Oral morphine drops for prompt relief of breathlessness in patients with advanced cancer—a randomized, double blinded, crossover trial of morphine sulfate oral drops vs. morphine hydrochloride drops with ethanol (red morphine drops)
- 27 Downloads
Episodic breathlessness is frequent in palliative cancer patients. Opioids are the only pharmacological agents with sufficient evidence in treatment. In Denmark, the main recommendation is red morphine drops (RMD), an off-label solution of morphine, ethanol, and red color (cochenille) described since 1893 (Pharmacopoea Danica). In 2015, the Danish Medicines Agency increased focus on off-label medicines and recommended registered morphine drops without ethanol instead. However, our palliative patients told us that RMD was better. For that reason, we conducted a clinical trial to clarify any perceived difference between the two types of drops.
We conducted a randomized, double blinded, crossover trial. Patients were asked to perform standardized activity (2-min walk) aiming to provoke breathlessness. Primary endpoint (breathlessness NRS) and secondary endpoints (saturation, pulse, respiratory frequency) were measured before (t = 0) and after test medicine at t = 1, t = 3, t = 5, t = 10, and t = 20 min. After 2–4 days (washout period), the patients repeated the test, receiving the alternative drops in a blinded setup (crossover).
In the first 3 min, the relative drop in breathlessness for morphine drops with ethanol (RMD) was significant more than for morphine drops without ethanol. We found no significant difference in secondary endpoints.
A conclusion could be that ethanol might facilitate morphine absorption in the mouth. Our results needs further research of opioid absorption in the mouth as well as trials, testing morphine vs. more lipophilic opioids. The RMD drops are cheap, easy to use, and noninvasive and keep the patient independent of health care professionals.
KeywordsBreathlessness Advanced cancer Opioids, Randomized crossover trial Sublingual administration
Zealand University Hospital, Oncology Department and Hospice Zealand financially supported this study.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
All procedures performed were in accordance with the ethical standards of Zealand University Hospital and Hospice Zealand and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The Regional Ethical Committee (SJ-502) approved the study.
The funding body had no role in the study design, collection, analysis or interpretation of data, writing of report, or decision to submit for publication. The authors have no financial relationship with the funding source. The authors have full control of all primary data and agree to allow the journal to review data if requested.
- 7.Mercadante S, Aielli F, Adile C, Valle A, Fusco F, Ferrara P, Caruselli A, Cartoni C, Marchetti P, Bellavia G, Cortegiani A, Masedu F, Valenti M, Porzio (2016) Epidemiology and characteristics of episodic breathlessness in advanced cancer patients: an observational study. J Pain Sympt Manage 51:17–24CrossRefGoogle Scholar
- 11.Weingartner V, Scheve C, Gerdes V, Schwartz M, Prenzel R, Otremba B, Muhlenbrock J, Bausewein C, Higginson IJ, Voltz R, Herich L, Simon ST (2015) Characteristics of episodic breathlessness as reported by patients with advanced chronic obstructive pulmonary disease and lung cancer: results of a descriptive cohort study. Palliat Med 29(5):420–428PubMedCrossRefGoogle Scholar
- 17.Simon ST, Weingartner V, Higginson IJ, Benalia H, Gysels M, Murtagh FEM, Spicer J, Linde P, Voltz R, Bausewein C (2016) “I can breathe again” self-management strategies for episodic breathlessness in advanced disease, derived from qualitative interviews. J Pain Sympt Manage 52(2):228–234CrossRefGoogle Scholar
- 22.Cherny N, Fallon M, Kaasa S, Portenoy RK, Currow DC (2015) Oxford textbook of palliative medicine. Oxford University Press ISBN 978-0-19-965609-7Google Scholar
- 26.Pfeiffer C (2011) Morphine-Induced Relief Dyspnea: what are the mechanisms. AJRCCM 184:8867–8869Google Scholar
- 28.Simon ST, Kloke M, Alt-Epping B, Gartner J, Hellmich M, Hein R, Piel M, Cornely OA, Nauck F, Voltz R (2016) 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 Sympt Manage 52(2):617–625CrossRefGoogle Scholar
- 36.Ekstrøm M, Currow DC, Johnson M (2015) Outcome measurement of refractory breathlessness: endpoints and important differences. Curr Opin Cardiol 9:238–243Google Scholar
- 37.Hui D, Sharmieh O, Paiva CE, Perez-Cruz PE, Kwon JH, Muckaden MA, Park M, Yenna S, Kang JH, Bruera E (2015) Minimal clinically important differences in the Edmonton Symptom assessment scale in cancer patients: a prospective multicenter study. Cancer 121:3027–3035PubMedPubMedCentralCrossRefGoogle Scholar