Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness

  • Protocol
  • Intervention



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

To determine the effectiveness of opioid drugs in relieving the symptom of breathlessness in patients with either advanced malignancy, or with advanced respiratory or cardiovascular disease, or receiving palliative care for any other disease.


Description of the condition

Breathlessness may be described as "a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity" (ATS 1999). Breathlessness, also termed dyspnoea, shortness of breath, air hunger, awareness of respiratory distress or laboured breathing, may be variably perceived by different patients, depending on multiple physiological, psychological, social, environmental and cultural factors (Guz 1997). It is a common symptom at the advanced stages of illness, and may be as disabling to the patient and their families as pain, nausea and vomiting, delirium and other palliative symptoms (Neumann 2006).

Respiratory motor activity is regulated by automatic centres in the brainstem and voluntary signals from the cortex, and controls chest wall expansion, lung inflation and ventilation. Feedback is provided by chemoreceptors, mechanoreceptors, and sensory receptors.

Breathlessness may be explained by a mismatch between afferent sensory information processed at the cortex and respiratory motor command from the cortex and brainstem.

Alterations in arterial blood pH (acidity), pCO2 (partial pressure of carbon dioxide), and pO2 (partial pressure of oxygen) stimulate central chemoreceptors in the medulla and peripheral chemoreceptors in the carotid and aortic bodies, which transmit impulses to the brainstem respiratory centres, and adjust breathing based on acid base homeostasis (Fitzgerald 1986; Nattie 1995).

Mechanoreceptors and stretch receptors located in the lung parenchyma and bronchioles sense changes in the expansion of the lung and become irritated by certain mechanical and chemical stimuli, and affect subsequent levels and patterns of breathing (Nishino 2011).

Changes in air flow, smooth muscle tone, and impulses from C fibres located adjacent to the alveoli and pulmonary capillaries respond to changes in pulmonary interstitial and capillary pressures (Widdicombe 1982).

Sensory receptors in respiratory muscle and the diaphragm involved in spinal and supraspinal reflexes influences central respiratory activity (Bolsher 1987; Bolsher 1988).

Each of these mechanisms may contribute to the mismatch of neural activity and consequent mechanical and ventilatory outputs, and create sensations of dyspnoea, air hunger, and increased desire to breathe, which may cause distress to the patient.

Recent neuroimaging studies also suggest that neural structures involving pain and dyspnoea might be shared, further contributing to the patient's discomfort and distress associated with an increased sensation of ventilation (Brannan 2001; Liotti 2001; Parsons 2001; Peiffer 2001; Evans 2002; von Leupoldt 2009).

There are a number of currently incurable and progressive cardiopulmonary, neuromuscular and malignant conditions in which dyspnoea is a common symptom in the advanced stages of disease. The dominant mechanism leading to dyspnoea may vary between conditions and in many conditions more than one mechanism may be responsible. Illnesses such as interstitial lung disease, pulmonary hypertension and congestive heart failure stimulate pulmonary receptors (irritant, mechanical and vascular) leading to an increased respiratory drive and increased afferent input to the respiratory centre. Chronic conditions which are severe enough might also lead to gas exchange abnormalities through mechanisms such as ventilation-perfusion (V/Q) mismatching (e.g. pulmonary vascular disease) or diffusion impairment (e.g. interstitial lung disease) leading to stimulation of chemoreceptors and increased respiratory drive. Conditions which reduce the oxygen carrying capacity of the blood (e.g. anaemia) or reduce cardiac output (e.g. cardiac failure) also stimulate chemoreceptors. Respiratory muscle weakness in conditions such as motor neurone disease or myopathy, and decreased compliance of the chest wall in conditions such as severe kyphoscoliosis and pleural effusion, impair ventilatory mechanics which reduces the afferent feedback for a given efferent input. There are multiple potential aetiological factors related to breathlessness in chronic obstructive pulmonary disease (COPD). There is an increased resistive load from narrowing of the airways and increased elastic load from hyperinflation resulting in impaired ventilator mechanics. In addition hypoxia and or hypercapnia may be present leading to stimulation of chemoreceptors and finally, dynamic airway compression may stimulate receptors within the airway (Manning 1995; Parshall 2012).

Multiple mechanisms for breathlessness have also been described in individuals with advanced cancer. Cancers involving the lungs may obstruct airways leading to ventilation perfusion mismatch and pleural effusions are common. Many patients with lung cancer also have COPD. Dudgeon 1998 showed that patients with terminal cancer often have abnormal spirometry (most commonly a mixed obstructive/restrictive pattern or a restrictive pattern). They also found that respiratory muscle weakness may be an important contributor to dyspnoea and that co-morbidities such as anaemia and cardiac disease are common.

Initial approaches should aim to treat the underlying causes of breathlessness. However, as the disease progresses, such treatments may be less appropriate due to decreased effectiveness and discomfort caused to the patient, and a more symptom based approach may be used.

A number of pharmacological and non-pharmacological interventions have been used to help alleviate symptoms of breathlessness in advanced disease. Management of symptoms is often multimodal, with varying treatments utilised depending on the patient's co-morbidities, psychosocial, environmental and cultural factors.

A recent Cochrane systematic review on non-pharmacological interventions demonstrated efficacy for neuro-electrical muscle stimulation, chest wall vibration, walking aids, breathing training and use of hand held fans (Bausewein 2008). Another Cochrane review demonstrated effectiveness of oxygen therapy in non-hypoxaemic COPD patients (Uronis 2011), and slight improvement with non-statistical significance in heart failure patients, cancer patients (but not at end stage) and kyphoscoliosis (Cranston 2008).

Some literature supports opioids as the first choice in the pharmacological management of breathlessness (ATS 1999; Mahler 2010; Parshall 2012; Mahler 2013; Wiseman 2013). A Cochrane review published in 2001 concluded that there was some evidence to support the use of oral and parenteral opioids to palliate breathlessness but the number of patients studied was small and they recommended that larger trials were needed using standard protocols and incorporating quality of life measures (Jennings 2001).

A recent Cochrane review, Simon 2010, found a slight, non-significant trend towards a beneficial effect for benzodiazepines in breathlessness, but the overall effect size was small and further research is required.

Description of the intervention

Opioids are chemical substances derived from the opium poppy. In the human body they bind to the μ, κ and δ receptors located in the cerebral cortex, limbic system, midbrain, brainstem and outside the CNS in the bronchioles, alveolar walls, myocardial cells, peripheral sensory nerve fibres and primary afferent neurons.

How the intervention might work

Exogenous and endogenous opioids specifically bind to the mu receptors to reduce transmission of pain signals (Chahl 1996). Opioids also depress respiratory drive by directly blunting the responsiveness of the brainstem centres which are affected by hypoxia and hypercapnia. Decreased respiratory output results in a decrease in corollary discharge from the brainstem to perceptual areas in the cerebral cortex and thus reduced the sensation of breathlessness. Corollary discharge describes the hypothesis that a sensory 'copy' of the motor output is sent from the motor cortex to the sensory cortex and imparts a conscious awareness of respiratory effort (Beach 2006).

Opioids may also cause blunting of perceptual sensitivity to sensations of breathlessness. Neuroimaging studies demonstrate that μ opioid receptor agonists can modulate the central processing of breathlessness similar to that of pain relief. Administration of opioids stimulate activity in the anterior cingulate cortex, thalamus, frontal cortex and brainstem, the same areas which are activated when breathlessness occurs (Banzett 2000; Peiffer 2001; Petrovic 2002; Pattinson 2009).

Peripheral opioid receptors are located in bronchioles and alveolar walls of the respiratory tract (Zebraski 2000). Opioid administration may modulate breathlessness by binding to these opioid receptors, though this has yet to be fully proven, and there is lack of efficacy when comparing nebulised opioids with systemically administered opioids (Polosa 2002; Mahler 2013).

Other effects of opioids include drowsiness, euphoria, confusion, peripheral vasodilation, constipation, nausea and vomiting, and cough suppression.

The choice of preparation and pharmacokinetics of opioids may vary depending on patients' needs. Small doses of short acting opioids may be commenced in opioid-naïve patients, and once a stable dose has been achieved, may be switched to long acting preparations. Currow 2011 found 70% of participants derived benefit from 10mg sustained release once daily preparations. Transmucosal, transdermal, subcutaneous or intravenous modes may be more appropriate for patients whose swallowing is impaired or who are approaching final stages of end of life.

Why it is important to do this review

The use of opioids in the treatment of breathlessness in advanced illness is variably accepted in medical practice, and some doctors and patients still question the efficacy and remain concerned about side effects (Oxberry 2012; Rocker 2012). Much of the literature around opioids for breathlessness are narrative reviews and opinion pieces and a systematic review is required to specifically examine the quality of evidence from randomised controlled trials, and to evaluate efficacy in terms of symptom control and quality of life and to assess adverse effects.

The present review will build on a previous Cochrane systematic review, Jennings 2001. In more recent years, additional randomised controlled trials (RCTs) have been published (Mazzocato 1999; Johnson 2002; Abernethy 2003), mechanisms of action have been further elucidated, and guidelines examining the risk of bias and assessment of heterogeneity in Cochrane reviews have been updated (Higgins 2011).


To determine the effectiveness of opioid drugs in relieving the symptom of breathlessness in patients with either advanced malignancy, or with advanced respiratory or cardiovascular disease, or receiving palliative care for any other disease.


Criteria for considering studies for this review

Types of studies

We will include parallel-group RCTs compared to either placebo or other treatment, as well as crossover studies in which participants are randomised to order of treatment. 'Randomised' will be defined as studies which are described by the author as 'randomised', anywhere in the manuscript. There will be no language restriction. All identified trials, published and unpublished, will be potentially eligible for inclusion.

Types of participants

We will consider adults with any type of advanced progressive illness with persistent breathlessness despite optimal or appropriate treatment of reversible factors.

We will also include patients suffering from breathlessness due to any type of illness, who are considered to be at an advanced stage of illness, or palliative stage, as defined by the authors of the manuscript.

Types of interventions

Any opioid drug, given by any route, in any dose, for the treatment of breathlessness, compared to placebo, or any pharmacological interventions, or any non-pharmacological interventions, which are directly compared with opioids.

Types of outcome measures

Primary outcomes

Subjective measure of breathlessness intensity or severity, including but not limited to Borg and modified Borg scale, verbal categorical scales of breathlessness, and visual analogue scales of breathlessness.

Secondary outcomes
  • -Quality of life measure by any scale

  • Any physiological and functional assessments of breathlessness including but not limited to 6 minute walk tests, shuttle tests and actigraphy

  • Performance status

  • Pulse oximetry

  • Arterial blood gas analysis

  • Adverse events including constipation, delirium, and others

  • Mortality

Search methods for identification of studies

Electronic searches

We will search the following electronic databases:

  • the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library);




  • Web of Science.

The search strategy for MEDLINE is shown in Appendix 1.

Searching other resources

For ongoing studies we will search:

We will handsearch reference lists of included studies, relevant chapters and review articles. We will use Google to search for grey literature and conference abstracts.

We will translate any relevant article into English for potential inclusion.

Where data are missing, we will attempt to contact the trial investigators.

Data collection and analysis

Selection of studies

Two independent review authors (RM, HB) will independently screen all abstracts to determine whether they meet the inclusion criteria. Full-text publications will be sought for those which definitely or may meet the inclusion criteria. Two independent authors (RM, HB) will then review these full-text articles to determine eligibility. Disagreement will be resolved with discussion and consensus with referral to a third author (NS or JM) where necessary.

We plan to include a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) study flow diagram in the full review to document the screening process (Liberati 2009), as recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

Data extraction and management

Two review authors (RM,HB) will independently extract data from eligible studies. Where appropriate, data will be imported and pooled in the Cochrane Collaboration's statistical software, Review Manager 2013, for further analysis.

Assessment of risk of bias in included studies

Two independent authors (HB, RM) will assess the included studies for risk of bias using the Cochrane Collaboration's tool for assessing risk of bias (Higgins 2011). We will assess the following: allocation (random sequence generation and allocation concealment); blinding of participants and personnel, blinding of outcome assessors; incomplete outcome data; and other bias. Each of these domains will be scored separately as low risk of bias, unclear risk of bias (insufficient information to make a judgement) or high risk of bias as outlined below.

  • Generation of allocation sequence:

    • for each included study we will describe the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

  • Allocation concealment:

    • for each included study we will describe the method used to conceal the allocation sequence in sufficient detail and determine whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

  • Blinding or masking (checking for possible performance bias):

    • for each included study we will describe the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. Studies will be judged at low risk of bias if they were blinded, or if we judge that the lack of blinding could not have affected the results. We will assess blinding separately for different outcomes or classes of outcomes.

  • Incomplete outcome data (checking for possible attrition bias through withdrawals, dropouts, protocol deviations)

  • Free of other bias (bias due to problems not covered elsewhere in the table):

    • for each included study we will describe any important concerns we have about other possible sources of bias (e.g. baseline imbalance, bias of the presentation data, etc.)

Any disagreement will be resolved by discussion and consensus.

Measures of treatment effect

We will present results from continuous variables such as the breathlessness scales using a fixed-effect model and calculate the mean differences (MDs), or standardised mean differences (SMDs) where scales are combined, with the corresponding 95% confidence intervals (CIs).

For dichotomous data, including adverse events, we will pool and present results using relative risks (RRs) and 95% CIs.

Unit of analysis issues

Our unit of analysis is the participant. We will utilise the Cochrane Handbook for Systematic Review of Interventions if the unit of analysis in trials is not the same as the unit of randomisation, as in cluster randomised controlled trials (Higgins 2011).

Dealing with missing data

Where possible we will attempt to contact the principal investigator to obtain missing data.

Assessment of heterogeneity

For pooled analyses, we will quantify statistical heterogeneity using the I2 statistic which describes the percentage of the total variation across trials due to heterogeneity rather than sampling error. Significant statistical heterogeneity will be considered to be present if the I2 is greater than 50%.

Where significant heterogeneity is identified, we will further assess using pre-determined subgroups.

Assessment of reporting biases

Where reporting bias may be apparent, we will attempt to contact the principal investigator for missing data. If serious bias is still suspected we will assess the impact of including such studies in a sensitivity analysis.

Data synthesis

We will present our primary outcomes in a 'Summary of findings' table.

Subgroup analysis and investigation of heterogeneity

If sufficient data are available, we will perform the following subgroup analyses:

  1. type of illness (e.g. COPD, heart failure, malignancy, and neuromuscular disorders);

  2. mode of delivery of opioid drug (e.g. oral, subcutaneous, intravenous, nebulised, intra-nasal, sublingual, buccal, transdermal, and other modes);

  3. dose;

  4. duration of treatment or study;

  5. type of intervention in comparison arm (e.g. placebo, non-opioid pharmacological intervention, non-pharmacological intervention);

  6. risk of bias assessment (low, medium or high).

Sensitivity analysis

We plan to perform sensitivity analyses by systematically excluding studies from the overall analysis based on the potential sources of heterogeneity outlined above, and if homogeneous subgroups have not already been identified and analysed separately.


Appendix 1. MEDLINE search strategy

1 Analgesics, Opioid/

2 (papaveretum or morphine or fentanyl or hydromorphone or oxycodone or pentazocine or methadone or opioid* or opiate* or codeine or dextromoramide or OTFC or diamorphine or dihydrocodeine or dextropropoxyphene or meptazinol or sufentanil or alfentanil or remifentanil or nalbuphine or meptazinol or dipipanone or pethidine or tramadol or buprenorphine).tw.

3 Dyspnea/

4 (dyspnea* or breathless* or (short* adj2 breath*)).tw.

5 or/1-2

6 or/3-4

7 5 and 6

8 randomized controlled trial.pt.

9 controlled clinical trial.pt.

10 randomized.ab.

11 placebo.ab.

12 drug therapy.fs.

13 randomly.ab.

14 trial.ab.

15 or/8-14

16 exp animals/ not humans.sh.

17 15 not 16

18 7 and 17

Contributions of authors

HB and RM drafted the protocol.

Declarations of interest

No conflicts of interest.

Sources of support

Internal sources

  • None, Not specified.

External sources

  • None, Not specified.