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(Chest. 2004;125:691-694.)
© 2004 American College of Chest Physicians

Nebulized Opioids Use in COPD*

Pamela A. Foral, PharmD, BCPS; Mark A. Malesker, PharmD; Guillermo Huerta, MD, FCCP and Daniel E. Hilleman, PharmD

* From Creighton University School of Pharmacy and Health Professions (Drs. Foral, Malesker, and Hilleman), Omaha; and Creighton University School of Medicine, Omaha, NE.

Correspondence to: Pamela A. Foral, PharmD, BCPS, Creighton University School of Pharmacy and Health Professions, 2500 California Plaza, Omaha, NE 68178; e-mail: pforal{at}creighton.edu


   Abstract
TOP
 Abstract
Introduction
 Literature Review
 Summary
 References
 
Objective: To evaluate the role of nebulized opioids in COPD.

Methods: A MEDLINE search was completed to obtain pertinent clinical literature. Key search terms included the following: nebulizer, opioids, COPD, dyspnea, morphine, and hydromorphone.

Results: Currently, the evidence in the literature is lacking regarding placebo-controlled studies to support nebulized morphine for the relief of dyspnea in patients with COPD. The studies reviewed varied considerably in the dose, opioid used, administration schedule, and methodology. One study found improved exercise capacity in 11 patients not reproducible in a larger sample, and another study found benefit in 54 terminal patients. All other studies found no benefit.

Conclusions: The recently published Global Initiative for Lung Disease guidelines have specifically stated that opioids are contraindicated in COPD management due to the potential respiratory depression and worsening hypercapnia. Nebulized opioids should be discouraged, as current data do not support their use.

Key Words: COPD • dyspnea • nebulizer • opioids


   Introduction
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 Abstract
 Introduction
Literature Review
 Summary
 References
 
COPD is characterized by progressive airflow limitation that is not fully reversible.1 A progressive dyspnea may be present in patients with mild-to-moderate COPD. The pharmacologic treatment of COPD typically includes bronchodilators, corticosteroids, antibiotics, and oxygen.1 2 As the disease progresses to severe COPD, dyspnea may often be debilitating, ie, decreasing quality of life and activities of daily living. Opioids have been utilized to suppress the sensation of dyspnea in the patient with chronic, stable COPD.3 In the patient with end-stage COPD, nebulized opioids may be considered as a potential treatment option.

Eaton and associates4 postulated that the mechanism of nebulized opioids in patients with lung disease, although not well understood, may be multifactorial. Depression of local opioid receptors in the lungs, depression of opioid receptors in the spinal cord, depression of central respiratory centers, and other systemic effects may all have a role.4 Morphine may also decrease anxiety and diminish ventilatory response to hypoxia and hypercapnia.5

Fewer side effects have been noted with inhaled morphine compared with injectable routes.6 This would offer an advantage if the relief of dyspnea could be relieved without the adverse effects of IV opioids. The absorption of nebulized morphine into the plasma is rapid, within 10 min, but has considerably less bioavailability when compared to oral administration: 5.5% vs 24%, respectively.7


   Literature Review
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 Abstract
 Introduction
 Literature Review
Summary
 References
 
Originally, a study by Young et al8 randomized 11 patients with advanced chronic lung disease into a double-blind, crossover study comparing the effects of inhaled low-dose morphine (mean dose delivered of 1.7 mg) and placebo on exercise endurance (Table 1 ). A significant positive correlation between nebulized morphine and improvement in exercise endurance time (35%) was demonstrated. There were no reported side effects.


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  		Table 1.. Summary of Studies Utilizing Nebulized Opioids in Predominantly COPD Patients*

 
In a follow-up study, Jankelson et al9 found that two patients who demonstrated a much greater improvement, with the other patients improving slightly, skewed the results. They investigated if high doses of inhaled morphine would have a positive impact on exercise endurance and relief of dyspnea in patients with COPD, as well as if there was significant absorption into the plasma. In a double-blind study, 16 patients with stable COPD were randomized to receive 0.9% saline solution, or 20 mg or 40 mg of morphine via nebulization (Table 1) . The patients performed 6-min walk tests immediately after the nebulized test solution, and again 60 min later. Although the 40-mg dose of nebulized morphine produced higher plasma concentrations than the 20-mg dose, there was no difference in exercise endurance or relief of dyspnea when comparing either morphine doses with placebo. There were no reported side effects with nebulized morphine, except for one patient who received a 40-mg dose and experienced lightheadedness.

Beauford et al10 investigated the effects of nebulized morphine (0 mg, 1 mg, 4 mg, and 10 mg) on exercise tolerance and psychological status in a double-blind, crossover study of eight patients with COPD (Table 1) . They found no significant differences between the placebo and treatment groups in spirometry at rest, exercise tolerance, visual vigilance, motor speed, or subjective moods of patients. The authors concluded that the morphine doses administered offered no benefit to exercise tolerance.

In a study by Masood et al,11 12 patients with stable, severe COPD were randomized in a double-blind, crossover study to evaluate nebulized morphine (10 mg and 25 mg), IV morphine (1 mg and 2.5 mg), and placebo on breathlessness, gas exchange, ventilation, and exercise endurance (Table 1) . There were no significant changes in any of the variables tested. Significant adverse effects were not experienced. Three patients experienced lightheadedness: one with placebo, and two with low-dose inhaled morphine.

A placebo-controlled, double-blind, crossover study by Noseda et al12 evaluated 17 hospitalized patients with severe lung or heart disease and disabling dyspnea (Table 1) . They were randomized over 4 days to receive nebulized saline solution with oxygen, 10 mg of morphine with oxygen, 20 mg of morphine with oxygen, and 10 mg of morphine without oxygen. The groups that received oxygen were administered 2 L/min via nasal prongs. The relief of dyspnea at rest was compared with morphine vs placebo. Twelve of the patients had COPD, 3 patients with malignancy, 1 patient with idiopathic pulmonary fibrosis, and 1 patient with heart failure. Three of the patients died during the study, not related to the protocol. There was no significant difference between morphine and placebo in the relief of dyspnea.

Two additional studies have evaluated the benefit of nebulized opioids for dyspnea, but included subjects with other disease states. Farncombe et al13 reported the results of a retrospective chart review involving 54 patients in the terminal stage of their illness who had received nebulized opioids for relief of dyspnea. Forty of the patients had a malignant diagnosis, while 14 patients had nonmalignant diagnosis, including 6 patients with lung disease. Initially, 34 patients received nebulized morphine, 5 mg q4h. Thirteen of these patients required further titration up to a maximum of 30 mg q4h nebulized morphine. Seventeen patients received nebulized hydromorphone, 1 mg q4h. While nine of these patients required further titration, one of the nine patients required a maximum of 20 mg q4h. Two patients received nebulized codeine, 15 mg q4h; one patient, due to previous morphine intolerance, received anileridine, 25 mg q4h. Twelve of the patients for varying reasons received the nebulized treatment for three or fewer doses. Eight patients received nebulized opioids for 1 to 2 days, 17 patients for 3 to 14 days, and 17 patients for > 15 days. Favorable results were reported in 63% of the patients. This represented 81% of patients having received more than three doses of nebulized opioids. Improvement in subjective symptoms ranged from less shortness of breath, increased exercise endurance, and the feeling of being relaxed. These changes were noted within 15 min of the administration of the nebulizer treatment, and lasted >= 4 h in over half of these patients. There were no reported adverse effects.

Another possible application to nebulized morphine sulfate may include use in patients with interstitial lung disease. In a double-blind, crossover, placebo-controlled trial by Harris-Eze et al,14 six patients with interstitial lung disease were evaluated on the effects of inhaled saline solution and 2.5 mg and 5 mg of morphine on exercise performance. The subjects underwent maximum incremental cycle ergometry for each treatment separated by 3 days. The patient’s perception of dyspnea was assessed before and after nebulization at rest, before exercise, during exercise, and at the completion of exercise. There was no significant difference in relief of dyspnea during exercise or improvement in exercise performance between the three groups. No side effects were noted.

While it appears that the majority of the studies have not reported serious adverse effects with inhaled morphine, there is a case of a 74-year-old woman with advanced metastatic disease who had respiratory depression 15 min after receiving one nebulized dose of morphine at 4 mg.15


   Summary
TOP
 Abstract
 Introduction
 Literature Review
 Summary
References
 
Opioids may have multiple mechanisms of action for symptomatic relief of dyspnea, both peripheral and central in origin. Conceptually, the nebulized route of administration should provide the benefit of dyspnea relief without systemic side effects. It is not understood if there are opioid receptors in the chest wall or lung. Currently, the evidence in the literature is lacking regarding placebo-controlled studies to support nebulized morphine for the relief of dyspnea or improvement of exercise tolerance in patients with COPD. Of the studies reviewed, five investigated patients primarily with COPD. The two remaining studies were of patients with a mix of pulmonary diseases. With the exception of the study by Farncombe et al,13 the other studies were prospective and double blind. Of the studies containing predominantly patients with COPD 4 were crossover in design, and all made use of placebo and evaluated small numbers of patients (8 to 16). Additionally, the studies reviewed varied considerably in the dose, opioid used, administration schedule, as well as methodology (concomitant oxygen use). The majority of the studies used morphine sulfate administered via a jet nebulizer over 10 to 12 min. It is unknown whether the underlying COPD, secretions, and/or airway narrowing may have altered the deposition characteristics of the nebulized opioid. Furthermore, morphine can stimulate histamine release and bronchoconstriction, and theoretically may have antagonized any central or peripheral effects from the nebulized opioids and diminished the clinical benefit.16 The clinical application of these studies is difficult based on the small sample size. Young et al8 found improved exercise capacity in 11 patients not reproducible in a larger sample, and Farncombe et al13 found benefit in 54 terminal patients. All others found no benefit. Furthermore, the recently published Global Initiative for Lung Disease guidelines have specifically stated that opioids are contraindicated in COPD management due to the potential respiratory depression and worsening hypercapnia.1 Nebulized opioids should be discouraged, as current data do not support their use.

Received for publication April 14, 2003. Accepted for publication September 2, 2002.


   References
TOP
 Abstract
 Introduction
 Literature Review
 Summary
 References
 

  1. Pauwels, RA, Buist, S, Calverley, PMA, et al (2001) Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163,1256-1276[Free Full Text]
  2. McCrory, DC, Brown, C, Gelfand, SE, et al Management of acute exacerbations of COPD. Chest 2001;119,1190-1209[Abstract/Free Full Text]
  3. Nicotra, MB, Carter, R The use of opiates in chronic obstructive pulmonary disease. Clin Pulm Med 1995;2,143-151
  4. Eaton, B, Hall, J, MacDonald, S Does nebulized morphine offer symptom relief to patients with disabling dyspnea during end-stage disease? Can Fam Physician 1999;45,319-320[ISI][Medline]
  5. 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 1998;8,221-225
  6. Mabe, SR, Connelly, JF Nebulized morphine for the relief of dyspnea. Am J Health Syst Pharm 1995;52,146-148[ISI][Medline]
  7. Masood, AR, Thomas, SHL Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol 1996;41,250-252[ISI][Medline]
  8. Young, IH, Daviskas, E, Keena, VA Effect of low dose nebulized morphine on exercise endurance in patients with chronic lung disease. Thorax 1989;44,387-390[Abstract]
  9. Jankelson, D, Hosseini, K, Mather, LE, et al Lack of effect of high doses of inhaled morphine on exercise endurance in chronic obstructive pulmonary disease. Eur Respir J 1997;10,2270-2274[Abstract]
  10. Beauford, W, Saylor, TT, Stansbury, DW, et al Effects of nebulized morphine sulfate on the exercise tolerance of the ventilatory limited COPD patient. Chest 1993;104,175-178[Abstract/Free Full Text]
  11. Masood, AR, Reed, JW, Thomas, SHL Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease. Thorax 1995;50,629-634[Abstract]
  12. Noseda, A, Carpiaux, JP, Markstein, C, et al Disabling dyspnoea in patients with advanced disease: lack of effect of nebulized morphine. Eur Respir J 1997;10,1079-1083[Abstract]
  13. Farncombe, M, Chater, S, Gillin, A The use of nebulized opioids for breathlessness: a chart review. Palliat Med 1994;8,306-312[Abstract/Free Full Text]
  14. Harris-Eze, AO, Sridhar, G, Clemens, RE, et al Low-dose nebulized morphine does not improve exercise in interstitial lung disease. Am J Respir Crit Care Med 1995;152,1940-1945[Abstract]
  15. Lang, E, Jedeikin, R Acute respiratory depression as a complication of nebulized morphine. Can J Anaesth 1998;45,60-62[Abstract/Free Full Text]
  16. Hutchison TA, Shahan DR. DRUGDEX® system. Greenwood Village, CO: Micromedix (edition expires September 2003)



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