Efficacy and Safety of Opioids in Treating Cancer-Related Dyspnea: A Systematic Review and Meta-Analysis Based on Randomized Controlled Trials



      Dyspnea is one of the most distressing symptoms encountered by advanced cancer patients. In this study, we aimed to evaluate the role of opioids in the management of cancer-related dyspnea.


      A systematic review and meta-analysis based on Randomized Controlled Trials was conducted in the databases PUBMED, EMBASE, and Cochrane Central Register of Controlled Trials testing the effect of opioids in relieving cancer-related dyspnea. Subgroup and sensitivity analyses were performed to evaluate various types of opioids in dyspnea management and stabilization of the study respectively.


      Eleven RCTs fulfilled the eligibility criteria and had a total of 290 participants. Nine of these studies were included in meta-analyses. Compared with control, opioid therapy showed a small positive effect in dyspnea, SMD-0.82 (95%CI = −1.54 to -0.10) and Borg score, WMD-0.95 (95%CI = −1.83 to -0.06); Opioid therapy did not increase the risk of somnolence, OR0.93 (95%CI = 0.34 to 2.58), whereas a negative effect on respiratory rate was observed,WMD-1.89 (95%CI = −3.36 to -0.43); Also, there was no evidence to suggest improved performance of the 6MWT test, WMD6.49 (95%CI = −34.23 to 47.21), or the level of peripheral oxygen saturation, WMD0.33 (95%CI = −0.59 to 1.24) after opioid therapy. Subgroup analysis yielded a small positive effect for morphine on dyspnea, SMD-0.78 (95%CI = −1.45 to −0.10), whereas fentanyl showed no improvement in dyspnea, SMD-0.44 (95%CI = −0.89 to 0.02). Sensitivity analysis showed no changes in the direction of effect when any one study was excluded from the meta-analyses.


      Our systematic review and meta-analysis indicated low quality evidence for a small positive effect of opioids in cancer-related dyspnea. Evidence for safety is insufficient as comprehensive adverse events were not adequately reported in studies.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Journal of Pain and Symptom Management
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


      1. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society.
        Am J Respir Crit Care Med. 1999; 159: 321-340
        • Ripamonti C.
        • Fulfaro F.
        • Bruera E.
        Dyspnoea in patients with advanced cancer: incidence, causes and treatments.
        Cancer Treat Rev. 1998; 24: 69-80
        • Yamaguchi T.
        • Matsunuma R.
        • Suzuki K.
        • Matsuda Y.
        • Mori M.
        • Watanabe H.
        The current practice of opioid for cancer dyspnea: the result from the Nationwide Survey of Japanese Palliative Care Physicians.
        J Pain Symptom Manage. 2019; 58: 672-677.e2
        • Reuben D.B.
        • Mor V.
        Dyspnea in terminally ill cancer patients.
        Chest. 1986; 89: 234-236
        • Booth S.
        Improving research methodology in breathlessness: a meeting convened by the MRC clinical trials unit and the Cicely Saunders Foundation.
        Palliat Med. 2006; 20: 219-220
        • Clemens K.E.
        • Quednau I.
        • Klaschik E.
        Use of oxygen and opioids in the palliation of dyspnoea in hypoxic and non-hypoxic palliative care patients: a prospective study.
        Support Care Cancer. 2009; 17: 367-377
        • Coyne P.J.
        • Viswanathan R.
        • Smith T.J.
        Nebulized fentanyl citrate improves patients' perception of breathing, respiratory rate, and oxygen saturation in dyspnea.
        J Pain Symptom Manage. 2002; 23: 157-160
        • Coons J.C.
        • McGraw M.
        • Murali S.
        Pharmacotherapy for acute heart failure syndromes.
        Am J Health Syst Pharm. 2011; 68: 21-35
        • Currow D.C.
        • Higginson I.J.
        • Johnson M.J.
        Breathlessness--current and emerging mechanisms, measurement and management: a discussion from an European Association of Palliative Care workshop.
        Palliat Med. 2013; 27: 932-938
        • Allard P.
        • Lamontagne C.
        • Bernard P.
        • Tremblay C.
        How effective are supplementary doses of opioids for dyspnea in terminally ill cancer patients? A randomized continuous sequential clinical trial.
        J Pain Symptom Manage. 1999; 17: 256-265
        • Bruera E.
        • MacEachern T.
        • Ripamonti C.
        • Hanson J.
        Subcutaneous morphine for dyspnea in cancer patients.
        Ann Intern Med. 1993; 119: 906-907
        • Yamaguchi T.
        • Matsuda Y.
        • Matsuoka H.
        • et al.
        Efficacy of immediate-release oxycodone for dyspnoea in cancer patient: cancer dyspnoea relief (CDR) trial.
        Jpn J Clin Oncol. 2018; 48: 1070-1075
        • Hui D.
        • Xu A.
        • Frisbee-Hume S.
        • et al.
        Effects of prophylactic subcutaneous fentanyl on exercise-induced breakthrough dyspnea in cancer patients: a preliminary double-blind, randomized, controlled trial.
        J Pain Symptom Manage. 2014; 47: 209-217
        • Charles M.A.
        • 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.
        J Pain Symptom Manage. 2008; 36: 29-38
        • Bruera E.
        • Macmillan K.
        • Pither J.
        • MacDonald R.N.
        Effects of morphine on the dyspnea of terminal cancer patients.
        J Pain Symptom Manage. 1990; 5: 341-344
        • Ekstrom M.
        • Bajwah S.
        • Bland J.M.
        • Currow D.C.
        • Hussain J.
        • Johnson M.J.
        One evidence base; three stories: do opioids relieve chronic breathlessness?.
        Thorax. 2018; 73: 88-90
        • 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 Syst Rev. 2016; 3: Cd011008
        • Johnson M.J.
        • Abernethy A.P.
        • Currow D.C.
        Gaps in the evidence base of opioids for refractory breathlessness. A future work plan?.
        J Pain Symptom Manage. 2012; 43: 614-624
        • Simon S.T.
        • Koskeroglu P.
        • Gaertner J.
        • Voltz R.
        Fentanyl for the relief of refractory breathlessness: a systematic review.
        J Pain Symptom Manage. 2013; 46: 874-886
        • Ben-Aharon I.
        • Gafter-Gvili A.
        • Leibovici L.
        • Stemmer S.M.
        Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis.
        Acta Oncol. 2012; 51: 996-1008
        • Pinna M.A.
        • Bruera E.
        • Moralo M.J.
        • Correas M.A.
        • Vargas R.M.
        A randomized crossover clinical trial to evaluate the efficacy of oral transmucosal fentanyl citrate in the treatment of dyspnea on exertion in patients with advanced cancer.
        Am J Hosp Palliat Care. 2015; 32: 298-304
        • Hui D.
        • Kilgore K.
        • Frisbee-Hume S.
        • et al.
        Effect of prophylactic fentanyl buccal tablet on episodic exertional dyspnea: a pilot double-blind randomized controlled trial.
        J Pain Symptom Manage. 2017; 54: 798-805
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.
        J Clin Epidemiol. 2009; 62: e1-e34
        • Higgins J.P.T.
        • Green S.
        Cochrane Handbook for Systematic Reviews of Interventions.
        • Higgins J.P.
        • Altman D.G.
        • Gotzsche P.C.
        • et al.
        The Cochrane Collaboration's tool for assessing risk of bias in randomised trials.
        BMJ. 2011; 343: d5928
        • Agarwala P.
        • Salzman S.H.
        Six-minute walk test: clinical role, technique, coding, and reimbursement.
        Chest. 2020; 157: 603-611
        • Borg G.A.
        Psychophysical bases of perceived exertion.
        Med Sci Sports Exerc. 1982; 14: 377-381
        • Higgins J.P.T.
        • Thompson S.G.
        Quantifying heterogeneity in a meta-analysis.
        Stat Med. 2002; 21: 1539-1558
        • Begg C.B.
        • Mazumdar M.
        Operating characteristics of a rank correlation test for publication bias.
        Biometrics. 1994; 50: 1088-1101
        • Hui D.
        • Kilgore K.
        • Park M.
        • Williams J.
        • Liu D.
        • Bruera E.
        Impact of prophylactic fentanyl pectin nasal spray on exercise-induced episodic dyspnea in cancer patients: a double-blind, randomized controlled trial.
        J Pain Symptom Manage. 2016; 52: 459-468.e1
        • Mazzocato C.
        • Buclin T.
        • Rapin C.H.
        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
        • Navigante A.H.
        • Castro M.A.
        • Cerchietti L.C.
        Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated.
        J Pain Symptom Manage. 2010; 39: 820-830
        • Simon S.T.
        • Kloke M.
        • Alt-Epping B.
        • et al.
        Effendys-fentanyl buccal tablet for the relief of episodic breathlessness in patients with advanced cancer: a multicenter, open-label, randomized, morphine-controlled, crossover, phase II trial.
        J Pain Symptom Manage. 2016; 52: 617-625
        • Davis C.L.
        • Penn K.
        • A'Hern R.
        • Daniels J.
        • Slevin M.
        Single dose randomised controlled trial of nebulised morphine in patients with cancer related breathlessness.
        Palliat Med. 1996; 10: 64-65
        • Sterne J.A.
        • Sutton A.J.
        • Ioannidis J.P.
        • et al.
        Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials.
        BMJ. 2011; 343: d4002
        • Jennings A.L.
        • Davies A.N.
        • Higgins J.P.
        • Broadley K.
        Opioids for the palliation of breathlessness in terminal illness.
        Cochrane Database Syst Rev. 2001; : Cd002066
        • Clemens K.E.
        • Klaschik E.
        Effect of hydromorphone on ventilation in palliative care patients with dyspnea.
        Support Care Cancer. 2008; 16: 93-99
        • Sarhill N.
        • Walsh D.
        • Khawam E.
        • Tropiano P.
        • Stahley M.K.
        Nebulized hydromorphone for dyspnea in hospice care of advanced cancer.
        Am J Hosp Palliat Care. 2000; 17: 389-391
        • Yamamoto Y.
        • Watanabe H.
        • Sakurai A.
        • et al.
        Effect of continuous intravenous oxycodone infusion in opioid-naive cancer patients with dyspnea.
        Jpn J Clin Oncol. 2018; 48: 748-752
        • Shinjo T.
        • Okada M.
        Gan To Kagaku Ryoho. 2006; 33: 529-532
        • Jensen D.
        • Alsuhail A.
        • Viola R.
        • Dudgeon D.J.
        • Webb K.A.
        • O'Donnell D.E.
        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: 706-719
        • Morgan J.P.
        American opiophobia.
        Adv Alcohol Subst Abuse. 1985; 5: 163-172
        • Gotay C.C.
        • Kawamoto C.T.
        • Bottomley A.
        • Efficace F.
        The prognostic significance of patient-reported outcomes in cancer clinical trials.
        J Clin Oncol. 2008; 26: 1355-1363