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REVIEW

Opioid effect on lungs

TRAVIS YAMANAKA1 AND RUXANA T. SADIKOT1,2
1

Department of Veterans Affairs, Jesse Brown VA Hospital, Section of Pulmonary, Critical Care, and Sleep Medicine,
University of Illinois, Chicago, and 2Section of Pulmonary and Critical Care Medicine, University of Florida,
Gainesville, Florida, USA

ABSTRACT
Opioids are widely used for their analgesic properties
for the management of acute and chronic pain related
to a variety of illnesses. Opioid usage is associated with
adverse effects on respiration which are often attributed to depression of the central nervous system.
Recent data indicate that opioid use has increased over
the last two decades. There is also increasing evidence
that opioids have a variety of effects on the lungs
besides suppression of respiration. Opioids can affect
immune cells function, increase histamine release
causing bronchospasm, vaso-constriction and hypersensitivity reactions. Together, these actions have a
variety of effects on lung function. Here, we provide a
comprehensive review of the effects of opioids on the
lungs including the respiratory centre, immune function, airways and pulmonary vasculature.
Key words: clinical allergy and immunology, clinical respiratory medicine, critical care medicine, molecular biology.
Abbreviations: NCPE, non-cardiogenic pulmonary oedema.

INTRODUCTION
Control of pain has a central role in the treatment of
patients with advanced cancer or other terminal illnesses and in acute postsurgical or chronic nonmalignant diseases. Opioids are among the most
commonly administered drugs in hospitals for pain
management. The legal use of narcotics also includes
patients who are recovering from drug addiction
which mainly constitutes the use of methadone. Illicit
use of opioids is reported in 12% of patients in developed countries, and opioid abuse is a significant contributor to mortality. Morphine is the prototype
opioid analgesic; and for more than two decades, oral

Correspondence: Ruxana T Sadikot, Section of Pulmonary and

Critical Care Medicine Malcom Randall VAMC, NF/SG VHS University of Florida, 1601 SW Archer Road, Room no. 111A, Gainesville, FL 32608, USA. Email: rtsadikot@ufl.edu
Received 29 June 2012; invited to revise 25 July and 21 August
2012; revised 18 August and 21 August 2012; accepted 29 August
2012 (Associate Editor: David Hui).
2012 The Authors
Respirology 2012 Asian Pacific Society of Respirology

morphine has been deemed the first drug of choice

for treating moderate to severe pain because of its
familiarity, availability and cost rather than proven
superiority. Many novel formulations of opioids,
such as oxycodone, hydromorphone and fentanyl
have been developed, and the availability of different
opioids across the world has improved. Whether
natural or synthetic, the opioid drugs show
some common structural features, morphine-like
pharmacological action and binding specificity for
complementary opioid receptors. The effects of
both endogenous and exogenous opioids appear to
depend on the type and their affinities to specific
receptors.
Recent data indicate that opioid use has increased
over the last two decades. With their wider application, it is also becoming evident that their usage is
associated with a variety of side effects. In general,
many of these side effects on the respiratory system
are attributed to their actions on the central nervous
system, however, it is increasingly recognized that
opioids can also affect the functioning of immune
cells and increase the release of histamine causing
bronchospasm, vaso-constriction and hypersensitivity reactions. Together, these actions have a myriad
of effects on lung function. In this review, we discuss
the effects of opioids on the respiratory centre,
immune function of the lungs, airways and pulmonary vasculature.

OPIOIDS, RESPIRATORY DEPRESSION

AND DYSPNOEA
Opioids are known to cause respiratory depression,
particularly in overdosed and in opioid naves.
Increased susceptibility to respiratory depression
can also occur in the elderly, obese, neonates, those
with comorbid cardiopulmonary disease or with
conditions affecting consciousness.1 This effect
results from the interaction of opioids with endogenous opioid receptors located throughout the body.
The respiratory centre of the brain is located in the
pons and medulla and provides the respiratory
drive as pacemaker neurons have been identified.
These areas interface with each other and receive
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256
input from cranial and spinal nerves. Both central
and peripheral pathways provide feedback into these
areas affecting respiration. There may also be some
limited influence by the cortex and baroreceptors.2,3
Mu (m), delta (d) and kappa (k) opioid receptors have
all been identified in these regions and react to both
endogenous and exogenous agonists and affect respiratory drive.
Stimulation of both m and d receptors in rat brainstems causes respiratory slowing and arrest.2 There
are at least three general classes of endogenous
opiates: b-endorphins, enkephalins and dynorphins.
These, along with exogenous opiates, act via different
receptors and with different effect depending on type,
receptor affinity and species. The effect of opioids on
respiration is multifaceted and affects tidal volume,
rate, mainly through prolongation of expiratory time
and response to other stimuli.4
Stimuli such as pain and hypoxemia increase respiratory drive, and this effect is blunted by stimulation
of the m or d receptors.1 A study of rat respiration
showed that administration of fentanyl or dermorphin (endogenous opioid peptide) both caused
decreased respiration. Co-administration of naloxonazine (m1 receptor antagonist) blocked the depressive effect of fentanyl (affinity for m1 >>> m2) but not
that of dermorphin (affinity for m1 ~ m2).5 While opioid
receptors are also found throughout the pulmonary
system, respiratory drive appears to be centrally controlled..6 Studies in dogs showed that b-endorphin
injected into cerebrospinal fluid (CSF) resulted in a
significant decrease in respiratory rate, tidal volume
and inspiratory pressure that was completely
reversed when naloxone was given. The increase in
CO2 which resulted from slowing of respiration also
decreased with naloxone administration.7 Studies in
rats showed cessation of phrenic nerve output
with systemic morphine injection and correlated with
apnoea observed. These effects were reversible with
naloxone. In rats in which vagal nerves were not
transected, a period of increased respiratory frequency was noted followed by a brief apnoeic period.
This may have been due to a reflexive morphine effect
on J-fibers.8 This effect of J-fibre stimulation and the
concurrent opioid-induced respiratory depression
has also been demonstrated in humans.9
While the effect of exogenous opioids has been
clear, the role of endogenous opioids on respiration is
less obvious. Willer demonstrated that intravenous
naloxone had no effect on healthy subjects respiration (Tidal volume, inspiratory and expiratory time,
Partial CO2 pressure (PaCO2) ) when compared to placebo.10 A randomized placebo-controlled trial assessing naloxones effects compared to placebo in
patients with chronic obstructive airways diseases
(COPD) showed that while naloxone administration
increased resting tidal volume, no other significant
differences were observed.11 A study by Mahler et al.
also showed similar findings in patients with COPD,
although there was a statistically significant increase
in breathlessness with naloxone administration.12
Human studies have also demonstrated that administration of morphine can lead to a decrease in tidal
volume and inspiratory pressure. This effect was
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T Yamanaka and RT Sadikot

decreased with painful stimuli, suggesting that pain

can attenuate opioid effects on respiration.13 The
modulation of opioid-induced respiratory depression
by pain also raises the question as to whether or not
other stimuli may produce a similar effect.
Dyspnoea reduction in terminally ill patients and
those with chronic lung disease is another situation
where opioid use plays an important role. A metaanalysis assessing the effect of opioids on dyspnoea
looked at nine studies in which opioids were given
orally or parenterally. The results showed a significant
improvement in dyspnoea with opioids compared to
placebo.14 However, one of the issues with oral or
parenteral opioids is side effects including nausea,
vomiting, constipation and sedation. Nebulized
opioids may provide similar benefits without these
systemic side effects. This is particularly appealing in
patients where dyspnoea is the main discomfort, as
tolerance to the respiratory effects of opioids is relatively low compared to the pain-reducing effects.15
Jankelson demonstrated that inhaled morphine does
enter the bloodstream in dose-dependent manner.16
Young et al. demonstrated a decrease in dyspnoea
following nebulized morphine compared to placebo.17 However, their data were not supported by
blinded placebo-controlled studies which have
shown no difference with inhaled opiates versus placebo.16,18 Thus, the current evidence continues to
support the use of oral or parenteral opioids for management of dyspnoea rather than inhaled or nebulized opioids. Future studies with newer preparations
may show promise with this route of administration.

OPIOIDS AND OBSTRUCTIVE

SLEEP APNOEA
In line with their effect on the respiratory drive,
opioids could also affect patients with sleep apnoea.
Cases series of sleep clinic patients have shown a
close relationship between chronic methadone use
and sleep apnoea. An increase in central sleep apnoea
(CSA) was suggested as one possible factor.19 When
compared with CSA in heart failure patients, CSA
induced by narcotics tend to a shorter cycle length
(30 s vs 60 s) and a higher basal PaCO2 (4550 vs
3040 mm Hg). Furthermore, Teichtahl et al. showed
that central chemosensitivity was depressed, whereas
peripheral was elevated.20 Further studies are needed
to assess the clinical relevance and to define the
mechanisms to explain the discrepancies and
similarities.
An observational study of 140 patients taking
opioids regularly showed that 75% of the patients had
either obstructive, central sleep apnoea or both.
Other studies have also shown a significant relationship between methadone dosing and apnoea hypopnoea index (AHI) as well as central apnoea index
which was not as evident with other opioids.21
Patients on methadone treatment in particular have
increased prevalence of sleep disordered breathing. A
study of 71 methadone maintenance treatment
patients found that 35% had obstructive sleep apnoea
and 14% central sleep apnoea. Additionally, patients
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Opioid effect on lungs

with sleep disrupted breathing had been on treatment

for significantly longer.22 A small study of 19 subjects
comparing patients who were on maintenance
methadone to matched controls demonstrated that
70% of patients on methadone developed an AHI
above 5 with most being from central apnoeas compared to 22% of control subjects.23 Another study by
Wang comparing patients on methadone to control
subject demonstrated a significantly higher central
apnoea index but no difference in the obstructive
sleep apnoea or hypopnoea index. In particular,
apnoeic events in patients with central sleep apnoea
were more often in the non-rapid eye movement
phase of sleep as compared to obstructive apnoeic
episodes which predominantly occurred during rapid
eye movement sleep. Furthermore, methadone blood
concentrations were noted to have significant relationship to central apnoea index.19 While chronic
methadone use seems to increase apnoeas while
sleeping, some limited data suggest that other opioids
may have a similar effect. A study of postoperative
patients treated with regional non-opioid pain
control versus morphine demonstrated a significant
increase in episodes of desaturation in the latter. Most
of these episodes were associated with obstruction or
paradoxical breathing. The morphine treated patients
also had a significantly higher number of central
apnoeas.24 Finally, one study also suggests that the
duration of treatment with opioids may play a role in
sleep apnoea and that the efficacy of continuous positive airway pressure (CPAP) treatment may also be
affected by administration of morphine.22 Together,
these data suggest that opioids can significantly contribute to worsening of both obstructive and central
sleep apnoea and may also lead to reduced efficacy of
CPAP.

OPIOIDS, PULMONARY OEDEMA AND

ENDOTHELIAL FUNCTION
Although morphine is an important component of
treatment of cardiogenic pulmonary oedema, noncardiogenic pulmonary oedema (NCPE) is a recognized complication of opiate overdose first described
by Osler in a case of morphine overdose. Usage of a
variety of opioids including morphine, heroin and
codeine25,26 have been associated with development
of pulmonary oedema. Features of opioid-induced
NCPE include acute onset of hypoxic respiratory
failure due to shunting usually 1224 h after use with
a restrictive physiology.27 Intubation with mechanical
ventilatory support is required in approximately a
third of these patients. In most cases, oedema resolves
within 2448 h which is evident clinically and radiographically. There is one small case series of three
patients with pulmonary oedema probably due to
heroin overdose that took 13 weeks to resolve.
However, all three patients had evidence of aspiration
which might have been confounding.28 These agents
may either contribute directly to pulmonary pathology, or may cause worsening mental status making
aspiration more likely. Additionally, alterations in
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257
haemodynamics may also influence the pathogenesis
of oedema.
Recent data suggest that an NCPE has an incidence
of 110%, lower than previous estimate. 29 NCPE is
quick in onset and does not extend beyond 2 h.30
While overdosing with heroin occurs more often in
long-time users, one retrospective review showed that
less experienced users were more likely to present
with NCPE.29
While heroin appears to be the most studied, legal
opiates used in a more controlled setting have also
been implicated in NCPE. One patient following
laparotomy developed bilateral pulmonary oedema
twice during the same admission to the ICU, both
times resolving with switch from morphine to other
analgesics.31 Besides morphine, oral opioids
including methadone and codeine may also cause
oedema.32,33 Flack et al. reported a patient developing
symptoms when naloxone was administered to
reverse the effects of morphine in the setting of heart
failure post-mitral valve replacement and coronary
artery bypass. It was thought to be related to a massive
sympathetic response making cardiogenic oedema a
confounding diagnosis.34 Raijmakers reported a case
of acute pulmonary oedema in a patient after using
cocaine and heroin. Pulmonary capillary wedge pressure, oncotic pressure and capillary permeability
(measured via gadolinium) were all reported as
normal. While the cause was not established, the
authors suggest that an impairment of sodium channels in alveoli by cocaine contributed to the prolonged course compared to other studies.35 Another
case was that of a woman with codeine abuse who
presented with altered mental status and was found
to be in hypercapnic respiratory failure. With administration of a single dose of naloxone she quickly
developed tachypnoea, tachycardia and diffuse bilateral rales. She was treated with furosemide, nitroglycerin and morphine with rapid improvement of
symptoms.36 Although these reports suggest an association, the mechanism by which naloxone induces
pulmonary oedema is not fully understood.
The development of pulmonary oedema is the
result of imbalance between hydrostatic and oncotic
pressure resulting in net positive pressure out of the
capillaries, an increase in capillary permeability or a
combination of both. Numerous small studies have
looked at the makeup of fluid from pulmonary
oedema to try to better define the mechanism for the
formation of the fluid. The protein content of pulmonary oedema fluid was 85% that of plasma. This is
much higher than that of approximately 50% in
oedema fluid due to cardiac causes.25 Frand noted
that the oedema fluid in case of methadone overdose
was similar in composition to that of plasma.32
Further evidence that opioid-induced fluid formation
is a distinct entity from cardiogenic pulmonary
oedema was shown in a case series comparing 24
patients with documented pulmonary oedema.
Patients with oedema secondary to heroin or phenobarbital overdose showed an average fluid protein
to serum protein ratio of 0.85 compared to 0.46 in
cardiogenic pulmonary oedema.37 These findings
were further supported by Carlson in a study of 37
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258
patients with pulmonary oedema.38 While most of the
data support an increase capillary permeability as a
cause of NCPE, it has also been suggested that opioids
produce oedema by mechanisms which are probably
related to endothelial dysfunction.27
More recent research has given additional insights
into the possible mechanism of endothelial dysfunction which may lead to pulmonary oedema by
opioids. In vitro, morphine alters the viability of
vascular endothelial cells in a dose and timedependent manner. Nitric oxide concentration and
the production of reactive oxygen species were
increased with morphine compared to control solution. Both these effects were reversed by treatment
with naloxone. Furthermore, addition of a nitric
oxide synthase inhibitor prevented morphineinduced apoptosis of endothelial cells.39 This study
demonstrated that morphine not only could affect
cell death in vascular endothelium but also suggests
a possible mechanism for morphine-induced endothelial dysfunction by production of reactive oxide
species. This was supported further by others in
experimental models. Lam et al. showed that morphine induced the production of reactive oxygen
species in a dose and time-dependent manner. Furthermore, following exposure to morphine for 14
days compared to placebo, aortic endothelium
showed an increase in superoxide anions along with
decreased endothelium-dependent relaxation by
acetylcholine. This impaired relaxation was normalized by addition of superoxide scavengers indicating
a more direct role for reactive oxide species in
morphine-induced endothelial dysfunction.40 These
experiments suggest that there may be a complex
interplay of morphine with endothelial cells. Liu
et al. studied the effects of morphine on endothelial
permeability in conjunction with Lipopolysaccharides (LPS). Compared to LPS alone, LPS plus morphine led to a statistically significant increase in
vascular permeability, decrease in cell viability and
cellular apoptosis.41 Together, these data indicate
that the increased vascular permeability and endothelial dysfunction both play a role in opiate induced
pulmonary oedema. However, some features of the
opiate related NCPE, particularly the rapid resolution and evidence of haemodynamic changes
suggest that increased hydrostatic pressure may also
play a role.27 It should be noted that morphineinduced pulmonary oedema is rare when used
within therapeutic range, and narcotics continue to
remain a drug of choice along with diuretics for the
treatment of cardiogenic pulmonary oedema.
Acute lung injury, as a complication of noncardiogenic pulmonary oedema, has been reported in
cases of opioid overdose, mostly heroin although
there are a few anecdotal reports with other opioid
use. While the exact mechanism for this phenomenon remains unknown, it is thought to result from
a combination of hypoxic alveolar damage and
negative-pressure barotraumas.42 Cases of diffuse
alveolar haemorrhage have been reported with
opioid intoxication.43 Pulmonary haemorrhage
induced by opioids may be a result of neurogenic
pulmonary oedema or negative pressure pulmonary
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oedema. Other mechanism of opioid-induced lung

injury include aspiration from central nervous
depression.44, immunosuppression and eosinophilic
pneumonia induced by hypersensitivity.45

OPIOIDS AND AIRWAY DISEASE

Opioids also appear to have a direct effect on
airways leading to bronchoconstriction and worsening of pre-existing airways disease. Opioid receptors
are present in bronchial epithelium, nerve fibres
and glands within the bronchial walls.46 Many
opioids are potent histamine releasers producing a
variety of haemodynamic changes and anaphylactoid reactions, but the relationship between histamine plasma concentration and these effects is
complex, and there is no direct pathway between the
two. Retrospective data of patients admitted with
asthma exacerbations also suggests a link with the
use of opioids.47 Multiple small case series have
demonstrated that patients using heroin, by nasal
insufflations for the majority, but also smoking or
intravenous injection, are more frequently admitted
with asthma exacerbations.47,48 A retrospective case
control study by Krantz et al. of 84 patients admitted
to the ICU for asthma exacerbations showed positive
urine drug screen for opioids in 65% of those who
were screened, nearly double the overall rate. Levine
observed that of 152 patients admitted to an ICU for
asthma exacerbations in Chicago, 17% of heroin
users were intubated versus 2.3% of other patients.49
A review of patients in a drug treatment facility
showed an overall asthma rate of approximately 5%
in drug users and when further analyzed, 97% of the
asthmatic patients were opioid users. Furthermore,
28% described a temporal relationship between
asthma symptoms and heroin use.50 These studies
suggest that asthma exacerbation is significantly
worsened by the use or abuse of opioids.
Contrary to these reports in asthma patients, some
experimental data suggest that triggering some of
the opioid receptors may decrease bronchoconstriction. Guinea pigs given citric acid to trigger cough
and bronchoconstriction showed that both
parenteral and inhaled opioids led to dose-related
decrease in bronchoconstriction. This effect was
blocked by naloxone.51 Another in vitro study of
guinea pig trachea and bronchi demonstrated that
while morphine and other endogenous opiate
ligands did not inhibit electrically stimulated bronchoconstriction, there was a longer acting reduction
on contraction amplitude.52 A similar study on
human airways tested m receptor agonists on electrical field and acetylcholine stimulated contraction.
Contraction by electrical stimulation was inhibited
in a dose-dependent manner with m agonist administration, and these effects were blocked by naloxone.53 In addition, two studies involving nociceptin
and its receptor, which shares 60% homology with
opioid receptors, showed that capsaicin induced
bronchoconstriction was attenuated by nociceptin.
It should also be mentioned that while naloxone had
no effect, selective nociception receptor antagonist
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Opioid effect on lungs

blocked this effect.54,55 Inhaled opioids showed a

trend to reduce capsaicin-induced bronchoconstriction, but this effect was not statistically significant.
Capsaicin-induced cough was reduced with oral
codeine and intravenous morphine but not with
inhaled agents.56
Some studies suggest that opioids do not have any
effect on airway resistance. A small study of asthma
patients compared naloxone versus placebo pretreatment followed by methacholine. Compared to
placebo, naloxone-treated patients showed a significant increase in respiratory rate, dyspnoea and a
drop in inspiratory time. However, there was no significant change in FEV1 compared to placebo.57 With
regards to patients with COPD and other chronic
lung diseases, although it has been postulated that
nebulized opioids may have an effect on airway
resistance, other studies have demonstrated that
opioids, nebulized or intravenous, do not have any
effect on spirometry or exercise tolerance.58,18 Thus,
the effect of opioids on airway resistance remains
enigmatic. Further studies that dissect the role of
individual opioid receptor will delineate if these
effects are specific to individual receptors, and development of agonists or antagonists of the specific
receptors will help clarify the role of opioids on
airway physiology.

OPIOIDS AND LUNG IMMUNE

RESPONSE
Pneumonias have been associated with opioids and
are often attributed to aspiration induced by depression of respiration. However, there is increasing
evidence suggesting that opioids have an immunosuppressive effect and inhibit host defenses. The
precise mechanisms by which opioids modulate host
immune response is not fully defined however in vitro
and in vivo data suggest that opioids have a variety of
effects on immune cells.59 These studies have suggested that morphine enhances macrophage apoptosis and may impair the innate immune system by
depleting macrophages.60 Frenklakh et al. reported
that macrophages isolated from mice receiving morphine demonstrate a greater apoptosis status than that
of the control mice. The increasing macrophage injury
by morphine can correlate with the degradation of the
host defence barrier.61 Morphine also inhibits the
phagocytotic activity of neutrophilsmonocytes and
macrophages. 6264 Shirzad et al. showed a significantly
decreased phagocytotic activity in vivo in animals with
long-term morphine treatment.65 In addition, morphine can also stimulate the release of nitric oxide,
which suppresses phagocytic activity.62
Studies have demonstrated that morphine also
affects the expression of innate immunity-related
cytokines. Morphine can inhibit the secretion of
various cytokines, which belong to the humoral component of innate immunity, including interleukine
(IL)-1b, IL-2 and tumour necrosis factor alpha (TNFa).6668 Using a drug abuse and Streptococcus pneumonia lung infection model, Wang et al. have shown that
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259
morphine suppresses NF-kB in resident lung cells
which in turn modulates the transcription of Macrophage inflammatory protein (MIP)-2 and TNF-a.69
These authors have further demonstrated that morphine decreases bacterial clearance by resident alveolar macrophages and impairs pneumococci-induced
Toll-like receptor (TLR)9-NF-kB signalling.70 Thus,
this leads to a decreased innate immune response at
an early stage of infection before the entry of circulating inflammatory cells. Together, these data suggest
that morphine can suppress the basic immune function of neutrophils and macrophages that are pivotal
for the bacterial clearance and host defence.
The immunosuppressive effects of morphine have
also been investigated on adaptive immune cells.
In vivo studies in animal models have demonstrated
that morphine administration reduces the number of
B lymphocytes in the spleen and peritoneal cavity.7173
Freier et al. showed that mice with a surgical implantation of time-released morphine pellet, demonstrated a rapid loss in the cellularity of the spleen and
thymus.74 These investigators have also shown that
morphine inhibits the function of natural killer cells.75
Using fragment cultures of ileal segments, Peng et al.
showed that morphine inhibits mucosal antibody
responses and TGF-b messenger ribonucleic acid
(mRNA) in the gut lymphoid tissue. Morphine
resulted in a highly significant inhibition of cholera
toxin specific IgA and IgG production in fragment
culture supernatants.76 In normal rats, CoussonsRead et al. showed that the activity of resident pulmonary lymphocytes and natural killer cells is inhibited
by morphine in vivo even in the absence of infection.77 In a recent study, Zhang et al. studied the effect
of chronic in vivo morphine administration on lymphoid subsets in various organs and bone marrow.
Their studies provide further evidence that morphine
decreases B cell and macrophage populations in
spleens and induced thymic atrophy. This study also
provides an in-depth analysis of how subset of lymphoid cells are altered by morphine administration.
Their results show that immature B cells were
depleted in spleen and bone marrow, while CD34+ B
cell precursors were not affected in bone marrow and
that recovery of splenic cellularity occurred via proliferation of bone marrow precursors.78 Detailed
analysis of cells in different stages of maturation in
the thymus also identified the T cell subsets that contribute to repopulation of the organ post-morphine
administration. These studies demonstrate the effects
of chronic morphine administration on adaptive
immunity and implicating these with an increased
preponderance to chronic infections or progression
of existing infection.
Opioid addicts in general are more susceptible to
mycobacterial infections and can show anergy
towards tuberculin test thus masking the diagnosis
of tuberculosis. 79,80 In a mouse model of tuberculosis,
Singh et al. showed that morphine exhibited a dosedependent effect. In low doses it had an immunostimulatory effect, however at higher doses, morphine
inhibited macrophage iNOS and NO production which are critical for immune response to
M. tuberculosis.81
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260
Evidence is also accumulating that high levels of
opioids in circulation in humans can accelerate viral
infections. There is a strong relationship between the
use of opioids, especially morphine, and HIV-1
infection/replication, disease progression and HIV-1
neuropathogenesis. Ronald et al. showed that high
levels of opioids in the circulation of HIV-1-infected
patients can impact disease progression. In fact,
slower disease progression was noted in an HIV-1infected cohort when drug use was disrupted.82
In vitro studies involving cells of the central nervous
system, like those involving cells of the immune
system, have shown increased HIV-1 replication when
treated with opioids.83,84 Studies have also investigated
the impact of opioids on neuropathogenesis of
viral infections and showed an increase in opioidmediated virus production that can further enhance
the neurotoxic effects of HIV-1. This further exacerbates the secretion of by-products and viral proteins
from microglia and astrocytes that lead to secondary
destabilization of neurons, ultimately leading to neuronal injury or death. In addition to viral proteins, the
levels of other potentially toxic products such as
proinflammatory cytokines, glutamate, arachidonic
acid, reactive oxygen species and nitric oxide that are
elevated during HIV-1 infection of the brain can also
be modulated by opioids.85 Together, these studies
demonstrate that opioids clearly have the capacity to
exert immunomodulatory activity and highlight the
fact that chronic use of morphine can be associated
with significant immunosuppression with an increase
in infections by mechanisms other than direct respiratory depression.
In conclusion, opioids are among the most commonly prescribed and frequently abused drugs. The
pharmacological and physiological actions of opioids
have been extensively studied both in vitro and
in vivo leading to a better understanding of the opioid
effects on the lungs. It is now recognized that chronic
use of opioids can affect lung function beyond respiratory depression. Opioids can affect the function of
immune cells, increase the release of histamine
causing bronchospasm, vaso-constriction and hypersensitivity reactions. The prolonged use of opiates is
associated with depression of the central nervous
system leading to suppression of respiration particularly in elderly patients, individuals with obesity
hypoventilation and those with sleep apnoea. Thus,
caution should be exerted while using these drugs in
patients with lung disease, central and obstructive
sleep apnoea, chronic obstructive airways disease,
elderly patients and in those patients who are
immunocompromised.

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