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).
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).