Biomedicine & Pharmacotherapy 60 (2006) 310–317

http://france.elsevier.com/direct/BIOPHA/

Dossier: Acute and chronic pain management

Pain management: is opioid immunosuppression a clinical problem?

Keith Budd, FRCA*
Emeritus Consultant in Pain Management, Newlands, Chevin Avenue, Menston LS29 6PE, UK

Received 21 March 2006; accepted 12 June 2006

Available online 30 June 2006

Abstract
For more than 100 years, the use of opioid analgesic agents has been linked with modulation of the immune system in man. More recently, it
has become apparent that both exogenous and endogenous opioids exert some effect upon the immune system but that this can be beneficial or
deleterious depending on numerous variables. Of the strong opioid analgesics in current use, the majority are seen to cause immunosuppression
in man. However, it still remains unclear whether this is clinically important in man although it would appear to be good practice to avoid such
agents in patients already immunosuppressed by disease or pharmacotherapy. Powerful opioid analgesics without immunosuppressive properties
can be selected and should be used in such situations and as these agents can offer additional benefits in addition to their non-immunosuppresive
analgesia, it should be considered whether to use them at all times in preference to immunosuppressive opioids.
© 2006 Elsevier SAS. All rights reserved.

Keywords: Opioids; Analgesics; Immunomodulation

1. Introduction suppression in the human in a variety of disparate situations

Opioid use and abuse has been linked to suppression of the
immune system in man for in excess of 100 years [1].
It is now well accepted that opioids and endogenous opioid
peptides modulate immune function and there is increasing evi-
dence that opioid use in the surgical patient and those critically
ill has a profound immunomodulatory effect. But, whilst this
has been clearly observed [2], there has been little written or
said that would indicate any change of attitude to the use of
opioids in the severely ill or those already immunosuppressed
by either their disease process or treatment, even though the
understanding of the peripheral actions of the neuroimmune
system has progressed markedly [3].
Whilst the inter-relationship between opioid analgesics and
the immune system is not a simple one and may appear to vary
depending on the opioid studied, dose range of the opioid, spe-
cies in which studied, immunological parameters measured and
the time course of the study, increasing availability of data
indicate that opioid prescription and usage is lagging behind
the available evidence of significant opioid-induced immuno-
* Correspondingauthor. Tel.: +44 1943 87 6331; fax: +44 1943 87 0456.
E-mail address: keithbudd@tiscali.co.uk (K. Budd).
0753-3322/$ - see front matter © 2006 Elsevier SAS. All rights reserved.
doi:10.1016/j.biopha.2006.06.015
[4].
It is, therefore, vitally important to examine the available
evidence to determine whether opioid immunosuppression is
real and significant or whether we can continue to, as it
would appear we have done this far, ignore a potential hazard
to many of our most seriously ill patients.
2. The evidence
In the human, all forms of trauma including surgery inevi-
tably result in immune system suppression [5] which is recog-
nised as depressed lymphocyte proliferative responses to mito-
gens and natural killer (NK) lymphocyte cellular activity [6–9],
decreased cell mediated immunity [10,11] and alterations in the
balance of T-lymphocytes (T-helper cells: Th-I, Th-2 cells)
compromising cellular immunity [12,13].
The invasiveness of the surgery has been associated with the
magnitude of the immune suppression [12] and immune func-
tion is comparatively more suppressed by surgery in indivi-
duals with cancer [11], although this finding does not always
appear to be consistent [14].
As the pain and the trauma of surgery each contribute to
immunosuppression, analgesic agents, at least in part, alleviate
that immunosuppression. For them to themselves produce addi-
 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
tional depression of the immune system is both counterproduc-
tive and illogical prescribing.
Immune outcomes, including NK-cell activity, have been
shown to improve when epidural and spinal anaesthesia is
used for lower body surgery when compared with general
(inhalational) anaesthesia [15–17]. Epidural analgesia has also
been associated with fewer postoperative infections when com-
pared with inhalational anaesthesia, further confirming the
aforementioned implications [18].
Interleukin-6 (IL-6) is produced by many immune cells such
as lymphocytes, macrophages and monocytes. It has an impor-
tant role in both the inflammatory process and the regulation of
metabolic and endocrine functions, particularly the hypothala-
mic–pituitary–adrenal (HPA) axis and catecholamines [19].
Raised levels of IL-6 accompany surgery with levels in both
plasma and cerebro spinal fluid (csf) being proportional to the
degree of invasiveness of the intervention [20,21]. Inflamma-
tory changes and hyperalgesia are promoted by prostaglandins
which also depress NK-cell activity [22]. In man, techniques
which reduce inflammation have been shown to alleviate pain
and immune suppression [20].
It has been recently demonstrated that spinal glia are
involved in the creation and maintenance of pathological pain
[23]. Animal models of neuropathic pain have shown that glial
cells (microglia and astrocytes) are activated and secrete a
number of substances which will excite pain transmission in
neurons [23,24]. These substances include the pro-
inflammatory cytokines interleukin-1β (IL-1β), IL-6 and
tumour necrosis factor-α (TNF-α) [25]. Spinal cord glial activ-
ity provides a major factor in creating and maintaining a wide
variety of exaggerated pain states. Trauma to peripheral nerves
causes intense microglial and astrocyte activation in the central
nervous system (CNS) [26]. Glial activation appears to corre-
late with the emergence of neuropathic pain syndromes. Of the
substances released by activated immune and glial cells, pro-
inflammatory cytokines appear to be of special importance in
the creation of peripheral nerve and neuronal hyperexcitability
[27]. Glial activation would seem to both create and maintain
exaggerated pain states since pharmacological disruption of the
spinal cord glial function disrupts pain induced by a variety of
means including peripheral nerve inflammation, spinal nerve
transaction and spinal cord immune challenges [28,29].
There is a large body of evidence implicating the pro-
inflammatory cytokines in the induction and facilitation of
inflammatory and neuropathic pain [30]. Whilst studies have
shown that patients with complex regional pain syndrome
(CRPS) have normal plasma levels of pro-inflammatory cyto-
kines [31,32], blister fluid samples from the affected limb
showed evidence of localised inflammation and raised levels of
IL-6 and TNF-α [31]. Treatment of CRPS with infleximab
(Remicade), a blocker of TNF-α, produced significant reduc-
tion of IL-6 and TNF-α in blister fluid together with improve-
ment of symptoms [33]. The study by Alexander et al. [34] is
the first to show elevation of pro-inflammatory cytokines in the
csf of CRPS patients. The most significant finding was the ele-
vation of IL-6 when compared with controls. The levels of IL-
311
1β were also elevated but the csf cytokine profile of CRPS
patients may differ at different stages of the disease process
with IL-1β and TNF-α being elevated acutely whilst others
such as IL-6, later in the process.
Many central pain syndromes have been shown to demon-
strate increased csf levels of pro-inflammatory cytokines [35–
37]. The involvement of pro-inflammatory cytokines in painful
disorders in humans suggests that part of the process, at least,
resulting in chronic pain, involves a central neuroimmune acti-
vation [31–33,38]. The pro-inflammatory cytokines, including
TNF-α and -β, IL-1, IL-2, IL-6, IL-8, interferon-gamma (IFN-
γ), granulocyte macrophage colony stimulating factor (GM-
CSF), induce the recognition of non-self or the injury of local
cells and lead to the generation of inflammatory signs via the
release of classical inflammatory mediators such as eicosa-
noids, biologically active amines and peptides, together with
the sensitisation of peripheral sensory neurones (hyperalgesia).
Anti-inflammatory cytokines, IL-4, IL-10, IL-13, IL-beta
receptor anatagonist (IL-βra) may well obtund this response,
with IL-βra being released together with the pro-inflammatory
cytokines or later in the process [39].
Immune cells are a natural and primary component of the
skin where nerves form their terminal receptive fields and
express receptors for immune products. They are also found
in peripheral nerves where multiple types of immune cells are
in constant intimate contact with nerve fibres and can midax-
onally alter nerve anatomy and physiology. Immune cells in
dorsal root ganglia ensheath and modulate every neuronal cell
body. Lastly, in the spinal cord, they form dynamic networks
well suited to maintaining and spreading excitation. It can,
therefore, be well appreciated how such cells are well placed
to provide the pathways by which immune activation can both
damage peripheral nerves and enhance their excitability and
how such immune-derived changes might participate in the
aetiology and symptomatology of various pathological pain
states [27].
As all available pain therapies exclusively target neurons,
the appreciation of peripheral and central immune cell involve-
ment in the production and maintenance of neuropathic pain,
whatever the aetiology, may offer alternative ways to approach
pain control.
The inflammatory cascade can be inhibited at various points
along its course, either single or multiple. As pro-inflammatory
antagonists are large proteins, antisera or soluble receptor/anti-
body hybrids, all of which do not cross the blood–brain barrier
effectively, there is a need to administer them centrally which
is not a clinically viable option. However, a variety of agents
which can penetrate the CNS have shown potential.
Thalidomide and a number of its analogues have been
shown to inhibit both the production of TNF and its release
from astrocytes and microglia [40–42]. These agents have
been shown to inhibit the increased pain caused by the periph-
eral administration of TNF [43] and thalidomide and the orally
active peptide Lys-d-Pro-Thr[K(d)PT] block the release of
TNF-α and the hyperalgesic effect of IL-1β, respectively.
312 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
Inhibitors of the matrix metalloproteases have also been
used to inhibit peripheral TNF-mediated neuropathic pain
[44]. The value of these agents is speculative as they only
block TNF without any effect upon IL-1 or IL-6 [40].
Glial metabolic inhibitors such as fluocitrate or fluoacetate
have shown, in animal studies, at low doses and short term
administration, certain potential but neuronal function is inhib-
ited at higher doses and longer term administration [45].
3. The problem
Whilst the likelihood of the future introduction of analgesics
acting in a highly specific manner is very likely, the present
agents of choice remain the opioids for the majority of painful
problems. However, these agents are not without their own
problems especially in terms of their effect upon the immune
system, an area which has been somewhat neglected until now.
There is ample evidence to show that the majority of opioid
analgesics significantly depress immune function when admi-
nistered at doses within the analgesic range [46–48].
The more profound effects of opioid analgesics generate an
increased susceptibility in patients to both bacterial and viral
infections especially following surgery and trauma [11]. In
addition, reduced defence mechanisms in cancer patients are
indicated by reduced survival times and increased susceptibil-
ity to secondary metastatic spread [49,50] and a greater sus-
ceptibility to HIV infection in drug abusers [51,52].
Generalised down regulation of immunity by the adminis-
tration of opioids, such as morphine, is shown by their inhibi-
tory effect upon monocyte macrophage function [53]. Prolif-
eration and differentiation of macrophage colony stimulating
factor (MCSF)-dependent macrophage progenitor cells in
bone marrow are inhibited together with the phagocytosis of
various pathogens [17,54,55].
In vivo administration of opioids to rodents induces a
decrease of multiple immune parameters affecting almost all
of the cell types of the immune system. NK-cells have been
shown to be particularly sensitive to morphine modulation
[56]. Following both acute and chronic opioid administration,
T-cell proliferation is decreased whilst the effect of B-
lymphocytes is less pronounced [57].
4. Opioid immunosuppression—mode of action
Opioids induce suppression of the immune system by inter-
action with the μ-opioid receptors on immune cells or those
within the CNS. This is instanced by:
1. Inhibition by opioid antagonists, such as naloxone, of the
opioid immunosuppressant effect [58].
2. The absence of opioid-induced immunosuppression in
rodents made knock-out for the μ-opioid receptor [59].
3. Activation of CNS μ-opioid receptors can regulate the per-
ipheral immune system by the activation of the HPA, pro-
ducing ACTH from the pituitary which elicits the release of
immunomodulatory glucocorticoids [60].
4. Activation of the CNS μ-opioid receptors will also stimulate
the SNS which innervates both primary and secondary lym-
phoid organs. These release catecholamines which have
been shown to suppress lymphocyte, NK-cell and macro-
phage function [57,61].
5. Evidence exists for the involvement of catecholaminergic
pathways in alteration of opioid mediated changes in
immune function. Bio- and histo-chemical studies have
shown a rich noradrenergic input into bone marrow, thy-
mus, spleen, lymph nodes and gut-related lymphoid tissue
with noradrenergic terminals in direct apposition of lympho-
cytes [62].
The site of the immunosupressive opioid activity has been
determined as the periaqueductal grey (PAG) matter in the
mesencephalon [63]. Opioid effects within the PAG are trans-
mitted by either hypothalamic efferents and HPA activation or
increases in peripheral sympathetic output, both suppressing
blood, splenic and thymic lymphocyte proliferation and NK-
cell activity [64].
Whilst chronic opioid treatment induces immunosuppres-
sion via glucocorticoid secretion, acute opioid effects appear
to be glucocorticoid-independent [61]. However, published
evidence on the effects of opioids, both endogenous and exo-
genous, on the immune system is inconsistent, which may be
due to a variety of reasons:
1. It is not yet clear which opioid receptors or subtypes are
present on which lymphocytes as there is evidence that sub-
types of opioid receptors function differentially [65].
2. The enkephalinase enzyme, neutral endopeptidase, CALLA
moiety in granulocytes and certain lymphocytes are the
same entity which suggests that enzymatic regulation of
opioid activity is a factor in opioid immunosuppression [8,
52].
3. In vivo secondary processes may mediate immunosuppres-
sive effect through the induction of corticosteroid or adre-
nergic pathways [66].
4. The kinetics of various responses may be an important fac-
tor as whilst some nearly instantaneous responses do occur,
such as NO induction, others which might be measured after
hourly or daily intervals might be due to secondary pro-
cesses [67].
5. A further reason for conflicting results may be that lym-
phoid cells are endogenous producers of opioids [68].
A further and most important factor in the variation of effect
of specific opioids upon the immune system is the type of
agent under consideration. Opioids of the phenanthrene group
suppress B- and T-cell proliferation [69]. In addition, they have
a negative effect upon T-cell mediated cytotoxicity [70], pro-
duction of INF-γ [71] and macrophage phagocytosis of Can-
dida albicans both by the direct and indirect routes [72].
The phenylpiperidine group of opioids has been shown to
have a differing spectrum of immunosuppressive effects to the
 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
phenanthrenes. Fentanyl, sufentanil, mirfentanil and remifenta-
nil have all been shown to depress NK-cell activity [73,74].
5. Variation in opioid effect
There is now ample evidence to show that both endogenous
and exogenous opioids modulate immune function to a signifi-
cant degree and that the process is not a simple one.
The results of many investigations show that the variation of
effect of individual opioids depends upon numerous factors
including not only the opioid studied but also the dose of the
agent, the dose range, in which species the study was carried
out, immunological parameters measured and the time course
of the study. These constraints apply to all studies whether
carried out in animals or humans.
The main differentiating factors between those opioids that
depress immune function to a significant extent and those
which do not appear to be opioid receptor affinity and molecu-
lar structure. It is, therefore, clinically important to define those
opioids that depress human immune function and those which
do not, also whether the effect is dose related.
In general, opioids with a high affinity at the μ-opioid
receptor have been shown to produce significant immunosup-
pression whilst those with κ- or δ-receptor affinity do not [14,
56].
Affinity to the nociceptin receptor and it relationship to
immune modulation has, to date, not been investigated.
Antagonists at the μ-opioid receptor appear to enhance the
function of the immune system [75].
It is important to note that the immunosuppressive modula-
tion of opioid analgesic drugs appears to be independent of
their analgesic effect [4]: the reason for this dissociation has
yet to be determined. All the immunosuppressive opioid
analgesics bind to the μ-opioid receptor and both their antino-
ciceptive and immunosuppressive effects are reversed by μ-
opioid receptor antagonists [76].
If morphine, which has marked immunosuppressant effects,
is taken to represent the basic opioid structure, a carbonyl sub-
stitution at C6, the introduction of a single bond at C7–8 and a
hydroxyl substitution at C14 produce agents with a potentiated
analgesic effect compared to the parent compound, whilst the
immunosuppression is abolished. Examples of such are hydro-
morphone compared with morphine and oxycodone compared
with codeine [75]. Opioid molecules with hydroxyl groups at
C3 and C6 possess the greatest immunosuppressive property
(morphine, nalorphine) whilst modification at C3 alone leads
to partial loss of immunosuppression (codeine, dihydroco-
deine) and substitution of a carbonyl group at C6 completely
abolishes immunosuppression (hydromorphone, oxycodone,
oxymorphone). Without modification at C3 and C6, alterations
of the piperidine ring have no effect upon current immune sta-
tus, for instance nalorphine [77]. The conversion of morphine
to codeine by the substitution of the C3 hydroxyl decreases
immunosuppression as well as analgesia. Clinically, codeine
decreases NK-cell function less than morphine at equianalgesic
doses.
313
Confirming structural specificity, diacetyl morphine, metha-
done and other phenanthrenes show immunosuppressive prop-
erties but not as great as morphine. Phenylpiperidines such as
pethidine, fentanyl and its derivatives including remifentanil,
have all been shown to have immunosuppressive properties in
man but, again, less than morphine [74,78,79].
Substituting the methyl group on the piperidine ring by a
larger alkyl chain gives compounds with minimal or absent
antinociceptive effect but with the property of opioid antagon-
ism. Included in this group are nalorphine, naloxone, naltrex-
one and nalmefene. Nalorphine with C3 and C6 hydroxyl
groups, similar to morphine, has a marked suppressant effect
upon all immune parameters. The allyl substitution on its pyr-
imidine ring gives a marked opioid antagonist effect whilst its
weak antinociceptive property derives from a κ-opioid receptor
agonism. This κ-agonism does not appear to play a role in the
immunosuppression as blockade with κ-antagonists, such as
MK-801, does not affect immune status.
Naloxone and naltrexone, having the same C6 carbonyl sub-
stitution as hydromorphone, an allyl substitution on the piper-
idine ring and a hydroxyl at C14, enhance rather than suppress
some aspects of the immune system which is due to a blockade
of the suppression by β-endorphin of mitogen-induced T-cell
depression [80,81].
Nalmefene has a single bond at C7–8, an unsaturated bond
at C6 and an allyl substitution of the piperidine ring. The intro-
duction of a hydroxyl at C14 completely antagonises the anti-
nociceptive effect of the parent compound, hydromorphone
[75].
There are a small number of opioid analgesics which do not
conform to the pattern stated above. Several studies have
shown that buprenorphine, an agonist at the μ-opioid receptor
in the clinical dose range for analgesia, has no significant
effects upon the immune system in man even at high doses
for a long period of treatment [82]. Structurally, buprenorphine
relates to those opioids having no immunosuppressant effects
in that it has a single bond at C7–8, an hydroxyl group at C14
and an endoetheno bridge between C6 and C14 together with a
1-hydroxy-1,2,2-trimethylpropyl substitution on C7. Its lack of
immunosuppressive effect appears to arise from a lesser neu-
roendocrine activity than other opioids and that it does not acti-
vate the HPA or SNS or their descending pathways [83,84].
Tramadol is more complex in that it produces analgesia both
by agonism at the μ-opioid receptor and by a catecholamine-
enhancing activity involving both noradrenaline and serotonin
in the dorsal horn of the spinal cord. These factors, together
with a structure unlike that of the immunosuppressant opioids,
would explain its lack of suppressive effect upon the human
immune system [85,86]. The enhancement of the immune sys-
tem following the acute administration of tramadol is similar to
studies showing that agents increasing serotonergic tone, such
as D-fenfluramine and fluoxetine, stimulate immune function
[8,87]. Such enhancement of the immune system by tramadol,
increasing NK-cell activity and lymphocyte proliferation, can
be reduced by the administration of the non-specific serotonin
antagonist, metergoline, thereby confirming the involvement of
314 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
the serotonergic system in immune system modulation [88].
Even at sub-analgesic doses, tramadol will stimulate T-
lymphocyte and NK-cell function in addition to increasing
the production of IL-2 by concavalin-A, a function mirrored
by other opioids [89].
6. Clinical implications
In the last two decades, over 600 papers have been pub-
lished emphasising the fact that, in both animals and humans,
opioid analgesic agents induce suppression of the immune sys-
tem.
In man, the clinical relevance has yet to be fully determined
but all the available evidence indicates that current analgesic
practice using opioid analgesics does not produce optimal con-
ditions for our patients.
The majority of opioid analgesics used in clinical practice
modulate the human immune system to varying degrees and as
there is an increasing number of patients who, for a variety of
reasons, are immunocompromised and who may present either
acutely or chronically for management of pain, it is vitally
important that analgesic selection is of the highest order to alle-
viate a worsening of that immunosuppression.
The increased incidence of cancer in elderly people has
been related to the age-associated changes occurring in the
immune system, so called immunosenescence (IS). This phe-
nomenon is best characterised by a remodelling of the immune
system which appears early on and progresses throughout a
persons life and mainly involves a decrease in cellular func-
tions [90]. Such changes concern primarily the adaptive
immune responses, including alterations in T-cell phenotype
and functions and a reduced ability of B-cells to mount specific
antibody responses. In the elderly, even the response to vacci-
nation is lower than in a young subject. The major problem
appears to be in finding adjuvants to improve the low effective-
ness of immunisation in this age group. In a similar manner,
the innate immune system serves an important role in prevent-
ing microbial invasion but it experiences significant changes
with advancing age [91]. In addition, IS is associated with
increased morbidity and mortality from infectious and autoim-
mune diseases. Consequently, with the increasing aging popu-
lation, these factors play an important role in the calculation of
future health care provision, particularly when pain and its
treatment will be implicated in 80% of the population and the
agents used in such treatment will be mainly opioids, not infre-
quently in large doses. It is, therefore, important that immuno-
suppressive effect is taken into consideration when analgesic
therapy is considered for this group of at risk patients.
In general, however, as in many areas of medicine, pain and
its treatment can be divided into acute and chronic. In the acute
area, the particular aspects which involve the immune system
are acute surgery and trauma, both of which have their own
specific effect upon the immune system, separate from what-
ever analgesic agents may be use in its treatment.
Studies in man have shown that both surgery and trauma are
associated with immunosuppression, mediated via the HPA
and SNS, leading to a reduction in lymphocyte proliferation,
cytokine production and NK-cell activity [92]. NK-cells have
a fundamental role in immunosurveillance against tumour cells,
being involved in controlling metastatic spread in a number of
animal models [93]. Decreases in NK-cell activity in the peri-
operative period and their association with greater rates of can-
cer recurrence and mortality have been described for cancers of
the breast, head and neck, colon and rectum and lung [94].
It is of note that such immunosuppressive changes are not
seen following the use of effective regional blockade, such as
spinal or epidural analgesia, rather than general anaesthesia
[13,15]. Epidural anaesthesia or analgesia is associated with
fewer postoperative infectious complications than general
anaesthesia alone [95].
There is conclusive evidence that acute pain is a stressor
impairing immune function, particularly NK-cell function.
The key role of NK-cells in organism defence against viral
and bacterial infection together with inhibition of tumour
metastasis would indicate an importance of preserving immune
function in those undergoing surgery [95].
Although most studies have been in adults, children have
also been studied [100]. In general, children show a lesser
effect of opioids upon the immune system for shorter duration
than adults but the immunosuppressive effect of the opioids
depends on the type of agent, its method of administration
and dose. In addition, variation in effect occurs depending
upon the immune parameter(s) measured and the age of the
child [96,97].
As in adults, in children neutrophil invasion of surgical
wounds is of importance in the resistance to infection.
Wound oxygen tension is directly related to bacterial killing
[98] and predicts the risk of wound infection [99].
With good anaesthetic and postoperative care, children tend
to show only minor changes in immunological responses, but
the type of analgesia has some effect on these. In severely
immunocompromised patients and in those with major opera-
tive complications, these changes may take on a much more
significant role [100].
Consequently, whatever the age of the patient, if any degree
of immunosuppression is present due to either disease process
or therapy, this will be increased if treatment with an immuno-
suppressive opioid analgesic is instituted. It follows, therefore,
that opioid analgesics which do not depress immune function
are the optimal agents with which to produce analgesia in such
patients.
In the patient with chronic pain, which may be due to cancer
or autoimmune, osteo- and neuro-degenerative problems, the
long term use of opioid analgesics presents a variety of pro-
blems. The majority of opioid analgesics in current clinical
use have been shown to have varying degrees of immunosup-
pressive properties [101]. It is, therefore, important to select for
prolonged therapy those agents which have not only the least
immunosuppressive effect but also the minimal adverse event
profile such that the total negative effect upon the patient is
minimal.
 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
The selection of opioid analgesics which do not depress the
immune system is reliant upon their molecular structural dis-
position. As stated previously, those opioids which have no
clinical immunosuppressive activity are those which structu-
rally have a carbonyl substitution at C6, a single bond between
C7–8 and, preferably, a hydroxyl group at C14. Agents com-
plying with these constraints have the pharmacological proper-
ties which make them suitable for therapy in patients with sup-
pressed immune systems from whatever cause.
These opioid analgesics are buprenorphine, hydromor-
phone, oxycodone, oxymorphone and tramadol [101].
7. Conclusions
There seems no doubt that the majority of opioid analgesics
in clinical use in the treatment of pain, both acute and chronic,
show suppressive effects upon the immune system in man.
Whilst in the healthy patient this may not be clinically sig-
nificant, in those with an immune system already suppressed
by pathology, trauma, stress, treatment both physical or phar-
macological, the addition of an opioid which will depress the
immune system yet further cannot be considered to be in the
best interest of the patient.
It is not difficult to select the opioid analgesics which are
effective and safe in both the acute and chronic situations.
They are, from a molecular structural aspect, those opioids
which have a carbonyl substitution at C6, a single bond
between C7-8 and, preferably, an hydroxyl group at C14, and
are, therefore, the most clinically acceptable: they are bupre-
norphine, hydrocodone, oxycodone, oxymorphone and trama-
dol, which not only have no immunosuppressant properties but
may have additional pharmacological and clinical advantages
over the immunosuppressant group of opioid analgesics.
In the prescription of opioid analgesic drugs, therefore, a
wide variety of properties need to be taken into consideration
before the ultimate selection is made.
Consequently, contemporary opioid prescription may need
to be reconsidered in the light of more informed knowledge
so that the optimal pharmacotherapy is applied to patients
whose need is paramount.
In the management of acute or chronic pain, the homeosta-
sis of the immune system is of the greatest importance and the
use or abuse of opioids can be of vital importance. Much of the
relevant information is already in the literature but it is scat-
tered across a large area including both basic science and clin-
ical medicine. It should be encouraged, therefore, that the clin-
ician is both aware of the importance of the immune system
and, also, how to use pharmacological knowledge to maintain
that system at its optimal function for the best protection of the
patient.
References
[1] Friedman F, Newton C, Klein TW. Microbial infections, immunomodu-
lation and drug abuse. Clin Microbiol Rev 2003;16(2):209–19.
[2] Webster NR. Opioids and the immune system. Br J Anaesth 1998;81:
835–6.
315
[3] Williams JP, Lambert DG. Opioids and the neuroimmune axis. Brit J
Anaesth BJA 2005;24:3–6.
[4] Budd K, Shipton EA. Acute pain, the immune system and opioimmu-
nosuppression. J Acute Pain 2004;6:123–35.
[5] Molina PE, Zambell KL, Van de Stouwe C, Carnal J. Haemodynamic
and immune consequences of opiate analgesia after trauma/haemor-
rhage. Shock 2004;21:204–11.
[6] Kutza J, Gratz J, Ashfar M. The effects of general anaesthesia and sur-
gery on basal and interferon stimulated natural killer cell activity of
humans. Anesth Analg 1997;85(4):918–23.
[7] Pollock RE, Letzova E, Stanford SD. Mechanism of surgical stress
impairment of human postoperative natural killer cell cytotoxicity.
Arch Surg 1991;126:338–42.
[8] Sacerdote P, Bianchi M, Gaspani L, Manfredi B, Manciane A, Terno G,
Ammatuna M, Panerai AE. The effects of tramadol and morphine on
immune responses and pain after surgery in cancer patients. Anesth
Analg 2000;90:1411–4.
[9] Sapira JD. The heroin addict as a medical patient. Am J Med 1968;45:
555–8.
[10] Ellis NK, Duffie GP, Young MR. The effects of 16,16-dimethyl PGE2
and phosphodiesterase inhibitors on Con-A blastogenic responses and
NK cytotoxic activity of mouse spleen cells. J Leukoc Biol 1990;47:
371–7.
[11] Risdahl JM, Khanna KU, Peterson KW. Opiates and infections. J Neu-
roimmunol 1998;83:4–18.
[12] Decker D, Schondorf M, Bidlingmaier F. Surgical stress induces a shift
in the type 1/type 2 T-helper cell balance, suggesting down-regulation
of cell mediated and up-regulation of antibody-mediated immunity com-
mensurate to trauma. Surgery 1998;119:457–63.
[13] Le Cras AE, Galley HF, Webster NR. Spinal but not general anaesthe-
sia increases the ratio of T helper-1 to T helper-2 cell subsets in patients
undergoing transurethral resection of the prostate. Anesth Analg 1998;
87:142–5.
[14] Band IC, Pert A, Williams W. Central mu opioid receptors mediate sup-
pression of natural killer cell activity in vivo. Prog Neuroendocrinol
1992;5:95.
[15] Koltun WA, Bloomer MM, Tilberg AF, et al. Awake epidural anaesthe-
sia is associated with improved natural killer cell cytotoxicity and a
reduced stress response. Am J Surg 1996;171:68–73.
[16] Tonnesen E, Mickley H, Grunnet N. Natural killer cell activity during
premedication, anaesthesia and surgery. Acta Anaesth Scand 1983;27:
233–41.
[17] Tonnesen E, Wahlgren C. Influence of extradural and general anaesthe-
sia on natural killer cell activity and lymphocyte subpopulations in
patients undergoing hysterectomy. Br J Anaesth 1988;60:500–7.
[18] Yeager MP, Glass DD, Neff RK. Epidural anesthesia and analgesia in
high risk surgical patients. Anesthesiol 1987;66:729–36.
[19] Papanicolou DA, Liden RL, Monoglas SC. The pathophysiologic role
of interleukin-6 in human disease. Ann Intern Med 1998;128:127–37.
[20] Chambrier C, Chassard D, Bienvenue J. Cytokine and hormonal
changes after cholecystectomy. Effect of ibuprofen treatment. Ann
Surg 1996;224:178–82.
[21] Yeager MP, Lunt P, Arruba J. Cerebrospinal fluid cytokine levels after
surgery with spinal or general anesthesia. Regul Anesth Pain Med 1999;
25:557–62.
[22] Portanova JP, Zhang Y, Anderson GB. Selective neutralisation of pros-
taglandin E2 blocks inflammation, hyperalgesia and interleukin-6 pro-
duction in vivo. J Exp Med 1996;184:883–91.
[23] Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force
for pathologic pain. Trends Neurosci 2001;24:450–5.
[24] Kreutzberg GW. Microglia: a sensor for pathological events in the CNS.
Trends Neurosci 1996;19:312–8.
[25] Wieseler-Frank J, Maier SF, Watkins LR. Glial activation and patholo-
gical pain. Neurochem Int 2004;45:389–95.
[26] Gehrmann J, Monaco S, Kreutzberg GW. Spinal cord microglial cells
and DRG satellite cells rapidly respond to transaction of the rat sciatic
nerve. Restorative Neurol Neurosci 1991;2:181–98.
316 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
[27] Watkins LR, Maier SF. Beyond neurons: evidence that immune and
glial cells contribute to pathological pain states. Physiol Rev 2002;82:
981–1011.
[28] Milligan ED, Mehmet K, Hindle JL. Thermal hyperalgesia and mechan-
ical allodynia produced by intrathecal administration of human immu-
nodeficiency virus-1 envelope glycoprotein gp120. Brain Res 2000;
861:105–16.
[29] Watkins LR, Maier SF. The pain of being sick; implications of immune-
to-brain communication for understanding pain. Ann. Rev. Psychol. 20;
(1):29–57.
[30] Sommer C, Kress HM. Recent findings on how pro-inflammatory cyto-
kines cause pain: peripheral mechanisms in inflammatory and neuro-
pathic hyperalgesia. Neurosci Lett 2004;361:184–7.
[31] Huygen FJPM, de Bruijn AGJ, de Bruijn MT, et al. Evidence for local
inflammation in Complex Regional Pain Syndrome type 1. Mediators
Inflamm 2002;11:47–51.
[32] Van de Beek WJT, Remarque EJ, Westendorp RGJ, van Hilten JJ.
Innate cytokine profile in patients with complex regional pain syndrome
is normal. Pain 2001;91:259–61.
[33] Huygen FJ, Niehof S, Zilstra FJ, et al. Successful treatment of CRPS 1
with anti-TNF. J Pain Symptom Manage 2004;27:101–3.
[34] Alexander GM, van Rijn MA, van Hilten JJ, et al. Changes in cere-
brospinal fluid levels of proinflammatory cytokines in CRPS. Pain
2005;116:213–9.
[35] Baraczka K, Nekam K, Pozsony T, et al. Investigation of cytokine
(tumour necrosis factor-alpha, interleukin-6, interleukin-10) concentra-
tions in the cerebrospinal fluid of female patients with multiple sclerosis
and systemic lupus erythematosus. Eur J Neurol 2004;11:37–42.
[36] Kotani N, Kudo R, Sakurai Y, Sato T, Wei Z. Cerebrospinal fluid
interleukin-8 concentrations and the subsequent development of post-
herpetic neuralgia. Am J Med 2004;116:318–24.
[37] Vila N, Castillo J, Davalos A, Chamorro A. Proinflammatory cytokines
and early neurological worsening of ischaemic stroke. Stroke 2000;31:
2325–9.
[38] Kikuchi A, Kotani N, Sato T, Kikuchi A, Kotani N, Sato T, Kudo R.
Evaluation of intrathecal versus epidural methylprednisolone for long
term analgesia in patients with intractable postherpetic neuralgia. Reg
Anesth Pain Med 1990;24:287–93.
[39] Cunha FQ, Ferreira SH. Peripheral hyperalgesic cytokines. In:
Machelska H, Stein C, editors. Immune mechanisms of pain and analge-
sia. New York: Kluwer Academic; 2001. p. 22–39.
[40] Corral LG, Muller GW, Moreira AL. Selection of novel analogues of
thalidomide with enhanced tumour necrosis alpha inhibitory activity.
Mol Med 1996;2:506–16.
[41] Peterson PK, Hu S, Sheng WS. Thalidomide inhibits tumour necrosis
factor alpha production by lipopolysaccharide- and lipoarabinomannan-
stimulated human microglial cells. J Infect Dis 1995;172:1137–40.
[42] Zwingenberger K, Wnendt S. Immunomodulation by thalidomide: sys-
tematic revue of the literature and of unpublished observations. J
Inflamm 1995;46:177–211.
[43] George A, Marziniak M, Schafers M. Thalidomide treatment in chronic
constrictive neuropathy decreases endoneurial tumour necrosis factor
alpha, increases interleukin-10 and has long term effects on spinal
cord dorsal torn met-enkephalin. Pain 2000;88:267–75.
[44] Sommer C, Schmidt C, George A. A metalloprotease-inhibitor reduces
pain associated behaviour in mice with experimental neuropathy. Neu-
rosci Lett 1997;237:45–8.
[45] Hassel B, Paulsen RE, Johnson A. Selective inhibition of glial cell
metabolism by fluocitrate. Brain Res 1992;249:120–4.
[46] McCarthy L, Wetzel M, Sliker JK, Eisenstein TK, Rogers TJ. Opioid
receptors and the immune response. Drug Alcohol Depend 2001;62:
111–23.
[47] Schocaht SJ, Miuer CA, Snyder P. Evaluation of cellular immunity and
adrenocortical activity in surgical patients. J Surg Res 1979;26:332–40.
[48] Wei G, Moss J, Yuan CS. Opioid induced immunosuppression: is it
centrally mediated or peripherally mediated? Biochem Pharmacol
2003;65:1761–6.
[49] Lewis JW, Shavit Y, Terman GW. Stress and morphine affects survival
of rats challenged with mammary ascites tumour (MAT 13762B). Nat
Immun Cell Growth Regul 1983;24:443.
[50] Yeager MP, Collachio TA, Yu CT. Morphine inhibits spontaneous and
cytokine-enhanced natural killer cell cytotoxicity in volunteers.
Anesthesiology 1995;83:500–8.
[51] Beagles K, Wallenstein A, Bayer B. Systemic morphine administration
suppresses genes involved in antigen presentation. Mol Pharmacol
2004;65:437–42.
[52] Hall DM, Suo J-L, Weber RJ. Opioid mediated effects on the immune
system: sympathetic nervous system involvement. J Neuroimmunol
1998;83:29–35.
[53] Menzebach A, Hirsch J, Nost R, Mogk M, Hemplemann G. Morphine
inhibits complement receptor expression, phagocytosis and oxidative
burst by a nitric oxide dependent mechanism. Anasthesiol Intensivmed
Notfallmed Schmerzther 2004;39:204–21.
[56] Carr DJJ, Gebhart BM, Paul D. α-Adrenergic and IL-2 opioid receptors
are involved in morphine-induced suppression of natural killer cell
activity. J Pharmacol Exp Ther 1993;264:1179–86.
[54] Rojavin M, Szabo I, Bussiere JL. Morphine treatment in vitro or in vivo
decreases phagocyctic functions. Int J Immunopharmacol 1987;9:79–88.
[55] Roy S, Rama Krishnan S, Loh HH. Chronic morphine treatment selec-
tively suppresses macrophage colony formation in bone marrow. Eur J
Pharmacol 1991;195:359–63.
[57] Flores LR, Dretchen KL, Martin FC. Potential role of the autonomic
nervous system in the immunosuppressive effect of acute morphine
administration. Eur J Pharmacol 1996;318:437–46.
[58] Flores LR, Webster RJ. Opioids, opioid receptors and the immune sys-
tem. In: Plotnikoff P, Firth JA, Murgo M, Good F, editors. Cytokines,
stress and immunity. London: CRC Press; 1999. p. 281–314.
[59] Gaveriaux-Ruff C, Metthes HWD, Peluso J. Abolition of morphine-
immunosuppression in mice lacking the mu opioid receptor gene. Proc
Natl Acad Sci USA 1998;95:6326–8.
[60] Pacifici R, Di Carlos S, Bacosi A. Pharmacokinetics and cytokine pro-
duction in heroin and morphine treated mice. J Immunopharmacol
23000;22:603–614.
[61] Flores LR, Hernandez MC, Bayer BM. Acute immunosuppressive
effects of morphine: lack of involvement of pituitary and adrenal fac-
tors. J Pharmacol Ther 1994;268:1129–34.
[62] Carr DJJ, Mayo G, Gebhardt BM. Central alpha-adrenergic involvement
in morphine-mediated suppression of splenic natural killer cell activity.
J Neuroimmunol 1994;53:53–63.
[63] Weber RJ, Peart A. The periaqueductal gray matter mediates opiate-
induced immunosuppression. Science 1989;245:188–90.
[64] Weber RJ, Ikejiri B, Rice KC. Opiate receptor-mediated regulation of
the immune response in vivo. NIDA Res Monogr 1987;36:341–8.
[65] Wang J, Charbonneau R, Balasubramian S, Liang Si, Watson R. The
effects of chronic morphine treatment are particularly dependent on cor-
ticosterone and mediated by the mu opioid receptor. J Leukoc Biol
2002;71:782–90.
[66] Shavit Y, Lewis JW, Terman GW. Opioid peptides mediate the suppres-
sive effect of stress on natural killer cell toxicity. Science 1984;223:
188–90.
[67] Fecho K, Masolonek KA, Dykstra LA, Lysle DT. Mechanisms whereby
macrophage-derived nitric oxide is involved in morphine-induced sup-
pression of splenic lymphocyte proliferation. J Pharmacol Exp Ther
1995;272:477–83.
[68] Stephanou A, Fitzharris P, Knight RA, Lightgman SL. Characteristics
and kinetics of proopiomelanocortin mRNA expression by human leu-
kocytes. Brain Behav Immun 1991;5:319–27.
[69] Carr DJJ, Carpenter GW. Morphine-induced suppression of cytotoxic
T-lymphocyte activity in alloimmunized mice is not mediated through
naltrindole-sensitive delta opioid receptor. Neuroimmunomod 1995;2:
44.
[70] Scott M, Carr DJJ. Morphine suppresses the alloantigen CTL response
in a dose dependent and naltrexone reversible manner. J Pharmacol Exp
Ther 1996;278:80–988.
[71] Fecho K, Masolonek KA, Dykstra LA. Assessment of the involvement
of central nervous system and peripheral opioid receptors in the immu-
 K. Budd / Biomedicine & Pharmacotherapy 60 (2006) 310–317
nomodulatory effect of acute morphine treatment in rats. J Pharmacol
Exp Ther 1996;276:626–36.
[72] Tubaro E, Borelli G, Croce C. Effect of morphine on resistance to infec-
tion. J Infect Dis 1983;148:656–66.
[73] Beilin B, Martin FC, Shavit Y. Suppression of natural killer cell activity
by high dose narcotic anesthesia in rats. Brain Behav Immunol 1989;3:
129–37.
[74] Sacerdote P, Gaspani L, Rossoni G, et al. Effect of the opioid remifen-
tanil on cellular immune response in the rat. Int Imunopharmacol 2001;
1:713–9.
[75] Sacerdote P, Manfredi B, Mantegazza P. Antinociceptive and immuno-
suppressive effects of opiate drugs: a structure-related activity study. Br
J Pharmacol 1997;121:834–40.
[76] Williams W, Rice KC, Weber RJ. Non-peptide opioids: in vivo effects
on the immune system. NIDA Res Mono 1991;105:404–7.
[77] Palm S, Magnar T, Kuhn K. Phytohaemagglutinin-dependent T-cell
proliferation is not impaired by morphine. Methods Find Exp Clin Phar-
macol 1996;18:159–65.
[78] Carr DJJ, Baker MI, Holmes C. OLM3292: a fentanyl-related 4-
heteroanilidopiperidine with analgesic but no suppressive effects on
splenic NK activity in mice. Int J Immunol 1994;16:835–44.
[79] Mantucci C, Panerai AE, Sacerdote P. Chronic fentanyl or buprenor-
phine infusion in the mouse: similar analgesic profile but different
effects on immune responses. Pain 2004;110:385–92.
[80] Carpenter GW, Breeden L, Carr DJJ. Acute exposure to morphine sup-
presses cytotoxic T-lymphocyte activity. Int J Immunopharmacol 1995;
17:1001–16.
[81] Sacerdote P, Manfredi B, Gaspani L, Panerai AE. The opioid antagonist
naloxone induces a shift from type 1 cytokine pattern to type 2 cytokine
pattern in BALB/J mice. Blood 2000;95:782–90.
[82] Sacerdote P. Buprenorphine and the immune system. In: Budd K,
Raffa RB, editors. Buprenorphine—the unique opioid analgesic. Stutt-
gart: George Thieme Verlag; 2005. p. 33–40.
[83] D’Elia M, Patenaude J, Hamelin C, Garrel DR, Bernier J. No detrimen-
tal effect from chronic exposure to buprenorphine on corticosteroid-
binding globulin and corticosensitive immune parameters. Clin Immu-
nol 2003;109:179–87.
[84] Gomez-Flores R, Weber R. Differential; effect of buprenorphine and
morphine on immune and neuroendocrine functions following acute
administration in the rat mesencephalon periaqueductal gray. Immuno-
pharmacol 2000;48:145–56.
[85] Liunat S, Felton SY, Carlsden SL. Involvement of peripheral and cen-
tral catecholamine systems in neural-immune interactions. J Neuroim-
munol 1985;10:5–10.
317
[86] Tsai Y-C, Won S-J. Effects of tramadol on T-lymphocyte proliferation
and natural killer cell activity in rats with sciatic constriction injury.
Pain 2001;92:63–9.
[87] Mossner R, Lesoh KP. Role of serotonin in the immune system and in
neuroimmune interactions. Brain Behav Immun 1988;12:249–71.
[88] Sacerdote P, Bianchi M, Manfredi B, Panerai A. Effects of tramadol on
immune responses and nociceptive thresholds in mice. Pain 1997;72:
325–30.
[89] Sacerdote P, Bianchi M, Gaspani L. Effects of tramadol and its enantio-
mers on concavaline-A induced proliferation and NK activity of mouse
splenocytes: involvement of serotonin. Int J Immunopharmacol 1999;
21:727–34.
[90] Provinciali M, Smorlesi A. Immunoprevention and immunotherapy of
cancer in aging. Cancer Immunol Immunother 2005;54:93–106.
[91] Plackett TP, Boehmer ED, Douglas EF, Kovacs EJ. Aging and innate
immune cells. J Leukoc Biol 2004;76:291–9.
[92] Gaspani L, Bianchi M, Limiroli E, Panerai AE, Sacerdote P. The drug
tramadol prevents the effects of surgery on natural killer call activity
and metastatic colonisation in rats. J Neuroimmunol 2002;129:18–24.
[93] Ben-Eliyahu S, Page GG, Yarmiya R, Shakar G. Evidence that stress
and surgical interventions promote tumour development by suppressing
natural killer cell activity. Int J Cancer 1999;80:80–888.
[94] Vallejo R, de Leon-Casasola O, Benyamin R. Perioperative immuno-
suppression in cancer patients. J Environ Pathol Toxicol Oncol 2003;
22:139–46.
[95] Page GG. Acute pain and immune impairment. Pain Clin Updates 2005;
13:1–4.
[96] Mollitt DL, Marmer DJ, Steele RW. Age-dependent variation of lym-
phocyte function in the postoperative child. J Pediatr Surg 1986;21:
633–5.
[97] Puri P, Blake P, Reen DJ, Guiney EJ. Lymphocyte transformation after
surgery in the neonate. J Pediatr Surg 1980;15:175–7.
[98] Allen DB, Maguire JJ, Mahdavian M, et al. Wound hypoxia and acido-
sis limit neutrophil bacterial killing mechanisms. Arch Surg 1997;132:
991–6.
[99] Hopf HW, Hunt TK, West JM, et al. Wound tissue oxygen tension pre-
dicts the risk of wound infection in surgical patients. Arch Surg 1997;
132:997–1004.
[100] Vuori A, Salo M, Viljanto J, et al. Effects of postoperative pain treat-
ment using non-steroidal anti-inflammatory analgesics, opioids or epi-
dural blockade on systemic and local immune response in children.
Acta Anaesthesiol Scand 2004;48:738–49.
[101] Budd K. Pain, the immune system and opioimmunotoxicity. Rev Analg
2004;8:1–10.