Our July Palliative Pearls Case Study highlights a patient who has a primary diagnosis of COPD and comorbidities of HTN and Afib. In this case, we will explore if opioids are a viable palliative treatment option for patients suffering from dyspnea. We encourage you to download this month’s case study to share with your colleagues or continue reading below.
TL is a 74-year-old male admitted to hospice 1 month ago. He has a primary diagnosis of COPD and comorbidities of HTN and Afib. He has no known drug allergies and lives at home with his wife.
Current medications include:
- Albuterol 0.083% solution for nebulization, 1 vial via nebulizer every 4 hours as needed
- Breo Ellipta® (fluticasone-vilanterol) 100-25mcg, inhale 1 puff by mouth daily
- Morphine 20 mg/ml oral concentrate, 0.25 ml (5 mg) by mouth every 4 hours as needed
- Lisinopril 10mg, 1 tablet by mouth daily
- Warfarin 2mg, 1 tablet by mouth daily
- Metoprolol ER 100mg, 1 tablet by mouth daily
TL’s heart rate and blood pressure are typically controlled, although he is now experiencing an increase in shortness of breath and increased anxiety and his heart rate is up. The shortness of breath has caused him to use his albuterol nebulizer treatments more frequently. His wife attributes the anxiety to the shortness of breath. She states he seems anxious all day. TL confirms he has been using his Breo Ellipta® every day but it doesn’t seem to be helping anymore. He has not been taking any morphine because he states he is not in pain.
TL also has trouble swallowing his food and reports mouth pain. He states that he has been eating only soft foods, such as applesauce, and drinking supplemental beverages that his wife picked up from the store. He has not experienced any weight loss since the last visit.
DYSPNEA AT END OF LIFE
The American Thoracic Society (ATS) defines dyspnea as “a subjective experience of breathing discomfort that comprises qualitatively distinct sensations that vary in intensity”.1 Dyspnea is the most common symptom in advanced COPD and has numerous contributors and exacerbators in “the physical, psychological, interpersonal and spiritual dimensions”.2 In advanced COPD, the disease is no longer in a modifiable state and despite maximizing inhalational therapies and non-pharmacologic methods, the dyspnea experience is often refractory. Some of the common causes seen at end of life are factors including, but not limited to, disease states (e.g., COPD, heart failure, anemia), pain, anxiety, and extreme temperatures.
To properly treat dyspnea, it is important to understand what is causing the dyspnea, the patient’s prognosis and goals of care when developing a treatment plan. Nebulized bronchodilator solutions and oral steroids are typically trialed first for patients at end of life. When dyspnea is persistent despite these measures, other factors should be assessed and managed for patient comfort.
- Reposition the patient to an upright position, as feasible
- Increase air movement throughout the room by opening a window
- Direct a fan to blow directly on the face
- Maintain a cool temperature
- Introduce bedside relaxation techniques such as music therapy
- Identify items that may be of need and placing them in proximity of patient so walking long distances is unnecessary
- Reduce anxiety with the presence of a companion at the bedside (for reassurance as well as reducing feelings of isolation), with the presence of a calming clinician and/or listening to calming music
Cost-Effective Pharmacologic Approaches:3
- Solutions for nebulization: Albuterol, ipratropium, or ipratropium-albuterol (Duoneb®)
- Oral corticosteroids: Prednisone or dexamethasone
- Supplemental oxygen for hypoxemic patients
- Benzodiazepines to manage anxiety-induced dyspnea (e.g., lorazepam)
- Diuretics to manage fluid-retention-induced dyspnea (e.g., furosemide)
- Antitussives for cough-related dyspnea (e.g., dextromethorphan, benzonatate)
- Opioids for refractory cases (e.g., morphine, oxycodone, hydromorphone)
ORAL & PARENTERAL OPIOID USE FOR DYSPNEA
Opioids, when added to standard therapy, have been shown to reduce the sensation of dyspnea. This therapy is well-supported, in oral and parental form, alongside a multidisciplinary approach to gain control of this symptom in patients with COPD2,5-9 and other conditions.
Although appreciated that opioids produce respiratory depression as an adverse effect, the precise mechanism of how they manage breathlessness remains unclear. Opioids may diminish the chemoreceptor response to hypercapnia and hypoxia, or they may cause vasodilation, leading to preload reduction and pulmonary congestion, and resulting in decreased dyspnea. Additionally, opioids can facilitate a decrease in anxiety and the subjective sensation of dyspnea without reducing respiratory rate or oxygen saturation.10
Many clinicians use opioids as drugs of choice for dyspnea at end-of-life including dyspnea that is refractory to the treatment of underlying conditions. Typically, in opioid naïve patients, the opioid is started at a low dose, such as oral morphine up to 5mg or parenteral morphine up to 2mg. These doses will usually provide relief for most patients. Patients on chronic opioids may need higher doses.3 Those clinicians hesitant to use opioids to manage dyspnea cite concerns of systemic side effects, such as respiratory depression and sedation, leading to increased rates of hospitalizations and/or death. Various studies refute the risk of systemic side effects is significant if dose is started low and titrated slowly to effect.5,11-13 In addition, the initiation of low-dose sustained-release morphine, even as little as 10mg daily, support that opioids can be both safe and effective for dyspnea.14,15
NEBULIZED OPIOID USE FOR DYSPNEA
Much of the support for nebulized opioid use is anecdotal. Clinician experience varies, and it is important to recognize that although there are a variety of small trials, case series and expert opinions in the literature, there remain no randomized, controlled studies to support this practice.
Specifically, no randomized controlled studies have demonstrated greater efficacy, or lower side effects, comparing nebulized morphine to oral or parental morphine.3 The one study that attempted this comparison used a limited sample size and did not have enough power to show a significant difference.16 Some experts have hypothesized that nebulized opioids do not act systemically and opioids must reach systemic blood levels to reduce dyspnea.17 Additionally, non-controlled trials have “consistently demonstrated a lack of effect of nebulized morphine” compared with placebo for dyspnea.18-21
Similarly, a study of nebulized or systemic hydromorphone compared to placebo, with a large enough sample size to detect an effect, found no difference between the three groups in dyspnea score 10 minutes post-treatment.18,22
Nebulized fentanyl, being lipophilic, is thought to be more readily absorbed than morphine or hydromorphone; such was the basis of one study’s conclusion that it was “superior to placebo” for dyspnea in a COPD sample population.18,23 Fentanyl via nebulization remains an area of interest for researchers encouraging study on a larger controlled population to truly measure efficacy.23-25
TL has reported increased dyspnea and anxiety. After further assessment, there is no reason to suspect fluid in the lungs. He has increased the frequency of albuterol via nebulizer usage to every 4 hours and rarely misses a dose. His wife notices that his heart rate and blood pressure increase when measured after a dose of albuterol. Albuterol, when used frequently, may cause cardiovascular side effects including tachycardia, hypertension, and arrhythmias.
Oral exam reveals a mild case of thrush. TL demonstrates how he is using his Breo Ellipta®. It is determined that he cannot take a deep breath nor hold his breath for more than 5 seconds. When an inhaler is not used properly, it does not produce the symptom relief intended and there is a potential for the active ingredients to get trapped in the throat and mouth. Recall that Breo Ellipta® contains the corticosteroid fluticasone. Inhaled corticosteroids are major contributors to the growth of Candida albicans, the fungal organism causing thrush, especially when users neglect to rinse their mouth and throat directly after use.
TL is willing to try low dose morphine to help with his dyspnea. He states that he will try a few doses to see if it helps.
- Discontinue Breo Ellipta® since patient can no longer utilize properly
- Initiate the morphine 20mg/mL solution at a low dose of 0.25mL (5mg) by mouth or under the tongue every 3 hours as needed for shortness of breath
- Recommend lorazepam 0.5mg by mouth or under the tongue every 4 hours as needed for anxiety
- Discourage the use of albuterol via nebulizer in lieu of trialing morphine for shortness of breath. Reassess to confirm improvement in blood pressure and heart rate.
- Initiate nystatin oral suspension, swish and swallow 5ml four times daily for 7 days for oral thrush
- Check INR and adjust dose of warfarin if decreased food intake continues after thrush improves. Consider risks and benefits of continuing anticoagulation.
- Parshall MB, et al. An official American Thoracic Society statement: Update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185(4):435.
- Vanston VJ, et al. UNIPAC 8: COPD, Heart Failure, and Renal Disease In: Essential Practices in Hospice and Palliative Medicine, 5th Shega JW, Paniagua MA, eds. Chicago, IL: American Academy of Hospice and Palliative Medicine, Inc; 2017.
- Weissman DE. Fast Facts & Concepts #27: Dyspnea at End-of-Life. Revised April 2015. https://www.mypcnow.org/fast-fact/dyspnea-at-end-of-life/
- Shega JW, Paniagua MA, eds. UNIPAC 4: Nonpain Symptom Management. Essential Practices in Hospice and Palliative Medicine, 5th edition. Chicago, IL: American Academy of Hospice and Palliative Medicine; 2017.
- Davis MP, et al. Looking both ways before crossing the street: Assessing the benefits and risk of opioids in treating patients at risk of sleep -disordered breathing for pain and dyspnea. J Opioid Manag. 2017 May/Jun;13(3):183-196
- Jennings AL, et al. A systemic review of the use of opioids in the management of dyspnea. 2002;57(11):939-944.
- Lorez KA, et al, Evidence for improving palliative care at the end of life: A systemic review. Ann Intern Med. 2008;148(2):147-159.
- Marciniuk D, et al. Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: A Canadian Thoracic Society clinical practice guideline. Can Respir J. 2011;18(2):69-78.
- Waseem A, et al. Diagnosis and management of stable chronic obstructive pulmonary disease: A clinical practice guideline update from the American College of Physicians, American College of Chest Physicians, American Thoracic Society, and European Respiratory Society. Ann Intern Med. 2011;155(3):179-191.
- Indelicato RA. The Advanced Practice Nurse’s Role in Palliative Care and the Management of Dyspnea. Topics in Advanced Practice Nursing eJournal. 2006;6(4). https://www.medscape.com/viewarticle/551364_5
- Abernethy AP, et al. Randomised, double-blind, placebo-controlled crossover trial of sustained release morphine for the management of refractory dyspnea. 2003;327: 523-528.
- Ekstrom M, et al. Safety of benzodiazepines and opioids in very severe respiratory disease: National prospective study. 2014;348:g445.
- Bales H, et al. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochran Database Syst Rev. 2016 Mar 31. https://doi.org/10.1002/14651858.CD011008.pub2
- Currow DC, et al. Once-daily opioids for chronic dyspnea: A dose increment and pharmacovigilance study. J Pain Symptom Manage. 42(3): 388-399.
- Rocker GM, et al. Opioid therapy for refractory dyspnea in patients with advanced chronic obstructive pulmonary disease: Patients’ experiences and outcomes. CMAJ Open. 2013; http://cmajopen.ca/content/1/1/E27.full.pdf+html
- Bruera E, et al. Nebulized versus subcutaneous morphine for patients with cancer dyspnea: A preliminary study. J Pain Symptom Manage. 2005;29:613.
- CAPC Online Clinical Training Courses. Symptom Management: Dyspnea. Reviewed November 12, 2015. Available from https://www.capc.org/training/symptom-management/dyspnea/
- Dudgeon et al. Assessment and Management of Dyspnea in Palliative Care. In: UpToDate, Bruera E, Givens J, Hollingsworth H, eds. Waltham, MA: UpToDate, Inc; Updated March 9, 2020.
- Davis C. The role of nebulised drugs in palliating respiratory symptoms from malignant disease. Eur J Palliat Care. 1995; 2:9.
- Booth S, et al. The etiology and management of intractable breathlessness in patients with advanced cancer: A systematic review of pharmacological therapy. Nat Clin Pract Oncol. 2008; 5:90.
- Barnes H, et al. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev. 2016; 3:CD011008.
- Charles MA, et al. Relief of incident dyspnea in palliative cancer patients: a pilot, randomized, controlled trial comparing nebulized hydromorphone, systemic hydromorphone, and nebulized saline. J Pain Symptom Manage. 2008; 36:29.
- Jensen D, et al. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage. 2012; 43:706.
- Coyne PJ, et al. Nebulized Fentanyl Citrate Improves Patients’ Perception of Breathing, Respiratory Rate, and Oxygen Saturation in Dyspnea. J Pain Symptom Manage. 2002 Feb;23(2):157-60. https://doi.org/10.1016/S0885-3924(01)00391-8
- Bausewein C, Simon S. Inhaled nebulized and intranasal opioids for the relief of breathlessness. Curr Opin Support Palliat Care. 2014 Sep;8(3):208-12. doi: 10.1097/SPC.0000000000000071.
- Higgins EA, et al. Nebulized Fentanyl for Dyspnea: A Retrospective Chart Review. J Pain Palliat Care Pharmacother. 2020 Jun;34(2):77-81. https://doi.org/10.1080/15360288.2019.1708529
- Clinical Pharmacology [database online]. Tampa, FL: Elsevier/Gold Standard, Inc.; 2020. Accessed 2020 Jun.