Nebulized Versus Subcutaneous Morphine for Patients with Cancer Dyspnea: A Preliminary Study

Vol. 29 No. 6 June 2005 Journal of Pain and Symptom Management 613 Clinical Note Nebulized Versus Subcutaneous Morphine for Patients with Cancer Dyspnea: A Preliminary Study Eduardo Bruera, MD, Raul Sala, MD, Odette Spruyt, MD, J. Lynn Palmer, PhD, Tao Zhang, MS, and Jie Willey, MSN The University of Texas M. D. Anderson Cancer Center (E.B., J.L.P., T.Z., J.W.), Houston, Texas, USA; Hospital Escuela Eva Peron (R.S.), Rosario, Argentina; and Peter MacCallum Cancer Institute (O.S.), East Melbourne, Victoria, Australia Abstract This study compared the effects of nebulized versus subcutaneous morphine on the intensity of dyspnea in cancer patients. Patients with a resting dyspnea intensity 3 on a 0 10 scale (0 no dyspnea, 10 worst possible dyspnea) who received regular oral or parenteral opioids were included. On day 1, patients received either subcutaneous (SC) morphine plus nebulized placebo or nebulized morphine plus SC placebo. On day 2, a crossover was made. Dyspnea intensity, side effects, and blinded preference of treatment were assessed. Eleven patients completed the study. Dyspnea decreased from a median of 5 (range, 3 8) to 3 (range, 0 7) after SC morphine (P 0.025) and from 4 (range, 3 9) to 2 (range, 0 9) after nebulized morphine (P 0.007). There was no significant difference in dyspnea intensity between nebulized and subcutaneous morphine at 60 minutes. Unfortunately, due to limited sample size, there was insufficient power to rule out a significant difference between both routes of administration. Nebulized morphine offered dyspnea relief similar to that of SC morphine. Larger randomized controlled trials in patients with both continuous dyspnea and earlier stages of dyspnea are justified. J Pain Symptom Manage 2005;29:613 618. 2005 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Dyspnea, opioids, nebulization, subcutaneous injection Introduction Dyspnea is a frequent and devastating symptom in patients with advanced cancer. 1,2 In most Address reprint requests to: Eduardo Bruera, MD, Department of Palliative Care and Rehabilitation Medicine, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 008, Houston, TX 77030, USA. Accepted for publication: August 24, 2004. 2005 U.S. Cancer Pain Relief Committee Published by Elsevier Inc. All rights reserved. of these patients, dyspnea is due to primary or metastatic invasion of the lungs, pleural effusions, underlying chronic obstructive pulmonary disease (COPD), infections, pulmonary embolism, or chronic heart failure. 1 Unfortunately, in most cases, the underlying mechanism is not reversible and symptomatic treatment therefore is required. Few studies have investigated therapeutic interventions for cancer dyspnea. This is partially because patients with early stages of dyspnea 0885-3924/05/$ see front matter doi:10.1016/j.jpainsymman.2004.08.016

614 Bruera et al. Vol. 29 No. 6 June 2005 have a rapidly changing syndrome that is difficult to study with therapeutic interventions. The smaller number of patients who have continuous dyspnea, which might make them good candidates for clinical trials, are usually already in severe distress or cognitively impaired. Systemic morphine administration is an effective symptomatic treatment for cancer dyspnea. 3 6 However, the limitations of this treatment are significant latency for maximal effect when given either orally or parenterally and the frequent presence of sedation or cognitive impairment in patients who already have borderline cognitive function. In recent years, there have been reports on the effectiveness of nebulized morphine. 6 16 This route is of interest because of its potential for rapid onset of action and ease of administration, both in hospices and at home. In addition, because the absorption of nebulized opioids seems to be low, 8 10 nebulized morphine might offer dyspnea relief with fewer adverse effects as compared to systemic administration. To compare the effects of subcutaneous (SC) versus nebulized morphine for the relief of dyspnea associated with advanced cancer, we conducted a double-blind, randomized controlled trial. Methods All participating sites institutional review boards approved the study. All patients provided written informed consent. Patients Patients were eligible for this study if they had dyspnea related to advanced cancer (primary or metastatic lung cancer, pleural effusion, or carcinomatous lymphangitis) with a predominant restrictive ventilation (no clinical evidence of significant bronchospasms); had a resting dyspnea intensity of at least 3 on a 0 10 scale (0 no shortness of breath; 10 worst possible shortness of breath); were receiving regular oral or parenteral opioids with no dose change for 72 hours; and had normal cognition status, defined as a normal state of arousal and absence of obvious clinical findings of confusion, memory loss, or concentration deficit. Patients were not eligible if they had contraindications for the administration of morphine or if dyspnea was related to acute complications, such as a sudden onset of pneumonia, embolism, or congestive heart failure. Procedure This was a double-blind, randomized controlled study. In addition to patients regularly scheduled opioid dose, eligible patients were randomly assigned to receive half of their scheduled equivalent opioid dose. For example, using standard conversion tables, if a patient was scheduled to receive 10 mg of hydromorphone orally every 4 hours, that was converted to 50 mg of equivalent oral morphine, and patients received, as part of the study, a subcutaneous injection or nebulization of 25 mg (equivalent to 2 hours of oral treatment). For patients receiving slow-release opioids every 12 hours, the slow-release dose was treated as 12 hourly doses, which were divided by 3 to determine the dose to be administered every 4 hours. We chose to give patients the same dose of morphine either SC or nebulized. In previous studies, we had observed that a ratio of 2:1 for SC morphine resulted in significant improvement in dyspnea. 3,5 Therefore, we maintained this dose in the present study. On day 1, patients received either nebulized morphine plus an SC injection of placebo (3 cc of normal saline) or an SC injection of morphine and nebulized placebo. On day 2, a crossover was made, and patients received the alternate treatment. Each day, before treatment, patients rested for 1 hour. At the end of the 1-hour period, the intensity of dyspnea was assessed. At the end of the observation period, if the patient did not meet the criteria of at least 3 on the 0 10 scale of intensity of dyspnea, the patient was not considered eligible for treatment. If the dyspnea intensity was 3 or more on the 0 10 scale, the patient would undergo treatment. Dyspnea intensity was assessed at baseline and every 15 minutes for the first 1.5 hours after the treatment and then every half hour for the next 3 hours. Two hours after treatment, patients were assessed for nausea, sleepiness, wheezing, sweating, and other symptoms. The same assessment was performed on day 2. Final blind preference of the treatment by the patients and investigators was assessed at the completion of the study.

Vol. 29 No. 6 June 2005 Opioids for Cancer Dyspnea 615 Statistical Analysis We defined the main outcome of this study as the intensity of dyspnea as measured 1 hour after the drug administration. A previous study 3 had compared subcutaneous injections of morphine with placebo and found more than a doubling of relief of dyspnea intensity at 60 minutes for morphine. The proposed study utilized a randomized, double-blind, crossover design to determine if there were significant differences between receiving morphine via injection or nebulization. If differences were as significant as those in the previous study (more than a doubling of effect, with mean values of 16 vs. 35 at 60 minutes, with standard deviations of 18 and 29), we would have needed a total of 38 patients to enter this trial. However, because we wanted to be able to detect a 75% difference or more from the effect of morphine by injection (difference of 16 to 28), the study was designed to enter a total of 100 patients. This number of patients was based on a conservative estimate of the standard deviation of 29, a twosided significance level of 0.05, and 80% power. Other variables would be evaluated and summarized for the two groups, including a global assessment of benefit, nausea, wheezing, and sedation. We also compared dyspnea ratings over time as compared to baseline separately for the two treatments using the Wilcoxon matched pairs signed rank sum test, and symptom ratings by treatment using the Wilcoxon two-sample test. The results were calculated using SPSS. Results Figure 1 shows patient randomization. Because of the difficulties in patient accrual, only 11 patients completed both phases of this crossover study. Patients received a median dose of 45 mg (range, 7.5 200 mg) of morphine equivalent daily dose during day 1 and day 2, either by SC or nebulization. Patient characteristics are summarized in Table 1. Table 2 summarizes the intensity of dyspnea during the first 60 minutes after drug administration. The results were calculated using SPSS. There was not a significant difference in dyspnea intensity between nebulized and SC morphine at 60 minutes. More sedation was observed in the SC morphine treatment. Table 3 summarizes the toxicities reported for both treatments. Figure 2 shows the range in median intensity of dyspnea over time in patients who received Potentially Eligible Patients Approached 28 Not eligible 13 Eligible 15 Randomized 12 Refused 3 SC morphine, Day 1; Nebulized, Day 2 7 Nebulized, Day 1; SC morphine, Day 2 5 Death (pulmonary edema) 1 Completed study 6 Fig. 1. Patient randomization. Completed study 5

616 Bruera et al. Vol. 29 No. 6 June 2005 Characteristic Table 1 Patient Characteristics Age (median) 58 (46 77) Sex (female/male) 8/4 Primary tumor Lung cancer 7 Gastrointestinal 2 Other 3 Main causes of dyspnea Lung cancer 4 Carcinomatous lymphangitis 2 Ascites 1 Pleural effusion 1 Pain 1 Unknown 3 Median performance status (range) 2.5 (2 4) nebulized and SC morphine. The intensity of dyspnea remained stable for approximately 4.5 hours in both groups. Statistical analysis also revealed that there was no significant period or interaction effect in this crossover trial. Upon completion of the study, patients blindly chose nebulized morphine in 6 cases, SC in 3 cases, and no preference in 2 cases. Investigators blindly chose nebulized morphine in 7 cases, SC in 2, and no preference in 2 cases. Discussion We found that both nebulized and SC morphine could decrease baseline dyspnea and that the response was sustained over several hours. Our findings were in agreement with those of previous studies of systemic morphine 3,4 and suggest that nebulized morphine may be effective at a similar dose. We believe our findings are useful to future researchers and to clinicians interested in cancer dyspnea. Previously, three randomized controlled trials involving patients with continuous cancer dyspnea encountered major patient accrual difficulties. 3,4,17 All three studies included less than n 20 evaluable patients. In one case, more than 107 patients were approached, but only 18 patients were capable of participating. The presence of continuous measurable dyspnea upon rest is important in order to minimize the potential confounding effect of spontaneous or movement-related variation in symptom intensity. However, at the time dyspnea becomes continuous, patients are frequently also cognitively impaired or in severe distress and, therefore, unable to participate in clinical trials. 3,4,14 In other conditions, such as COPD or congestive heart failure, patients with earlier stages of dyspnea undergo exercise tests such as the treadmill or 6-minute walk. 1 Cancer patients frequently have pain, cachexia, and fatigue that might make the interpretation of the response to exercise more difficult. However, preliminary findings suggest that the 6-minute walk can be useful for dyspnea studies in ambulatory patients with lung cancer. 18 Our results should be interpreted with caution because our patients had relatively mild dyspnea. These results may not be generalizable to other patient groups in more severe respiratory distress. The absence of a difference in dyspnea relief between SC and nebulized morphine in our study cannot be taken as proof that such a difference does not exist, particularly with this very small sample size. However, it supports a potential role for nebulized morphine and encourages further research in this area. Our study differed from other clinical studies with nebulized opioids 7 16 in that a larger opioid dose was used (the same as the scheduled systemic dose). There has been some debate about the potential ability of nebulized opioids to act by stimulation of local opioid receptors as opposed to their traditional central nervous system effects. 8,10,18 The concentration of opioid receptors in the lung is much higher in the alveoli Table 2 Intensity a of Dyspnea at Baseline and After Morphine Administration Route Baseline 15 min P-value b 30 min P-value b 45 min P-value b 60 min P-value b SC c 5 (3 8) 4 (0 8) 0.017 3 (0 8) 0.005 4 (0 7) 0.005 3 (0 7) 0.025 Nebulized c 4 (3 9) 3 (0 9) 0.027 2 (0 9) 0.011 2 (0 9) 0.005 2 (0 9) 0.007 Unfortunately, there was insufficient power to rule out a significant difference between both routes of administration. a Median (range): 0 no dyspnea, 10 worst possible dyspnea. b Between baseline and the time of measurement. c There was no significant difference between SC and nebulized morphine for each time period.

Vol. 29 No. 6 June 2005 Opioids for Cancer Dyspnea 617 Table 3 Median Symptom Intensity at 2 Hours After Treatment Treatment Subcutaneous injection Nebulization Symptoms a median (range) median (range) P-Value Nausea 0 (0 2) 0 (0 7) ns Sweat 0 (0 3) 0 (0) ns Sedation 3 (0 9) 2 (0 5) 0.14 Wheezing 0 (0 6) 0 (0 5) ns a Rated on 0 to 10 numerical scale where 0 no symptom, 10 worst possible symptom. the bioavailability of various nebulized opioids and their association with symptom relief. Our findings strongly encourage such studies. On the other hand, SC morphine was very well tolerated (Table 3) and systemic opioids have demonstrated effectiveness for dyspnea associated with cancer and COPD. 1 6,15 Therefore, until more clinical trials better establish the role of nebulized opioids, systemic opioids should remain the treatment of choice for dyspnea. and bronchioles as compared to the trachea and bronchioles where nebulized opioids are much more likely to reach. 18 From a pragmatic perspective, our main interest was to determine whether nebulized opioids offered similar dyspnea relief, because this mode of administration might prove to be simple and fast, both for hospital and community intervention. The results are encouraging and justify randomized controlled trials both in patients with continuous dyspnea and in patients with earlier stages of dyspnea. Other researchers have suggested that nebulized opioids can cause adverse effects, such as bronchospasm. 6 8 We did not observe any adverse effects in this study; therefore, the administration of relatively large opioid doses by nebulization appears to be safe in cancer patients who are already opioid tolerant. Future studies will need to determine the role of different opioids, such as fentanyl or methadone, and Intensity of dyspnea 10 9 8 7 6 5 4 3 2 1 0 0 15' 30' 45' 60' 1h15' 1h30' 2h Time 2h30' 3h Subcutaneous Nebulized 3h30' 4h Fig. 2. Median dyspnea intensity at baseline and after treatment. 4h30' References 1. Bruera E, Sweeney C, Ripamonti C. Management of dyspnea. In: Berger A, Portenoy R, Weissman D, eds. Principles and practice of palliative care and supportive oncology. Philadelphia: Williams & Wilkins, 2002:357 371. 2. Ripamonti C, Fulfaro F, Bruera E. Dyspnoea in patients with advanced cancer: incidence, causes and treatments. Cancer Treat Rev 1998;24:69 80. 3. Bruera E, MacEachem T, Ripamonti C, et al. Subcutaneous morphine for dyspnea in cancer patients. Ann Intern Med 1993;119:906 907. 4. Mazzocato C, Buclin T, Rapin C. The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double blind controlled trial. Ann Oncol 1999; 10:1511 1514. 5. Bruera E, Macmillan K, Pither J, et al. Effects of morphine on the dyspnea of terminal cancer patients. J Pain Symptom Manage 1990;5:341 344. 6. Abernathy A, Currow D, Frith P, et al. Randomized, double-blind, placebo-controlled crossover trial of sustained release morphine for the management of refractory dyspnea. Br Med J 2003;327(7414): 523 528. 7. Chandler S. Nebulized opioids to treat dyspnea. Am J Hospice Palliat Care 1999;16:418 422. 8. Masood A, Macmillan K, Pither J, et al. Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects. Br J Clin Pharmacol 1996;41:250 252. 9. Quelch P, Faulkner D, Yun J. Nebulized opioids in the treatment of dyspnea. J Palliat Care 1997;13: 48 52. 10. Davis C, Lam W, Butcher M, et al. Low systemic bioavailability of nebulized morphine: Potential therapeutic role for the relief of dyspnea. Proc Ann Meeting Am Soc Clin Oncol 1992;11:A359. 11. Stein W, Min Y. Nebulized morphine for paroxysmal cough and dyspnea in a nursing home resident with metastatic cancer. Am J Hospice Palliat Care 1997;14:52 56.

618 Bruera et al. Vol. 29 No. 6 June 2005 12. Davis C, Penn K, A Hern R, et al. Single-dose randomized controlled trial of nebulized morphine in patients with cancer related breathlessness. Palliat Med 1996;10:64 65. 13. Masood A, Reed J, Thomas S. Lack of effect of inhaled morphine on exercise-induced breathlessness in chronic obstructive pulmonary disease. Thorax 1995;50:629 634. 14. Davis C, Hodder C, Love S, et al. Effect of nebulized morphine and morphine 6-glucuronide on exercise endurance in patients with chronic obstructive airway disease. Thorax 1994;49:393. 15. Jennings AL, Davies AN, Higgins JP, et al. A systematic review of the use of opioids in the management of dyspnea. Thorax 2002;57:939 944. 16. Polosa R, Simidchiev A, Walters EH. Nebulised morphine for severe interstitial lung disease. Cochrane Database Syst Rev 2002;3:CD002872. 17. Bruera E, de Stoutz N, Velasco-Leiva A. Effects of oxygen on dyspnea in hypoxaemic terminal-cancer patients. Lancet 1993;342:13 14. 18. Zebraski SE, Kochenash SM, Raffa RB. Lung opioid receptors: Pharmacology and possible target for nebulized morphine in dyspnea. Life Sci 2000; 66:2221 2231.