Evidence for the use of Nebulized Opioids for the treatment of Dyspnea
Dyspnea is a subjective experience of breathing discomfort and is often reported by patients with advanced terminal illness. Dyspnea is a debilitating symptom often associated with fear and anxiety. The subjective nature of the condition makes assessing dyspnea difficult. Dyspnea significantly affects the quality of life for both patients and caregivers and presents as a challenge for clinicians today despite advances in palliative care 2.
To understand the treatment of dyspnea with opioids, we first must understand the etiology. Opioid receptors are found both centrally in the medulla and peripherally in the lung parenchyma.11 Opioids acting centrally in the brain decrease sensation of dyspnea by desensitizing the medulla to afferent signals or by suppressing impulses from, the medulla to the lungs. While the mechanisms are not fully understood, it has been proposed that opioids acting peripherally in the lungs may inhibit the release of acetylcholine to reduce dyspnea.
In general, nebulization is a rapid method of administering morphine, but has been shown in studies to be an inefficient route of administration. Nebulized morphine has shown limited systemic absorption in clinical studies when compared to oral morphine (5.5% vs 24%) 8. The low bioavailability of nebulized drug may be due to a number of factors that affect the delivery of the drug to pulmonary beds. Particle size, temperature, pressure and humidity play a role in the stability of particles in the nebulizer contributing to low bioavailability. In addition, low bioavailability of nebulized morphine may be a reason why there are so few reported side effects.
Systemic Opioids have been well-established as first line agents for the symptomatic management of dyspnea in patients with advanced illness. The American College of Chest Physicians, the American College of Physicians, the American Thoracic Society, the Canadian Thoracic Society and the National Comprehensive Cancer Network all recommend the use of systemic opioids for relief of dyspnea with appropriate caution regarding respiratory depression.3 Several randomized studies have demonstrated sufficient evidence for the benefits of systemic opioids in managing dyspnea.1,4,6,,9
There have been case reports on the use of nebulized morphine to prevent the systemic side effects often associated with oral morphine. These reports found symptomatic relief of dyspnea with administration of nebulized opioids with fewer reported adverse events. However, much of the data is subjective in nature and is currently insufficient to validate the use of inhaled opioids over oral opioids for the relief of dyspnea. A controlled double-blind study comparing the effects of nebulized hydromorphone and systemic hydromorphone vs placebo, found no clinically significant difference between the groups for the treatment of dyspnea.6 Other placebo-controlled trials have consistently demonstrated a lack of additional benefit or superiority of nebulized opioids when compared to placebo. 3, 5, 7, 10, 11
Presently, systemic opioids remain the treatment of choice for dyspnea in the terminally ill population. As the studies show, any benefit received from nebulized opioids is not well-established and may be due to placebo-effect. Optimal management must be a multifaceted approach with pharmacological treatment (anxiolytics, opioids, bronchodilators) and non-pharmacological interventions (oxygen, environment, psychosocial support, psychotherapy).12 This whole-person approach should be comprehensive with the goal of addressing the patient’s perception and experience of dyspnea and to reduce the distress, improve quality of life, and have an impact on the patient and family’s sense of wellbeing.
Christine Pham, PharmD., BCGP
- Abernethy AP. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. Bmj. 2003;327(7414):523-528. doi:10.1136/bmj.327.7414.523.
- Afolabi TM, Nahata MC, Pai V. Nebulized opioids for the palliation of dyspnea in terminally ill patients. American Journal of Health-System Pharmacy. 2017;74(14):1053-1061. doi:10.2146/ajhp150893.
- Barnes H, Mcdonald J, Smallwood N, Manser R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database of Systematic Reviews. 2016. doi:10.1002/14651858.cd011008.pub2.
- Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM. Interventions for alleviating cancer-related dyspnea: A systematic review and meta-analysis. Acta Oncologica. 2012;51(8):996-1008. doi:10.3109/0284186x.2012.709638.
- Booth S, Moosavi SH, Higginson IJ. The etiology and management of intractable breathlessness in patients with advanced cancer: a systematic review of pharmacological therapy. Nature Clinical Practice Oncology. 2008;5(2):90-100. doi:10.1038/ncponc1034.
- Charles MA, Reymond L, Israel F. Relief of Incident Dyspnea in Palliative Cancer Patients: A Pilot, Randomized, Controlled Trial Comparing Nebulized Hydromorphone, Systemic Hydromorphone, and Nebulized Saline. Journal of Pain and Symptom Management. 2008;36(1):29-38. doi:10.1016/j.jpainsymman.2007.08.016.
- Lanken PN, Terry PB, Delisser HM, et al. An Official American Thoracic Society Clinical Policy Statement: Palliative Care for Patients with Respiratory Diseases and Critical Illnesses. American Journal of Respiratory and Critical Care Medicine. 2008;177(8):912-927. doi:10.1164/rccm.200605-587st.
- Masood AR, Thomas SHL. Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. British Journal of Clinical Pharmacology. 1996;41(3):250-252. doi:10.1111/j.1365-2125.1996.tb00192.x.
- Schmitz A, Schulz C, Friebel U, Hohlfeld T, Bausewein C. Patient-Controlled Therapy of Breathlessness in Palliative Care: A New Therapeutic Concept for Opioid Administration? Journal of Pain and Symptom Management. 2016;51(3):581-588. doi:10.1016/j.jpainsymman.2015.10.015.
- Viola R, Kiteley C, Lloyd NS, et al. The management of dyspnea in cancer patients: a systematic review. Supportive Care in Cancer. 2008;16(4):329-337. doi:10.1007/s00520-007-0389-6.
- Westphal CG, Campbell ML. Nebulized Morphine for Terminal Dyspnea. American Journal of Nursing. 2002;102(Supplement):11-15. doi:10.1097/00000446-200205001-00004.
- Current Opinion in Supportive and Palliative Care: June 2009 – Volume 3 – Issue 2 – p 98–102 doi: 10.1097/SPC.0b013e32832b725e