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The Role of Inhaled Opioids and Furosemide Introduction
Psychophysical Dimensions of Dyspnea
Etiology of Dyspnea in Terminal Illness
Pharmacology
Pharmacokinetics
Aerosolized Opioids in the Management of Dyspnea
Aerosolized Opioids in the Management of Pain
Occupational Exposure Risks to Health Care Providers
Aerosolized Furosemide in the Treatment of Dyspnea
Summary
Numerous case reports, uncontrolled studies, and small randomized placebo-controlled trials have
investigated the role of aerosolized opioids in the treatment of both dyspnea and pain. Recently,
aerosolized furosemide was studied for the treatment of dyspnea. A direct effect on either pulmo-
nary stretch receptors or irritant receptors has been proposed to explain the apparent effectiveness
of these drugs. A review of the literature found 37 studies and reports: 23 on aerosolized opioids to
treat dyspnea, 7 for analgesia, and 7 on aerosolized furosemide. In general, prospective double-blind
randomized placebo-controlled trials have investigated the effects of aerosolized opioids on dyspnea
and exercise tolerance in patients with stable chronic cardiopulmonary disease, and found no effect.
In contrast, the vast majority of studies found that aerosolized opioids relieved dyspnea better than
parenteral opioids and with less systemic adverse effects in patients with terminal lung cancer and
cystic fibrosis. However, most of these findings come from uncontrolled studies and case reports.
Aerosolized opioids also have been found to provide effective analgesia, again with less systemic
adverse effect. Small, generally uncontrolled, studies suggest that aerosolized furosemide may
relieve dyspnea both in patients with terminal cancer and those with chronic obstructive pulmonary
disease. Routine clinical use of aerosolized opioids to treat dyspnea in terminal illness will require
large randomized placebo-controlled trials. However, until these studies are done, the risk/benefit
ratio favors use of aerosolized opioids and furosemide in selected patients, based on the principle of
compassionate care. Key words: dyspnea, breathlessness, aerosolized morphine, aerosolized furosemide,
palliative care, chronic obstructive pulmonary disease. [Respir Care 2007;52(7):900 –910. 2007 Daeda-
lus Enterprises]
Richard H Kallet MSc RRT FAARC is affiliated with the Cardiovascular the American Association for Respiratory Care, held December 11–14, Research Institute, and with Respiratory Care Services, Department of Anesthesia, University of California, San Francisco at San Francisco The author reports no conflicts of interest related to the content of this General Hospital, San Francisco, California.
Correspondence: Richard H Kallet MSc RRT FAARC, Respiratory Care The author presented a version of this paper at the 22nd Annual New Services, San Francisco General Hospital, NH:GA-2, 1001 Potrero Av- Horizons Symposium at the 52nd International Respiratory Congress of enue, San Francisco CA 94110. E-mail: [email protected].
RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA Introduction
Dyspnea is commonly encountered in patients with a variety of terminal diseases, such as metastatic cancer,chronic obstructive pulmonary disease (COPD), idiopathicpulmonary fibrosis, congestive heart failure, and severalneurological conditions. Between 33% and 47% of thegeneral cancer population experience dyspnea,1,2 and theincidence increases to 55–70% for those in the terminalstage.3,4 In over 20% of these patients, dyspnea is reportedto be the primary symptom.5 In contrast to pain, whichtends to be well-controlled in the final weeks of life, dys-pnea progressively increases in frequency and intensity,particularly in those with primary lung cancer.6 As breath-ing is the primal sensation of life, its disturbance evokesthe most profound sense of dread. And in those grapplingwith terminal illness, dyspnea provokes psychological suf-fering, as it is invariably associated with impending death.
Often, reversing the underlying cause of dyspnea in the terminally ill is not feasible, so palliation of the symptombecomes the primary goal. Opioids have been used to treat Fig. 1. A schematic representation of 3 categories of sensory in- dyspnea since the late 19th century, but their use fell from puts that, when integrated in the central nervous system, may favor in the 1950s, once a clear relationship with respira- contribute to the sensation of dyspnea. (1) Central chemorecep-tors located in the brain stem are stimulated by carbon dioxide, tory depression was established.7 In the 1980s, peripheral whereas peripheral chemoreceptors are located in the aortic arch opioid receptors were discovered throughout the body,8 and the carotid arteries and are sensitive to both arterial carbon thus raising the possibility that a direct pulmonary-tar- dioxide and oxygen tension. (2) Chest wall mechanoreceptors lo- geted treatment for dyspnea with aerosolized opioids might cated in the muscle spindles and at the origins and insertions of be possible with less adverse effect.
the ribs provide information on displacement, whereas muscletendons provide information regarding tension development.
This paper will review the scientific literature on the use (3) Pulmonary receptors include irritant receptors in the central of inhaled opioids for the treatment of dyspnea. This will and peripheral airways (C-fibers), J-receptors, and stretch recep- be preceded by a brief review of the theoretical mecha- tors located in the alveolar walls (see text).
nisms of dyspnea, the pharmacology of opioids, and thecauses of dyspnea in terminal illness. The paper will con-clude with a description of new research that suggests physiologic derangements.11 Moreover, dyspnea involves aerosolized furosemide may be an effective alternative for not only the generation of an unpleasant sensation, but a subjective response to it.12 As with all perception, dyspneais interpreted within the context of previous experience Psychophysical Dimensions of Dyspnea
and learning, so that an individual’s reaction to dyspneafrequently changes over time.13 Therefore, the intensity of The perception of difficult breathing is a complex phe- distress that accompanies dyspnea is highly individual- nomenon, possessing diverse qualities best illustrated by ized, and objective measures of lung function often bear the distinction between 2 words that are often used inter- little resemblance to how patients assess their quality of changeably: dyspnea and breathlessness. Whereas dyspnea breathing.12 Is important to emphasize that efferent dis- refers to excessive exertion during the act of breathing, charge from the respiratory centers in the brain stem rep- breathlessness is the unpleasant urge to breath that is closely resents a complex processing and integration of multiple associated with suffocation and breath-holding.9 For sim- inputs, which include: afferent information regarding pe- plicity, the term dyspnea will be retained in this paper.
ripheral chemoreceptor stimulation; force-displacement in Contemporary theories posit that dyspnea emanates from the chest wall; lung stretch; central chemoreceptor stimu- multiple sensory inputs that are integrated in the brain, lation; and information from higher levels in the brain which then evokes a response, both in terms of efferent discharge to the breathing muscles and to the sensory cor- A useful concept for understanding dyspnea is length- tex (corollary discharge).10 A shared characteristic between tension inappropriateness14 or neuromechanical dissocia- dyspnea and pain is the existence of a diverse vocabulary tion.15 When efferent signals to the respiratory muscles expressing sensational nuances related to underlying patho- cause contraction, mechanoreceptors in muscle fibers, ten- RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA dons and joints, and also in the airways and alveoli, evoke lar, muscle weakness, anxiety, and panic appear to be afferent information that conveys both the velocity and common features of advanced disease that greatly impact degree of displacement occurring in the chest wall and dyspnea but may not be amenable to standard therapies, lungs. In this way, effort (efferent discharge from the re- and thus may form a strong rationale for using aerosolized spiratory centers in the brain stem), force developed in the inspiratory muscles, velocity, and displacement of the lungsand chest wall are integrated. Through habituation we come Pharmacology
to experience a specific relationship between these ele-ments as “normal breathing.” Minor breath-to-breath im-balances that develop between force and displacement are In the 1970s it was discovered that the central nervous used as a servo-mechanism, processed either at the spinal system produces endogenous opioids (endorphins) that are or medullary level, to adjust breathing effort and maintain important in regulating not only the perception of pain, but minute ventilation. However, when tension in the ventila- also sleep, learning, memory, and appetite.19 In particular, tory muscles is excessive, relative to both the shortening of endorphins are up-regulated in response to both stress and the muscle fibers and the stretch of the lung tissue, dys- chronic pain.19,20 In brief, endorphins modulate afferent pnea is evoked, as heightened efferent discharge to the impulses, so that the perception of pain (nocioception) is respiratory muscles also causes stimulation of the reticular either altered or inhibited. That the medulla was discov- system, which evokes conscious awareness.16 Likewise, ered to be rich in opiate receptors21 provided the first dyspnea can occur in the presence of muscle weakness or anatomic evidence for the long-recognized effects of ex- fatigue, when length-tension appropriateness may be pre- served but effort is disproportional to chest displacement.
Although they do not play a regulatory role in the con- Of particular interest is the fact that breathlessness can be trol of breathing in normal subjects, endorphins blunt the evoked independently of other stimuli, by elevated carbon ability of patients with COPD to compensate for increased resistive work load (but not carbon dioxide sensitivity).22 Furthermore, the context in which these signals occur Similar to the body’s response to chronic pain, the brain impacts the interpretation of breathing sensations. For ex- up-regulates endorphins as an adaptive response to the ample, during heavy exercise the corresponding respira- chronic stress associated with increased work of breathing.
tory effort and work load are elevated, but this does not A similar effect is achieved with oral dihydrocodeine, which provoke distress because it is appropriate to the circum- improves mobility and dyspnea in ambulatory patients with stances, and respiratory effort can be reduced simply by COPD,23 and with subcutaneous morphine sulfate to ame- decreasing the activity level. However, if the same breath- liorate dyspnea in patients with terminal cancer.24 ing pattern were to occur when sitting quietly in bed, it By the early 1980s, opioid receptors were discovered on would elicit alarm, as the breathing pattern is inappropri- peripheral sensory nerves throughout the body. These re- ate. More importantly, it implies that the subject cannot do ceptors, which are found at multiple locations, are up- anything to rectify the abnormality.18 regulated during inflammation, as a result of interactionswith the immune system.8 In brief, opioids decrease cal- Etiology of Dyspnea in Terminal Illness
cium currents within the cell bodies, which inhibits neu-ronal firing and transmitter release. In addition, opioids Because multiple physiologic inputs are responsible for depress the release of pro-inflammatory “Substance P,” generating dyspnea, numerous pathophysiologic distur- which may help to decrease local inflammation.25 It is bances can impact the intensity and quality of the sensa- postulated that during inflammation the normally imper- tion. When examining factors that contribute to dyspnea in meable perineurium sheath that protects nerve fibers is advanced diseases, it is apparent that some factors can be disrupted, allowing access to opioid agonists and possibly treated readily, whereas others are not amenable to rapid the activation and peripheral migration of opioid receptors reversal (Table 1). Thus, treatment should focus initially on salient causes of dyspnea, such as correction of hypox- Three main opioid receptors have been identified in the emia with supplemental oxygen, acute hypercapnia with respiratory tract: ␮ (MOR), ␦ (DOR), and ␬ (KOR), which noninvasive positive-pressure ventilation, reversal of bron- mediate the effects of the 3 primary families of endoge- chospasm with ␤ agonist and steroids, relief of chest wall nous opioids (endorphins, enkephalins, and dynorphins, restriction by drainage of pleural effusions or ascites, and respectively) as well as exogenous opioids such as mor- reduction of pulmonary edema with diuretics. Palliative phine and codeine.25 In addition, the lungs also may con- therapy with aerosolized opioids should be considered only tain a novel opioid receptor.26 Animal studies have re- when conventional approaches do not produce satisfactory vealed the presence of opioid receptors in the trachea, results or corrective treatment is not plausible. In particu- bronchi, and pulmonary arteries, but these receptors are RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA Pathophysiology of Dyspnea in Terminal Illness Muscle weakness: 2 muscle bulk, deconditioning, electrolyte imbalance, malnutrition, anemia, tumor infiltration 2 lung compliance: pneumonia, pulmonary abscess 2 chest wall compliance: pleural effusion, tumor infiltration 1 V /V : pulmonary embolism 3 hypercapnia, pulmonary hypertension, stimulation of pulmonary C-fibers 1 respiratory drive, 1 perceptual focus on Superior vena cava syndrome: vascular wall obstruction Muscle weakness: 2 muscle bulk, deconditioning, 2 perfusion 2 lung compliance: engorgement/pulmonary edema.
1 airways resistance and bronchial sensitivity 1 V /V : 2 V and 2 lung perfusion 3 hypercapnia 1 respiratory drive, 1 perceptual focus on Muscle weakness: 2 muscle bulk, deconditioning 1 respiratory drive, 1 perceptual focus on Muscle weakness: deconditioning, altered geometry from hyperinflation 1 respiratory drive, 1 perceptual focus on 1 airways resistance: retained secretions 1 respiratory drive, 1 perceptual focus on VD/VT ϭ ratio of dead space to tidal volumeCOPD ϭ chronic obstructive pulmonary diseaseV particularly prominent in the bronchioles and the alveolar lated, typically by large tidal volumes, reduce the sensa- tion of air hunger. Inhaled opioids also may act on these Pulmonary opioid receptors are associated primarily with vagal afferent C-fibers (irritant or rapidly-adapting fibers)and the juxta-pulmonary capillary receptors (J-receptors), Pharmacokinetics
which are located in the alveolar wall.27 Stimulation ofC-fibers in the small airways and J-receptors in the alveoli Despite the anatomic evidence cited above, it remains by acute pulmonary congestion and edema, multiple pul- unclear whether the effects of aerosolized opioids on dys- monary embolisms, and inflammation may be responsible, pnea are due to modifications in peripheral afferent sig- in part, for triggering the sensation of dyspnea, as well as naling that alters proprioception, or that opioids absorbed tachypnea, bronchoconstriction, and increased airway se- into the systemic circulation act on central nervous system cretions.27,28 In a manner analogous to pain, opioids may control of breathing. Most studies that have examined in- alter the perception of dyspnea by modifying signals from haled opioids did not observe signs of sedation or respi- pulmonary afferent C-fibers. A third type of vagal afferent ratory depression.29–34 However, hypercapnia35 and pro- fiber is the pulmonary stretch receptors that, when stimu- found respiratory depression36 occasionally have been RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA reported. Inhaled opioids also provide effective analge- reflect variability in jet nebulizer performance, coupled sia,37–41 which suggests the possibility that dyspnea is mod- with the limitations of drug delivery imposed by the arti- ified, at least in part, through a central mechanism. Sys- ficial airway and a passive breathing pattern. These studies temic absorption of opioids may occur from the pulmonary also have limited relevance to patients with advanced pul- circulation. But a more likely source is absorption from the monary disease, because pathologic alterations in airway gastrointestinal tract, due to aerosol impaction in the oro- geometry and pulmonary perfusion, along with abnormal pharynx and subsequent swallowing of opioid-containing breathing patterns, would probably alter drug deposition.
secretions. Yet in cancer patients who suffer from intrac-table dyspnea, relatively small amounts of inhaled opioids Aerosolized Opioids in the Management of Dyspnea
appear to improve breathing comfort, despite the fact thatthese patients already are receiving high levels of paren- A PubMed title word search from 1965 through 2006 teral opioids for pain management.29,30,42–44 was done, using various combinations of the terms dys- Six studies have assessed absorption and bioavailability pnea, breathlessness, aerosolized, nebulized, opioids, mor- of morphine, morphine-6-glucuronide (a potent metabolite phine, fentanyl, and hydromorphine. The references for of morphine), and fentanyl, administered via jet nebulizer each found paper also were searched to cull additional with mask, during spontaneous breathing,39,45–47 via en- publications. A total of 30 studies were found (Table 2).
dotracheal tube during passive mechanical ventilation,48 or Seven of these were small prospective randomized place- with a prototype breath-actuated unit-dose nebulizer dur- bo-controlled trials that examined the effects aerosolized ing spontaneous breathing.49 All of these studies were car- morphine sulfate on exercise endurance in patients with ried out on healthy volunteers with normal pulmonary func- stable COPD50–54 or idiopathic pulmonary fibrosis,55 or in tion. In the most widely cited study, Chrubasik et al48 healthy volunteers.56 There also have been 13 (mostly un- reported that serum morphine levels following inhalation controlled) studies and case reports on the effects of aero- varied widely among individuals, with a relative systemic solized opioids in end-stage cardiopulmonary disease bioavailability of 17% (range 9 –35%). The maximum se- (COPD, idiopathic pulmonary fibrosis, and congestive heart rum morphine concentration was achieved by 45 min and failure),43 advanced cancer,29–33,36,42,57,58 and cystic fibro- was approximately 6 times lower than with intramuscular sis.35,59,60 In an unusual case report,61 a patient with se- verely debilitating paroxysmal coughing was successfully Penson et al45 found that plasma concentration of mor- phine-6-glucuronide rose slowly, reaching a peak at 1.2 h, Five of the 6 double-blinded randomized placebo-con- with a significantly prolonged elimination half-life. This trolled studies that examined the effects of aerosolized was attributed to continued prolonged absorption from the opioids in patients with COPD or idiopathic pulmonary lungs, buccal cavity, or stomach after nebulization. The fibrosis reported no improvement either in exercise toler- relative bioavailability was only 6% (range 4 –11%). Sim- ance or dyspnea, compared to placebo.51–55 In the one ilarly, Quigley et al47 reported that peak plasma concen- positive study,50 the improvement in exercise endurance tration of morphine-6-glucuronide occurred between 2 h was minor. In contrast, all the uncontrolled trials29–31,43,47,58 and 3 h and was dose-dependent. Although Masood and and case studies35,36,42,44,57,59,60,62 that examined the effects Thomas46 reported that peak plasma concentration was of aerosolized opioids in patients with end-stage disease achieved within 10 min with aerosolized morphine, sys- (usually metastatic cancer) reported subjective improve- temic bioavailability was only 5%, compared to 24% with ments in dyspnea, paroxysmal coughing, and breathing oral administration. In contrast, Ward et al49 reported sim- pattern following aerosolized opioids. Characteristically, ilar time course and bioavailability profiles for the inhaled in these studies patients appeared to have intractable dys- and intravenous administration routes. This may be ex- pnea despite receiving generous amounts of intravenous or plained by the use of a highly efficient, nonconventional oral opioids for pain management. Yet supplementation nebulizer, and measurement of arterial plasma rather than with 5–10 mg of aerosolized morphine sulfate, repeated venous plasma concentration. With nebulized fentanyl, either as-necessary or every 4 h, almost uniformly im- which is highly lipid soluble, peak serum levels were proved dyspnea, breathing pattern, and the general appear- achieved by 15 min, but with low systemic bioavailabil- ance of these patients. In patients with opioid tolerance the dose often needed to be increased to approximately 20 mg,7 These pharmacokinetics studies suggest that systemic and in the final days of life, doses as high as 45–70 mg absorption and a central action of aerosolized opioids can- not fully explain the apparent effects on dyspnea, partic- As morphine sulfate can cause bronchospasm from his- ularly in patients already receiving systemic opioids for tamine release, some have added a 2– 4-mg dose of dexa- analgesia. The wide range in systemic bioavailability found methasone as prophylaxis.36,59 Others have used an initial in mechanically ventilated subjects with normal lungs may test dose of only 2.5 mg morphine sulfate to evaluate any RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA tendency for bronchospasm prior to administering a higher Occupational Exposure Risks
dose.7 Fentanyl does not cause histamine release and there- to Health Care Providers
fore is an attractive alternative in severely dyspneic pa-tients with reactive airways disease. Doses of 20 –100 ␮g Health care professionals have a propensity for devel- of fentanyl have been used to treat dyspnea.7,31,60 With oping chemical dependencies.64 Anesthesiologists appear hydromorphone an initial aerosolized dose of 1–2 mg ev- to be at particular risk, and this has been attributed to a ery 4 h has been recommended,7 but doses as high as combination of high job stress and extraordinary access to 4 – 8 mg every 4 h have been used.44,58,63 controlled substances.65 Yet others postulate that inadver- Only 2 prospective, randomized, double-blinded, place- tent aerosolization of intravenously administered opiates bo-controlled trials have examined the efficacy of aero- in the exhaled gas may sensitize health care workers through“second-hand” exposure.64 Over time this sensitization may solized opioids on dyspnea in patients with advanced dis- enhance the probability of addiction.
ease. Noseda et al32 found no benefit from 10 mg or 20 mg Aerosolized fentanyl and propofol have been detected of aerosolized morphine citrate on dyspnea in 17 patients in the operating theater and in the expiratory limb of an- with severe chronic lung disease or metastatic cancer. In esthesia ventilator circuits.66 This raises concern regarding contrast, Bruera et al33 found that aerosolized morphine occupational risk. However, the potential for aerosolized sulfate given to patients with metastatic cancer was as opioid exposure is much greater in the critical care envi- effective as subcutaneous administration in reducing dys- ronment, given the tremendous frequency of intravenous pnea. These discrepant results may be explained by the infusions of high-dose opioids and the elevated minute fact that 12 of the 17 patients in the study by Noseda et al32 ventilation demands of patients. Yet there is no evidence had COPD, whereas only 3 had metastatic cancer. Two of of widespread opiate addiction among critical care practi- the patients with cancer died before completing the pro- tioners, which suggests that access to these drugs without tocol, and their data were not included in the analysis. In stringent accountability is a more likely explanation. At addition, Noseda et al32 measured dyspnea only 10 min this juncture, theoretical concerns over health care worker after completion of nebulization, which based on the re- exposure should not preclude consideration of aerosolized sults of aerosolized opioid studies for pain manage- opioid therapy in patients with terminal illness. Neverthe- ment,34,38,41 may have been an insufficient amount of time less, future prospective studies of aerosolized opioid ther- apy should evaluate environmental pollution to assess po-tential risks to health care providers.
Aerosolized Opioids in the Management of Pain
Aerosolized Furosemide in the Treatment of Dyspnea
Seven studies have evaluated aerosolized opioids for The potential effectiveness of aerosolized furosemide to analgesia in postoperative management following general treat dyspnea was first reported in a patient with end-stage surgery,38–40 chest trauma,34 sickle cell crisis,62 and man- Kaposi’s sarcoma.67 Recent uncontrolled studies68,69 ex- agement of pain in the emergency department setting.37,41 amined the potential of aerosolized furosemide to reduce All the studies found that aerosolized opioids provide ad- dyspnea in patients with terminal cancer. Shimoyama and equate analgesia, and several reported a lower incidence of Shimoyama68 reported 3 patients with dyspnea that wasrefractory to treatment, including parenteral morphine sul- adverse effects, including sedation.34,37,38 Average doses fate. Aerosolized delivery of 20 mg furosemide reduced that provide adequate analgesia appear to be 12–20 mg dyspnea and respiratory rate, with the onset of effect oc- morphine sulfate every 4 – 6 h,34,38,62 and 150 –300 ␮g fen- curring within 20 –30 min and lasting for more than 4 h. In tanyl citrate.37,40,41 Only one of the studies with fentanyl some patients, both respiratory rate and use of accessory allowed repeated supplemental administration, which was muscles also diminished. In each case, diuresis could not explain the improvement in dyspnea, as urine output did When compared to intravenous administration, aerosol- not increase during the study period.
ized opioids tend to have a slower onset of action, but the Kohara et al69 reported that dyspnea was significantly quality of analgesia is not different by 30 min.34,38,41 Some reduced in 12 of 15 patients who received 20 mg of aero- studies reported onset of pain relief in 3–5 min.37,40,62 solized furosemide. No change was observed in arterial Although routinely administering aerosolized opioids for blood gases, respiratory rate, or heart rate. However, a analgesia has been criticized as awkward and inefficient,40 it may be useful as a temporizing measure in patients in study70 with 7 patients with advanced cancer found that whom either intravenous access is difficult or the adverse dyspnea tended to worsen after aerosolized furosemide, effects of sedation must be avoided.
but the difference was not significant.
RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA Aerosolized furosemide prevents bronchospasm71,72 and REFERENCES
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