BJA Education, 17 (3): 105110 (2017)

doi: 10.1093/bjaed/mkw030
Advance Access Publication Date: 10 May 2016
Matrix reference 1A02,
1D02, 2E01, 3E00

Antinociceptive and immunosuppressive effect

of opioids in an acute postoperative setting: an
evidence-based review
S Ramaswamy MBBS MD FRCA FFPMRCA EDRA1, *
and RM Langford MBBS FRCA FFPMRCA2
1
Post-CCT Research Fellow, Pain and Anaesthesia Research Centre, Barts Health NHS Trust, St Bartholomews
Hospital, 1st Floor, King George V Building, West Smitheld, London EC1A 7BE, UK and 2Consultant
in Anaesthesia and Pain Medicine, Director, Pain and Anaesthesia Research Centre, Barts Health NHS Trust,
London, UK
*To whom correspondence should be addressed. Tel: +44 20 3465 6010/55010; Fax: +44 20 3465 5011; E-mail: s.ramaswamy@nhs.net

occurrence of acute tolerance, hyperalgesia, and immunosuppres-

Key points
Opioids remain the mainstay for acute periopera-
tive pain management, but could be clinically less
effective due to development of either tolerance or
opioid-induced hyperalgesia.
Both tolerance and hyperalgesia can occur simul-
taneously and it can be difcult to differentiate be-
tween them.
Although different opioids vary in their effects on
the immune system, any clinical relevance is still
to be determined.
A number of adjuvant, opioid-sparing analgesic
strategies may be used to diminish the dose-related
adverse effects of opioids.
Opioids remain the mainstay of perioperative pain management
for many surgical procedures and settings. However, they are
well known to cause side-effects, including nausea, vomiting, hal-
lucinations, urinary retention, constipation, somnolence, and re-
spiratory depression. More recently, there have been some
concerns regarding their long-term antinociceptive effects due to
the development of tolerance or hyperalgesia.1 There have also
been reports of suppression of the immune system by opioids.1
In this review, the evidence and the possible mechanisms for the
sion in the perioperative setting will be explored. Evidence-based
opioid-sparing treatments may be used in the perioperative setting
to diminish the dose-related adverse effects of opioids.
Antinociceptive effects of opioids
Opioid tolerance and hyperalgesia
Tolerance occurs when a patients response to a drug reduces
over time and necessitates an increase in dose to maintain the
desired result. This results from desensitization of opioid recep-
tors due to a number of mechanisms as outlined below.
Opioid-induced hyperalgesia (OIH) is a state of pain receptor
sensitization caused by exposure to opioids. Clinically, this is re-
cognized by a paradoxical response to opioid analgesics. While
opioids are being used to manage the pain, they may actually re-
sult in an increase in sensitivity to painful stimuli. Therefore, any
further increase in the opioid dose could result in an increased
perception of painful stimuli.2
There is strong positive evidence from animal studies, which
suggest that opioid tolerance and OIH do exist in an acute peri-
operative setting. But the evidence from clinical studies is at
best equivocal, questioning if the dose and duration of opioid
use is signicant enough to cause acute tolerance or OIH. A recent
systematic review and meta-analysis demonstrated that high in-
traoperative doses of opioids were associated with signicantly
higher postoperative pain intensity, and morphine consumption,
supporting the existence of OIH in the postoperative setting.3

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105
Antinociceptive and immunosuppressive effect of opioids
Fig 1 Pain score in response to additional opioid doses differentiates OIH from
tolerance.
The prevalence of tolerance and OIH in acute pain remains un-
known. Diagnosis of tolerance, OIH, or both is difcult and to com-
plicate matters, can co-exist. Distinguishing OIH from tolerance may
be achieved by increasing the opioid dose and observing the effect
on the patients pain levels. Increased pain implies OIH, whereas re-
duction suggests tolerance (Fig. 1).2 OIH can also be characterized
using tools such as quantitative sensory testing (QST).2 QST changes
suggesting increased sensitivity to stimuli have been demonstrated
both locally at the site of pain and at remote non-painful sites, such
as a contralateral limb. Opioid use has been associated with de-
creased heat pain threshold and tolerance, exaggerated response
to temporal summation, and abnormal conditioned pain modula-
tion (diffuse noxious inhibitory control) paradigms.4 This may
help to differentiate tolerance from hyperalgesia.
Current literature suggests that higher early postoperative
pain scores and associated greater opioid dose could be attribu-
ted to OIH, whereas greater requirement for opioids later during
recovery may be attributed to tolerance.
Mechanisms of tolerance5
Up-regulation of the cAMP pathway resulting in phosphorylation
of the -receptor by a variety of intracellular second messengers,
including G-protein-coupled receptor kinase, mitogen-activated
protein kinase, protein kinase C, and phospholipase C.5
Functional decoupling of receptors from G-proteins or -opioid
receptor internalization, receptor down-regulation, or both.5
N-methyl--aspartate receptor (NMDAR), nitric oxide
systemacute opioid administration has been shown to
increase NMDAR activity in mouse models resulting in toler-
ance, and NMDA antagonists have been shown to suppress
the development of acute tolerance.
On exposure to opioids, glial cells expressing opioid receptors
release pro-inammatory neurotransmitters such as NO and
protein kinase C. Opioids also activate glial cells via Toll-like
receptor-4 (TLR-4). The inhibition of TLR-4 has been shown
to reduce tolerance and thereby improve opioid analgesia.
Mechanisms of OIH
The mechanisms of OIH are well illustrated in a previous CEACCP
article.2 In summary, the proposed mechanisms include NMDAR
106 BJA Education | Volume 17, Number 3, 2017
activation, increased spinal dynorphins stimulating -receptors,
decreased inhibitory descending modulation of central pain
pathways, genetic variation in catecholamine-O-methyl-trans-
ferase (COMT), and activation of glial cells via TLR-4.2 5 6 Most ani-
mal and human studies have concentrated on NMDARs using
antagonists such as ketamine, which have shown a reduction
in the occurrence of OIH.
Increased nociceptive activity leads to increased NMDAR
activation by the neurotransmitter, glutamate. Opioid-induced
NMDAR activation results in further glutamate release. In the dor-
sal horn, -opioid receptors co-localize at the same neurones as
those that use glutamate to transmit pain signals. Although the in-
uence of these receptors is usually to dampen pain sensation, a
still poorly understood mechanism appears to exist, in which acti-
vation of these receptors leads to a calcium inux, rendering the
neurones more excitable, predisposing to hyperalgesia. In addition,
the calcium inux activates nitric oxide synthase (NOS) which pro-
duces nitric oxide, a pain-signalling neurotransmitter.2 6
Remifentanil: antinociceptive effect
Remifentanil is a highly potent, ultra-short-acting opioid analgesic
used for intraoperative sedation and analgesia. Both tolerance and
hyperalgesia have been implicated even with short-term infusion
of remifentanil. This is supported by studies on animal models,
human volunteer, and clinical studies.3 A recent systematic review
showed an association between intraoperative remifentanil use
and increased postoperative pain intensity at rest, and also higher
morphine consumption (by as much as 18 mg morphine equivalent
dosage) in the rst 24 h after surgery. Remifentanil was also asso-
ciated with measurable hyperalgesia as assessed by a decreased
nociceptive threshold.3
A study based on a large cohort of Chinese patients showed that
age <16 yr, duration of surgery (>2 h), and dose of remifentanil (>30
g kg1) are risk factors for developing remifentanil-induced hyper-
algesia (RIH). High-dose remifentanil infusions, over a prolonged
duration followed by rapid withdrawal, may result in the develop-
ment of hyperalgesia and possibly tolerance. Genetic factors such
as homozygous polymorphism for the met (158) allele of the COMT
gene and chronic preoperative opioid use have also been asso-
ciated with higher risk of RIH.7 RIH has also been cited as a possible
factor in the development of chronic pain.8
Opioid-induced immunosuppression
Perioperative immunosuppression should be minimized in order
to facilitate recovery from the surgery without complications
such as wound infection. It has also been surmised that impaired
immune function may play a role in the spread of cancer, although
this is not clinically proven and remains highly controversial. A
number of perioperative factors have been shown to have a bear-
ing on the immune status including surgery and tissue handling,
anaesthetics, pain, and analgesics. Research interest has focused
on possible differences in the effects on immune function of dif-
ferent opioids, local anaesthetics, and regional anaesthetic techni-
ques, and on rates of cancer recurrence.
Studies have suggested that pain itself is associated with im-
paired immune function by affecting the hypothalamopituitary
adrenal (HPA) system, and by suppressing natural killer (NK) cells.1
In the acute postoperative period, analgesics can potentially
offset the deleterious effects of pain on the immune system by
reducing nociception and the stress response. However, both ani-
mal and human studies show that opioids themselves may have
deleterious effects on immune function.9 Several mechanisms

have been proposed, although the exact mechanism of opioid-in-
duced immunosuppression (OII) is still not clear.
Opioids impair the phagocytic and chemotactic function of
neutrophils, monocytes, and macrophages and the response of
B and T lymphocytes and also promote their apoptosis. They
also suppress NK cell, antibody function, and lymphocyte prolif-
eration in response to mitogens.9 Central actions on corticoster-
oid production and norepinephrine levels, involving the HPA axis
and the sympathetic nervous system, have been described, and
also peripheral mechanisms involving opioid and non-opioid re-
ceptors, although whether lymphocytes express opioid receptors
remains highly controversial.1 9 A study on a mouse model
showed that administration of morphine suppressed the NK
cell activity and the splenic T-cell proliferation in a normal ani-
mal but not in a -opioid receptor-decient animal, suggesting
the role of the -opioid receptor in mediating the immunosup-
pressive effect of opioids.10
In contrast, perioperative and especially preoperative admin-
istration of morphine resulted in attenuation of surgery-induced
tumour retention in rats undergoing laparotomy.9 In another
study, when morphine was used to treat cancer pain in rat mod-
els inoculated with melanoma cells, it resulted in the suppres-
sion of the tumour growth and metastasis.9
After careful consideration of the conicting evidence on OII,
and cancer spread, the British Journal of Anaesthesia published a
consensus statement recently on cancer and anaesthesia,
which states that there is currently insufcient evidence to asso-
ciate opioid use with cancer promotion or spread.11
Opioid-sparing strategies
The majority of the opioid-related side-effects are dose-related
and hence the rationale for opioid-sparing strategies, to de-
crease the opioid dose. Such dose reduction may also serve to re-
duce the likelihood and degree of OIH and OII. The adjuvant
analgesic measures include local anaesthetic techniques and
systemic pharmacological analgesia as summarized in Table 1
and is explained in greater detail below.
Local anaesthetic techniques
Regional anaesthesia decreases opioid requirement and may
suppress the stress response to surgery. The benets of regional
techniques such as central neuraxial blocks (spinal, epidural, and
paravertebral blocks) and peripheral local anaesthetic techni-
ques (nerve blocks and wound inltration/catheter) are well es-
tablished in both animal and human studies.9 They not only
provide good analgesia but also have extra-analgesic benets in-
cluding improved respiratory and gut function. In addition, a Co-
chrane systematic review and meta-analysis suggest that
regional anaesthesia techniques such as epidural or paraverteb-
ral analgesia for thoracotomy and breast surgery may result in a
decreased incidence of chronic pain.12
Both lidocaine and ropivacaine have also been shown to have
anti-tumour effects. They inhibit epidermal growth factor recep-
tor (EGFR), voltage-gated sodium channels (VGSC), kinesin motor
machinery, and inammatory Src signalling in vitro.9 13 Local
anaesthetics are also cytotoxic to mesenchymal stem cells and
impair human broblast growth. They result in the suppression
of tumour cell proliferation, differentiation, and metastasis. Lido-
caine inltration has been shown to protect against tumour cell
invasion at concentrations used routinely in surgical practice.13
So, the use of regional anaesthesia using local anaesthetics
may decrease the degree of immunosuppression by a
Antinociceptive and immunosuppressive effect of opioids
combination of direct drug effect and by sparing the use of
opioids. A retrospective study on the use of epidural analgesia
for open prostate surgery showed a 57% reduction in biochemical
cancer recurrence.9 Another retrospective study showed that
general anaesthesia along with paraverebral block for mastec-
tomy and axillary clearance for breast cancer was associated
with signicantly decreased cancer recurrence and greater me-
tastasis-free survival compared with general anaesthesia and
standard PCA morphine {94% [95% condence interval (CI), 87
100%] vs 82% (7491%) at 24 months (P=0.038) and 94% (87
100%) vs 77% (6887%) at 36 months (P=0.007); P=0.012}. Contrary
to these small retrospective positive studies, the Cochrane re-
view, which included four studies involving 746 patients, con-
cluded that currently there is insufcient evidence to support
the benet of regional anaesthesia techniques on tumour recur-
rence.14 However, the authors of the Cochrane review commen-
ted that overall, the studies comprised low to very low quality
evidence for the outcome measures. A longer-term evaluation
(ranging from 9 to 15 yr) has been based on a follow-up of patients
from the MASTER trial, who had undergone major abdominal
surgery for cancer. Epidural analgesia was not associated with
an improved cancer-free survival [2.8 (95% CI 0.78.7) yr in the
control group vs 2.6 (0.78.7) yr in the epidural group (P=0.61)].15
Currently, there is an ongoing large multicentre trial looking at
the role of i.v. lidocaine in improving perioperative analgesia and
cancer recurrence (http://clinicaltrials.gov/show/NCT01204242).
Systemic pharmacological interventions
As described in a previous CEACCP article, several adjuvant
drugs have been used as part of balanced multimodal analgesia
to improve perioperative analgesia, minimize opioid-related
side-effects, or both.16
Ketamine
Ketamine is a non-competitive inhibitor of NMDAR. It prevents
central sensitization and decreases mechanical hyperalgesia
surrounding the surgical incision. Perioperative ketamine infu-
sion has been found to signicantly decrease the hyperalgesia
and allodynia in patients receiving high-dose remifentanil infu-
sion.6 Ketamine has been successfully used for rescue analgesia
in opioid-resistant pain and also for RIH.6 16
-2 receptor agonists
Clonidine has been shown to reverse remifentanils lowering of
pain thresholds, suggesting a potential role for -2 receptor ago-
nists in the modulation of OIH.6
Propofol
Fletcher and Martinez,3 in the subgroup analysis of their system-
atic review, found that propofol had a strong preventive effect in
the development of hyperalgesia after high-dose remifentanil in-
fusion. Although the exact mechanism of this effect is not
known, this is most likely mediated via the GABA receptors at
the supraspinal level.6
Nitrous oxide (N2O)
Nitrous oxide is an NMDAR antagonist. Patients receiving N2O-
based anaesthetic may have a higher mechanical threshold to
pain after operation. This suggests that N2O may have some
BJA Education | Volume 17, Number 3, 2017 107
 Table 1 Opioid-sparing strategies: effect on analgesia, immunosuppression, and riskbenets
108
Adjuvant intervention
Local anaesthetic (i.v. and
local inltration)
Regional and neuraxial
local anaesthetic
techniques
Ketamine (sub-anaesthetic
dosage)
-2 receptor agonists Useful adjuvant analgesia, and
COX-2 inhibitors
BJA Education | Volume 17, Number 3, 2017
Propofol
Nitrous oxide (N2O)
Gabapentinoids
Effect of different opioids
Miscellaneous Useful adjuvants
paracetamol,
magnesium, and
propranolol
Impact on analgesia/hyperalgesia
Given locally and systemically (i.v.
lidocaine) can decrease opioid
requirements and improve analgesia
Analgesic and extra-analgesic
benet
May decrease chronic pain incidence
Useful adjuvant analgesia, may
decrease opioid tolerance, and
hyperalgesia including RIH
anxiolysis. May reverse OIH
Useful opioid-sparing adjuvant
analgesics.
Reduced opioid dose may decrease
opioid tolerance, hyperalgesia
Modulates OIH
Modulates OIH
Useful adjuvant analgesia
VariableOIH established with
remifentanil but can occur with
any opioids
Less with methadone and
buprenorphine
Impact on immune function Comments/risk prole
Direct anti-tumour effect inhibits EGFR, VGSC, Useful adjuvant analgesia.
kinesin motor machinery, and inammatory Src Promising in vitro effects but need further clinical evidence
signalling in vitro
Supported by smaller retrospective studies, but not Assess riskbenet individually
by Cochrane review or large prospective studies. Need for expertise
Need further evidence Clinical benet of reduced immunosuppression not proven in
clinical practice
Evidence currently not known/available Riskbenet: side-effects include sedation, visual disturbance,
hallucinations (and at higher dosage psychosis)
Evidence currently not known/available Riskbenet: side-effects include hypotension, bradycardia, sedation
By inhibiting PG secretion has anti-tumour and Riskbenet: side-effects include adverse gastrointestinal and
anti-angiogenesis properties cardiovascular risks
Evidence currently not known/available Propofol infusion can be considered in patients with high analgesic
requirements
Antinociceptive and immunosuppressive effect of opioids
Evidence currently not known/available Riskbenet: N2O is a less favoured anaesthetic adjuvant in modern
anaesthesia. Caution especially required if risk of closed air-lled
cavity such as pneumothorax. Increased risk of postoperative nausea
and vomiting
Evidence currently not known/available Riskbenet: side-effects include dizziness, sedation, somnolence,
vomiting, and visual disturbance
Morphine suppresses T-lymphocyte, B- Consider opioid switch or adjuvants to improve analgesia
lymphocyte, NK-cells, and monocytes/ Clinical impact of the differential effect of opioids on
macrophages. immunosuppresion not proven and hence remains a theoretical
Immunosuppressive opioids consideration
Codeine
Methadone
Morphine
Remifentanil
Fentanyl
Less immunosuppressive
Opioids
Buprenorphine
Hydromorphone
Oxycodone
Tramadol
Evidence currently not known/available Always consider paracetamol as part of balanced analgesia unless
contraindicated
Riskbenet: use magnesium (hypotension, adverse neurological,
and neuro-muscular effect) and propranolol (hypotension,
bradycardia) with caution

role in attenuating the OIH, although we need further evidence to
conrm this.3
Gabapentinoids
Gabapentinoids such as gabapentin and pregabalin act on the
21 subunit of pre-synaptic calcium channels and thereby de-
crease the calcium ion current. They have signicant opioid-
sparing effect and also decrease the incidence of opioid-related
side-effects. Gabapentinoids may prevent central sensitization
and subsequent hyperalgesia and allodynia.16 Thus, they may
be useful to prevent and treat OIH, although to date this has
not been investigated.
COX-2 inhibitors
Prostaglandins (PG) are implicated in pro-nociceptive processing
and stimulate the release of excitatory amino acids, such as glu-
tamate, in the dorsal horn. Studies on both animal and human
pain models have supported the role of COX-2 inhibitors in at-
tenuating opioid tolerance and hyperalgesia.6 9
Some tumour cells secrete PG, which oppose host cell immun-
ity. Animal models show that COX-2 inhibitors, by inhibiting this
PG secretion, have anti-tumour and anti-angiogenesis proper-
ties.7 Long-term COX-2 inhibitor use has also been associated
with lower incidence of breast cancer in women.9
Inter-opioid variability
Not all opioids have the same propensity to cause hyperalgesia
and immunosuppression. Sacerdote and colleagues17 showed
that modications at C6, the C78 bond, C14, and the piperidine
ring result in variation in the antinociceptive and immunosup-
pressive properties of opioids.
Differential effect of opioids on hyperalgesia
In both the chronic non-cancer and cancer pain settings, opioid
switching or rotation is one of the strategies used to manage ei-
ther opioid tolerance or OIH.5 This strategy could also be tried as a
rst step in an acute setting in patients either developing opioid-
related side-effects or in whom there appears to be diminishing
response to a particular opioid. For example, morphine may be
substituted with fentanyl.
With regard to alternative opioids, methadone and buprenor-
phine stand out due to their unique mechanisms of action.
Methadone is a weak NMDAR antagonist. Studies have shown
that methadone may be effective in reducing the OIH due to pro-
longed high doses of other opioids.5 But its long duration of ac-
tion and possibility of cumulative toxicity means that it is less
practical to use methadone for perioperative analgesia. Bupre-
norphine is a partial -receptor agonist and -receptor antagon-
ist. Spinal dynorphin (-receptor agonist) concentration has been
found to increase with opioid administration, which is one of the
postulated mechanisms of OIH. Buprenorphine, by blocking the
-receptor, can potentially offset this effect, and has been
shown to have an antihyperalgesic effect in human volunteers.
Tapentadol is a newer opioid, which has both agonist actions
on -receptors and inhibition of norepinephrine reuptake. Both
animal and human studies suggest that tapentadol has a super-
ior effect on mechanical and thermal hyperalgesia and also on
conditional pain modulation.18 19 However, there are currently
no studies evaluating OIH with tapentadol.
The development of RIH is dose-related, and hence there is a
potential benet of limiting the dose infused. Several adjuvants
Antinociceptive and immunosuppressive effect of opioids
have been studied to counteract the RIH. A large number of adju-
vants have been shown to prevent the development of RIH, includ-
ing ketamine, propofol, nitrous oxide, paracoxib, magnesium,
propranolol, and pre-induction paracetamol.3 6 Although the
strength of this evidence remains weak and controversial, it is
worth considering these adjuvants, for example, if a high dose of
intraoperative remifentanil is anticipated or required.
Differential effect of opioids on immunosuppression
Not all opioids induce the same immunosuppressive effects. In a
surgical model, NK-lymphocyte activity was maintained at pre-
operative levels after buprenorphine administration, while in
morphine-treated rats, NK-lymphocyte activity was suppressed
partially by morphine and maximally by fentanyl. Differential ef-
fects have also been demonstrated in chronic opioid administra-
tion: fentanyl (but not buprenorphine) signicantly affected
immune parameters such as lymphoproliferation, NK-lympho-
cyte activity, cytokine production, and lymphocyte number.20
Studies have shown that both morphine and fentanyl are as-
sociated with suppression of cellular immunity and NK cell activ-
ity.9 Buprenorphine, oxycodone, and hydromorphone are known
to lack an immunosuppressive effect, whereas tramadol has
been found to have an immunoprotective effect.1 9 Tramadol
has been shown to increase NK cell activity as opposed to mor-
phine in both animal and human studies and hence found to
have a potential immunoprotective effect.7 Despite these effects,
clinical relevance of the effect of different opioids is largely un-
known and hence there is not a compelling need to change prac-
tice. There is a need for studies to establish whether OII is
clinically relevant, and whether it should inform the choice of
opioids for immunocompromised or cancer patients.
Conclusion
We need to be aware of some lesser-known and rarer side-effects
of opioids, such as acute tolerance, OIH, and immunosuppres-
sion. There are several strategies that may be used as part of
multimodal analgesia, including regional anaesthesia and adju-
vant pharmacological interventions, to mitigate these adverse
effects. Currently, the evidence to support such strategies includ-
ing the choice of opioids is at best low. But this area has attracted
a lot of research interest and hence it is hoped that in future we
will have more concrete evidence.
Declaration of interest
None declared.
MCQs
The associated MCQs (to support CME/CPD activity) can be
accessed at https://access.oxfordjournals.org by subscribers to
BJA Education.
References
1. Raghavan S, Harvey AD, Humble SR. New opioid side effects
and implications for long-term therapy. Trends Anaesth Crit
Care 2011; 1: 1821
2. Velayudhan A, Bellingham G, Morley-Forster P. Opioid-
induced hyperalgesia. Contin Educ Anaesth Crit Care Pain
2014; 14: 1259
BJA Education | Volume 17, Number 3, 2017 109
Antinociceptive and immunosuppressive effect of opioids
3. Fletcher D, Martinez V. Opioid-induced hyperalgesia in pa-
tients after surgery: a systematic review and a meta-analysis.
Br J Anaesth 2014; 112: 9911004
4. Zhang Y, Ahmed S, Vo T et al. Increased pain sensitivity in
chronic pain subjects on opioid therapy: a cross-sectional
study using quantitative sensory testing. Pain Med 2015; 16:
91122
5. DuPen A, Shen D, Ersek M. Mechanisms of opioid-induced
tolerance and hyperalgesia. Pain Manag Nurs 2007; 8: 11321
6. Lee M, Silverman S, Hansen H, Patel V, Manchikanti L. A com-
prehensive review of opioid-induced hyperalgesia. Pain
Physician 2011; 14: 14561
7. Jensen KB, Lonsdorf TB, Schalling M, Kosek E, Ingvar M.
Increased sensitivity to thermal pain following a single
opiate dose is inuenced by the COMT val (158) met poly-
morphism. PLoS One 2009; 4: e6016
8. van Gulik L, Ahlers SJ, van de Garde EM et al. Remifentanil
during cardiac surgery is associated with chronic thoracic
pain 1 year after sternotomy. Br J Anaesth 2012; 109: 61622
9. Snyder GL, Greenberg S. Effect of anaesthetic technique and
other perioperative factors on cancer recurrence. Br J Anaesth
2010; 105: 10615
10. Weber RJ, Gomez-Flores R, Sora I, Uhl GR. Loss of morphine-
induced suppression of NK cell activity and T-cell functions
in m receptor knockout mice. Am J Immunol 2006; 2: 359
11. Buggy DJ, Borgeat A, Cata J et al. Consensus statement from
the BJA Workshop on Cancer and Anaesthesia. Br J Anaesth
2015; 114: 23
110 BJA Education | Volume 17, Number 3, 2017
12. Andreae MN, Andreae DA. Regional anaesthesia to prevent
chronic pain after surgery: a Cochrane systematic review
and meta-analysis. Br J Anaesth 2013; 111: 71120
13. Mao L, Lin S, Lin J. The effects of anesthetics on tumor
progression. Int J Physiol Pathophysiol Pharmacol 2013; 5: 110
14. Cakmakkaya OS, Kolodzie K, Apfel CC, Pace NL. Anaesthetic
techniques for risk of malignant tumour recurrence. Cochrane
Database Syst Rev 2014; 11: CD008877
15. Myles PS, Peyton P, Silbert B et al. Perioperative epidural
analgesia for major abdominal surgery for cancer and recur-
rence-free survival: randomised trial. Br Med J 2011; 342:
d1491
16. Ramaswamy S, Wilson JA, Colvin L. Non-opioid adjuvant an-
algesia in perioperative care. Contin Educ Anaesth Crit Care Pain
2013; 13: 1527
17. Sacerdote P, Manfredi B, Mantegazza P, Panerai AE. Antinoci-
ceptive and immunosuppressive effects of opiate drugs: a
structure-related activity study. Br J Pharmacol 1997; 121:
83440
18. Smith HS. Opioids and neuropathic pain. Opioids and
neuropathic pain. Pain Physician 2012; 15(3 Suppl.): ES93110
19. Niesters M, Proto PL, Aarts L, Sarton EY, Drewes AM, Dahan A.
Tapentadol potentiates descending pain inhibition in chron-
ic pain patients with diabetic polyneuropathy. Br J Anaesth
2014; 113: 14856
20. Sacerdote P. Opioids and the immune system. Palliat Med
2006; 20(Suppl. 1): s915