A total of 70 patients with heart failure were assessed in the 4 clinical trials. In their study, Chua et al15 sought to test the hypothesis on the use of dihydrocodeine in patients with chronic heart failure for improving dyspnea and tolerance to exercise. The study included 12 adult men with compensated chronic heart failure NYHA II–III and left ventricle ejection fraction (LVEF) < 40%, in medical management with diuretic and angiotensin converting enzyme (ACE) inhibitor. Of them, 6 individuals received dihydrocodeine at a dose of 1 mg/kg, and 6 were in the placebo group. Dyspnea was measured using the modified Borg scale at 3 and 6 minutes, and at the peak of exercise. The mean baseline rating on the modified Borg scale was 1.33 and 1.17 for dihydrocodeine and placebo, respectively. At 6 minutes, there was a significant difference in reduction between the 2 groups on the Borg scale, 2.91 for dihydrocodeine versus 3.60 for placebo (P < 0.003). During exercise, longer duration of physical activity (P < 0.001) and higher oxygen consumption (P < 0.002) were observed in the group treated with dihydrocodeine. One patient reported nausea in the intervention group.
The study by Johnson et al13 assessed whether the use of oral morphine in outpatients with severe heart failure improved dyspnea. It included 10 patients between 45 and 85 years of age, NYHA functional class III–IV, clinically stable (with no changes in functional class during 1 month or changes in medication for 2 weeks), receiving optimal therapy (diuretics and renin–angiotensin–aldosterone axis blockers), All the subjects were treated with placebo and morphine 5 mg oral solution once a day for 4 days (2-day washout period). Dyspnea and quality of life were measured before and after each intervention using the 100 mm visual analog scale (VAS), where 0 mm represented mild dyspnea and 100 mm represented intense or severe dyspnea. Regarding results for dyspnea, the baseline VAS score in the opioid group was 36 mm (15–51 mm) and the final score was 13 mm (4–40 mm) (P = 0.022), while the patients in the placebo group had a baseline score of 47 mm (12–63 mm) and the final score was 47 mm (9–61 mm) (P = 0.953). In terms of quality of life of patients receiving opioids, the initial score on the VAS was 29 mm (1–56 mm) and the final score was 32 mm (9–52 mm) (P = 0.678), while in the placebo group the baseline score was 41 mm (25–52 mm) and the final score was 46 mm (20–52 mm) (P = 0.6383). Regarding reported adverse effects, of the patients in the morphine group 4 had constipation, 2 had drowsiness and 1 presented vomiting, while in the placebo group, 2 had nausea and 1 had constipation.
The study by Oxberry et al16 explored the same objective of the previous studies and included 35 patients with a mean age of 70.2 ± 11.1 with chronic heart failure NYHA III–IV and LVEF < 45%, receiving standard management with ACE inhibitor and diuretic over the previous month. All patients received oral morphine 5 mg 4 times a day, oral oxycodone 2.5 mg 4 times a day and placebo for 4 days with a washout period of at least 3 days before the administration of the next intervention. Dyspnea was measured at different time points (before the intervention, at the time of the intervention and every day during the 4 days of the intervention) using the Numerical Rating Scale (NRS), where 0 is very mild and 10 very marked or severe. The mean NRS dropped from −1.37 in the placebo group versus −0.41 in the morphine group (P = 0.13) and to −1.29 in the oral oxycodone group (P = 0.90). In terms of adverse events, 5 patients had nausea (morphine 3; oxycodone 2), 26 patients had constipation (morphine 12; oxycodone 10; placebo 4), 12 patients had vertigo (morphine 7; oxycodone 0; placebo 1), and 3 patients developed headache (morphine 2; placebo 1).
The study by Oxberry et al17 is an extension of the study conducted in 2011. This study documents part of the group of patients initially randomized in the first study who decided they wanted to continue the treatment with opioids. They were followed during 3 months in a randomized observational extension study; 13 patients continued and 20 decided not to do so, but they were all followed over time. Dyspnea intensity was assessed in these 33 participants using the 2 scales (NRS and modified Borg) during a 24-hour period. Later, in a logarithm analysis of main components, the 2 scales were combined in order to render them comparable. The mean baseline scores were 5.31 and 4.95 on the NRS, and 3.23 and 2.80 on the Borg scale, in patients with and without opioids, respectively. At 3 months, the NRS scores were 3.31 and 4.95 in patients with and without the opioid, respectively, and the scores on the modified Borg scale were 1.92 and 2.88 in patients with and without opioid treatment, respectively, showing long-term improvement of dyspnea perception in the group receiving the pharmacological intervention with an opioid (P = 0.017).
The systematic review assessed the benefit from the use of opioids for the symptomatic treatment of dyspnea in patients with heart failure. The quality of the studies included in this review is acceptable according to the quality assessment. The studies included are cross-over clinical trials assessed for the power of the sample size, where a power of more than 80% and a statistical P of 0.05% were selected, explaining, in general, the relatively small number of patients studied with this condition. Morphine is the most commonly used drug for symptomatic relief of dyspnea, with advantages in terms of lower scores for this symptom within the first few hours, as well as lower use of the drug at 3 months of follow-up.
Although in the study by Chua et al15 no mean reduction of 1 point is achieved on the Borg scale for symptom assessment (which would be considered as a clinically significant response),18,19 the authors were able to demonstrate a statistically significant difference between the interventions. This result differs from the study by Oxberry et al17 which does show a statistically and clinically significant reduction in the Borg scale at rest (the usual state of patients with advanced disease), comparable also with the results of the study by Johnson et al,13,18 which showed clinically and statistically significant improvement of dyspnea in the patients receiving opioids, as measured on the VAS. It is worth noting that, in the study by Chua et al,15 patients in the intervention group with dihydrocodeine show higher oxygen consumption and greater performance, suggesting an effect in favor of the use of this medication, possibly associated to opioid action on chemoreceptors, allowing patients to remain on the treadmill during a longer period of time.
Despite the use of low opioid doses, there were significant changes in dyspnea perception based on the assessment using the different scales. In the study by Currow et al20 with the use of titratable doses, there were some favorable results for dyspnea during exercise. The use of titratable doses in patients at rest may probably improve dyspnea, although at the expense of an increased risk of adverse effects such as nausea, vomiting, and constipation. Another important aspect related to safety is the duration of the intervention. In the study by Oxberry et al,17 cardiorespiratory variables remained stable even in those patients who continued on opioids for 3 months, consistent with the study by Currow et al,20 which showed that long-term use of morphine was safe, although at the expense of a higher incidence of adverse gastrointestinal effects.
In the literature, a systematic review published by the Cochrane Collaboration in 2016,21 assessed the effectiveness of opioids for the management of dyspnea in patient with a different disease profile than the group of interest in our study, namely, patients with advanced condition, either due to malignancy or respiratory or cardiovascular disease. In that review, the authors identified methodological limitations in the majority of the studies, sample size being the greatest source of bias risk among the points assessed. Consequently, the strength of the available evidence is limited, leading to the conclusion that there is low-quality evidence showing dyspnea improvement in certain patients with advanced and end-stage disease. Although they did not include patients with heart failure only, most of the studies mentioned in our review are included in their analysis.13,15,16 However, no subgroup assessment by patient diagnosis, which might change the result, was done.
Gastrointestinal symptoms such as nausea, vomiting, and constipation were the most frequent among patients who received opioids. Only the study by Oxberry et al16 reports the concomitant use of anti-emetics and laxatives, which is part of the adequate use of opioids, with a significant reduction of gastrointestinal symptoms. Likewise, adverse effects on the central nervous system, such as drowsiness, were reported as frequent in the study by Oxberry et al,16 and less frequent in the study by Johnson et al,13 although in the latter, drowsiness led to 1 patient having to leave the study.
The limitations of this study have to do with the use of different scales for assessing change in dyspnea over time, hampering the statistical analysis and making it impossible to carry out a meta-analysis. Consequently, greater uniformity in terms of symptomatic measurement of dyspnea is required. Moreover, the studies did not report overall quality-of-life perceptions in relation to improvement on the symptomatic assessment scales. Likewise, the number of patients included in this systematic review is small and does not allow to compare effective doses or the various types of opioids for symptomatic control of dyspnea in patients with heart failure.
In adult patients with advanced compensated heart failure receiving optimum treatment, the use of opioids as adjuvant therapy is shown to be of some benefit on dyspnea perception according to symptomatic assessment scales; however, randomized controlled clinical trials with a larger number of patients and medium and long-term follow-up are needed to determine not only the effectiveness of pharmacological treatment on dyspnea but also the impact of these interventions on the quality of life of patients with advanced heart failure. Morphine is the most frequently used opioid, but its superiority over other opioids has not been compared for dyspnea control in patients with advanced heart failure.
The authors did not receive sponsorship for this article.
Conflict of interest
The authors declare having no conflict of interest.
“Heart Failure”[Mesh] OR “Heart Failure, Diastolic”[Mesh] OR “Heart Failure, Systolic”[Mesh] AND “Morphine”[Mesh] OR “Morphine Derivatives”[Mesh] OR “Analgesics, Opioid”[Mesh] OR “Narcotics”[Mesh] AND “Therapeutics”[Mesh] OR “therapy”[Subheading] OR “Conservative Treatment”[Mesh]) OR “Placebos”[Mesh]) OR “Drug Therapy”[Mesh]) AND “Dyspnea”[Mesh].
(Heart Failure or Heart Failure, Diastolic or Heart Failure, Systolic) and (Morphine or Morphine Derivatives or Analgesics, Opioid or Narcotics) and (Therapeutics or therapy or Conservative Treatment or Placebos or Drug Therapy) and (Breathlessness or Dyspnea).
(tw:(Falla Cardiaca)) OR (tw:(Insuficiencia Cardiaca)) AND (tw:(Morfina)) OR (tw:(Opioides)) AND (tw:(Disnea)).
(‘heart failure’/exp OR ‘congestive heart failure’/exp OR ‘systolic heart failure’/exp OR ‘diastolic heart failure’/exp) AND (‘opiate agonist’/exp OR ‘morphine derivative’/exp) AND ‘placebo’/exp AND (‘dyspnea’/exp OR ‘breathing difficulties’ OR ‘breathing difficulty’ OR ‘breathlessness’ OR ‘difficult breathing’ OR ‘difficult repiration’ OR ‘difficulty breathing’ OR ‘dyspnea’ OR ‘dyspneas’ OR ‘dyspneic syndrome’ OR ‘dyspnoea’ OR ‘dyspnoeae’ OR ‘dyspnoeas’ OR ‘effort dyspnea’ OR ‘effort dyspnoea’ OR ‘labored respiration’ OR ‘laboured respiration’ OR ‘lung dyspnea’ OR ‘lung dyspnoea’ OR ‘shortness of breath’).
(heart failure) AND (opioids OR morphine) AND (dyspnea OR breathlessness).
1. Ghashghaei R, Yousefzai R, Adler E. Palliative care
in heart failure
. Prog Cardiovasc Dis 2016;58:455–460.
2. Yancy CW, Jessup M, Bozkurt B, et al 2013 ACCF/AHA guideline for the management of heart failure
: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2013;62:e147–e239.
3. Saldarriaga C, Flórez N, Buitrago R, et al Consenso colombiano para el diagnóstico y tratamiento de la insuficiencia cardíaca crónica. 1st ed.Sociedad Colombiana de Cardiología y Cirugía Cardiovascular, Bogotá: 2014.
4. Go AS, Mozaffarian D, Roger VL, et al Heart disease and stroke statistics-2013 update: a report from the American Heart Association. Circulation 2013;127:e841.
5. Bekelman DB, Hutt E, Masoudi FA, et al Defining the role of palliative care
in older adults with heart failure
. Int J Cardiol 2008;125:183–190.
6. Fang JC, Ewald GA, Allen LA, et al Advanced (stage D) heart failure
: a statement from the Heart Failure
Society of America Guidelines Committee. J Card Fail 2015;21:519–534.
7. Paulo Solano J, Gomes B, Higginson IJ. A comparison of symptom prevalence in far advanced cancer, AIDS, heart disease, chronic obstructive pulmonary disease and renal disease. J Pain Symptom Manage 2006;31:58–69.
8. Lemond L, Allen LA. Palliative care
and hospice in advanced heart failure
. Prog Cardiovasc Dis 2011;54:168–178.
9. Ozben T, Sadan G, Trakya A, et al Morphine
increases plasma immunoreactive atrial natriuretic peptide levels in humans. Ann Clin Biochem 1990;27:21–24.
10. Wuerz RC, Meador SA. Effects of prehospital medications on mortality and length of stay in congestive heart failure
. Ann Emerg Med 1992;21:669–674.
11. Peacock WF, Hollander JE, Diercks DB, et al Morphine
and outcomes in acute decompensated heart failure
: an ADHERE analysis. Emerg Med J 2008;25:205–209.
12. Miró Ò, Gil V, Martín-Sánchez FJ, et al Morphine
use in the ED and outcomes of patients with acute heart failure
: a propensity score-matching analysis based on the EAHFE registry. Chest 2017;152:821–832.
13. Johnson MJ, McDonagh T, Harkness, et al Morphine
for the relief of breathlessness in patients with chronic heart failure
—a pilot study. Eur J Hear Fail 2002;4:753–756.
14. Ponikowski P, Voors AA, Anker SD, et al 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure
. Eur Heart J 2016;37:2129–2200m.
15. Chua TP, Harrington D, Ponikowski P, et al Effects of dihydrocodeine on chemosensitivity and exercise tolerance in patients with chronic heart failure
. J Am Coll Cardiol 1997;29:147–152.
16. Oxberry SG, Torgerson DJ, Bland JM, et al Short-term opioids for breathlessness in stable chronic heart failure
: a randomized controlled trial. Eur J Heart Fail 2011;13:1006–1012.
17. Oxberry SG, Bland JM, Clark AL, et al Repeat dose opioids may be effective for breathlessness in chronic heart failure
if given for long enough. J Palliat Med 2013;16:250–255.
18. Johnson MJ, Oxberry SG, Cleland JGF, et al Measurement of breathlessness in clinical trials in patients with chronic heart failure
: the need for a standardized approach: a systematic review. Eur J Heart Fail 2010;12:137–147.
19. Johnson MJ, Abernethy AP, Currow DC. Gaps in the evidence base of opioids for refractory breathlessness. A future work plan? J Pain Symptom Manage 2012;43:614–624.
20. Currow DC, McDonald C, Oaten S, et al Once-daily opioids for chronic dyspnea
: a dose increment and pharmacovigilance study. J Pain Symptom Manage 2011;42:388–399.
21. Barnes H, McDonald J, Smallwood N, et al Opioids for the palliation of breathlessness in advanced disease and terminal illness. Cochrane Database Syst Rev 2016;3:CD002066.
Palliative Care; Heart Failure; Dyspnea; Analgesics, Opioid; Morphine; Cuidados Paliativos; Insuficiencia cardiaca; Disnea; Analgésicos opiodes; Morfina
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