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REVIEW

Opioid effect on lungs

TRAVIS YAMANAKA1 AND RUXANA T. SADIKOT1,2

1Department 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 propertiesfor the management of acute and chronic pain relatedto a variety of illnesses. Opioid usage is associated with

adverse effects on respiration which are often attrib-uted to depression of the central nervous system.Recent data indicate that opioid use has increased overthe last two decades. There is also increasing evidencethat opioids have a variety of effects on the lungsbesides suppression of respiration. Opioids can affectimmune cells function, increase histamine releasecausing bronchospasm, vaso-constriction and hyper-sensitivity reactions. Together, these actions have avariety of effects on lung function. Here, we provide acomprehensive review of the effects of opioids on thelungs including the respiratory centre, immune func-tion, airways and pulmonary vasculature.

Key words: clinical allergy and immunology, clinical respira-

tory medicine, critical care medicine, molecular biology.

Abbreviations: NCPE, non-cardiogenic pulmonary oedema.

INTRODUCTION

Control of pain has a central role in the treatment ofpatients with advanced cancer or other terminal ill-nesses and in acute postsurgical or chronic non-malignant diseases. Opioids are among the mostcommonly administered drugs in hospitals for painmanagement. The legal use of narcotics also includespatients who are recovering from drug addiction

which mainly constitutes the use of methadone. Illicituse of opioids is reported in 12% of patients in devel-oped countries, and opioid abuse is a significant con-tributor to mortality. Morphine is the prototypeopioid analgesic; and for more than two decades, oral

morphine has been deemed the first drug of choicefor treating moderate to severe pain because of itsfamiliarity, availability and cost rather than provensuperiority. Many novel formulations of opioids,such as oxycodone, hydromorphone and fentanyl

have been developed, and the availability of differentopioids across the world has improved. Whethernatural or synthetic, the opioid drugs showsome common structural features, morphine-likepharmacological action and binding specificity forcomplementary opioid receptors. The effects ofboth endogenous and exogenous opioids appear todepend on the type and their affinities to specificreceptors.

Recent data indicate that opioid use has increasedover the last two decades. With their wider applica-tion, it is also becoming evident that their usage isassociated 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 nervoussystem, however, it is increasingly recognized thatopioids can also affect the functioning of immunecells and increase the release of histamine causingbronchospasm, vaso-constriction and hypersensitiv-ity reactions. Together, these actions have a myriadof effects on lung function. In this review, we discussthe effects of opioids on the respiratory centre,immune function of the lungs, airways and pulmo-nary vasculature.

OPIOIDS, RESPIRATORY DEPRESSIONAND DYSPNOEA

Opioids are known to cause respiratory depression,particularly in overdosed and in opioid naves.Increased susceptibility to respiratory depressioncan also occur in the elderly, obese, neonates, thosewith comorbid cardiopulmonary disease or withconditions affecting consciousness.1 This effectresults from the interaction of opioids with endog-enous opioid receptors located throughout the body.The respiratory centre of the brain is located in thepons and medulla and provides the respiratorydrive as pacemaker neurons have been identified.These areas interface with each other and receive

Correspondence: Ruxana T Sadikot, Section of Pulmonary and

Critical Care Medicine Malcom Randall VAMC, NF/SG VHS Uni-

versity of Florida, 1601 SW Archer Road, Room no. 111A, Gaines-

ville, FL 32608, USA. Email: [email protected]

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).

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2012 The AuthorsRespirology 2012 Asian Pacific Society of Respirology

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input from cranial and spinal nerves. Both centraland peripheral pathways provide feedback into theseareas affecting respiration. There may also be somelimited influence by the cortex and baroreceptors.2,3

Mu (m), delta (d) and kappa (k) opioid receptors haveall been identified in these regions and react to bothendogenous and exogenous agonists and affect res-piratory drive.

Stimulation of bothm and d receptors in rat brain-stems causes respiratory slowing and arrest.2 Thereare at least three general classes of endogenousopiates:b-endorphins, enkephalins and dynorphins.These, along with exogenous opiates, act via differentreceptors and with different effect depending on type,receptor affinity and species. The effect of opioids onrespiration is multifaceted and affects tidal volume,rate, mainly through prolongation of expiratory timeand response to other stimuli.4

Stimuli such as pain and hypoxemia increase respi-ratory drive, and this effect is blunted by stimulationof the m or d receptors.1 A study of rat respirationshowed that administration of fentanyl or dermor-

phin (endogenous opioid peptide) both causeddecreased respiration. Co-administration of nalox-onazine (m1receptor antagonist) blocked the depres-sive effect of fentanyl (affinity for m1 >>>m2) but notthat of dermorphin (affinity for m1~ m2).5While opioidreceptors are also found throughout the pulmonarysystem, respiratory drive appears to be centrally con-trolled..6 Studies in dogs showed that b-endorphininjected into cerebrospinal fluid (CSF) resulted in asignificant decrease in respiratory rate, tidal volumeand inspiratory pressure that was completelyreversed when naloxone was given. The increase inCO2 which resulted from slowing of respiration alsodecreased with naloxone administration.7 Studies in

rats showed cessation of phrenic nerve outputwith systemic morphine injection and correlated withapnoea observed. These effects were reversible withnaloxone. In rats in which vagal nerves were nottransected, a period of increased respiratory fre-quency was noted followed by a brief apnoeic period.This may have been due to a reflexive morphine effecton J-fibers.8 This effect of J-fibre stimulation and theconcurrent opioid-induced respiratory depressionhas also been demonstrated in humans.9

While the effect of exogenous opioids has beenclear, the role of endogenous opioids on respiration isless obvious. Willer demonstrated that intravenousnaloxone had no effect on healthy subjects respira-tion (Tidal volume, inspiratory and expiratory time,Partial CO2pressure (PaCO2) ) when compared to pla-cebo.10A randomized placebo-controlled trial assess-ing naloxones effects compared to placebo inpatients with chronic obstructive airways diseases(COPD) showed that while naloxone administrationincreased resting tidal volume, no other significantdifferences were observed.11 A study by Mahleret al.also showed similar findings in patients with COPD,although there was a statistically significant increasein breathlessness with naloxone administration.12

Human studies have also demonstrated that admin-istration of morphine can lead to a decrease in tidalvolume and inspiratory pressure. This effect was

decreased with painful stimuli, suggesting that paincan attenuate opioid effects on respiration.13 Themodulation of opioid-induced respiratory depressionby pain also raises the question as to whether or notother stimuli may produce a similar effect.

Dyspnoea reduction in terminally ill patients andthose with chronic lung disease is another situationwhere opioid use plays an important role. A meta-

analysis assessing the effect of opioids on dyspnoealooked at nine studies in which opioids were givenorally or parenterally. The results showed a significantimprovement in dyspnoea with opioids compared toplacebo.14 However, one of the issues with oral orparenteral opioids is side effects including nausea,vomiting, constipation and sedation. Nebulizedopioids may provide similar benefits without thesesystemic side effects. This is particularly appealing inpatients where dyspnoea is the main discomfort, astolerance to the respiratory effects of opioids is rela-tively low compared to the pain-reducing effects.15

Jankelson demonstrated that inhaled morphine doesenter the bloodstream in dose-dependent manner.16

Younget al. demonstrated a decrease in dyspnoeafollowing nebulized morphine compared to pla-cebo.17 However, their data were not supported byblinded placebo-controlled studies which haveshown no difference with inhaled opiates versus pla-cebo.16,18 Thus, the current evidence continues tosupport the use of oral or parenteral opioids for man-agement of dyspnoea rather than inhaled or nebu-lized opioids. Future studies with newer preparationsmay show promise with this route of administration.

OPIOIDS AND OBSTRUCTIVESLEEP 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 aclose relationship between chronic methadone useand sleep apnoea. An increase in central sleep apnoea(CSA) was suggested as one possible factor.19 Whencompared with CSA in heart failure patients, CSAinduced by narcotics tend to a shorter cycle length(30 s vs 60 s) and a higher basal PaCO2 (4550 vs3040 mm Hg). Furthermore, Teichtahl et al. showedthat central chemosensitivity was depressed, whereasperipheral was elevated.20 Further studies are neededto assess the clinical relevance and to define themechanisms to explain the discrepancies andsimilarities.

An observational study of 140 patients takingopioids regularly showed that 75% of the patients hadeither obstructive, central sleep apnoea or both.Other studies have also shown a significant relation-ship between methadone dosing and apnoea hypop-noea index (AHI) as well as central apnoea indexwhich was not as evident with other opioids.21

Patients on methadone treatment in particular haveincreased prevalence of sleep disordered breathing. Astudy of 71 methadone maintenance treatmentpatients found that 35% had obstructive sleep apnoeaand 14% central sleep apnoea. Additionally, patients

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with sleep disrupted breathing had been on treatmentfor significantly longer.22 A small study of 19 subjectscomparing patients who were on maintenancemethadone to matched controls demonstrated that70% of patients on methadone developed an AHIabove 5 with most being from central apnoeas com-pared to 22% of control subjects.23 Another study byWang comparing patients on methadone to control

subject demonstrated a significantly higher centralapnoea index but no difference in the obstructivesleep apnoea or hypopnoea index. In particular,apnoeic events in patients with central sleep apnoeawere more often in the non-rapid eye movementphase of sleep as compared to obstructive apnoeicepisodes which predominantly occurred during rapideye movement sleep. Furthermore, methadone bloodconcentrations were noted to have significant rela-tionship to central apnoea index.19 While chronicmethadone use seems to increase apnoeas whilesleeping, some limited data suggest that other opioidsmay have a similar effect. A study of postoperativepatients treated with regional non-opioid pain

control versus morphine demonstrated a significantincrease in episodes of desaturation in the latter. Mostof these episodes were associated with obstruction orparadoxical breathing. The morphine treated patientsalso had a significantly higher number of centralapnoeas.24 Finally, one study also suggests that theduration of treatment with opioids may play a role insleep apnoea and that the efficacy of continuous posi-tive airway pressure (CPAP) treatment may also beaffected by administration of morphine.22 Together,these data suggest that opioids can significantly con-tribute to worsening of both obstructive and centralsleep apnoea and may also lead to reduced efficacy ofCPAP.

OPIOIDS, PULMONARY OEDEMA ANDENDOTHELIAL FUNCTION

Although morphine is an important component oftreatment of cardiogenic pulmonary oedema, non-cardiogenic pulmonary oedema (NCPE) is a recog-nized complication of opiate overdose first describedby Osler in a case of morphine overdose. Usage of avariety of opioids including morphine, heroin andcodeine25,26 have been associated with developmentof pulmonary oedema. Features of opioid-inducedNCPE include acute onset of hypoxic respiratoryfailure due to shunting usually 1224 h after use witha restrictive physiology.27 Intubation with mechanicalventilatory support is required in approximately athird of these patients. In most cases, oedema resolveswithin 2448 h which is evident clinically and radio-graphically. There is one small case series of threepatients with pulmonary oedema probably due toheroin overdose that took 13 weeks to resolve.However, all three patients had evidence of aspirationwhich might have been confounding.28 These agentsmay either contribute directly to pulmonary pathol-ogy, or may cause worsening mental status makingaspiration more likely. Additionally, alterations in

haemodynamics may also influence the pathogenesisof oedema.

Recent data suggest that an NCPE has an incidenceof 110%, lower than previous estimate. 29 NCPE isquick in onset and does not extend beyond 2 h.30

While overdosing with heroin occurs more often inlong-time users, one retrospective review showed thatless experienced users were more likely to present

with NCPE.29While heroin appears to be the most studied, legal

opiates used in a more controlled setting have alsobeen implicated in NCPE. One patient followinglaparotomy developed bilateral pulmonary oedematwice during the same admission to the ICU, bothtimes resolving with switch from morphine to otheranalgesics.31 Besides morphine, oral opioidsincluding methadone and codeine may also causeoedema.32,33 Flacket al. reported a patient developingsymptoms when naloxone was administered toreverse the effects of morphine in the setting of heartfailure post-mitral valve replacement and coronaryartery bypass. It wasthought to be related to a massive

sympathetic response making cardiogenic oedema aconfounding diagnosis.34 Raijmakers reported a caseof acute pulmonary oedema in a patient after usingcocaine and heroin. Pulmonary capillary wedge pres-sure, oncotic pressure and capillary permeability(measured via gadolinium) were all reported asnormal. While the cause was not established, theauthors suggest that an impairment of sodium chan-nels in alveoli by cocaine contributed to the pro-longed course compared to other studies.35 Anothercase was that of a woman with codeine abuse whopresented with altered mental status and was foundto be in hypercapnic respiratory failure. With admin-istration of a single dose of naloxone she quickly

developed tachypnoea, tachycardia and diffuse bilat-eral rales. She was treated with furosemide, nitroglyc-erin and morphine with rapid improvement ofsymptoms.36 Although these reports suggest an asso-ciation, the mechanism by which naloxone inducespulmonary oedema is not fully understood.

The development of pulmonary oedema is theresult of imbalance between hydrostatic and oncoticpressure resulting in net positive pressure out of thecapillaries, an increase in capillary permeability or acombination of both. Numerous small studies havelooked at the makeup of fluid from pulmonaryoedema to try to better define the mechanism for theformation of the fluid. The protein content of pulmo-nary oedema fluid was 85% that of plasma. This ismuch higher than that of approximately 50% inoedema fluid due to cardiac causes.25 Frand notedthat the oedema fluid in case of methadone overdosewas similar in composition to that of plasma.32

Further evidence that opioid-induced fluid formationis a distinct entity from cardiogenic pulmonaryoedema was shown in a case series comparing 24patients with documented pulmonary oedema.Patients with oedema secondary to heroin or phe-nobarbital overdose showed an average fluid proteinto serum protein ratio of 0.85 compared to 0.46 incardiogenic pulmonary oedema.37 These findingswere further supported by Carlson in a study of 37

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patients with pulmonary oedema.38While most of thedata support an increase capillary permeability as acause of NCPE, it has also been suggested that opioidsproduce oedema by mechanisms which are probablyrelated to endothelial dysfunction.27

More recent research has given additional insightsinto the possible mechanism of endothelial dysfunc-tion which may lead to pulmonary oedema by

opioids. In vitro, morphine alters the viability ofvascular endothelial cells in a dose and time-dependent manner. Nitric oxide concentration andthe production of reactive oxygen species wereincreased with morphine compared to control solu-tion. Both these effects were reversed by treatmentwith naloxone. Furthermore, addition of a nitricoxide synthase inhibitor prevented morphine-induced apoptosis of endothelial cells.39 This studydemonstrated that morphine not only could affectcell death in vascular endothelium but also suggestsa possible mechanism for morphine-induced endot-helial dysfunction by production of reactive oxidespecies. This was supported further by others in

experimental models. Lam et al. showed that mor-phine induced the production of reactive oxygenspecies in a dose and time-dependent manner. Fur-thermore, following exposure to morphine for 14days compared to placebo, aortic endotheliumshowed an increase in superoxide anions along withdecreased endothelium-dependent relaxation byacetylcholine. This impaired relaxation was normal-ized by addition of superoxide scavengers indicatinga more direct role for reactive oxide species inmorphine-induced endothelial dysfunction.40 Theseexperiments suggest that there may be a complexinterplay of morphine with endothelial cells. Liuet al. studied the effects of morphine on endothelial

permeability in conjunction with Lipopolysaccha-rides (LPS). Compared to LPS alone, LPS plus mor-phine led to a statistically significant increase invascular permeability, decrease in cell viability andcellular apoptosis.41 Together, these data indicatethat the increased vascular permeability and endot-helial dysfunction both play a role in opiate inducedpulmonary oedema. However, some features of theopiate related NCPE, particularly the rapid resolu-tion and evidence of haemodynamic changessuggest that increased hydrostatic pressure may alsoplay a role.27 It should be noted that morphine-induced pulmonary oedema is rare when usedwithin therapeutic range, and narcotics continue toremain a drug of choice along with diuretics for thetreatment of cardiogenic pulmonary oedema.

Acute lung injury, as a complication of noncardio-genic pulmonary oedema, has been reported incases of opioid overdose, mostly heroin althoughthere are a few anecdotal reports with other opioiduse. While the exact mechanism for this phenom-enon remains unknown, it is thought to result froma combination of hypoxic alveolar damage andnegative-pressure barotraumas.42 Cases of diffusealveolar haemorrhage have been reported withopioid intoxication.43 Pulmonary haemorrhageinduced by opioids may be a result of neurogenicpulmonary oedema or negative pressure pulmonary

oedema. Other mechanism of opioid-induced lunginjury include aspiration from central nervousdepression.44, immunosuppression and eosinophilicpneumonia induced by hypersensitivity.45

OPIOIDS AND AIRWAY DISEASE

Opioids also appear to have a direct effect onairways leading to bronchoconstriction and worsen-ing of pre-existing airways disease. Opioid receptorsare present in bronchial epithelium, nerve fibresand glands within the bronchial walls.46 Manyopioids are potent histamine releasers producing avariety of haemodynamic changes and anaphylac-toid reactions, but the relationship between hista-mine plasma concentration and these effects iscomplex, and there is no direct pathway between thetwo. Retrospective data of patients admitted withasthma exacerbations also suggests a link with theuse of opioids.47 Multiple small case series havedemonstrated that patients using heroin, by nasal

insufflations for the majority, but also smoking orintravenous injection, are more frequently admittedwith asthma exacerbations.47,48 A retrospective casecontrol study by Krantz et al. of 84 patients admittedto the ICU for asthma exacerbations showed positiveurine drug screen for opioids in 65% of those whowere screened, nearly double the overall rate. Levineobserved that of 152 patients admitted to an ICU forasthma exacerbations in Chicago, 17% of heroinusers were intubated versus 2.3% of other patients.49

A review of patients in a drug treatment facilityshowed an overall asthma rate of approximately 5%in drug users and when further analyzed, 97% of theasthmatic patients were opioid users. Furthermore,

28% described a temporal relationship betweenasthma symptoms and heroin use.50 These studiessuggest that asthma exacerbation is significantlyworsened by the use or abuse of opioids.

Contrary to these reports in asthma patients, someexperimental data suggest that triggering some ofthe opioid receptors may decrease bronchoconstric-tion. Guinea pigs given citric acid to trigger coughand bronchoconstriction showed that bothparenteral and inhaled opioids led to dose-relateddecrease in bronchoconstriction. This effect wasblocked by naloxone.51 Another in vitro study ofguinea pig trachea and bronchi demonstrated thatwhile morphine and other endogenous opiateligands did not inhibit electrically stimulated bron-choconstriction, there was a longer acting reductionon contraction amplitude.52 A similar study onhuman airways tested m receptor agonists on electri-cal field and acetylcholine stimulated contraction.Contraction by electrical stimulation was inhibitedin a dose-dependent manner with m agonist admin-istration, and these effects were blocked by nalox-one.53 In addition, two studies involving nociceptinand its receptor, which shares 60% homology withopioid receptors, showed that capsaicin inducedbronchoconstriction was attenuated by nociceptin.It should also be mentioned that while naloxone hadno effect, selective nociception receptor antagonist



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blocked this effect.54,55 Inhaled opioids showed atrend to reduce capsaicin-induced bronchoconstric-tion, but this effect was not statistically significant.Capsaicin-induced cough was reduced with oralcodeine and intravenous morphine but not withinhaled agents.56

Some studies suggest that opioids do not have anyeffect on airway resistance. A small study of asthma

patients compared naloxone versus placebo pre-treatment followed by methacholine. Compared toplacebo, naloxone-treated patients showed a signifi-cant increase in respiratory rate, dyspnoea and adrop in inspiratory time. However, there was no sig-nificant change in FEV1compared to placebo.57Withregards to patients with COPD and other chroniclung diseases, although it has been postulated thatnebulized opioids may have an effect on airwayresistance, other studies have demonstrated thatopioids, nebulized or intravenous, do not have anyeffect on spirometry or exercise tolerance.58,18 Thus,the effect of opioids on airway resistance remainsenigmatic. Further studies that dissect the role of

individual opioid receptor will delineate if theseeffects are specific to individual receptors, and devel-opment of agonists or antagonists of the specificreceptors will help clarify the role of opioids onairway physiology.

OPIOIDS AND LUNG IMMUNERESPONSE

Pneumonias have been associated with opioids andare often attributed to aspiration induced by depres-sion of respiration. However, there is increasing

evidence suggesting that opioids have an immuno-suppressive effect and inhibit host defenses. Theprecise mechanisms by which opioids modulate hostimmune response is not fully defined however in vitroandin vivodata suggest that opioids have a variety ofeffects on immune cells.59 These studies have sug-gested that morphine enhances macrophage apopto-sis and may impair the innate immune system bydepleting macrophages.60 Frenklakh et al. reportedthat macrophages isolated from mice receiving mor-phinedemonstrateagreaterapoptosisstatusthanthatof the control mice. The increasing macrophage injuryby morphine can correlate with the degradation of thehost defence barrier.61 Morphine also inhibits thephagocytotic activity of neutrophilsmonocytes andmacrophages. 6264 Shirzad et al. showed a significantlydecreasedphagocytoticactivityinvivo inanimalswithlong-term morphine treatment.65 In addition, mor-phine can also stimulate the release of nitric oxide,which suppresses phagocytic activity.62

Studies have demonstrated that morphine alsoaffects the expression of innate immunity-relatedcytokines. Morphine can inhibit the secretion ofvarious cytokines, which belong to the humoral com-ponent of innate immunity, including interleukine(IL)-1b, IL-2 and tumour necrosis factor alpha (TNF-a).6668 Using a drug abuse and Streptococcus pneumo-nia lung infection model,Wanget al. have shown that

morphine suppresses NF-kB in resident lung cellswhich in turn modulates the transcription of Mac-rophage inflammatory protein (MIP)-2 and TNF-a.69

These authors have further demonstrated that mor-phine decreases bacterial clearance by resident alveo-lar macrophages and impairs pneumococci-inducedToll-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 circulat-ing inflammatory cells. Together, these data suggestthat morphine can suppress the basic immune func-tion of neutrophils and macrophages that are pivotalfor the bacterial clearance and host defence.

The immunosuppressive effects of morphine havealso been investigated on adaptive immune cells.In vivo studies in animal models have demonstratedthat morphine administration reduces the number ofB lymphocytes in the spleen and peritoneal cavity.7173

Freieret al. showed that mice with a surgical implan-tation of time-released morphine pellet, demon-strated a rapid loss in the cellularity of the spleen andthymus.74 These investigators have also shown that

morphine inhibits the function of natural killer cells.75

Using fragment cultures of ileal segments, Penget al.showed that morphine inhibits mucosal antibodyresponses and TGF-b messenger ribonucleic acid(mRNA) in the gut lymphoid tissue. Morphineresulted in a highly significant inhibition of choleratoxin specific IgA and IgG production in fragmentculture supernatants.76 In normal rats, Coussons-Read et al. showed that the activity of resident pulmo-nary lymphocytes and natural killer cells is inhibitedby morphine in vivo even in the absence of infec-tion.77 In a recent study, Zhanget al. studied the effectof chronicin vivo morphine administration on lym-phoid subsets in various organs and bone marrow.

Their studies provide further evidence that morphinedecreases B cell and macrophage populations inspleens and induced thymic atrophy. This study alsoprovides an in-depth analysis of how subset of lym-phoid cells are altered by morphine administration.Their results show that immature B cells weredepleted in spleen and bone marrow, while CD34+Bcell precursors were not affected in bone marrow andthat recovery of splenic cellularity occurred via pro-liferation of bone marrow precursors.78 Detailedanalysis of cells in different stages of maturation inthe thymus also identified the T cell subsets that con-tribute to repopulation of the organ post-morphineadministration.These studies demonstrate the effectsof chronic morphine administration on adaptiveimmunity and implicating these with an increasedpreponderance to chronic infections or progressionof existing infection.

Opioid addicts in general are more susceptible tomycobacterial infections and can show anergytowards tuberculin test thus masking the diagnosisof tuberculosis. 79,80 In a mouse model of tuberculosis,Singh et al. showed that morphine exhibited a dose-dependent effect. In low doses it had an immuno-stimulatory effect, however at higher doses, morphineinhibited macrophage iNOS and NO produc-tion which are critical for immune response toM. tuberculosis.81



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Evidence is also accumulating that high levels ofopioids in circulation in humans can accelerate viralinfections. There is a strong relationship between theuse of opioids, especially morphine, and HIV-1infection/replication, disease progression and HIV-1neuropathogenesis. Ronald et al. showed that highlevels of opioids in the circulation of HIV-1-infectedpatients can impact disease progression. In fact,

slower disease progression was noted in an HIV-1-infected cohort when drug use was disrupted.82

In vitrostudies involving cells of the central nervoussystem, like those involving cells of the immunesystem, have shown increased HIV-1 replication whentreated with opioids.83,84 Studies have also investigatedthe impact of opioids on neuropathogenesis ofviral infections and showed an increase in opioid-mediated virus production that can further enhancethe neurotoxic effects of HIV-1. This further exacer-bates the secretion of by-products and viral proteinsfrom microglia and astrocytes that lead to secondarydestabilization of neurons, ultimately leading to neu-ronal injury or death. In addition to viral proteins, the

levels of other potentially toxic products such asproinflammatory cytokines, glutamate, arachidonicacid, reactive oxygen species and nitric oxide that areelevated during HIV-1 infection of the brain can alsobe modulated by opioids.85 Together, these studiesdemonstrate that opioids clearly have the capacity toexert immunomodulatory activity and highlight thefact that chronic use of morphine can be associatedwith significant immunosuppression with an increasein infections by mechanisms other than direct respi-ratory depression.

In conclusion, opioids are among the most com-monly prescribed and frequently abused drugs. Thepharmacological and physiological actions of opioids

have been extensively studied both in vitro andin vivo leading to a better understanding of the opioideffects on the lungs. It is now recognized that chronicuse of opioids can affect lung function beyond respi-ratory depression. Opioids can affect the function ofimmune cells, increase the release of histaminecausing bronchospasm, vaso-constriction and hyper-sensitivity reactions. The prolonged use of opiates isassociated with depression of the central nervoussystem leading to suppression of respiration particu-larly in elderly patients, individuals with obesityhypoventilation and those with sleep apnoea. Thus,caution should be exerted while using these drugs inpatients with lung disease, central and obstructivesleep apnoea, chronic obstructive airways disease,elderly patients and in those patients who areimmunocompromised.

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