Dyspnea, or shortness of breath, is a very common complaint in hospice and palliative care. Up to 70% of end stage cancer or COPD patients experience dyspnea.1 Opioids, such as morphine, have been used to relieve the uncomfortable sensation associated with dyspnea. Oral and parenteral morphine are the most well studied routes of administration for this indication. Unfortunately, systemic absorption of opioids can cause adverse events that may be considered unbearable in the hospice population such as nausea, vomiting, drowsiness, constipation, and respiratory depression. Oral administration of morphine takes 15-30 minutes to take effect and lasts about four hours.2,3 While parenteral administration of morphine takes 6-10 minutes to take effect and also last about four hours. Inhaled opioids have a faster onset of action than the oral route and considered less invasive than the parenteral route.2
The use of nebulized opioids can be considered an appealing option compared to the oral and parenteral routes of administration. However, nebulized opioids are not routinely recommended. This is because there is conflicting data as to their benefit. There are no large-scale studies testing the efficacy of nebulized opioids, and smaller studies show conflicting evidence. Some studies show that nebulized opioids are less effective compared to oral or parenteral administration while others show that nebulized morphine is equally efficacious to subcutaneous morphine.1,4 Some patients are noted to prefer nebulized morphine over other routes of administration.4
A systematic review of 18 clinical trials that evaluated all routes of opioids in the management of dyspnea found a statistically significant benefit with the oral and parenteral routes of administration but found the nebulized route of administration to be no more effective than nebulized saline. However, the authors of this review did note that there might have been insufficient data with the nebulized route of administration to make this claim.8 Another review of 9 clinical trials looking at efficacy of nebulized morphine in the management of dyspnea found that 3 of the trials had positive results, but the rest failed to show improvement after treatment. The authors note that the small number of subjects, variety of disease states, and different outcome measures limited the interpretation of the results.9 Based upon these varying results, the use of nebulized opioids for the management of dyspnea are not routinely recommended. If you are going to consider a trial of a nebulized opioid, then it is recommended to use an injectable vial and not the oral morphine concentrate. A review of the literature will find no place where the oral concentrate has been evaluated and one article that directly states that the oral elixir should not be used.10 There is some belief that the sugar-free formulation of the oral morphine solution can be used via nebulizer, however, there is not literature to support this. It is of note that all current oral morphine solutions are sugar free and that the sugar containing oral morphine solutions are no longer on the market.7 There is some concern if the injectable vial needs to be preservative free for use via nebulizer. This concern comes from the fact the preservatives can induce bronchospasm in some patients. This is a rare but sometimes serious side effect. The preservatives of most concern are sulfites and edetate disodium (EDTA), found in both oral and parenteral preparations of morphine.5,6 It is not necessary to use preservative-free morphine, but caution should be used in patients susceptible to bronchospasms. If you are not using a preservative free product, then it is recommended to monitor your patient during the first administration of the nebulized opioid for this side effect. Typical starting dose for nebulized morphine is 2.5-10 mg; this can be titrated up to 30 mg per dose. Alternatives to morphine include hydromorphone 0.25- mg or fentanyl 25 mcg.1 Doses can be repeated every 4 hours as needed.3 Morphine for injection should be diluted to 2 mL volume with normal saline solution, if needed.1
Submitted by: Shawn Millsop, PharmD Candidate 2016 at Duquesne University School of Pharmacy and Lorin Yolch, PharmD, CGP, FASCP, Director of Professional Education at Delta Care Rx
1 Ferraresi V. Inhaled opioids for the treatment of dyspnea. Am J Health-Syst Pharm. 2005; 62: 319-320.
2 Bausewein C, Simon ST. Inhaled nebulized and intranasal opioids for the relief of breathlessness. Curr Opin Support Palliat Care. 2014; 8: 208-212.
3 Sarhill N, Walsh D, Khawarm E, Tropiano P, Stahley MK. Nebulized hydromorphone for dyspnea in hospice care of advanced cancer. Am J Hosp Palliat Care. December 2000; 17(6): 389-391.
4 Bruera E, Sala R, Spruyt, et al. Nebulized Versus Subcutaneous Morphine for Patients with Cancer Dyspnea: A Preliminary Study. J Pain Symptom Manage. June 2005: 29(6): 613-618.
5 Excipients in the label and package leaflet of medicinal products for human use. European Commission. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003412.pdf Published July 2003. Accessed June 2, 2015.
6 Beasley R, Fishwick D, Miles JF, Hendeles L. Preservatives in nebulizer solutions: risk without benefit. Pharmacotherapy. January-February 1998; 18(1): 130-139.
7 Gold Standard, Inc. Morphine. Clinical Pharmacology [database online]. Available at: http://www.clinicalpharmacology.com. Accessed June 25, 2015.
8 Jennings AL, Davies AN, Higgins JP, Gibbs JSR, Boardley KE. A Sytematic Review of the use of Opioids in the management of dyspnoea. Thorax. 2002;57:939-44.
9 Brown SJ, Eichner SF, Jones JR. Nebulized Morphine for Relief of Dyspnea Due to Chronic Lung Disease. The Annals of Pharmacotherapy. June 2005;29:1088-92.
10 Ahmedzai S, Davis C. Nebulised drugs in palliative care. Thorax. 1997;52(Suppl 2):S75-77.