Morphine versus methylprednisolone or aminophylline for relieving dyspnea in patients with advanced cancer in China: a retrospective study
© The Author(s) 2016
Received: 14 March 2016
Accepted: 4 November 2016
Published: 9 November 2016
Dyspnea is one of the most common and distressing symptoms that occurs in terminal cancer patients. However, there are no existing treatment guidelines for this condition in China.
This single-center, retrospective, observational study aimed to compare the efficacy of using morphine, methylprednisolone, or aminophylline to relieve the symptom of breathlessness in patients with advanced malignant tumors and to investigate the safety of these regimens during the treatment of dyspnea.
Between August 2011 and January 2015 we retrospectively reviewed the medical records of 343 terminally ill cancer patients with dyspnea who received morphine, methylprednisolone, or aminophylline. The therapeutic effect of each treatment by means of visual analogue scale (VAS) scores was assessed and compared. Statistical methods included Chi square and analysis of variance tests. Differences were considered significant when P < 0.05.
VAS scores after treatment were (16.82 ± 10.89), (25.72 ± 15.03), and (31.95 ± 16.00) points in the morphine, methylprednisolone, and aminophylline group, respectively. These differences were found to be significantly different (P < 0.05). The effectiveness ratings were 86.44, 62.16, and 49.12%, respectively (P < 0.05).
We found that morphine subcutaneous injection for advanced cancer patients with dyspnea was safe and typically more effective than methylprednisolone or aminophylline. Therefore, morphine treatment could significantly improve the quality of life in terminal cancer patients with short life expectancies who are experiencing shortness of breath.
KeywordsChina Morphine Methylprednisolone Aminophylline Dyspnea Advanced cancer
Dyspnea, or breathlessness, is a subjective sensation described as uncomfortable or unpleasant labored breathing (air hunger) (Williams 2006). It is a devastating symptom that frequently occurs in advanced cancer patients. In advanced cancer, patients with any tumor, regardless of its primary site, may experience breathlessness. However, it is the most common in primary pulmonary carcinomas and in patients with metastatic lung disease (Parshall et al. 2012). Almost 50–70% of patients with advanced cancer experience intractable dyspnea in the last 6 weeks, and dyspnea is the main symptom in more than 20% of patients within their final 48 h of life (Williams 2006; Parshall et al. 2012; Navigante et al. 2006). Symptoms such as loss of appetite, fatigue, pain, and dyspnea reduce the quality of life (QoL) in cancer patients (Polanski et al. 2016). These symptoms usually become gradually aggravated as the tumor progression.
Assessment of dyspnea, as presented in the published medical literature, follows a pattern similar to that of pain. However, all of the objective data, such as respiratory rate, arterial blood gases, and oxygen saturation, cannot be used to quantitatively measure dyspnea. Therefore, assessing dyspnea relies on subjective measures, and the patient’s subjective self-report of breathlessness is the most valid and reliable indicator of its presence (Thomas and von Gunten 2002; Mancini and Body 1999). Respiratory depression severely impairs the quality of life in these patients, and is usually accompanied by anxiety, depression, fear, and even panic (Polanski et al. 2016). These extremely unpleasant feelings further exacerbate the problem and immensely reduce the patient’s self-esteem and self-confidence. The development of standardized treatments for cancer pain has received considerable attention throughout the world (Caraceni et al. 2012). However, in contrast to pain, breathlessness in terminally ill cancer patients is often not taken seriously and is frequently poorly managed in China (Lai et al. 2007).
The most effective measures to alleviate dyspnea are to address the underlying cause(s) of the breathlessness, such as resolving infection, controlling tumor growth, correcting anemia, and draining malignant pleural effusions (Williams 2006; Dy et al. 2008). Nevertheless, there is often no discernable treatable cause or patients are not eligible for etiological treatment due to their poor clinical state and overall health. Therefore, symptomatic treatment is often necessary, and palliative care then focuses on the relief of suffering and on symptom control.
At present, morphine sulfate is internationally recommended as the first-line therapy for cancer-related dyspnea (Ben-Aharon et al. 2008, 2012). However, in China, primary interventions, including oxygen, methylprednisolone, antiasthmatic drugs and benzodiazepine are often used to alleviate the symptoms of breathlessness in patients with advanced cancer. At the same time, morphine may be used for cancer-related dyspnea in terminally ill cancer patients, although many physicians and patients are reluctant to use morphine because of the concern for respiratory depression and the lack of comprehensive understanding about morphine.
Currently, there are only few high-quality, large-sample randomized controlled trials (RCTs) that assess the effects of morphine in the palliation of cancer-related breathlessness (Barnes et al. 2016). Therefore, we retrospectively reviewed the medical records to evaluate the efficacy of using morphine to alleviate dyspnea sensations during the last 6 weeks of life in terminally ill cancer patients. To our knowledge, this is the first report to compare morphine, methylprednisolone, and aminophylline therapy for patients with cancer-related breathlessness. The aim of this retrospective study was to provide significant information for clinical use and to improve our understanding of how beneficial/safe morphine may be for the treatment of cancer-related breathlessness in China.
Study design and patient population
A single-center, retrospective study was conducted in the department of Oncology, at Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University from August 2011 to January 2015. This study was approved by the Regional Ethics Committee of our hospital and the study complied with the Declaration of Helsinki. The patient’s information was anonymized and de-identified prior to analysis. Patients with advanced, stage III or IV cancer undergoing palliative treatment (alleviating the suffering and improving the life quality of patients) were eligible to participate in the study. Patients with advanced malignant tumors were confirmed by clinical and imaging diagnosis. Demographic patient- and disease-related data, such as the type and dose of drugs, visual analogue scale scores, side effects during admission were evaluated and documented by the physician in charge at our palliative care unit, including all clinically relevant laboratory parameters.
We retrospectively selected patients who met the following criteria: (1) those that were at least 18 years old, (2) those that were diagnosed pathologically with cancer, (3) those that had provided the subjective self-report of moderate-to-severe dyspnea, such as uncomfortable, distressful, or labored breathing, (4) those with a serum creatinine concentration within twice the normal range, (5) those with a life expectancy less than one month, and (6) those undergoing medicine intervention for dyspnea.
Patients were excluded if they met any of the following criteria: (1) had a serious renal or hepatic failure (biochemically and/or clinically detected), (2) had active or uncontrolled chronic obstructive pulmonary disease (COPD) and serious lung infection, (3) were diagnosed with hemoglobin saturation by pulse oximetry (SaO2) <85%, (4) had superior vena cava syndrome (SVCS), (5) had non-compensated congestive heart failure, or 6) had a contraindication to morphine, benzodiazepine drugs, and hormones.
All eligible patients complaining of shortness of breath in bed received non-pharmacological support (oxygen therapy using nasal prongs at a rate of 2–6 L/min) as the foundation of treatment. According to the treatment received, we divided patients into the three groups as follows. In the morphine group, opioid-naïve patients were given 5 mg morphine subcutaneously, and opioid-tolerant patients were injected subcutaneously with 10% of the total opioid taken in the previous 24 h. In the methylprednisolone group, 40 mg methylprednisolone in 100 ml normal saline was administered intravenously by drip for 30 min. In the aminophylline group, 0.25 g aminophylline with 5% glucose injection was administered intravenously by drip for 30 min.
As is the case with pain, adequate assessment of dyspnea depends on self-report. A 100 mm visual analogue scale (VAS) was used to quantify breathlessness. The VAS scores were performed according to standard procedures. VAS is a measurement apparatus that tries to measure a characteristic or attitude that is believed to range across a continuum of values and cannot easily be directly measured (Pianosi et al. 2016). Operationally, a VAS is usually a horizontal line, 100 mm in length, anchored by word descriptors at each end. Anchors are “no breathlessness’’ at 0 mm and “worst imaginable breathlessness” at 100 mm (Gould et al. 2001). The patient makes a mark on a 100-mm line with descriptors at each end corresponding to the extent of their symptom before and after treatment. Intensity of breathlessness was recorded by our palliative care unit before using any drugs and 1 h after one dose. Dyspnea relief was considered effective when the VAS numerical value decreased by more than 50%. The study’s principal endpoint was the effective rate of the intervention. Additional endpoints included the frequency and severity of medication-related side effects. After 1 h of a single-dose, adverse effects were assessed and documented on a daily basis.
Descriptive statistics including frequencies, means, standard deviation (SD), medians, and ranges were used to examine the distribution of measures as appropriate. The Pearson’s Chi squared test was undertaken to examine bivariate associations between categorical variables, and analysis of variance (ANOVA) was undertaken to examine the associations between categorical and continuous variables. The data were reported as mean SD. The P-values cited were derived from a two-tailed test, and P values less than 0.05 were considered statistically significant. All calculations were performed with SPSS software version 19.0 (SPSS, Inc., Chicago, IL, USA).
Characteristics of the patients (n = 343)
Age in years (mean)
A decline in VAS scores was more obvious in the morphine group
Before and after treatment VAS score comparison
VAS score before treatment
65.06 ± 13.27
64.04 ± 12.09
64.43 ± 11.86
VAS score after treatment
16.82 ± 10.89
24.58 ± 17.51
31.95 ± 16.00
The effective rate was statistically different between the three groups
Comparison of effective rate between morphine and the other two groups
Effective rate (%)
χ 2 value
Adverse events related to the treatments
Breathlessness, or shortness of breath, refers to discomfort and difficulty in breathing. The medical terminology for breathlessness is dyspnea or respiratory depression (Williams 2006). People describe the feeling of breathless in different ways. Patients often use the phrases “shortness of breath,” “cannot get enough air,” “out of breath,” or “tightness in my chest.” Dyspnea is one major cause of suffering in cancer patients, and it impairs the patient’s quality of life as severely as cancer pain.
In Western countries, exogenous opioid drugs, such as morphine sulfate, are recognized as the first-line of therapy in the symptomatic treatment of breathlessness in patients with advanced malignant tumors (Williams 2006; Dy et al. 2008; Ben-Aharon et al. 2012; Cheung and Zimmermann 2011). In China, corticosteroids and bronchodilators are widely used to treat the bronchoconstriction associated with asthma and chronic obstructive pulmonary disease (COPD) (Walters et al. 2014; Nardini et al. 2014). These medications can reduce airway inflammation and edema and reduce the sense of effort with breathing. Therefore, clinicians empirically apply methylprednisolone and aminophylline to relief dyspnea in patients that have terminal cancer. However, morphine is still rarely used by Chinese doctors for the treatment of cancer-related dyspnea. Many clinicians are uncertain as to which drug might be most effective and whether or not morphine should be used to be treat cancer-related dyspnea. At present there is a lack of related literature that directly compares these three drugs, and there are no existing guidelines for the management of dyspnea in China.
In this research, 343 patients were divided into three groups based on the treatment received. Subcutaneous and intravenous routes of administration were used in the study, because the ability to swallow declines and consciousness often wanes during the last weeks of life. Our results showed that morphine was superior to methylprednisolone and aminophylline for controlling the symptoms of cancer-related dyspnea. The VAS scores were 16.82 ± 10.89, 25.72 ± 15.03, and 31.95 ± 16.00 mm (P = 0.000) after treatment in the morphine, methylprednisolone, and aminophylline groups, respectively. Moreover, the effective rate of morphine was also obviously higher than that of the other drugs. The symptom improvement was more apparent in the morphine treatment group, while patients treated with methylprednisolone and aminophylline usually required repeat doses.
At the same time, this study implied that adverse effects of morphine treatment were generally well tolerated, with somnolence and constipation being the most common AEs. Neither respiratory depression nor severe sedation was observed in the morphine group. In China, clinicians, patients, and their families are still reluctant to use morphine, because of the fear of respiratory depression. In fact, there is no need to be overly concerned with respiratory depression. Morphine has been widely used to treat cancer pain, and the incidence of respiratory depression has been proven to be uncommon (Mercadante 2010). Even if respiratory depression were to occur, the opioid antagonist naloxone can quickly and effectively reverse respiratory depression (Howlett et al. 2016; Taylor et al. 2013). There are few reports concerning morphine poisoning deaths, and no evident serious adverse effects (respiratory depression) were observed in the recent literature concerning the use of morphine for alleviating cancer-related dyspnea (Ben-Aharon et al. 2012).
Morphine is often used to treat severe cancer pain and acute heart failure (Nardini et al. 2014; Iakobishvili et al. 2011). However, the use of morphine is at risk of addiction and respiratory depression (Chidambaran et al. 2015). Many physicians and patients are reluctant to use morphine for fear of respiratory depression and the lack of comprehensive understanding about morphine. Hence, in China, morphine is considered to be the contraindicated for dyspnea (due to the risk of respiratory depression). Additionally, although morphine has been prohibited to treat COPD for a long time, it is presently the first-line drug used to alleviate breathlessness for patients with COPD (Zebraski et al. 2000; Mahler et al. 2010; Verberkt et al. 2016). Increasing numbers of clinical studies support the notion that morphine should be a first-line drug that is effective and safe for the treatment of dyspnea in terminal cancer. It does not accelerate the deterioration of the patient’s condition or hasten death (Bonnichon et al. 2008). The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology palliative care recommend that opioids are one class of effective drugs available for cancer-related dyspnea, especially those patients who have a shorter life expectancy. Morphine sulfate, a representative opioid is effective in alleviating the symptoms of breathlessness, decreasing the ventilator response to hypoxia and hypercapnia, while decreasing oxygen consumption at rest and exercise (Williams 2006).
In contrast to vision, hearing, and pain, the neurophysiology of cancer-related dyspnea is far less understood. The reason why morphine relieves dyspnea may include the following aspects. Dyspnea in cancer patients is usually associated with the degree of anxiety, fear, panic, and depression, which can be improved by morphine arising to be mixed undisturbedly demulcent action (Polanski et al. 2016). Morphine probably acts both by depressing spontaneous respiratory drive and by modulating cortical activity, much like what happens with morphine treatment for pain. Current studies have shown that dyspnea and pain are both influenced by a common central nervous control area; there is speculation that the mechanism of morphine-mediated dyspnea relief is similar to the mechanisms that alleviate pain (Clemens et al. 2008). In addition, morphine may also play a role in decreasing the sensitivity to dyspnea, improving the body’s tolerance and cardiovascular function, reducing the ventilator response to hypoxia and hypercapnia (Zebraski et al. 2000). It is possible that the influence of these different mechanisms varies in different patients.
Undoubtedly, it is also extremely important to treat the underlying cause of the breathlessness, such as a reduction hydrothorax and ascites (Williams 2006; Dy et al. 2008; Bausewein et al. 2008). Moreover, benzodiazepines (BZDs) may be considered as a second- or third-line treatment in patients when dyspnea is not relieved by opioids, particularly if anxiety is a significant coexisting symptom (Clemens and Klaschik 2011).
The present work has several limitations. First, this study is a retrospective study. Data collection relied on medical record review, and the documentation may have been limited. Second, our sample size is not large enough to definitively state that morphine is superior to other treatments for dyspnea. Third, there may be the potential for confounding factors, such as psychosocial and patient factors that were not measured in the context of this study, but could impact our results.
Morphine is generally safe and significantly more effective than methylprednisolone and aminophylline in management of dyspnea for terminal cancer patients. This treatment could significantly help improve the quality of life in such patients, although further research is needed to detail and clarify the efficacy of morphine for the treatment of dyspnea in patients with advanced malignant tumors. It is our opinion that Chinese oncologists should consider changing their static/conservative views on morphine, and strive towards understanding the special role of morphine in the management of cancer-related dyspnea to better control/minimize suffering in terminal cancer patients.
The authors indicated in parentheses made substantial contributions of each author to the following tasks of research: initial conception (CT, FL, BJ); design (CT, JYW, FL); Collection of data (JYW, MLW, LLZ); Analysis and interpretation of data (CT, FL, MLW, LLZ); writing and revision of paper (CT, FL, BJ). All authors read and approved the final manuscript.
The authors would like to thank the Duoease Scientific Service Center for excellent language editing service. The authors acknowledge the staff from the Department of Oncology, Shanghai Ninth People’s Hospital, China for their support during the study.
The authors declare that they have no competing interests.
This work was supported by Grants from the National Natural Science Foundation of China (81572796).
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- Barnes H, McDonald J, Smallwood N, Manser R (2016) Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst Rev 3:11008Google Scholar
- Bausewein C, Booth S, Gysels M, Higginson I (2008) Non-pharmacological interventions for breathlessness in advanced stages of malignant and nonmalignant diseases. Cochrane Database Syst Rev 2:CD005623Google Scholar
- Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM (2008) Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol 26:2396–2404View ArticlePubMedGoogle Scholar
- Ben-Aharon I, Gafter-Gvili A, Leibovici L, Stemmer SM (2012) Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. Acta Oncol 51:996–1008View ArticlePubMedGoogle Scholar
- Bonnichon A, Le Floch H, Riviere F, Staub E, Mairovitz A, Marotel C, Vaylet F, Margery J (2008) Dyspnea in lung cancer. Article in French. Rev Pneumol Clin 64:62–68View ArticlePubMedGoogle Scholar
- Caraceni A, Hanks G, Kaasa S, Bennett MI, Brunelli C, Cherny N, Dale O, De Conno F, Fallon M, Hanna M, Haugen DF, Juhl G, King S, Klepstad P, Laugsand EA, Maltoni M, Mercadante S, Nabal M, Pigni A, Radbruch L, Reid C, Sjogren P, Stone PC, Tassinari D, Zeppetella G (2012) Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC. Lancet Oncol 13:e58–e68View ArticlePubMedGoogle Scholar
- Cheung WY, Zimmermann C (2011) Pharmacologic management of cancer-related pain, dyspnea, and nausea. Semin Oncol 38:450–459View ArticlePubMedGoogle Scholar
- Chidambaran V, Mavi J, Esslinger H, Pilipenko V, Martin LJ, Zhang K, Sadhasivam S (2015) Association of OPRM1 A118G variant with risk of morphine-induced respiratory depression following spine fusion in adolescents. Pharmacogenomics J 3:255–262View ArticleGoogle Scholar
- Clemens KE, Klaschik E (2011) Dyspnoea associated with anxiety–symptomatic therapy with opioids in combination with lorazepam and its effect on ventilation in palliative care patients. Support Care Cancer 19:2027–2033View ArticlePubMedGoogle Scholar
- Clemens KE, Quednau I, Klaschik E (2008) Is there a higher risk of respiratory depression in opioid-naïve palliative care patients during symptomatic therapy of dyspnea with strong opioids? J Palliat Med 1:204–216View ArticleGoogle Scholar
- Dy SM, Lorenz KA, Naeim A, Sanati H, Walling A, Asch SM (2008) Evidence-based recommendations for cancer fatigue, anorexia, depression, and dyspnea. J Clin Oncol 26:3886–3895View ArticlePubMedGoogle Scholar
- Gould D, Kelly D, Goldstone L, Gammon J (2001) Examining the validity of pressure ulcer risk assessment scales: developing and using illustrated patient simulations to collect the data. J Clin Nurs 10:697–706View ArticlePubMedGoogle Scholar
- Howlett C, Gonzalez R, Yerram P, Faley B (2016) Use of naloxone for reversal of life-threatening opioid toxicity in cancer-related pain. J Oncol Pharm Pract 22:114–120View ArticlePubMedGoogle Scholar
- Iakobishvili Z, Cohen E, Garty M, Behar S, Shotan A, Sandach A, Gottlieb S, Mager A, Battler A, Hasdai D (2011) Use of intravenous morphine for acute decompensated heart failure in patients with and without acute coronary syndromes. Acute Card Care 13:76–80View ArticlePubMedGoogle Scholar
- Lai YL, Chan CW, Lopez V (2007) Perceptions of dyspnea and helpful interventions during the advanced stage of lung cancer: Chinese patients’ perspectives. Cancer Nurs 2:E1–E8View ArticleGoogle Scholar
- Mahler DA, Selecky PA, Harrod CG, Benditt JO, Carrieri-Kohlman V, Curtis JR, Manning HL, Mularski RA, Varkey B, Campbell M, Carter ER, Chiong JR, Ely EW, Hansen-Flaschen J, O’Donnell DE, Waller A (2010) American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest 137:674–691View ArticlePubMedGoogle Scholar
- Mancini I, Body JJ (1999) Assessment of dyspnea in advanced cancer patients. Support Care Cancer 7:229–232View ArticlePubMedGoogle Scholar
- Mercadante S (2010) Intravenous morphine for management of cancer pain. Lancet Oncol 11:484–489View ArticlePubMedGoogle Scholar
- Nardini S, Camiciottoli G, Locicero S, Maselli R, Pasqua F, Passalacqua G, Pela R, Pesci A, Sebastiani A, Vatrella A (2014) COPD: maximization of bronchodilation. Multidiscip Respir Med 9:P50View ArticleGoogle Scholar
- Navigante AH, Cerchietti LC, Castro MA, Lutteral MA, Cabalar ME (2006) Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manage 31:38–47View ArticlePubMedGoogle Scholar
- Parshall MB, Schwartzstein RM, Adams L, Banzett RB, Manning HL, Bourbeau J, Calverley PM, Gift AG, Harver A, Lareau SC, Mahler DA, Meek PM, O’Donnell DE (2012) An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med 185:435–452View ArticlePubMedGoogle Scholar
- Pianosi PT, Zhang Z, Hernandez P, Huebner M (2016) Measuring dyspnea and perceived exertion in healthy adults and with respiratory disease: new pictorial scales. Sports Med Open 2:17View ArticlePubMed CentralGoogle Scholar
- Polanski J, Jankowska-Polanska B, Rosinczuk J, Chabowski M, Szymanska-Chabowska A (2016) Quality of life of patients with lung cancer. Oncol Targets Ther 9:1023–1028Google Scholar
- Taylor R Jr, Pergolizzi JV Jr, Porreca F, Raffa RB (2013) Opioid antagonists for pain. Expert Opin Investig Drugs 22:517–525View ArticlePubMedGoogle Scholar
- Thomas JR, von Gunten CF (2002) Clinical management of dyspnea. Lancet Oncol 3:223–228View ArticlePubMedGoogle Scholar
- Verberkt CA, van den Beuken-van Everdingen MH, Franssen FM, Dirksen CD, Schols JM, Wouters EF, Janssen DJ (2016) A randomized controlled trial on the benefits and respiratory adverse effects of morphine for refractory dyspnea in patients with COPD: protocol of the MORDYC study. Contemp Clin Trials 47:228–234View ArticlePubMedGoogle Scholar
- Walters JA, Tan DJ, White CJ, Gibson PG, Wood-Baker R, Walters EH (2014) Systemic corticosteroids for acute exacerbations of chronic obstructive pulmonary disease. Cochrane Database Syst Rev 9:CD001288Google Scholar
- Williams CM (2006) Dyspnea. Cancer J 12:365–373View ArticlePubMedGoogle Scholar
- Zebraski S, Kochenash S, Raffa R (2000) Lung opioid receptors: pharmacology and possible target for nebulized morphine in dyspnea. Life Sci 66:2221–2231View ArticlePubMedGoogle Scholar