The Role of Inhaled Opioids and Furosemide Introduction
Psychophysical Dimensions of Dyspnea
Etiology of Dyspnea in Terminal Illness
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

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].
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
may ameliorate dyspnea because of its bronchodilatoryeffects.73–75 Moreover, in experimental models of dyspnea 1. Dudgeon DJ, Kristjanson L, Sloan JA, Lertzman M, Clement K.
induced by breath-holding,76 resistive-loading with and Dyspnea in cancer patients: prevalance and associated factors. J PainSymptom Manage 2001;21(2):95–102.
without hypercapnia,76 and hypercapnia with constrained 2. Hayes AW, Philip J, Spruyt OW. Patient reporting and doctor rec- ventilation,77 40 mg of aerosolized furosemide increased ognition of dyspnoea in a comprehensive cancer centre. Intern Med breath-holding time and reduced dyspnea.
In theory, aerosolized furosemide may reduce dyspnea 3. Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest by suppressing pulmonary C-fibers in bronchial epitheli- um.76 Inhaled furosemide inhibits cough and prevents bron- 4. Bruera E, Schmitz B, Pither JP, Neumann CNM, Hanson J. The frequency and correlates of dyspnea in patients with advanced can- chospasm when the lungs are exposed to aerosolized low- cer. J Pain Symptom Manage 2000;19(5):357–362.
chloride solutions.78 This suggests that ionic changes in 5. Higginson I, McCarthy M. Measuring symptoms in terminal cancer: the cellular environment are circumvented, which prevents are pain and dyspnoea controlled? J R Soc Med 1989;82(5):264–267.
6. Mercadante S, Casuuccio A, Fulfaro F. The course of symptom On the other hand, dyspnea can be relieved by deep lung frequency and intensity in advanced cancer patients followed at home.
inflation through the stimulation of pulmonary stretch re- J Pain Symptom Manage 2000;20(2):104–112.
7. Chandler S. Nebulized opioids to treat dyspnea. Am J Hosp Palliat ceptors.79 Furosemide also stimulates pulmonary stretch receptors80 and may relieve dyspnea by mimicking the 8. Stein C. The control of pain in peripheral tissue by opioids. N Engl effects of large tidal volumes.77 Aerosolized furosemide is believed to stimulate pulmonary stretch receptors by in- 9. Killian K. History of dyspnea. In: Mahler DA, O’Donnell DE, edi- hibiting cellular ionic transport mechanisms and thus in- tors. Dyspnea: mechanisms, measurement and management, 2nd ed.
creasing local sodium concentrations.76 Although most Boca Raton, Florida: Taylor & Franci; 2005: 1–18.
10. Peters MM, O’Donnell DE. Dyspnea in chronic obstructive pulmo- studies have not observed renal effects from aerosolized nary disorder. In: Booth S, Dudgeon D, editors. Dyspnoea in ad- furosemide,68,76 Moosavi et al77 reported brisk diuresis vanced disease: a guide to clinical management. Oxford: Oxford among normal study subjects. Therefore, another potential effect of inhaled furosemide on dyspnea in patients with 11. Simon PM, Schwartzstein RM, Weiss JW, Fencl V, Teghtsoonian M, cardiopulmonary disease may emanate simply from a re- Weinberger SE. Distinguishable types of dyspnea in patients with duction in pulmonary edema that decreases either respira- shortness of breath. Am Rev Respir Dis 1990;142(5):1009–1014.
12. Comroe JH. Some theories of the mechanism of dyspnoea. In: How- tory effort or J-receptor stimulation.
ell JBL, Campbell EJM, editors. Breathlessness. Oxford: Blackwell Reported adverse effects from aerosolized furosemide Scientific Publications; 1965: 1–7.
were generally mild and included transient nausea, and 13. Tobin MJ. Dyspnea: pathophysiologic basis, clinical presentation sleeplessness in some patients.69 Among normal research and management. Arch Intern Med 1990;150(8):1604–1613.
subjects the most frequent adverse effects were pharyngeal 14. Campbell EJM, Howell JBL. The sensation of breathlessness. Br and substernal irritation, intermittent cough, and a strong 15. O’Donnell DE, Webb KA. Exertional breathlessness in patients with chronic airflow limitation: the role of hyperinflation. Am Rev RespirDis 1993;148(5):1351–1357.
16. Campbell EJM. The relationship of the sensation of breathlessness to the act of breathing. In: Howell JBL, Campbell EJM, editors. Breath-lessness. Oxford: Blackwell Scientific Publications; 1965: 55–63.
17. Banzett RB, Lansing RW, Reid MB, Adams L, Brown R. “Air In conclusion, higher-level clinical evidence consistently shows that aerosolized opioids are not effective in improv- riplegics. Respir Physiol 1989;76(1):53–67.
ing dyspnea or exercise tolerance in patients with chronic 18. Howell JBL. Breathlessness in pulmonary disease. In: Howell JBL, cardiopulmonary diseases, including COPD and idiopathic Campbell EJM, editors. Breathlessness. Oxford: Blackwell Scien- pulmonary fibrosis. Predominantly low-level clinical evi- tific Publications; 1965: 165–177.
dence supports aerosolized opioids for palliation of dys- 19. Bostwick DG, Null WE, Holmes D, Weber E, Barchas JD, Bensch KG. Expression of opioid peptides in tumors. N Engl J Med 1987; pnea in patients with advanced cancer and cystic fibrosis.
There is some higher level clinical evidence that aerosol- 20. Davis GC. Studies of the role of endorphins in normal subjects and ized opioids can be utilized for systemic analgesia. How- psychiactric patients. In: Bunney WE Jr, moderator. Basic and clin- ever, this should be restricted to circumstances where ef- ical studies of endorphins. Ann Intern Med 1979;91(2):246–248.
fective parenteral administration is delayed because of 21. Snyder SH. Opiate receptors in the brain. N Engl J Med 1977;296(5): difficulty in achieving intravenous access. Alternatively, 22. Santiago TV, Remolina C, Scoles V 3rd, Edelman NH. Endorphins lower-level clinical evidence suggests that aerosolized fu- and the control of breathing: ability of naloxone to restore flow- rosemide may reduce dyspnea both in patients with ad- resistive load compensation in chronic obstructive pulmonary dis- vanced cancer and in those with COPD.
ease. N Engl J Med 1981;304(20):1190–1195.
RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA 23. Johnson MA, Woodcock AA, Geddes DM. Dihydrocodeine for 45. Penson RT, Joel SP, Roberts M, Gloyne A, Beckwith S, Slevin ML.
breathlessness in “pink puffers.” Br Med J (Clin Res Ed) 1983; The bioavailability and pharmacokinetics of subcutaneous, nebu- lized and oral morphine-6-glucuronide. Br J Clin Pharmacol 2002; 24. Mazzocato C, Buclin T, Rapin C-H. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced 46. Masood AR, Thomas SH. Systemic absorption of nebulized mor- cancer: a randomized double-blind controlled trial. Ann Oncol 1999; phine compared with oral morphine in healthy subjects. Br J Clin 25. Barber A, Gottschlich R. Opioid agonists and antagonists: an eval- 47. Quigley C, Joel S, Patel N, Baksh A, Slevin M. A phase I/II study of uation of their peripheral actions in inflammation. Med Res Rev nebulized morphine-6-glucuronide in patients with cancer-related breathlessness (letter). J Pain Symptom Manage 2002;23(1):7–9.
26. Zebraski SE, Kochenash SM, Raffa RB. Lung opioid receptors: phar- 48. Chrubasik J, Wust H, Friedrich G, Geller E. Absorption and bio- macology and possible target for nebulized morphine in dyspnea.
availability of nebulized morphine. Br J Anaesth 1988;61(2):228– 27. Paintal AS. Thoracic receptors connected with sensation. Br Med 49. Ward ME, Woodhouse A, Mather LE, Farr SJ, Okikawa JK, Lloyd P, et al. Morphine pharmacokinetics after pulmonary administration 28. Roberts AM, Bhattacharya J, Schultz HD, Coleridge HM, Coleridge from a novel aerosol delivery system. Clin Pharmacol Ther 1997; JCG. Stimulation of pulmonary vagal afferent C-fibers by lung edema in dogs. Circ Res 1986;58(4):512–522.
50. Young IH, Daviskas E, Keena VA. Effect of low dose nebulized 29. Zeppetella G. Nebulized morphine in the palliation of dyspnoea.
morphine on exercise endurance in patients with chronic lung dis- 30. Tanaka K, Shima Y, Kakinuma R, Kubota K, Ohe Y, Hojo F, et al.
51. Beauford W, Saylor TT, Stansbury DW, Avalos K, Light RW. Effect Effect of nebulized morphine in cancer patients with dyspnea: a pilot of nebulised morphine sulfate on the exercise tolerance of the ven- study. Jpn J Clin Oncol 1999;29(12):600–603.
tilatory limited COPD patient. Chest 1993;104(1):175–178.
52. Masood AR, Reed JW, Thomas SHL. Lack of effect of inhaled 31. Coyne PJ, Viswanathan R, Smith TJ. Nebulized fentanyl citrate im- morphine on exercise-induced breathlessness in chronic obstructive proves patients’ perception of breathing, respiratory rate, and oxygen pulmonary disease. Thorax 1995;50(6):629–634.
saturation in dyspnea. J Pain Symptom Manage 2002;23(2):157– 53. Leung R, Hill P, Burdon J. Effect of inhaled morphine on the de- velopment of breathlessness during exercise in patients with chronic 32. Noseda A, Carpiaux J-P, Markstein C, Meyvaert A, de Maertelaer V.
lung disease. Thorax 1996;51(6):596–600.
Disabling dyspnoea in patients with advanced disease: lack of effect 54. Jankelson D, Hosseini K, Mather LE, Seale JP, Young IH. Lack of of nebulized morphine. Eur Respir J 1997;10(5):1079–1083.
effect of high doses of inhaled morphine on exercise endurance in 33. Bruera E, Sala R, Spruyt O, Palmer JL, Zhang T, Willey J. Nebulized chronic obstructive pulmonary disease. Eur Respir J 1997;10(10): versus subcutaneous morphine for patients with cancer dyspnea: a preliminary study. J Pain Symptom Manage 2005;29(6):613–618.
55. Harris-Eze AO, Sridhar G, Clemens RE, Zintel TA, Gallagher CG, 34. Fulda GJ, Giberson F, Fagraeus L. A prospective randomized trial of Marciniuk DD. Low-dose nebulized morphine does not improve nebulized morphine compared with patient-controlled analgesia mor- exercise in interstitial lung disease. Am J Respir Crit Care Med phine in the management of acute thoracic pain. J Trauma 2005; 59(2):383–388; discussion 389–390.
56. Masood AR, Subhan MMF, Reed JW, Thomas SHL. Effects of 35. Cohen SP, Dawson TC. Nebulized morphine as a treatment for dys- inhaled nebulized morphine on ventilation and breathlessness during pnea in a child with cystic fibrosis. Pediatrics 2002;110(3):e38-e40.
exercise in healthy man. Clin Sci (Lond) 1995;88(4):447–452.
36. Lang E, Jedeikin R. Acute respiratory depression as a complication 57. Stein WM, Min YK. Nebulized morphine for paroxysmal cough and of nebulised morphine. Can J Anaesth 1998;45(1):60–62.
dyspnea in a nursing home resident with metastatic cancer. Am J 37. Lefevre I, D’Aguanno S, Michel C, Morin L, Simon N. Nebulized Hosp Palliat Care 1997;14(2):52–56.
opioid analgesia: a comparative study of morphine, fentanyl and 58. Farncombe M, Chater S. Clinical application of nebulized opioids alfentanyl. Eur J Emerg Med 2006;13(5):328.
for treatment of dyspnoea in patients with malignant disase. Support 38. Chrubasik J, Geller E, Niv D, Zindler M. Morphine inhalation versus intravenous infusion in pain treatment after abdominal surgery. Anesth 59. Janahi IA, Maciejewski SR, Teran JM, Oermann CM. Inhaled mor- phine to relieve dyspnea in advanced cystic fibrosis lung disease.
39. Worsley MH, MacLeod AD, Brodie MJ, Asbury AJ, Clark C. In- Pediatr Pulmonol 2000;30(3):257–259.
haled fentanyl as a method of analgesia. Anaesthesia 1990;45(6): 60. Graff GR, Stark JM, Grueber R. Nebulized fentanyl for palliation of dyspnea in a cystic fibrosis patient. Respiration 2004;71(6):646–649.
40. Higgins MJ, Asbury AJ, Brodie MJ. Inhaled nebulised fentanyl for 61. Rutherford RM, Azher T, Gilmartin JJ. Dramatic response to nebu- postoperative analgesia. Anaesthesia 1991;46(11):973–976.
lized morphine in an asthmatic patient with severe chronic cough. Ir 41. Bartfield JM, Flint RD, McErlean M, Broderick J. Nebulized fent- anyl for relief of abdominal pain. Acad Emerg Med 2003;10(3):215– 62. Ballas SK, Viscusi ER, Epstein KR. Management of acute chest wall sickle cell pain with nebulized morphine. Am J Hematol 2004;76(12): 42. Tooms A, McKenzie A, Grey H. Nebulised morphine (letter). Lancet 63. Davis CL. The use of nebulized opioids for breathlessness (letter).
43. Farncombe M, Chater S. Case studies outlining use of nebulized morphine for patients with end-stage chronic lung and cardiac dis- 64. Gold MS, Byars JA, Frost-Pineda K. Occupational exposure and ease. J Pain Symptom Manage 1993;8(4):221–225.
addictions for physicians: case studies and theoretical implications.
44. Sarhill N, Walsh D, Khawam E, Tropiano P, Stahley MK. Nebulized Psychiatr Clin North Am 2004;27(4):745–753.
hydromorphone for dyspnea in hospice care for advanced cancer.
65. Berry CB, Crome IB, Plant M. Substance misuse amongst anaesthe- Am J Hosp Palliat Care 2000;17(6):389–391.
tists in the United Kingdom and Ireland. The results of a study RESPIRATORY CARE • JULY 2007 VOL 52 NO 7 INHALED OPIOIDS AND FUROSEMIDE FOR DYSPNEA commissioned by the Association of Anaesthetists of Great Britain 73. Ono Y, Kondo T, Tanigaki T, Ohta Y. Furosemide given by inha- and Ireland. Anaesthesia 2000;55(10):946–952.
lation ameliorates acute exacerbation of asthma. J Asthma 1997; 66. McAuliffe PF, Gold MS, Bajpai L, Merves ML, Frost-Pineda K, Pomm RM, et al. Second-hand exposure to aerosolized intravenous 74. Pendino JC, Nannini LJ, Chapman KR, Slutsky A, Molfino NA.
anesthetics propofol and fentanyl may cause sensitization and sub- Effect of inhaled furosemide in acute asthma. J Asthma 1998;35(1): sequent opiate addiction among anesthesiologists and surgeons. Med 75. Ong K-C, Kor A-C, Chong W-F, Earnest A, Wang Y-T. Effects of 67. Stone P, Kurowska A, Tookman A. Nebulized frusemide for dys- inhaled furosemide on exertional dyspnea in chronic obstructive pul- pnoea (letter). Palliat Med 1994;8(3):258.
monary disease. Am J Respir Crit Care Med 2004;169(9):1028–1033.
68. Shimoyama N, Shimoyama M. Nebulized furosemide as a novel 76. Nishino T, Ide T, Sudo T, Sato J. Inhaled furosemide greatly alle- treatment for dyspnea in terminal cancer patients. J Pain Symptom viates the sensation of experimentally induced dyspnea. Am J Respir Crit Care Med 2000;161(6):1963–1967.
69. Kohara H, Ueoka H, Aoe K, Maeda T, Takeyama H, Saito R, et al.
77. Moosavi SH, Binks AP, Lansing RW, Topulos GP, Banzett RB, Effect of nebulized furosemide in terminally ill cancer patients with Schwartzstein RM. Effect of inhaled furosemide on air hunger in- dyspnea. J Pain Symptom Manage 2003;26(4):962–967.
duced in healthy humans. Respir Physiol Neurobiol 2007;156(1): 70. Stone P, Rix, Kurowska A, Tookman A. Re: nebulized furosemide for dyspnea in terminal cancer patients (letter). J Pain Symptom 78. Ventresca PG, Nichol GM, Barnes PJ, Chung KF. Inhaled furo- semide inhibits cough induced by low chloride solutions but not by 71. Bianco S, Pieroni MG, Refini RM, Rottoli L, Sestini P. Protective capsaicin. Am Rev Respir Dis 1990;142(1):143–146.
effect of inhaled furosemide on allergen-induced early and late asth- 79. Manning HL, Shea SA, Schwartzstein RM, Lansing RW, Brown R, matic reactions. N Engl J Med 1989;321(16):1069–1073.
Banzett RB. Reduced tidal volume increases ‘air hunger’ at fixed 72. Shimizu T, Mochizuki H, Morikawa A, Kuroume T. Inhaled furo- in ventilated quadriplegics. Respir Physiol 1992;90(1):19–30.
semide prevents ultrasonically nebulized water bronchoconstriction 80. Sudo T, Hayashi F, Nishino T. Responses of tracheobronchial re- in children with both atopic and nonatopic asthma. Chest 1993; ceptors to inhaled furosemide in anesthetized rates. Am J Respir Crit Care Med 2000;162(3 pt 1):971–975.

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Talbot School of Theology: Christian Educators Christian Educators Kendig B. Cully By Sharon Warner Biography Contributions to Christian Education Bibliography Excerpts from Publications Recommended Readings Author Information Dr. Kendig Brubaker Cully was born November 30, 1913. Originally ordained in the Congregational church he became an Episcopal in mid life. Kendig served the chur

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Date: 26/9/2012 Imtiaz Cajee - Biography: I was born in August 1966 at my maternal grand-parents’ residence. As per Indian tradition, a first time mother is expected to return to her parents’ home for maternity, thus I was born in Roodepoort on the West Rand. However, forty days after my birth my mother returned to her matrimonial home in Standerton, the Eastern Transvaal (now Mpumalan

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