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The Effects of Opioids on the Lung

Abstract

The term opioid refers to a broad class of medications that are used most frequently for their analgesic effects. Along with this effect, they also produce euphoria, and it is for this reason that they have been used illicitly, as well as medicinally, for thousands of years. While the most well-known complications of opioid use and misuse include respiratory and central nervous system depression, there are many other toxicities that have been associated with these drugs. Many complications can occur with multiple different opioids, such as non-cardiogenic pulmonary edema, while many of the complications are unique to the opioid used as well as the route of administration. This review focuses on the pulmonary complications associated with opioid use and abuse, but opioids can affect nearly every organ system. Their effects on the pulmonary system can be direct, such as causing granulomatous change, but they can also work indirectly. For example, opioids cause respiratory depression by decreasing sensitivity of peripheral chemoreceptors to carbon dioxide and decreasing activity in the central respiratory centers. Opioids have also been reported to affect the immune system, and place users at increased risk for many different infectious complications. Patients can have a wide array of signs and symptoms, sometimes making it difficult to recognize opioids as a cause for a patient’s clinical picture. Due to the sedative effects of opioids, patients are also often not able to provide a reliable history. Knowledge of the possible toxicities of opioids can help prepare a physician to recognize the many complications associated with opioid use.

Introduction

Opiates are naturally occurring alkaloids derived from the poppy plant, Papaver somniferum. They derive their name from opium, Greek for “juice,” which is obtained from the poppy fruit. The first recorded medical use of opium was found in an ancient Egyptian text from 1550 BC [1]. Opium contains over 20 alkaloids, including morphine, codeine, and thebaine. While the term opiate refers to naturally occurring alkaloids, the term opioid includes opiates, semi-synthetic derivatives of opiates, and synthetic compounds that cause similar clinical effects as opiates and bind to opioid receptors. Semi-synthetic opioids are created through modification of an opiate, usually thebaine or morphine. Examples include heroin, hydrocodone, and hydromorphone. Fully synthetic opioids are not derived from an opiate but still bind the opioid receptor. Examples include fentanyl and methadone [2]. Opioids are often used medically for pain relief but are also used non-medically for their psychoactive and euphoric effects.

While abuse of illicit opioids such as heroin and opium has been prevalent for hundreds, if not thousands of years, an increasingly common source of opioid abuse is prescription narcotics. The 2010 National Survey on Drug Use and Health reported that prescription medication abuse and misuse is becoming increasingly common. An estimated 5.1 million people (2.0 %) had abused prescription pain medication in the past months, compared with 2.6 million (1.2 %) in 1999 [3]. In 2011, the combination prescription of hydrocodone and acetaminophen was the most frequently prescribed medication in the USA, with 136.7 million prescriptions written [4].

Opioids exert their effects through the opioid receptors. There are three major classes of opioid receptors, including the mu, kappa, and delta receptors [5]. Opioid receptors are G protein linked and exert their effects through secondary messenger systems such as phospholipase C and adenylate cyclase 2. Activation of the opioid receptors results in increased inhibitory signaling to the nociceptive neurons within the nervous system. Each of the opioid receptors has a role in the analgesic effects of opioids [6].

In addition to the clinically desired effect of analgesia, opioids used both therapeutically and illicitly can cause many adverse effects. Opioids can cause toxicities in many different organ systems, including central nervous system (CNS), cardiovascular, and pulmonary (Table 1). This paper will review the unique effects and toxicities that opioids have on the lungs. These are summarized in Table 2.

Table 1 The reported effects of opioids on different organ systems
Table 2 Pulmonary complications from opioid use

Routes of Administration

Intravenous

Toxicity of opioids can vary according to the route of administration. Table 3 summarizes complications that are associated with each route of administration. Multiple different forms of opioids can be used intravenously. Medicinally, fentanyl, morphine, hydromorphone, and meperidine all have preparations to allow for intravenous (IV) administration. While complications from IV injection performed in hospitals by professionals are uncommon, heroin users and those who misuse other opioids intravenously are rarely trained in proper use and sterile technique [1].

Table 3 The route of administration of opioids affects the toxicities that can be expected

Heroin (3,6-diacetylmorphine) is synthesized from morphine and acetic anhydride. Heroin is rapidly metabolized in vivo to 6-monoacetylmorphine (6-MAM), which is then metabolized to morphine. Both heroin and 6-MAM are more efficacious mu receptor activators than morphine [7]. There are two different forms of heroin; a base and a salt. The salt form is a white or beige powder. This form is highly water soluble which allows for IV administration. The base form is often referred to as “black tar heroin” as it is brown or black. In order to inject to drug intravenously, it must be solubilized in an acid or heated until it liquefies [2].

Intravenous heroin use has been associated with multiple pulmonary complications, including non-cardiogenic pulmonary edema, acute respiratory distress syndrome, pneumonia, lung abscess, and septic pulmonary emboli [8]. A case report from 2008 described a 24-year-old female who developed bronchiolitis obliterans with organizing pneumonia after 7 years of heroin use [8]. Heroin is often adulterated with fillers such as caffeine, barbiturate, cotton fibers, or potato starch which are used to dilute, increase yield, or augment its physical effects. These fillers can often cause pulmonary granulomatoses in long-time IV drug users [9]. Talc granulomas have also been reported in users who inject drugs, including methadone and other non-opioids, which are intended for oral use [10].

Intravenous opioid users also are at increased risk for many different infectious processes, ranging from skin infections to other processes such as endocarditis, septic emboli, and pneumonia. Needle exchange programs have been implemented around the world in an attempt to limit the transmission of disease amongst intravenous drug abusers, most notably human immunodeficiency virus (HIV) and hepatitis C. Multiple cities have showed decreased HIV rates among IV drug abusers after implementation of such programs [11].

Subcutaneous

Most opioids can be administered or abused by multiple routes (Table 4). Heroin users frequently avoid the difficulties associated with intravenous access and inject the drug subcutaneously or intramuscularly, practices known as “skin popping” or “muscle popping,” respectively. Reported infections include cellulitis, abscess, osteomyelitis, and necrotizing fasciitis. The predominant bacteria involved in these infections are usually Staphylococcus and Streptococcus species [12]. One study showed that subcutaneous or intramuscular administration puts patients at higher risk for bacterial infection (abscess or cellulitis) when compared with intravenous administration [13]. Other factors that increased the risk of infection included the injection of heroin and cocaine (also known as a “speedball”). The authors proposed that the cocaine induced local tissue ischemia, which increased the risk of abscess formation. Cleaning the skin with alcohol had a protective effect, while HIV status had no effect on risk of developing a soft tissue infection [13].

Table 4 Common opioids and their common routes of administration for abuse

Intranasal

Intranasal opioid administration is used both therapeutically and illicitly. Its advantages include rapid onset, ease of administration, and the avoidance of first pass metabolism in the liver [14]. Intranasal fentanyl has been Federal Drug Administration-approved for the treatment of breakthrough cancer pain. Butorphanol is another opioid that can be administered intranasally and is frequently used for postoperative pain, especially dental and ear, nose, and throat surgeries [15, 16]. Oxycodone, a prescription opioid, is frequently misused via intranasal administration and has led to complications such as soft palate and sinus necrosis [17]. A study of the pharmacokinetics of intranasal oxycodone showed that there was rapid onset and greater bioavailability of intranasal as compared to oral [18].

Inhalational

Inhalation of heroin vapors is commonly referred to as “chasing the dragon.” This method is gaining popularity as it avoids the use of needles, as well as the inherent risks associated with needles [19]. This technique involves heating heroin base on aluminum foil and then inhaling the vapors. Though the pharmacodynamics is similar to IV administration, chasing the dragon has a unique toxicity in that it causes a spongiform leukoencephalopathy. This results in a clinical syndrome consisting of hyperreflexia, spastic hemiplegia, myoclonus, akinetic mutism, and sometimes death [19]. This was first described in a case series from the Netherlands in 1982 of 47 patients. The cause of this toxicity is still unknown. Hypotheses include a metabolite of heroin or from a substance released from the foil when it is heated [20]. Chasing the dragon has also been associated with other pathological processes within the lungs, including interstitial pneumonitis, bronchiectasis, aspiration pneumonitis, non-cardiogenic pulmonary edema, and emphysema [21].

Patients have also been reported to smoke fentanyl patches, which can cause direct toxicity to the lungs. A case report from Vancouver in 2012 described a 50-year-old female who presented with dyspnea on exertion, productive cough, and fevers after smoking fentanyl patches for 3–4 months. Biopsy was consistent with pulmonary alveolar proteinosis. It is unclear whether the toxicity was a direct effect of the fentanyl or was related to another component of the patch. The patient’s symptoms resolved after she stopped smoking fentanyl patches [22].

Dermal

Fentanyl is a synthetic opioid that is frequently used for the treatment of chronic pain. It is commonly prescribed for chronic use as a transdermal sustained-release patch. Abusers will often apply multiple patches, but other methods of abuse include rectal insertion, buccal absorption, and ingestion of whole patches, as well as removal of the drug from the patch with subsequent ingestion. Other unique methods of administration include smoking the patch and brewing a tea with the patch [23, 24]. Patches are designed to have enough fentanyl in order to get a specified amount of drug per hour for 72 h and continuous drug absorption relies on concentration gradients. These factors necessitate a large amount of fentanyl in each patch. A 50-mcg/h fentanyl patch is estimated to contain 8,400 mcg of fentanyl [25]. When ingested, even used patches have a significant amount of fentanyl in them and can lead to severe opioid intoxication. The patch can also cause airway obstruction as demonstrated in a case from 2010. An autopsy of a 28-year-old male thought to have died secondary to opioid overdose revealed a fentanyl patch lodged in a mainstem bronchus [26].

Airway Complications

Pneumothorax

With chronic IV heroin use, a user’s veins often become sclerosed. Once they are unable to access peripheral veins, chronic users will often begin to use the large veins in the neck and groin. Injection via the veins in the neck in the supraclavicular fossa is known as a “pocket shot” [1]. A 2006 case described a patient with bilateral pneumothoraces after failed pocket shots. The patient had attempted to inject heroin into his left internal jugular vein, and when that was unsuccessful, he attempted his right internal jugular vein, again, unsuccessfully. The patient presented with shortness of breath and chest pain and was found to have large bilateral pneumothoraces, which were treated with tube thoracostomy [27]. A pneumothorax may also be caused secondary to infectious complications of IV drug use. Two patients with tricuspid endocarditis secondary to IV heroin use developed septic emboli with pneumothoraces. Other infections commonly described in IV drug abusers such as miliary tuberculosis and pneumonia also put patients at a higher risk for pneumothorax [28].

Barotrauma leading to pneumothorax or pneumomediastinum is a well-known consequence of cocaine and methamphetamine inhalation and insufflation. Users often forcefully inhale, which results in a large increase in intraalveolar pressure. Users also may perform a valsalva maneuver in an effort to enhance drug delivery [29]. These maneuvers cause an increased pressure gradient across the alveoli, making them more prone to rupture [30]. Though no specific case reports of pneumothorax or mediastinum involving inhalation of opioids were found, one could expect this complication as similar mechanisms are employed in smoking opioids.

Nasal Perforation

While nasal perforation secondary to cocaine insufflation is a well-known complication, this has recently reported after opioid use as well. The newer trend of insufflating opioid medications intended for oral use has led to several cases of necrosis of the nasal cavity as well as other structures in the pharynx. A case series from 2012 identified 35 patients who had used a combination hydrocodone–acetaminophen that were crushed up and intranasally administered. In this series, 51 % of the patients had nasal septum perforations and 26 % had palatal perforations [31]. A 37-year-old man who regularly inhaled oxycodone was found to have necrosis of his soft palate, nasal septum, and sinuses [17]. There have also been reports of invasive fungal infections in patients who use intranasal opioids [32].

Vocal Cord Paralysis

Another complication of the pocket shot is vocal cord paralysis secondary to recurrent laryngeal nerve injury. Though this is a rare event, a case series from 2009 reported nine cases of unilateral or bilateral vocal cord paralysis resulting from cervical injection of heroin. In six of these cases, the patients presented within hours of injection with hoarseness or shortness of breath. Two of the patients presented several days later with neck pain, fever, and swelling from a neck abscess, while the last patient presented 3 weeks post-injection with a neck abscess. In each of the latter cases, the hoarseness began shortly after injection and before the development of an abscess. Five of the patients had tracheostomies performed due to the airway obstruction resulting from the vocal cord paralysis. All nine patients were followed up to 4.5 years post-injury and none had return of normal vocal cord function [33].

Indirect Effects on the Lung

Respiratory Depression

Opioid action at both mu and delta receptors has been linked to respiratory depression. Opioids produce this effect through two different mechanisms; decreased sensitivity of chemoreceptors and decreased activity in the central respiratory centers [34]. Peripheral chemoreceptors are found in the carotid and aortic bodies, as well as within the lungs. They respond to decreased partial pressure of oxygen (pO2) or increased partial pressure of carbon dioxide (pCO2) by increasing signal transduction. Central receptors respond only to increased pCO2 and are located in the medulla but are separate from the main respiratory center. Morphine has been shown to decrease the sensitivity of these chemoreceptors to pCO2 [35].

Central respiratory centers within the medulla contain both mu and delta opioid receptors. Opioid action within the respiratory center results in decreased respiratory rate, as well as decreased tidal volumes, both of which can result in decreased minute ventilation [34]. These effects also appear to be dose-dependent, with low doses of opiates decreasing tidal volume, while high doses decrease both tidal volume and respiratory rate [36].

Opioids may also have an effect on respiratory drive during sleep. A study from 2012 showed that in chronic pain patients, opioid medications increased the number of apneic sleep episodes. There was no change in obstructive sleep apnea signs; however, there was a mean increase of 3.2 central apneic events per hour in those with chronic pain who were taking opioids compared to those who did not have chronic pain and did not take opioids. It is unclear if this difference causes clinically significant morbidity [37].

Truncal Rigidity

Muscle rigidity has been a reported adverse effect of opioid administration. This rigidity can involve any muscle or muscle group. Most concerning, however, is truncal rigidity with involvement of the respiratory muscles, laryngeal structures, or the chest wall, as it can be a life-threatening complication, requiring neuromuscular blockade and intubation [38]. A study from 1993 showed an incidence of 50 % for rigidity in male volunteers. The patients received a total of 15 mcg/kg fentanyl as an infusion of 150 mcg/min [39]. While rigidity is much more likely with high-dose fentanyl, it has been reported after lower doses as well. A pregnant woman developed rigidity of her trunk and extremities after she was given a total of 150 mcg of fentanyl to facilitate a pelvic exam. The rigidity prevented both spontaneous and assisted ventilation, and she required neuromuscular blockade and intubation [40]. While rigidity is more commonly associated with synthetic opioids, such as fentanyl, remifentanil, and methadone, cases have also been reported after administration of morphine. The mechanism for this rigidity is unclear, but studies in rats have implicated stimulation of both alpha-2 adrenergic receptors and serotonin receptors [41].

Direct Effects on the Lung

Bullae

Both IV and inhalational heroin use may also lead to bullous pulmonary changes. Intravenous illicit drug users have a different pattern of lung disease than non-IV drug users. The bullae in drug users are more likely to be larger, bilateral, and in the upper lobes. The bullae in non-users often vary in size and are more diffuse [42]. A case series of opium smokers in Singapore showed 24 % prevalence of bullae on radiographic imaging [43].

In a study from 2011, pulmonary function tests (PFTs) were performed on 32 patients who were prescribed inhaled heroin for treatment of opioid addiction. PFTs were repeated 10 months after the start of therapy, and there were no statistically significant differences in forced expiratory volume in 1 s (FEV1) [44]. Another study from 2002 measured the FEV1 of patients who were in a methadone maintenance program. In contrast, they found that patients had a lower FEV1 when compared with a prior population study [45]. A confounding factor in many of these studies is that most patients who inject or inhale heroin also smoke cigarettes, which also increases the risk for bullous changes and decreased FEV1.

Pulmonary Edema

Non-cardiogenic pulmonary edema (NCPE) has been associated with multiple opioids, including heroin, methadone, morphine, and propoxyphene [46]. This was first described by Osler in 1880 from heroin use [1]. The incidence of NCPE in patients hospitalized for heroin overdose is estimated to be around 3 % [46]. Characteristics that have been associated with increased risk of NCPE include male sex, short duration of heroin use (mean, 2.9 years), being found obtunded (GCS < 8), and requiring naloxone in the pre-hospital setting [46]. Up to 50 % of the time, there is co-intoxication with ethanol or cocaine [47].

The pathogenesis from NCPE from opioid use is still unknown. Some studies suggest that naloxone plays a role, but NCPE has also been seen in patients and autopsies of patients suspected of heroin overdose that never received naloxone [46]. Possible mechanisms include hypoxia, direct effects of heroin, neurogenic effect, hypersensitivity reaction, and increased capillary permeability [1].

One mechanism proposed for NCPE from opioids involves the negative pressure that can be created with inspiration against an obstructed airway. In one case, a post-op patient was given 0.8 mg of naloxone for respiratory depression with hypoxia thought to be secondary to fentanyl. The patient began having abnormal respirations after administration and was thought to be breathing against an obstructed airway. With chin lift, the patient began breathing normally. Shortly afterward, he developed hypoxia with bilateral lung infiltrates consistent with pulmonary edema [48]. The negative pressure created is thought to draw fluid into the alveoli, leading to pulmonary edema. While this case involves the use of naloxone, a similar mechanism is hypothesized for cases in which no naloxone was given.

Cases have reported the development of NCPE with both high and low doses of naloxone. It has also been reported secondary to sustained-release naltrexone, given subcutaneously for opioid detoxification [49]. One possible mechanism for naloxone-induced NCPE is the large increase in catecholamines that often accompanies naloxone administration. Epinephrine concentration increased 30-fold in opioid-addicted patients after naloxone administration. This was accompanied by increases in heart rate, stroke volume, and systolic arterial pressure, with a decrease in systemic vascular resistance. One hypothesis is that long-term opioid use causes changes in cardiovascular and sympathoadrenal function that leads to this large catecholamine response from naloxone [50].

The effects of NCPE associated with opioid overdose on lung function are similar to other causes of pulmonary edema. Hypoxemia, with a right-to-left shunt develops with both a metabolic and respiratory acidosis. Pulmonary function tests have shown decreased lung volumes, decreased compliance, with unchanged expiratory flow rates [51]. Diffusing capacity is moderately decreased. Vital capacity and compliance improve more quickly than diffusing capacity, which may remain unchanged for several weeks [51].

Treatment for opioid-induced pulmonary edema is supportive, with oxygen and mechanical ventilation if needed. Data suggest that NCPE will present within 4 h of overdose, and a majority of patients will have evidence of NCPE on presentation. Signs and symptoms of NCPE will usually resolve within 24–48 h [46]. Approximately 39 % of patients with NCPE will require mechanical ventilation [52].

Pulmonary Hemorrhage

Pulmonary hemorrhage is also reported from severe opioid intoxication. A case from 2011 described a 16-year-old male who ingested a large amount of morphine sulfate and presented to the emergency department with altered mental status and respiratory distress. Upon intubation he was noted to have large amounts of blood with suctioning from the endotracheal tube. The patient did not receive naloxone, as his presentation did not completely match what one would expect from an opioid intoxication. Extensive testing was performed for other causes of pulmonary hemorrhage, all of which were negative. The proposed mechanism for pulmonary hemorrhage is similar to that of pulmonary edema with a combination of hypoxic alveolar damage and negative-pressure barotrauma. In this case, the patient had a history of asthma, which may have led to the hemorrhage, as studies have shown increased bronchial blood flow in patients with asthma [53]. Pulmonary hemorrhage from opioid use is rare, and this was the only case reported in the literature.

Granulomatous Change

As mentioned previously, medications intended for oral use are often ground up or melted and injected intravenously. This exposes the blood vessels, lungs, and other organs to a variety of compounds that were not intended for IV administration. As previously noted, street drugs also often contain insoluble filler material used to increase the mass [54]. At autopsy, patients who were IV drug users have evidence of multiple filler materials in the lungs, including talc, starch, cellulose, magnesium stearate, and siliciumoxid. While these different fillers were all identified in the lungs, talc was found in other organs as well, including the spleen, liver, lymph nodes, and bone marrow. Of these materials, talc was the only filler associated with granulomatous reactions [55].

Intravascular talcosis is a well-described cause of granulomatous disease in IV drug abusers. Talc becomes lodged in the pulmonary vasculature leading to granulomas and eventually pulmonary fibrosis. A review of the histologic findings of pulmonary talcosis showed perivascular talc that resulted in macrophage and giant cell accumulation in the perivascular space. Increased fibrosis in these areas is felt to contribute to the development of pulmonary hypertension [54].

Computed tomography findings of talc granulomatosis include centrilobular nodules with heterogeneous conglomerate masses, with or without emphysema [56]. Talcosis can often be mistaken for other disease processes, such as sarcoid or asbestosis. A 50-year-old man with X-ray findings suggestive of asbestosis was found to have granulomatoses from chronic heroin abuse on lung biopsy [57]. Patients with talcosis can present anywhere on the spectrum from asymptomatic to severe dyspnea. Late findings in the disease process include chronic respiratory failure, pulmonary hypertension, and cor pulmonale [56]. Symptoms may also manifest years after discontinuation of IV drug abuse [1].

Lung Cancer

The role of opioids in the development and progression of lung cancer is unclear. A 2011 study showed that mortality rates from lung and anogenital cancers may be increased in opioid-dependent persons, while there may be decreased mortality from breast cancer. Tobacco smoking may have been a significant confounder in this study [58]. The data regarding opioid effects on tumor cells is conflicting. Some studies have shown that opioids induce tumor growth and inhibit apoptosis, while promoting angiogenesis and migration of tumors cells. Other studies have shown that morphine inhibits angiogenesis and promotes apoptosis of tumor cells [59]. One study showed an increase in cell death in response to opioids, but the amount of cells that died was only 1–2 % of the total cell population [60].

Immunogenic Complications

Bronchospasm

Bronchospasm has been reported to be associated with both inhalational and intravenous use of heroin. It has occurred in patients who have asthma as well as those without [61]. Multiple cases have been described of patients who present to the emergency department in status asthmaticus shortly after heroin use [62].

The mechanism for bronchospasm is thought to involve histamine release. Opiates and opioids have been reported to cause histamine release from mast cells [63]. This increase in histamine results in bronchoconstriction and reversible airway obstruction. This effect has been reported with medicinal opioids, but the bronchospasm may also be related to contaminants or fillers within the heroin [62].

It is unclear whether long-term heroin use increases the risk for obstructive lung disease. Prior epidemiology studies have shown that the prevalence of asthma was similar between those who were and were not opioid users [62].

Eosinophilic Pneumonia

There have been multiple cases of eosinophilic pneumonia associated with inhalational heroin abuse. In one case, a 41-year-old man who inhaled heroin daily for 10 years presented with fever, cough, and dyspnea, and was found to have a unilateral pleural effusion and bilateral pulmonary infiltrates. Bronchoalveolar lavage and pleural fluids showed elevated eosinophils. Cultures for common bacteria, fungi, ova, and parasites were all negative, as was testing for HIV and viral antibodies. The patient recovered quickly after cessation of heroin inhalation and with corticosteroid therapy [64].

Depressed Immunity

Heroin users are at high risk for human immunodeficiency virus type 1 (HIV-1) as they often share needles, as well as engage in other high-risk behaviors which increase this risk. Opioids may also act with HIV-1 proteins to deregulate immune cell function [65]. Multiple mechanisms for increased pathogenesis from HIV-1 have been found, including increased HIV-1 viral replication, increased expression of HIV-1 genes within infected cells, and increased expression of HIV-1 binding sites on T cells and monocytes [65].

Opioids may also lead to accelerated neurotoxicity and dementia in patients with HIV-1 infection. Microglia and astrocytes are the main sites of viral replication within the CNS. These cells, once infected, can release viral proteins which are toxic to other neurons [66]. These cells express mu opioid receptors, and opioid abuse may compromise cell function and survival. HIV patients who abuse opioids are more likely to have diminished cognitive function, even in those receiving antiretroviral therapy [67].

Chronic opioid use has been reported to increase susceptibility to bacterial infections as well. Studies have shown that chronic morphine use inhibits multiple components of the innate immune response, including neutrophil migration, phagocytosis, and expression of pro-inflammatory cytokines [68]. In a mouse model, chronic morphine administration was associated with decreased expression of cytokines such as tumor necrosis factor alpha, interleukin-1, and interleukin-6, in mice that were exposed to Streptococcus pneumoniae. This resulted in increased bacterial burden and increased mortality [68].

While there is much experimental evidence in vitro and in animal models to suggest that opioids cause immune suppression, studies in humans have been inconclusive regarding clinically significant increases in rates of infectious complications. At this time there is not enough data to determine whether or not opioids induce a clinically relevant immune suppression in humans [69].

Infectious Complications

Illicit drug use has long been a significant risk factor for infectious complications. Users are more susceptible to pulmonary infections, as well as endovascular, skin, soft tissue, bone, joint, and sexually transmitted infections [70]. There are multiple factors that cause this increased risk, including unsterile injection practices, contaminated products, increased exposure to pathogens, as well as changes to the host immunity, as described above [70]. Drug users often also engage in other high-risk practices, such as multiple sexual partners.

Pneumonia

In elderly patients, opioid use increased the risk of pneumonia (odds ratio, 1.38 [1.08–1.76]) and benzodiazepines did not increase the risk of pneumonia (odds ratio, 1.08 [0.80–1.47]). This risk was the highest with recent initiation of opioid use (within the last 14 days) and with long-acting opioids (sustained release morphine, controlled release oxycodone, transdermal fentanyl, methadone, and levorphanol). It is possible that this difference may be secondary to the immuno-modulatory effects of opioids [71].

Endocarditis

The tricuspid valve is the most commonly involved valve in infectious endocarditis from IV drug abuse. Intravenous heroin users are more likely to develop right-sided infectious endocarditis compared with IV cocaine and/or methamphetamine users [72]. The reason for this difference is unknown but is possibly related to fibrosis as a result of increased inflammation in response to opioids. Postmortem samples of myocardium from chronic drug users who died from opioid intoxication showed a fivefold increase in the number of inflammatory cells within the myocardium compared to controls [73]. Staphylococcus aureus is the most common pathogen implicated in infectious endocarditis worldwide, and enters the bloodstream by way of non-sterile technique [74]. Despite advances in health care, neither the incidence nor mortality from infective endocarditis has changed over the past two decades. The in-hospital mortality is estimated to be 10–16 % [75]. Most patients will require prolonged antibiotic courses and 25–30 % of patients will require surgery during the acute infection [76]. Surgical options include vegectomy, valve repairs, and radical valve replacement [75].

Septic Pulmonary Emboli

The most frequent complication of right-sided endocarditis is pulmonary infarction, which can be seen in 60–100 % of all cases [28]. Septic emboli may also originate from infected subcutaneous, intramuscular, or intravenous injection sites [77]. The incidence of septic pulmonary emboli from illicit drug abuse appears to be decreasing. It is possible that this decrease is due to improved awareness of needle hygiene [78]. Just as with endocarditis, the most frequent organism isolated is Staphylococcus aureus [77]. There are also cases of pneumothoraces resulting from septic emboli [28].

Tuberculosis

The prevalence of mycobacterium tuberculosis (TB) is much higher in injection drug users than it is in the general public. The prevalence in North America is estimated to be 12–39 %, depending on local epidemiology. There are multiple reasons why people who inject drugs are at increased risk of TB, including homelessness, poverty, overcrowding and imprisonment. Patients with HIV infection are at an increased risk for TB, and as discussed earlier, IV drug users are at higher risk for HIV [79]. Once diagnosed with TB, patients require regular contact with health services, which is also challenging in this population with poor access and adherence [79].

Spore-Forming Bacteria

While the incidence of infections with spore-forming bacteria (Clostridium and Bacillus species) in the general public is decreasing, the incidence of these infections among IV drug abusers is increasing [80]. Infections usually result from contaminated heroin. The spores produced by both Clostridium and Bacillus species can be found in soil and dust, as well as aquatic environments. They are also capable of remaining dormant and viable for long periods of time [80]. Infections start locally but can become systemic within 1 week as the bacteria begin to produce toxins.

An epidemic amongst IV drug users in California of wound botulism, caused by Clostridium botulinum, started around 1994. The infections were associated with skin popping black tar heroin, thought to be from Mexico, and often presented with cranial nerve palsies and descending flaccid paralysis. These cases in California accounted for three quarters of the cases of wound botulism in the USA. There have also been 17 cases involving patients who have had recurrent wound botulism due to continued IV drug abuse [81]. Black tar heroin has also been associated with cases of tetanus caused by Clostridium tetani, and increasing numbers of necrotizing soft-tissue infections caused by Clostridium perferingens and other Clostridium species [82]. Black tar heroin is likely contaminated with the Clostridium and Bacillus species after the manufacture or during distribution [83].

Newer Opioids

Krokodil

Krokodil, also known as Crocodile, Krok, or Croc, is a newer designer drug that is used mainly in Russia. Krokodil has become a heroin substitute for many heroin users as it has the same effects as heroin, but is easy to make and is roughly one third of the cost [84]. The active component of Krokodil is desomorphine, which is synthesized from codeine, iodine, and red phosphorous. Other components used in the synthesis of Krokodil include paint thinner, which may contain lead zinc, iron, and antimony, lighter fluid or gasoline, and hydrochloric acid [85]. While there are very few scientific articles on Krokodil, many local and systemic effects have been described with IV use. The name refers to the discoloration and desquamation at the injection site which is said to resemble crocodile scales. Other toxicities include damage to blood vessels, muscles, cartilage, and bone, inflammatory reactions in the liver and kidneys, as well as decreased cognitive functions [85]. Due to the highly addictive nature of the drug and the toxicity associated with its use, it is estimated that the average life span of a Krokodil user is less than 3 years [84].

Kratom

Kratom is the common name for the plant Mitragyna speciosa, a medicinal plant in Southeast Asia. The leaves of the plant are chewed, smoked, or made into an extract. They can also be brewed and drank as a tea [86]. The leaves have been used medicinally for many years in Southeast Asia for diarrhea, coughing, muscle pain, and intestinal infections [86]. Twenty-five different alkaloids have been identified in the leaves of M. speciosa, and the major constituent is called mitragynine, which acts at the mu opioid receptor to produce opioid effects [87]. Toxicities reported include seizures, intrahepatic cholestasis, and pulmonary edema [86]. Death has also been reported from the combination of Kratom and O-desmethyltramadol, which is the active metabolite of tramadol. This combination, called Krypton, and other formulations of Kratom can be purchased easily online [87].

Norjizak

Norjizak is a designer drug that has been reported amongst IV drug users in Iran. This combination drug gets its name from Norgesic, which is the trade name of buprenorphine (Reckitt Benckiser PLC, London, UK) [88]. Data regarding toxicity of this new drug is very limited. The drug is thought to be a combination of opioids plus glucocorticoids and benzodiazepines. Thirty patients in Iran developed exogenous Cushing’s syndrome from IV use of Norjizak. Samples of the drug analyzed contained several different glucocorticoids, including dexamethasone, hydrocortisone, prednisone, beclomethasone, triamcinolone, and prednisolone [88].

Conclusion

Since the first reports of pulmonary edema from opioids in 1880, there have been many more pathologic pulmonary processes associated with opioid use and misuse. Whether it is direct lung injury or indirect effects, the toxicity depends on both the opioid and the route of administration. Opioids can affect virtually any aspect of respiration, whether it is the airway, the lung parenchyma, or the respiratory drive centers. The use of opioids also places patients at risk for numerous infections, which can affect any organ system. By being familiar with these adverse effects from opioids, clinicians can more effectively manage these patients, whether it is in the clinic, the wards, the emergency department, or the intensive care unit.

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Radke, J.B., Owen, K.P., Sutter, M.E. et al. The Effects of Opioids on the Lung. Clinic Rev Allerg Immunol 46, 54–64 (2014). https://doi.org/10.1007/s12016-013-8373-z

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Keywords

  • Opioid
  • Opiate
  • Toxicity
  • Pulmonary toxicity
  • Intravenous drug abuse