Opioids for treating dyspnoea in patients with chronic heart failure

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess whether opioid analgesics have a role in the control of dyspnoea in adults (aged 18 and over) with chronic heart failure. If the opioid reduces breathlessness in heart failure, this could potentially markedly improve the quality of life of people with this problem, as breathlessness is a major adverse symptom in heart failure. What is not entirely clear is whether opioids really do reduce breathlessness in heart failure and, if so, by how much and is it is enough to impact on quality of life?


Description of the condition

Heart failure is a common and frequently life-limiting illness with increasing prevalence, particularly among the ageing population. During the 1980s the age-adjusted prevalence of overt heart failure in the United States was 24/1000 in men and 25/1000 in women (Kalon 1993). Over the 40 years of observation in the Framingham study, despite improvements in the treatment of ischaemic heart disease and hypertension, the age-adjusted incidence of heart failure has declined by only 11% per calendar decade in men and by 17% per calendar decade in women (Kalon 1993). The incidence rate increases with age, with a European incidence of 1.4 per 1000 person-years in the 55 to 59 age band, rising to 47.4 per 1000 person-years in the over-90s. Heart failure remains a highly lethal condition, with a five-year survival rate of 25% in men and 38% in women (Bleumink 2004).

The term heart failure covers a complex clinical syndrome that can result from a number of underlying disorders that impair the ability of the heart to respond to physiological demands for increased cardiac output (McMurray 2012). It encompasses a large spectrum of disease, from people with mild heart failure and minimal symptoms to those who have severe disease with symptoms at rest.

Chronic heart failure is characterised by symptoms that include exertional breathlessness (dyspnoea), fatigue, lower limb swelling, dyspnoea on lying flat or abrupt onset dyspnoea, which wakens patients from sleep (McMurray 2012).

Heart failure is often a progressive condition, beginning with predisposing factors and leading to the development and worsening of clinical illness. There are several stages in the evolution of heart failure, as outlined by an American College of Cardiology/American Heart Association (ACC/AHA) task force (Hunt 2006).

  • Stage A: high risk for heart failure, without structural heart disease or symptoms

  • Stage B: heart disease with asymptomatic left ventricular dysfunction

  • Stage C: prior or current symptoms of heart failure

  • Stage D: refractory end-stage heart failure

People with end-stage heart failure have marked symptoms of dyspnoea, fatigue and other symptoms at rest or with minimal exertion. Identifying those likely to die soon from heart failure is challenging and the course to death varies with illness severity and adherence to treatment. Management of symptoms such as dyspnoea is essential to provide an acceptable quality of life for people with heart failure as their disease progresses (Zambroski 2008).

Description of the intervention

The terms 'opiates' and 'opioids' are sometimes used interchangeably. An opiate, strictly speaking, is one of a group of drugs derived from the opium poppy that have narcotic and sedative effects. Opioids are synthetic compounds that resemble opiates in terms of their clinical effects (Martin 2002). The term opioid is used throughout this review to encompass all compounds meeting either of these definitions. Opioids can be given by any route (oral, subcutaneous or intravenous).

The most common forms used in heart failure are morphine sulphate oral solution (Oramorph), morphine sulphate long-acting oral tablets (MST Continus), oxycodone hydrochloride modified-release oral (OxyContin) and diamorphine hydrochloride subcutaneous injection or infusion. The dose range is very wide as tolerance occurs during chronic therapy (starting at 5 mg with no real upper limit). Adverse effects are respiratory depression and constipation. Parenteral doses last four hours whereas long-acting oral preparations need to be repeated 12-hourly. The main interactions are with other opioids, pethidine and monoamine oxidase inhibitors (BNF 2013).

How the intervention might work

Opioids have several actions other than analgesia and it is these secondary actions that may help reduce the sensation of dyspnoea (Hallenbeck 2012), which many people with end-stage heart failure describe.

Opioids exert their effect through at least three groups of receptors which are distributed throughout the body, accounting for the global and varied effects of these drugs. The primary receptors opioids work on are mu receptors. Within the central nervous system, mu receptors are found in large numbers in the mid-brain, periaqueductal grey matter and dorsal horn of the spinal cord. At these sites they induce intense analgesia and also a number of other effects, including bradycardia, sedation, euphoria and respiratory depression (Rosenquist 2013). Another mechanism of action suggested is that opioids may ameliorate the sensation of dyspnoea by reducing hypercapnic chemosensitivity (Chua 1997). Indeed, opioids are widely used in people with cancer to treat the symptom of dyspnoea.

Opioids are available in a variety of oral and intravenous preparations; additional options are transdermal patches and transmucosal or intraspinal preparations. In addition, long-acting forms of the drug are available, with a variety of methods of delivery.

Alternative medications often used to alleviate the anxiety associated with dyspnoea are benzodiazepines such as lorazepam (Dudgeon 2013).

Why it is important to do this review

Knowledge about symptom management in heart failure lags behind knowledge about how to improve other outcomes. The lack of clearly identified interventions for palliative care in heart failure presents significant challenges to ensuring these people are provided with optimal care.

The use of opioids for the treatment of dyspnoea in cancer is well established within palliative care. However, as opioids are extensively used for pain management in cancer, it is difficult to separate out the effects on dyspnoea. Although the majority of people with advanced chronic heart failure suffer pain (O'Leary 2009), it is rare for this to be treated with opioids.

Other reviews have combined heart failure patients with other conditions (Oxberry 2008), particularly chronic obstructive pulmonary disease (COPD). Published data for cancer and COPD patients cover different opioids at a range of doses (Jennings 2001), making it difficult to identify suitable dose regimes for dyspnoea in heart failure. Reviews that focus on heart failure are either based on a limited literature review (Hochgerner 2009) or on uncontrolled trials or studies (Lowey 2013).

Opioids are commonly used in palliative care to relieve dyspnoea. Existing heart failure guidelines either do not discuss dyspnoea (McKelvie 2013; McMurray 2012; NICE 2010), or are limited to a good practice point due to a lack of robust evidence (SIGN 2007). A review that either provides evidence on the effectiveness of this treatment in the context of chronic heart failure, or confirms the lack of clear evidence, would be of benefit to both front-line clinicians and researchers with an interest in this area.


To assess whether opioid analgesics have a role in the control of dyspnoea in adults (aged 18 and over) with chronic heart failure. If the opioid reduces breathlessness in heart failure, this could potentially markedly improve the quality of life of people with this problem, as breathlessness is a major adverse symptom in heart failure. What is not entirely clear is whether opioids really do reduce breathlessness in heart failure and, if so, by how much and is it is enough to impact on quality of life?


Criteria for considering studies for this review

Types of studies

We will consider randomised controlled trials or controlled clinical trials involving the use of opioid analgesics as a treatment for dyspnoea in people with heart failure.

Types of participants

We will focus on adults (aged 18 years or older) with diagnosed heart failure.

There are two separate but related versions of heart failure, both of which cause major breathlessness. The first one is heart failure due to left ventricular systolic dysfunction (LVSD), which is often a terminal disease characterised at its end by 'difficult to treat breathlessness'. 'Difficult to treat breathlessness' is also a feature of the second disease, which is heart failure with preserved left ventricular systolic function. The two diseases differ in their pathophysiology, but both can produce terminal breathlessness. Both types of heart failure will be included in this review as both produce severe breathlessness, but it might well be that the effect of opioids in one form of heart failure will not be the same as in the other form: hence two separate analyses will be necessary if data are available.

COPD is a major comorbidity but it also produces terminal breathlessness which, for symptomatic reasons, is treated with opioids despite the fact that they might well hasten death in COPD. Since some patients will inevitably have heart failure and COPD, and will need relief of their breathlessness, we will not exclude people with concurrent heart failure and COPD but will take note of where it occurs.

Types of interventions

We will be looking at the use of opioid drugs administered by any route compared with placebo, other drug classes or no other add-on therapy.

Types of outcome measures

Primary outcomes
  • Reduced degree of dyspnoea, as indicated by hypoxic and hypercapnic chemosensitivities, tidal volume and ventilatory response to exercise.

  • Patient important outcomes: dyspnoea subjective severity, exercise capacity and quality of life.

Secondary outcomes
  • Common adverse effects of opioids: level of consciousness, constipation, nausea, confusion and drowsiness.

Subjective measures will be based on validated scales including the University of California San Diego Shortness of Breath Questionnaire (SOBQ), Borg Scale (Borg), Minnesota Living with Heart Failure questionnaire, Kansas City Cardiomyopathy Questionnaire and visual analogue scales (VAS).

Search methods for identification of studies

Electronic searches

We will carry out electronic searches of the Cochrane Central Register of Controlled trials (CENTRAL), the Cochrane Database of Systematic Reviews (CDSR) and the Database of Abstracts of Reviews of Effects (DARE). We will carry out additional searches of MEDLINE (using the Ovid interface), EMBASE, CINAHL (through the Elsevier interlace), Google Scholar and the Web of Knowledge (through Thomson Reuters). We will check the grey literature through OpenGrey. We will adapt the preliminary search strategy for MEDLINE (OVID) (Appendix 1) for use in the other databases.

We will check ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform (ICTRP) for relevant current trials.

We will search the Guidelines International Network (GIN) database, National Guideline Clearinghouse and NHS Evidence for existing guidelines.

We will also check the websites of major medical societies specialising in chest diseases. These will include the British Thoracic Society, American Thoracic Society, American College of Chest Physicians, American Heart Association, American College of Cardiology, European Society for Cardiology and the American Academy of Hospice and Palliative Medicine.

As the number of relevant studies is expected to be limited, we will not look further for adverse events reports but rely on the reporting of events within the included studies.

We will impose no language restrictions.

Searching other resources

We will check the reference lists for existing guidelines and reviews relevant to this question, as well as those for key papers identified as the review progresses, for further trials.

We will check systematic reviews of the use of opioids for the treatment of dyspnoea generally for articles specific to heart failure.

We will contact trial authors for information about any other completed or ongoing work.

Data collection and analysis

Selection of studies

We will obtain the full text of articles identified as possibly relevant trials on the basis of the titles and abstracts. We will also obtain the full text in cases of uncertainty. Two authors (RH, FS) will independently identify and select papers for inclusion. In cases where there is disagreement, we will resolve this by discussion or referral to a third author (AS). In cases where there is insufficient information to make a decision, we will contact trial authors where possible.

Data extraction and management

We will use data abstraction forms developed specifically for this review to abstract data on participants, interventions and outcomes. RH and FS will abstract data independently. Differences will be resolved by discussion or, where necessary, consultation with AS. Where data are lacking in the published papers, we will write to the original authors requesting further information.

Assessment of risk of bias in included studies

RH and FS will independently assess the risk of bias in the included studies using The Cochrane Collaboration's recommended tool, which is a domain-based critical evaluation of the following domains: sequence generation; allocation concealment; blinding of outcome assessment; incomplete outcome data and selective outcome reporting (Higgins 2008). We will provide assessments of risk of bias, indicating whether this is rated as high, low or unclear, for each study.

Measures of treatment effect

We expect studies to report continuous outcomes and we will use the mean difference (MD) with 95% confidence interval (CI) to summarise the pooled effect. In the event that some studies use dichotomous outcomes, we will report both risk ratios and absolute risk reductions.

Unit of analysis issues

Data from non-standard study designs, such as cross-over or cluster-randomised trials, are likely to feature in this review. We aim to follow the recommendations from the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2008), following advice from the Cochrane Heart Group or other statisticians as appropriate.

Dealing with missing data

Where there are insufficient data available from the published studies, we will write to the original authors for clarification/additional data. Where this is not forthcoming, we will carry out the analysis using the available data and discuss the potential impact of the missing data on our findings.

Assessment of heterogeneity

We will assess the level of heterogeneity in pooled data analyses using the I2 statistic. Where no heterogeneity is present we will perform a fixed-effect meta-analysis. If substantial heterogeneity is detected (I2 > 50%), we will consider the use of a random-effects model or present a descriptive analysis only.

Assessment of reporting biases

We will use a funnel plot to assess the risk of publication bias, if sufficient trials are found. We will discuss any asymmetry in the plot along with other potential reporting biases.

Data synthesis

We will pool data using a fixed-effect meta-analysis unless substantial heterogeneity is detected (I2 > 50%). In this case, we will look for consistency of effect, check the robustness of the findings by using a random-effects model and consider a narrative synthesis rather than a pooled estimate of effect.

Subgroup analysis and investigation of heterogeneity

There is evidence of a worse prognosis for heart failure patients of Afro-Caribbean origin and we will check for any specific evidence relating to that sub-population (Shah 2012).

If numbers are sufficiently large, we will check for differences between people with or without comorbid COPD.

Socioeconomic factors have been mooted as leading to inequality in heart failure outcomes between different social groups, but in the light of recent evidence that these inequalities are reducing, we will not explore this further (Hawkins 2012).

Sensitivity analysis

If heterogeneity is found, we will examine the methodological and clinical characteristics of the included trials. If there are differences, we will use a sensitivity analysis to see what effect these differences may have had on the results. We anticipate that analyses including and excluding concurrent COPD will be required.


The support of Nicole Martin (Trials Search Co-ordinator for the Cochrane Heart Group) in developing the search strategies is gratefully acknowledged.


Appendix 1. MEDLINE search strategy

1. exp dyspnea/

2. breathless$.mp.

3. dyspn?ea*.tw.

4. ((shortness* or labor* or difficult*) adj2 breath*).tw.

5. (cardiac adj2 asthma).tw.

6. dyspneic*.tw.

7. or/1-6

8. exp heart failure/

9. ((heart or cardiac or myocard*) adj2 (fail* or insufficien* or decomp*)).tw.

10. (congestive adj2 heart).tw.

11. exp cardiac output/

12. or/8-11

13. 7 and 12

14. exp analgesics, opioid/

15. (opioid* or opoid* or opiod*).tw.

16. Alfentanil.tw.

17. alphaprodine.tw.

18. bruprenorphine.tw.

19. butorphanol.tw.

20. codeine.tw.

21. Dextromoramide.tw.

22. Dextropropoxyphene.tw.

23. Dihydromorphine.tw.

24. Diphenoxylate.tw.

25. Enkephalin*.tw.

26. Ethylketocyclazocine.tw.

27. Etorphine.tw.

28. fentanyl.tw.

29. heroin.tw.

30. hydrocodone.tw.

31. hydromorphone.tw.

32. Levorphanol.tw.

33. Meperidine.tw.

34. Meptazinol.tw.

35. Methadone.tw.

36. Methadyl Acetate.tw.

37. morphine.tw.

38. Nalbuphine.tw.

39. Opiate Alkaloid*.tw.

40. opium.tw.

41. oxycodone.tw.

42. oxymorphone.tw.

43. Pentazocine.tw.

44. Phenazocine.tw.

45. Phenoperidine.tw.

46. Pirinitramide.tw.

47. Promedol.tw.

48. Sufentanil.tw.

49. Tilidine.tw.

50. Tramadol.tw.

51. or/14-50

52. 13 and 51

Contributions of authors

RH and FS drafted the protocol.

AS checked and approved the draft.

RH developed the search strategies.

RH is guarantor of the review.

Declarations of interest

RH participated in this review as part of his work for the Scottish Intercollegiate Guidelines Network (SIGN). He is a Working Party lead in the European Union's DECIDE project and has been funded by them to attend conferences and meetings related to the project. He has also been a member of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) group since 2001.

Allan Struthers has been a consultant and speaker for companies developing aldosterone-modulating drugs. He also owns share in Astra Zeneca and GlaxoSmithKline.

Fiona Shearer has no known conflict of interest.

Sources of support

Internal sources

  • Healthcare Improvement Scotland, UK.

    RH is employed by Healthcare Improvement Scotland who supported this review by allowing time for the work, and providing access to literature and other resources required to complete the review.

  • University of Dundee, UK.

    The University of Dundee is providing the group with free access to relevant articles via PubMed etc.

External sources

  • New Source of support, Not specified.