Jason Tarlow, 62 years old, has a 10-year history of chronic obstructive pulmonary disease (COPD) with numerous hospital admissions for respiratory problems. He is becoming increasingly dyspneic despite the use of oxygen, bronchodilators, inhaled and systemic steroids, breathing exercises, and relaxation. Mr. Tarlow complains that his inability to do anything but “think about my next breath” is making him depressed and anxious. He is willing to try anything to breathe more easily—except going back on mechanical ventilation. Mr. Tarlow is started on nebulized morphine at 2 mg every four hours to relieve the dyspnea. His dose is titrated upward during the next few days. At 10 mg he notes significant improvement in his breathing.
Why did nebulized morphine seem to work for Mr. Tarlow when other therapies made little difference? Could it be beneficial to other patients? What are the side effects? This article discusses the use of nebulized morphine as a treatment option for reducing terminal dyspnea in patients with COPD or congestive heart failure (CHF).
THE MAGNITUDE OF THE PROBLEM
Terminal dyspnea is defined as unrelenting difficulty in breathing in patients with progressive, life-limiting illnesses including, but not limited to, end-stage heart and lung failure. Heart disease and COPD are among the five leading causes of death in the United States, where approximately 550,000 new cases of CHF and 16 million cases of COPD are reported annually. 1 As CHF and COPD progress, patients may experience terminal dyspnea, which causes physical and emotional suffering to patients and loved ones. 2,3 Providing relief of dyspnea at the end of life presents a challenge to nurses in acute, long-term, home, and hospice settings.
THE BASIS OF DYSPNEA
Respiration is influenced by physiologic and psychological factors. The major physiologic influences are neural (cortical and autonomic), chemical, and mechanical. Respiratory centers, located in the pons and medulla, modulate inspiration and expiration via afferent (sensory) signals from chemoreceptors, baroreceptors, and several types of receptors located in the lung and chest wall. Arterial blood gas imbalances, changes in intrathoracic pressure, or thoracic displacement are communicated to the central nervous system through afferent fibers. Subsequent activation of the sympathetic nervous system stimulates the release of catecholamines (epinephrine and norepinephrine) from the adrenal medulla. The catecholamines produce compensatory responses including bronchodilation, tachypnea, and increased lung volumes. 4
Psychological factors such as anxiety, fear, and emotional distress can stimulate the sympathetic nervous system and influence respiration. Voluntary control of respiration is mediated through the cortex and the corticospinal tract to neurons that innervate respiratory muscles. As a result, the patient is able to voluntarily hyperventilate or hypoventilate at times. Ultimately, autonomic and chemical responses vital to the existence of the individual override conscious efforts to alter breathing patterns. 4
The mechanisms of dyspnea are not well understood and a number of theories have been proposed. Because patients can distinguish the physical intensity of dyspnea from the distress it causes, the phenomenon is thought to have both sensory and affective components. It has been postulated that, since the cortical structures in the brain are responsible for perception, afferent signals must be transmitted to the cortex. Hypoxia, hypercapnia, or other afferent input increases respiratory drive and results in a sensation of dyspnea. Afferent feedback from mechanical receptors in the lungs and metabolic receptors in peripheral muscles also has been considered to play a role in the perception of dyspnea. 5 Intrapulmonary capillary receptors (J receptors) located at the junction of the capillaries and alveoli are excited by chemical stimuli (histamine, certain prostaglandins, bradykinins, and serotonin) and mechanical stimuli (pulmonary congestion, inflammation, and emboli). Stimulation of these receptors may also contribute to the sensation of discomfort and the rapid, shallow breathing that accompanies breathlessness. 4–6
The physiologic basis of dyspnea in COPD is attributed to bronchoconstriction resulting in increased airway resistance and the coalescence of alveoli that decrease diffusion capacity and impair gas exchange. Subsequent hypoxia and hypercapnia result in tachypnea and air hunger. In CHF increasing pulmonary capillary pressure leads to engorgement of vessels and transudation of fluid into lung tissue and alveoli (pulmonary edema), resulting in impaired gas exchange and increased respiratory effort. 4
The distress associated with dyspnea is influenced by the individual’s emotional state, personality, past experience, cognitive function, and the significance of the event. 5 The meaning he ascribes to it can modify an individual’s perception of dyspnea: His perception of the etiology, seriousness, and effects of the dyspnea (death, for example) can influence how he responds to the episode. 6
ASSESSMENT OF DYSPNEA
The ability to measure dyspnea is critical to assessing its impact on the individual and the effectiveness of interventions intended to alleviate it. However, the subjective nature of the syndrome makes this difficult. 7 As with pain, dyspnea should be considered to exist when the person says it does and accepted as whatever the patient says it is. 6,7
The dyspneic patient is uncomfortably aware of his breathing and may state, “It’s hard to breathe” or “I can’t get enough air.” As breathing rate and effort increase, respiratory and accessory muscles increase in length and tension, leading to fatigue, inability to function, anxiety, and fear of suffocation. A complex interaction exists between physiologic abnormalities and the cognitive awareness of those abnormalities. 6
The visual analog scale (VAS) is commonly used to assess dyspnea. The VAS uses a line anchored by numeric values to indicate the severity of dyspnea (from “none” to “worst”). The individual assigns a numeric value or points to a position on the line that correlates to the severity of his dyspnea. 8 Categorical scales, such as the Borg Scale, 9 are also used. These scales use words (none, mild, moderate, and severe) that are anchored to numeric values to describe symptoms of breathlessness. Zeppetella 10 developed a scoring system, the Dyspnea Quality and Quantity Score (DQQS), which combines the quantitative score of the VAS with a qualitative score. Regardless of the measure used, consistency in assessment approaches is essential. 7
OPIOIDS IN THE RELIEF OF DYSPNEA
A variety of strategies have been used to treat dyspnea. They include use of oxygen, bronchodilators, steroids, sedatives, positioning, fans, rest, controlled breathing, relaxation, and massage. 5–7 Since the first documented case reports using nebulized morphine for terminal dyspnea were published in 1993 11 and 1994, 12 increasing attention has been given to the role of opioids, particularly morphine, in relieving dyspnea.
Opioids work both centrally and locally to reduce dyspnea. Opioid receptors in the brain may decrease the sensation of dyspnea by making the medulla less sensitive to afferent signals, reducing the perception of dyspnea at the cortical level, or by suppressing impulses from the medulla to the respiratory muscles. 6
Opioid receptors are also found throughout the respiratory tract, with the most abundant localized within the alveolar walls. Other receptor sites appear to line the smooth muscle of the trachea and the lumen of the main bronchus. Receptor sites for endogenous opioids (endorphins, enkephalins, and dynorphins), natural opiates (morphine and codeine), and related opioid compounds have been found. “Nonconventional” receptor sites also have been found; however their function is not clear. There is speculation that these sites may play a role in the way morphine acts within lung tissue. It has been proposed that morphine stimulation of these receptors may inhibit the release of acetylcholine and also act on J receptors within the alveolar wall to produce a beneficial pulmonary effect. 13
NEBULIZED MORPHINE: MECHANISM AND FACTORS INFLUENCING EFFICACY
The mechanism by which nebulized morphine acts to relieve dyspnea is not fully understood. A comparison of plasma morphine concentration after morphine 50 mg nebulized, 10 mg oral, or 5 mg intravenous was administered revealed mean systemic bioavailabilities of 5% for nebulized and 24% for oral routes. 14 The lack of reported systemic side effects and bioavailability data suggest a local site of action at opioid or nonconventional receptor sites within the lung.
A number of factors may affect delivery of the drug to the pulmonary beds via nebulizer. Absorption is highly variable and based on the type of delivery system used. 15 The actual dose of nebulized medication that reaches the lungs is only about 2% to 10%, as most of the drug is retained in the nebulizer. 5 Delivery of drugs to the airways requires particles of 1 to 10 μm, with particles of 4 μm having the highest deposition in the alveolar areas of the lungs. Aerosols produced by nebulizers have an average size of 2 to 4 μm and are capable of reaching the alveoli. Temperature, pressure, and humidity may affect the stability of particles in the nebulizer system, resulting in variable drug delivery. Rate and depth of inhalation may also impact delivery of the drug. 5
EFFECTIVENESS OF NEBULIZED MORPHINE
Some authors have reported the use of nebulized morphine to prevent the systemic side effects associated with oral and parenteral administration. Our review of the scope of published literature on this topic in PubMed and Medline showed that the majority of data are descriptive in nature. Fancombe and Chater 11 published case reports of two patients with end-stage CHF and two patients with pulmonary fibrosis, all of whom reported relief of dyspnea with doses titrated according to each one’s need. Dosages for these four patients ranged from 2.5 mg to 25 mg of nebulized morphine every four hours. Arterial blood gases and vital signs monitored in two patients, one with COPD and one with CHF, demonstrated no adverse effects. On the favorable side, patients reported an increased ability to ambulate and to participate in activities of daily living, improvement in breathing at rest and with activity, improved mood, and less anxiety.
In a retrospective chart review of 54 patients suffering from dyspnea related to malignant (n = 40) or nonmalignant (n = 14) etiologies, 63% reported unquantified, subjective improvement in dyspnea with doses of nebulized morphine ranging from 5 mg to 30 mg. 12 Other case reports also have described the effectiveness of nebulized morphine in relieving severe dyspnea in patients with COPD who were dying. 16
Only two studies have been published regarding the use of nebulized morphine for advanced lung or heart disease. A descriptive study 10 reported the use of face masks to administer 20 mg of morphine every four hours to 18 terminally ill hospice patients with primary or secondary intrathoracic malignancies. Six of them also had COPD. A significant reduction in dyspnea, as measured by DQQS, was demonstrated after 24 hours, but no further improvement was shown in 48 hours. As a subgroup, the patients with COPD demonstrated benefit, but appeared to derive less benefit than did the patients without COPD. Patients already receiving opioids reported greater relief of dyspnea than did opioid-naïve patients (those not already receiving it). The authors suggest that the prevalence or binding affinity of opioid receptors in the lungs is influenced by the presence or absence of systemic opioids. The authors reported that the length of time it took to administer the treatment reduced its acceptability for the weakened patient. Six patients were unable to tolerate treatment because of weakness. Two patients were uncomfortable with the face mask: One was offered a hand-held nebulizer as an alternative, but was too weak to continue. Eleven patients, including 50% of the COPD subgroup, continued taking the nebulized morphine for relief of dyspnea after the study was concluded.
Noseda and colleagues 17 describe the results of a placebo-controlled, double-blind randomized study of 17 hospitalized patients who had severe dyspnea unrelieved by other therapies. Twelve of them had COPD; the remaining subjects had malignancies. All treatments showed improvement in dyspnea with no difference between saline and 10 mg or 20 mg of morphine as measured by VAS. The researchers concluded that “the subjects benefited from saline or morphine via a placebo effect, and that nebulized morphine had no specific effect on dyspnea.” No significant systemic side effects were reported in either group.
In an ongoing investigation funded by the American Lung Association, Spector and colleagues 18 are conducting a comparative study to evaluate the relief of dyspnea by nebulized morphine versus oral morphine. There are 15 hospice patients in each group. Data collection will include 1) patient diaries reporting dyspnea according to a modified Borg instrument and recording adverse effects; 2) nurse evaluations of functional status; 3) weekly respiratory assessment including rate, pulse oximetry, and peak expiratory flow rates; and 4) serum morphine levels before and after the first treatment of patients receiving nebulized morphine.
Preliminary data suggest that nebulized morphine may be beneficial to these patients. A case report from this study, presented at the 7th Annual National Research Utilization Conference, describes a patient with end-stage COPD who experienced confusion, constipation, and urinary retention with doses of oral morphine that relieved his dyspnea. After starting nebulized morphine, the patient’s side effects were alleviated while dyspnea continued to be relieved. Case reports and limited clinical trials, although involving small numbers of patients, suggest that nebulized morphine may be effective in relieving intractable dyspnea in some end-stage COPD and CHF patients, while producing no systemic opioid side effects.
Because the available data show variability in patient response to nebulized morphine, results may be influenced by patient variables. Are there factors that make some patients more responsive to the therapy? Does pathology within the lung make morphine receptor sites more available or responsive to the drug? Are there factors that compete with morphine? What are the onset, peak, and duration of action? When is the optimal time to assess the response to nebulized doses? What difference does the drug delivery system make? Research studies conducted from biochemical and histologic perspectives may help clinicians understand the mechanism of action.
Data suggest that there are little or no systemic side effects of nebulized morphine. However, there is a risk of bronchoconstriction related to inhalation of high doses of heroin, which has precipitated sometimes fatal asthma attacks. 13 Smoked cocaine also can cause acute bronchoconstriction that has caused wheezing in nonasthmatic individuals and asthma attacks in those with a history of asthma. The mechanism suggested is local irritation of the airways. 19 However, none of the cited studies of the use of nebulized morphine in terminal dyspnea reported this side effect (one patient reported a fit of coughing after a 20-mg dose). 17 Some patients were too weak to use a nebulizer system or found it uncomfortable. 10 At this point, there are more questions than answers regarding the use of nebulized morphine to relieve dyspnea at the end of life; however, there are implications for nursing practice.
IMPLICATIONS FOR PRACTICE
Although controlled clinical trials are difficult to conduct in patients with terminal dyspnea (and clinicians are hesitant to burden patients with a modality that may not benefit them), the effectiveness of nebulized morphine will not be fully understood until such investigations are undertaken. If treatment with nebulized morphine is under consideration, the clinician must be knowledgeable in patient selection, dosing guidelines, administration, as well as the assessment of effectiveness and monitoring for the occurrence of side effects (see TABLEClinical Implications for Nebulized Opioid Administration, page 13). Well-documented, systematically conducted studies may provide information about the efficacy of nebulized morphine; however, large-scale, randomized, controlled trials are essential for providing substantive evidence that can significantly affect practice.
2. Claessens MT, et al. Dying with lung cancer or chronic obstructive pulmonary disease: insights from SUPPORT. Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments. J Am Geriatr Soc 2000; 48(5 Suppl):S146–53.
3. Levenson JW, et al. The last six months of life for patients with congestive heart failure. J Am Geriatr Soc 2000; 48 (5 Suppl):S101–9.
4. Guyton AC, Hall JE, editors. Textbook of medical physiology.
10th ed. Philadelphia: Saunders; 2000.
5. Murray JF, et al., editors. Textbook of respiratory medicine
. 3rd ed. Philadelphia: Saunders; 2000.
6. Ahmedzai S. Palliation of respiratory symptoms. In: Doyle D, et al., editors. Oxford textbook of palliative medicine
. 2nd ed. Oxford: Oxford University Press; 1998. p. 583–616.
7. Campbell ML. Managing terminal dyspnea: caring for the patient who refuses intubation or ventilation. Dimens Crit Care Nurs 1996; 15 (1):4–13.
8. Hayes M, Patterson D. Experimental development of the graphic rating method. Psych Bull 1921; 18:98–9.
9. Borg G. Subjective effort and physical abilities. Scand J Rehabil Med Suppl 1978; 6:105–13.
10. Zeppetella G. Nebulized morphine in the palliation of dyspnea. Palliat Med 1997; 11 (4):267–75.
11. Farncombe M, Chater S. Case studies outlining use of nebulized morphine for patients with end-stage chronic lung and cardiac disease. J Pain Symptom Manage 1993; 8 (4):221–5.
12. Farncombe M, et al. The use of nebulized opioids for breathlessness: a chart review. Palliat Med 1994; 8 (4):306–12.
13. Zebraski SE, et al. Lung opioid receptors: pharmacology and possible target for nebulized morphine in dyspnea. Life Sci 2000; 66 (23):2221–31.
14. Masood AR, Thomas SH. Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol 1996; 41 (3):250–2.
15. Chandler S. Nebulized opioids to treat dyspnea. Am J Hosp Palliat Care 1999; 16 (1):418–22.
16. Lord E. Nebulized morphine: one intervention for end-stage chronic obstructive pulmonary disease (COPD). AARN News Lett 1997; 53 (10):10–1.
17. Noseda A, et al. Disabling dyspnea in patients with advanced disease: lack of effect of nebulized morphine. Eur Respir J 1997; 10 (5):1079–83.
18. Spector NM, et al. Use of nebulized morphine to relieve dyspnea in a hospice population.
Paper presented at the Seventh National Research Utilization Conference “Evidence-Based Interventions for Symptom Management”; 2000 Apr 13–14; Iowa City (IA).
19. Tashkin DP, et al. Acute effects of inhaled and iv cocaine on airway dynamics. Chest 1996; 110 (4):904–10.