Palliative Medicine 2006; 20: s9
/s15

Opioids and the immune system

Paola Sacerdote Department of Pharmacology, University of Milan, Milan

Opioid compounds such as morphine produce powerful analgesia that is effective in

treating various types of pain. In addition to their therapeutic efficacy, opioids can
produce several well known adverse events, and, as has recently been recognized, can
interfere with the immune response. The immunomodulatory activities of morphine have
been characterized in animal and human studies. Morphine can decrease the effective-
ness of several functions of both natural and adaptive immunity, and significantly
reduces cellular immunity. Indeed, in animal studies morphine is consistently associated
with increased morbidity and mortality due to infection and worsening of cancer.
However, from several animal studies it emerges that not all opioids induce the same
immunosuppressive effects, and evaluating each opioid’s profile is important for
appropriate analgesic selection. Buprenorphine is a potent opioid that is frequently
prescribed for chronic pain. Acute intracerebroventricular administration of buprenorphine
has been shown in rats not to affect cellular immune responses, while a statistically
significant inhibition of the immune response was observed with morphine. In mouse
studies, chronic administration of buprenorphine led to immune parameters important for
antimicrobial responses or for anti-tumour surveillance (lymphoproliferation, natural killer
(NK)-lymphocyte activity, cytokine production, lymphocyte number) being unaffected. In
contrast, levels of these immune markers were significantly reduced when the potent m-
agonist fentanyl was administered, but recovered after longer periods as tolerance
developed. Because the intrinsic immunosuppressive activity varies between individual
opioids, predicting the outcome on immunity can be difficult. To study this, the effects
of morphine, fentanyl and buprenorphine on NK-lymphocyte activity depressed by
experimental surgery were examined in rats. Treating animals immediately after surgery
with equianalgesic doses of morphine and buprenorphine significantly reduced surgery-
induced immunosuppression. However, buprenorphine reverted NK-lymphocyte activity
to preoperative levels, while in morphine-treated rats NK-lymphocyte activity was
ameliorated, although not completely. In contrast, fentanyl did not prevent immunosup-
pression induced by surgery. Overall, from several animal studies it emerges that
buprenorphine has the more favourable profile, being a potent analgesic devoid of
intrinsic immunosuppressive activity. Palliative Medicine 2006; 20: s9
/s15

Key words: analgesic; anti-tumour surveillance; buprenorphine; fentanyl; intrinsic immuno-

suppression; morphine; NK-cell activity; opioids, preclinical studies

Introduction found to induce expression of a coreceptor for HIV on

The idea that opioids suppress the immune system and
lower resistance to infections is not new.1 There is
evidence that opioids modulate both innate and acquired
immune responses, altering resistance to a variety of
infectious agents.2,3 Studies of drug abuse with heroin, for
example, have shown that this opioid attenuates the
immune response, and is, therefore, a cofactor in the
pathogenesis of human immunodeficiency virus (HIV)
infection.1,3,4 Another opioid, methadone, has been
Address for correspondence: Paola Sacerdote, Department of
Pharmacology, University of Milan, Via Vanvitelli 32, 20129
Milan, Italy.
E-mail: paola.sacerdote@unimi.it
# 2006 Edward Arnold (Publishers) Ltd
human lymphocytes.5 The possible immunosuppressive
effect of some opioids is becoming a relevant factor to
prescribers, a fact that has recently been demonstrated
through the provision of recommendations by the UK
Pain Society for the appropriate use of opioids in chronic
situations.6 Although lacking detail, one of the recom-
mendations makes the point that opioids can affect
immunity (Table 1).
Effects of opioids on immune system
Acute and chronic administration of opioids is known
to have inhibitory effects on humoral and cellular
immune responses, including antibody production,
10.1191/0269216306pm1124oa
s10 P. Sacerdote
Table 1 Extract from The Pain Society (UK) recommenda-
tions for appropriate use of opioids (The Pain Society 2004)6
Adverse effects of chronic opioid use:
+
Classical opioid adverse events of nausea, vomiting, itching and
somnolence are common. Constipation is common and tends
to persist.
+
Other more serious problems include ventilatory depression,
weight gain and hormonal effects.
+
Patients and their partners should be warned of the effects of
maternal opioid consumption on neonatal well being.
+
The immunological effects of using long-term opioids are
well described. However, their clinical importance is
not clear.
natural killer (NK)-lymphocyte activity, cytokine expres-
sion and phagocytic activity. The immunomodulatory
activities of morphine, the ‘gold standard’ strong
opioid and a powerful m-agonist, have been well char-
acterized both in preclinical and clinical studies.1,7
9
Morphine decreases several functions of both natural
and adaptive immunity. A significant reduction of
cellular immunity has been described both in animal
and human studies after acute and chronic administra-
tion of morphine.10,11 Moreover, treatment using mor-
phine has been associated with increased morbidity and
mortality on artificial infection and faster cancer pro-
gression in animals.3 A link between immunosuppression
of some components of the cellular immune system in
cancer patients and morphine has also been pro-
posed.12,13
Mechanism of morphine-induced
immunosuppression
Why are opioids immunosuppressive? Opioids such
as morphine modulate the immune system either directly
Hypothalamo-
Morphine
pituitary axis
Glucocorticoids
Figure 1 Mechanism of morphine-induced immunosuppression
by binding to m-opioid receptors present on immune
cells (T lymphocytes, B lymphocytes, NK lymphocytes,
monocytes, macrophages), or through an indirect cen-
trally mediated pathway by binding to m-opioid receptors
within the central nervous system. Opioids activate
the descending pathways of the hypothalamic
/
pituitary
/adrenal (HPA) axis and the sympathetic
nervous system (SNS)1 (Figure 1). Activation of the
HPA axis elicits the production of immunosuppres-
sive glucocorticoids in the periphery, while activation of
the SNS through the innervation of primary and
secondary lymphoid organs elicits the release of
noradrenalin.9,14 Both noradrenalin and glucocorticoids
act on leucocytes to negatively modulate immune
capability.
Preclinical studies indicate that some opioids
are more immunosuppressive than others
Not all opioids induce the same degree of immunomo-
dulatory effects. From reviewing the literature, it is
evident that the majority of studies investigating the
effects of opioids on the immune system have been
conducted in animals. From these animal studies con-
clusions have been drawn that opioids can be divided into
those that are immunosuppressive, such as codeine,
methadone, morphine and remifentanil, and those that
are less immunosuppressive, including buprenorphine,
hydromorphone, oxycodone and tramadol.7,10 For a long
time it was unclear as to which group fentanyl belonged,
but it is now accepted that it falls into the immunosup-
pressive group.15 Variations between the two groups have
been exemplified in a study by Martucci et al . that
compared the effect of fentanyl and buprenorphine on
splenic cellular immune response after continuous infu-
Brain
mu-opioid receptors
Sympathetic
nervous system
mu
Noradrenalin
Leucocyte

sion in the mouse model.16 In contrast to fentanyl-treated
animals, no immune alterations ever occurred in those
treated with buprenorphine.16 Recently, however, re-
search into the comparative immunosuppressive proper-
ties of different opioid analgesics in humans has
begun.11,17
19
Therefore, it is important to evaluate each opioid’s
impact on the immune system, whether given acutely or
chronically, in order to select the appropriate analgesic
for a particular clinical situation. It will be therefore of
great importance starting to project clinical trials aimed
at identifying opioids with minimal negative immuno-
modulatory properties to be used in critical conditions
where a patient’s immune system may already be
impaired.
The risk factors and vulnerability of an individual
can significantly impact health while treatment with
opioids is received. Immunosuppressive drugs should
be used with caution in individuals who already have
an immunosuppressed status because they are elderly,
suffering from a disease that diminishes their immu-
nity, such as cancer or HIV, or have recently undergone
an invasive surgical procedure. Normal healthy indivi-
duals can tolerate some opioid-induced immune pertur-
bations without developing a pathological event, but
vulnerable groups, such as those described above, may
not be so fortunate. Thus, opioid-induced immunomo-
dulation becomes more relevant when immunosuppres-
sive factors are already present. The most clinically
relevant situation is the decline of the immune response
related to ageing, psychosocial stress, surgical stress
or even exposure to a high level of pathogens at a
critical moment.
(A) Morphine
80
60
CPM × 1000
40
20
0 0
0.25 1 4
PHA (mcg/mL)
Figure 2 Comparative immune responses in patients administered morphine (A) or tramadol (B) after surgery for cancer.
PHA-stimulated proliferation of lymphocytes obtained from patients before the beginning of surgery (basal), immediately after
surgery and predrug (postsurgery) and 2 hours after treatment with 10 mg/kg of morphine i.m. or 100 mg of tramadol i.m.
(post-treatment). Values are expressed as cpm (counts/minute) of [3H]thymidine incorporation. *PB/0.05 versus basal (one
way analysis of variance).
s11
Surgery-induced immunosuppression and
opioids
Pain is an exquisite stressor as it has both psychological
and physiological components. The linked responses of
the central nervous system and the HPA axis to a
perceived stress involves a complex network of signals,
including catecholamines, peptides such as endorphins
and corticosteroids such as cortisol. All of these factors
can lead to immunosuppression.20 Additionally, pain is
an important factor in postoperative immune impair-
ment, relief of which should be beneficial in preventing
immunosuppression.21 In rat studies, surgery-induced
stress has been shown to be particularly associated
with decreased NK-lymphocyte activity and enhanced
tumour metastasis.22,23 Suppression of NK lymphocyte
activity is the primary mediator of the tumour-enhancing
effects of stress.1,11,21,23
In healthy patients who can tolerate a certain level
of immune perturbation, surgery-induced stress and
consequent immunosuppression may not be harmful.
However, in more vulnerable sections of the population
this might not be the case, and such stress could tilt the
immunomodulative balance towards a pathological
scenario, which, if a poor choice of opioid was made to
control pain, could progress to further suppression of
the immune system. In two studies conducted in patients
during surgery and anaesthesia, it has been shown that
morphine and high fentanyl doses could worsen the
immunosuppressive effect of surgery.18,19
The consequences of the varied immunosuppressive
effects of opioids were also demonstrated in a study of
two established analgesics, morphine and the atypical
(B) Tramadol
80
60
CPM × 1000
40
20 Basal
Post surgery
Post treatment
0.25 1 4
PHA (mcg/mL)
s12 P. Sacerdote

opioid tramadol, in patients undergoing surgery for
uterine carcinoma.11 (Figure 2).
Measurements of phytohaemagglutinin (PHA)-in-
duced T-lymphocyte proliferation and NK-lymphocyte
activity before surgery, immediately after surgery and
2 hours after surgery showed that lymphoproliferation
was significantly suppressed by surgical stress in all
patients. However, in the morphine-treated group, pro-
liferative values remained lower than basal levels for
2 hours after treatment, whereas in tramadol-adminis-
tered patients proliferative values returned to basal levels.
NK-lymphocyte activity was not significantly affected by
surgery or by morphine administration, whereas trama-
dol significantly enhanced the activity of NK lympho-
cytes. Both drugs were shown to produce a comparable
reduction in postoperative pain, but tramadol, in con-
trast to morphine, induced an improvement of post-
operative immunosuppression. Although the long-term
clinical impact of these immune modifications remain to
be defined, it can be hypothesized that it is possible to
choose, given that a similar pain control is achieved,
drugs devoid of immunosuppressive effects for treating
postoperative pain.
Further confirmation that some opioids are more
immunosuppressive than others can again be shown by
comparing tramadol and morphine, this time investigat-
ing the development of experimental tumours after
injecting rats with MADB106 cells in surgicalized and
non-surgicalized animals.23 Surgery-induced immuno-
suppression may underlie the promotion of metastatic
development that is associated with surgery. Administer-
ing tramadol (20 and 40 mg/kg) before and after
laparotomy significantly blocked the development of
lung metastasis induced by surgery (Figure 3). In
contrast, administration of morphine (10 mg/kg) did
not modify the increased lung metastasis. The modula-
tion of NK lymphocyte activity seemed to play a central
role in how MADB106 cells were affected by tramadol.
In fact, both doses of tramadol prevented suppression of
surgery-induced NK activity, while the drug significantly
increased NK lymphocyte activity in normal non-surgi-
calized animals. In normal rats, morphine significantly
decreased NK lymphocyte cytotoxicity and did not
prevent surgery-induced immunosuppression.23
Shavit et al . demonstrated the immunosuppressive
effects of fentanyl, again in rats inoculated with
MADB106 cells.15 After sacrificing the animals 3 weeks
after inoculation and removing and counting the metas-
tases in both groups, more than two-fold higher metas-
tases were observed in the fentanyl group than in the
control group. There was also a diminished NK lympho-
cyte activity in the fentanyl group, an important indicator
in tumour and metastasis surveillance. These findings
indicate that fentanyl suppresses NK lymphocyte cyto-
toxicity and increases the risk of tumour metastasis.
Suppression of NK lymphocytes at a time when surgery
may induce tumour dissemination can prove critical to
the spread of metastases.15
Buprenorphine: an opioid devoid of
immunosuppressive effects
A search of the literature has indicated that there are a
number of preclinical publications that show that bupre-
norphine, a semi-synthetic derivative of thebaine, is
particularly favourable to the immune system.16,24,25
For example, in a study by Gomez-Flores and Weber,
buprenorphine administered acutely in the rat mesence-
phalon periaqueductal grey caused no alteration in
splenic NK-lymphocyte, T-cell or macrophage function,
whereas morphine significantly suppressed immunity.24
In another study,16 buprenorphine (300 mg/day/
mouse) was continuously infused over 24 hours in a

(A) Normal rats (B) Surgery rats

20 20
#
16 16

Number 12 12
of lung
metastases 8 8

4 4
0 0
Saline Morphine Tramadol Tramadol
10 mg/kg 20 mg/kg 40 mg/kg
*
*
Saline Morphine Tramadol Tramadol
10 mg/kg 20 mg/kg 40 mg/kg
# = P < 0.05 versus saline in normal rats;
* = P < 0.05 versus saline in surgery rats

Figure 3 Comparative effect of treatment with tramadol and morphine on the number of tumour metastases in rats that
underwent an experimental surgery. As reported in Ref.17, tramadol was able to prevent surgery-induced immunosuppression
and related increase of number of metastases, while morphine, due to its intrinsic immunosuppressive properties, was not.
#P B/0.05 versus saline non-operated rats (one way analysis of variance). *P B/0.05 versus saline-treated operated animals
(one way analysis of variance).
 s13

mouse model and compared with the potent m-agonist
fentanyl (180 mg/day/mouse) and saline controls. Equia-
nalgesic doses of both drugs were delivered by osmotic
pump, and, after 1 day of fentanyl administration,
lymphoproliferation, NK-lymphocyte activity, interleu-
kin-2 and interferon-gamma production were signifi-
cantly reduced. After only 3 days, NK lymphocyte
activity had returned to normal, while all other para-
meters were still significantly reduced in the fentanyl
group, and by day 7 immunological tolerance had
developed. In contrast, no immune alterations occurred
in buprenorphine-treated animals, even after 7 days of
infusion with fentanyl or buprenorphine when new
pumps were implanted releasing doubled drug dosages
in respective groups. The data clearly indicate that
buprenorphine is protective of immune responses as
immune parameters were little affected by buprenorphine
(Figure 4). In contrast, fentanyl actively suppresses
immune response parameters, including those of impor-
tant cytokines such as interferon-gamma that are re-
sponsible for keeping viral infection and cancer activity
in check.16
These results underline the differential effects on
immunity of fentanyl and buprenorphine, and highlight
the variability between opioids.
In another study designed to demonstrate the varia-
bility between opioids of surgery-induced immunosup-
pression in surgicalized rats, the effects of morphine,
fentanyl and buprenorphine were compared (Sacerdote
et al. , manuscript in preparation). After surgery, differ-
ences in suppression of NK-lymphocyte activity were
observed (Figure 5). When animals were treated imme-
diately after surgery with equianalgesic doses of mor-
phine or buprenorphine, there was a significant reduction
of surgery-induced immunosuppression. Buprenorphine,
being devoid of an intrinsic immune effect, was asso-
ciated with a return of NK-lymphocyte activity back to
preoperative levels, while in those rats treated with

(A) Natural killer activity (B) Lymphoproliferation

35 140
H thymidine (CPM × 103)

30 120
Cytotoxicity (%)

25 100
*
20 80 * *
*
15 60

10 40
*
5 20
3

0 0
100/1 200/1 2.5 5 10
Effector/target Con-A (mcg/mL)

(C) Interferon-gamma (D) Interleukin-2

80 800

70 700
IFN-gamma (ng/mL)

60 600
IL-2 (pg/mL)

50 500
40 400
*
30 300
20 200 *
10 100
0 0
0 10 0 10
Con-A (mcg/mL) Con-A (mcg/mL)
Saline
Fentanyl (180 mg/mouse/day)
Buprenorphine (300 mg/mouse/day)

Figure 4 Immune parameters after 24 hours of continuous infusion with equianalgesic doses of fentanyl or buprenorphine in
the mouse. Spleen cells were collected and their functionality tested in vitro for NK-cell activity, lymphoproliferation and
cytokine (IL-2 and IFN-g) production. In fentanyl-treated animals a significant decrease of all immune parameters is present,
while buprenorphine does not affect immune responses. *PB/0.05 versus saline (one way analysis of variance). CPM, counts
per minute; Con-A, concanavalin A.
s14 P. Sacerdote

60

50

40

Cytotoxicity 30 *
(%) *
20 * *

10

0
C F M B C C0 F0 M0 B0
Effector/target (100/1)
Control Fentanyl (0.1 mg/kg)

Morphine (10 mg/kg) Buprenorphine (0.1 mg/kg)

C, F, M, B = Non-surgery rats; C0, F0, M0, B0 = Surgery rats.
* P < 0.01 versus control

Figure 5 Effect of buprenorphine, fentanyl and morphine on NK-cell activity in rats with and without surgery. Spleen NK
activity was measured 5 hours after surgery. C, F, M, B: non-surgicalized rats; C0, F0, M0, B0: surgicalized rats. *PB/0.01 versus
control (saline non-surgicalized animals).

morphine, NK-lymphocyte activity was ameliorated,
although not completely. In contrast, fentanyl was not
able to prevent surgery-induced immunosuppression.
Thus, buprenorphine, being a potent analgesic without
immunosuppressive activity, appears to have the most
favourable profile after surgery with respect to how
immunity is affected.
In experimental studies, at least, buprenorphine has
demonstrated its immunoprotective nature after both
acute and chronic administration.
Why is buprenorphine different from other opioids?
One hypothesis is that, unlike morphine, buprenorphine
does not activate the descending endocrine pathway
(HPA axis) or the sympathetic pathway.24,25 As a
consequence, it does not cause increased release of
noradrenalin or glucocorticoids, both of which are
responsible for immunomodulation and the resultant
negative impact on lymphocytes. The possibility remains,
therefore, that the immunological safety of buprenor-
phine is due to its lack of neuroendocrine activity.
Further investigations will be required in future to
support this hypothesis.
different ways. It is clear from experimental animal
evidence that, comparatively, morphine and fentanyl
seem to have a negative impact on the immune system,
tramadol a positive impact, while buprenorphine is
devoid of any intrinsic immunosuppressive effect.
Indeed, it is evident that the possibility to reach
adequate and equivalent pain control choosing either
immunosuppressive drugs or drugs without effect on
immune responses could represent an important point to
be considered in the future in opioid therapy.
Opioid-induced immunosuppressive effects could be
clinically relevant in the treatment of acute pain,
especially in concomitance with other immune-threaten-
ing situations. In chronic pain treatment, a certain degree
of tolerance to the immune effects of opiates appears to
develop.16,26 However, chronic morphine administration
in animals and long-term heroin intake in humans have
consistently been associated with immunosuppression
and a higher rate of infection.4,27,28
Further clinical studies are needed in order to fully
understand the impact of chronic opioid treatment on
immunity.

Conclusions
Although many advances have been made in under-
standing the effects of opioid drugs on immune re-
sponses, the real clinical relevance of these effects is not
completely clear. However it has definitively emerged that
not all opioid drugs share the same immune profile. In
summary, there are many examples that show that
individual opioids can affect the immune system in
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