to surgical trauma and anesthesia can modulate the cytokine
profile. In the perioperative period, prostaglandin E2 is
produced by inhibitory monocytes and results in downregulated interleukin (IL)-2 production [55]. Decreased synthesis and release of IL-2, in addition to decreased interferon
(IFN)-, lead to T-cell dysfunction and impaired NK cell
activity [56,57] Interluekin-12 is another potent stimulator of

Editorial
growth and activation of NK cells. Interleukin-2 and IL-12
stimulate production of IFN- [41]. The combination of
decreased IL-2, IL-12, and IFN- levels (from the nonspecific immune system) inhibits the development of Th1
cell-mediated immunity and NK cell activity and enhances
the development of Th2 antibody-mediated humoral immunity [58]. Stimulation of NK cells and development of Th1
cell-mediated immunity are inhibited by IL-4 and IL-10 in
response to decreased production of IL-2, IFN-, and
prostaglandin E2 [41,59]. The end result of the surgical
and anesthesia-induced cytokine cascade is decreased innate
NK cellular immunological function and decreased Th1
cell-mediated immunity. Importantly, MOR gene expression
is upregulated in response to IL-1, IL-4, and tumor necrosis
factor and is downregulated by IFN-, which is
potentially important for observed MOR expression in
malignant tissue [60].

4. Conclusion
Basic science research and retrospective clinical studies
have provided growing evidence of an association between
postsurgical cancer recurrence and the perioperative use of
opioid analgesics. It is likely that multiple pathways are
responsible for this observation including the suppression of
NK cells with immediate opioid administration and direct
stimulation of neoplastic pathways with more prolonged
opioid use. Although direct stimulation of neoplastic cellular
growth pathways likely occurs with long-term high-dose
opioid use in a small subset of patients, this does not explain
the observed association between opioid use and tumor
recurrences in the setting of minimally invasive surgical
procedures because the vast majority of these patients do not
require long-term postoperative opioid analgesic therapy.
Furthermore, the suppression of innate immunity due to
perioperative opioid use is likely of little consequence
beyond the initial recovery phase after surgery. Although
research related to surgery, anesthesia, and tumor recurrences remains controversial because of the preliminary
nature of many of the reported findings, it is an exciting and
rapidly expanding field of study for both anesthesiologists
and oncologic surgeons. The implications of these early
findings for patients undergoing cancer-related surgery are
critically important. These preliminary data suggest that the
analgesic management of oncologic patients by anesthesiologists and pain management physicians may have significant
long-term implications with respect to cancer recurrence and
5-year survival rates. The eventual explanation of the
pathophysiologic changes responsible for the observed association between opioid use and cancer recurrence will likely be
the result of a combination of the above-mentioned hypotheses.
Well-designed prospective clinical trials will be necessary to
support or refute the different hypotheses that have been
proposed. Until such time, both theories must be regarded as
speculative. Although it remains an ethical responsibility of all

Editorial
physicians caring for oncologic surgical patients to provide
optimal perioperative and long-term pain management, consideration should be given to avoid the use of large dosages of
opioid analgesics. The use of a multimodal opioid-sparing
strategy for pain management involving a combination of
opioid and nonopioid analgesics will reduce opioid-related
adverse effects and may improve long-term outcome.
Dermot P. Maher, MD, MS
(Clinical Fellow, Pain Medicine)
Department of Anesthesia, Critical Care and Pain Medicine
Massachusetts General Hospital, Harvard School of Medicine
55 Fruit Street, GRB 444, Boston, MA 02114
Corresponding author at: 8700 Beverly Blvd Room 4209
Los Angeles, CA 90048 USA
Tel.: +1 310 423 1682; fax: +1 310 423 4119
E-mail address: dpmaher@mgh.harvard.edu
Paul F. White, PhD, MD
(Consultant, Visiting Scientist, President)
Department of Anesthesiology at Cedars-Sinai Medical Center
in Los Angeles, CA
Instituto Ortopedico Rizzoli, University of Bologna, IT
The White Mountain Institute, The Sea Ranch, CA
E-mail addresses: paul.white@cshs.org
whitemountaininstitute@hotmail.com

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