The symptomatic treatment of the subjective sensation of breathlessness has a strengthening evidence base to help to inform practice. The efficacy of several pharmacological measures is established and there are emerging data to support the safety of these interventions. Given the complexity of the sensation of refractory breathlessness, pharmacological approaches account for only part of the comprehensive management of this symptom, and other therapies with high levels of evidence, such as nurse-led interventions, should also be employed [1,2]. Improved correlative science in understanding the transmission and processing of stimuli generating ‘breathlessness’ is also providing evidence on which to base current and future pharmacological interventions [3,4].
Opioids: mechanism of action on respiration
Functional magnetic resonance imaging has been used to determine in vivo the anatomical location of increased neuronal activity due to induced air hunger in normal volunteers. Air hunger from decreased tidal volume stimulates a marked response in the limbic and paralimbic regions including the insula, cingulate gyrus and amygdala; areas shared with pain, hunger and thirst .
By contrast, the major respiratory depressant effect of mu opioid agonists is likely to be their action on the dorsolateral and medial parts of the nucleus tractus solitarus in the dorsal medulla, and the midline medullary raphe, both sites rich in central chemoreceptors . Of note, such depression is negated by pain as a stimulus to breathing.
Peripherally, opioid receptors are widespread including in the peripheral chemoreceptors in type I glomus cells in the carotid bodies, the vagus nerve, and mechanosensory receptors throughout the lungs (epithelial, submucosal and muscular layers of airways) . The major clinical action of opioids in helping to relieve breathlessness across the candidate sites rich in mu opioid receptors is yet to be resolved.
Opioids remain the class of medications with the best level of evidence of benefit in reducing the subjective sensation of refractory breathlessness [7–9]. Their use in clinical practice for breathlessness is not well quantified. Opioids are now acknowledged in the Global Initiative for Chronic Obstructive Lung Disease's  recommendations, with the caveat that they are of likely benefit in ‘only a few sensitive individuals’ . By contrast, a recent review published in Chest acknowledges the role of opioids in treating refractory breathlessness in people with advanced lung cancer . Importantly, this discussion, although based around people with lung cancer, sets the therapy of refractory breathlessness in the context of comorbid illnesses [notably chronic obstructive lung disease (COLD) and heart failure, symptomatic pulmonary emboli, prior lung resection and cachexia], the complications of cancer treatment (direct pulmonary toxicity including inflammatory response to radiotherapy, airway stenosis, fistula formation and haemoptysis from neovascularization) and anxiety . The ideal parenteral or oral opioid has not been defined, but most controlled clinical trials have used morphine . Importantly, tachyphylaxis has not been reported with opioid use for refractory breathlessness . There remains no systematic evidence of benefit from nebulized opioids .
Evidence of benefit includes people with COLD, cancer and heart failure [7,8,12•,13,14]. The issue of people with heart failure is of particular interest. Although the study by Johnson et al.  was reported as a pilot study, it found a significant difference between placebo and low-dose regular morphine. Likewise, the secondary analysis published by Currow et al.  of a double-blind, placebo-controlled, crossover trial of sustained release morphine for breathlessness showed the small subgroup with a predominantly cardiac cause for breathlessness to have the most marked response.
Despite several systematic reviews that continue to confirm the efficacy of low-dose opioids in people with refractory breathlessness, the few data available suggest very limited clinical use of this therapy [7,12•,15•]. Arguably, the major reasons that opioids are not used more widely in clinical practice are concerns about addiction and respiratory depression. All evidence to date about respiratory depression is drawn from the acute care setting where opioids have been used for analgesia usually in the postoperative or trauma settings. This is not an evidence base that can be readily adapted to the regular use of low-dose oral or parenteral opioids in the chronic setting carefully titrated to effect. Indeed, there are data in healthy human volunteer studies that distinguish the effects of acute intravenous bolus of opioids (which will in high enough doses lead to apnoea until CO2 drive cuts in) from slowly titrated opioids (where progressive dose increases can, if needed, be offset by increasing levels of hypercapnia) on the overall process of respiratory drive .
The systematic review by Jennings et al.  of opioids for the relief of refractory breathlessness also reports that in 11 of the 18 studies cited, oxygenation and carbon dioxide levels were reported and did not change with the introduction of opioids. To date, despite widespread concerns, there have not been cases of documented respiratory depression in those treated with regular low-dose opioids for refractory dyspnoea. More recent studies have confirmed that in populations already on opioids and in those who are opioid naïve, there is no evidence of respiratory compromise (as measured by respiratory rate, oxygen saturation or levels of carbon dioxide) when morphine or hydromorphone are used for breathlessness or pain [9,15•,16,17]. Extrapolating from the acute care sector where bolus doses of opioids for analgesia in people who are opioid naïve have been well documented to cause significant respiratory depression, to the clinical setting of chronic provision of low-dose opioids for the symptomatic relief of dyspnoea is a non sequitur.
Although studies report adverse events, no study has been powered to address the issue of serious adverse events such as respiratory depression causing death [15•,18]. Given the absence of evidence that this is a clinical issue in the doses used in the target population, any phase III randomized safety study would need to have a very large recruitment. Instead, effective phase IV (postmarketing) monitoring may need to be formalized to address concerns of clinicians and patients about adverse events from long-term low-dose opioids.
Better targeting therapy
Pharmacogenomic studies are now allowing a better understanding of interindividual variations in response to opioids for pain . The application of such genetic variation in the metabolism of opioids has not yet been reported in breathlessness, but investigation is underway. Such work may not only help to predict the likelihood of net clinical benefit but also identify people at particular risk of opioid toxicity when morphine is used for breathlessness.
Nonopioid interventions: nebulized frusemide
Although one of the most widely prescribed diuretics in the world, frusemide may have effects on breathlessness independent of diuresis. The use of nebulized frusemide in the symptomatic treatment of breathlessness has now been evaluated in studies of healthy populations, and results suggest that adequately powered phase III studies to establish the role of frusemide in the symptomatic relief of refractory breathlessness are warranted. This is despite some evidence of systemic absorption when frusemide is administered by nebulizer [20•].
The strongest evidence for frusemide in breathlessness is in people with asthma and other reversible airways diseases. The review by Newton et al. [21•] confirms that in single-dose and long-term use in healthy volunteer populations and in people with documented reversible airways disease, frusemide has a mild bronchodilator effect or, as a minimum, stops bronchoconstriction, and is relatively well tolerated when nebulized [22,23]. Such studies have defined endpoints with either pulmonary function tests, exercise tolerance or both.
The same systematic review by Newton et al. [21•] explored the use of frusemide both in well volunteers where breathlessness was artificially induced and in people with irreversible causes of breathlessness.
At a symptomatic level, there are seven studies of interest because they explicitly measured breathlessness as an end-point. Three of these studies are in healthy volunteers and four in people with established disease (two in cancer [24,25], one in COLD  and one in individuals at the end of life) . All studies show symptomatic benefit of nebulized frusemide over placebo.
Three studies in healthy volunteers are randomized placebo-controlled trials [20•,27,28]. The most recently reported study was a double-blind placebo-controlled trial of 40 mg of inhaled frusemide used in the setting of induced air hunger [20•]. By increasing inspired CO2 through a closed breathing circuit and controlling minute ventilation, a sensation of air hunger was created without the sensation of increasing the work of breathing. On separate days, participants were administered either placebo or inhaled frusemide. In the 10 participants, there was a significant trend for a reduced sensation of air hunger in the active arm by an absolute mean of 13 mm on a 100 mm visual analogue scale compared with 5 mm for placebo (P = 0.05). There were repeated breathing tests after the nebulized intervention was administered, and after each breathing test, the participants emptied their bladders, drinking an equivalent amount of isotonic fluid at that time. There was evidence of a diuretic effect seen with frusemide that was not seen with normal saline, suggesting some systemic absorption.
The onset of action was relatively rapid, but the duration of benefit of 40 mg of nebulized frusemide was relatively short-lived (1 h only for the majority of participants) [20•]. These last two observations are in contrast to at least one open label, uncontrolled study in people with refractory dyspnoea who reported no diuresis and symptomatic benefits lasting in excess of 4 h .
The study evaluating nebulized frusemide in 19 people with COPD is a double-blind placebo-controlled trial and measures both exercise tolerance and breathlessness, both of which improved significantly as a result of the active arm of therapy . Because of the potential bronchodilating effects of frusemide, it is difficult to interpret the effect of frusemide that can be attributed to symptomatic relief of breathlessness when both forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) improved in a statistically and clinically significant way.
The study at the end of life was a small double-blind pilot study of a single dose of frusemide one day and saline on the other day measuring distress of breathing and difficulty breathing in seven participants . Interestingly, neither measure is purely of breathlessness and reflects aspects that may be associated with some types of breathlessness. All participants had lung cancer. This study did not favour frusemide in the description of outcomes.
The other two studies on the symptomatic benefits of frusemide for breathlessness are uncontrolled studies [24,25]. One was a series of three cases. The perceived benefits of nebulized frusemide were seen in three of the four papers reporting patient breathlessness.
The other perennial question is whether frusemide is efficacious in all types of breathlessness. One of the studies in healthy volunteers deliberately focused on creating air hunger without causing an increase in the work of breathing [20•]. It may be that, with time, the different sensations of breathlessness can be better matched to specific types of therapies to relieve them .
Implications for research
There is an urgent need to further understand the safety of opioids in people with advanced respiratory disease causing breathlessness, given that this is a continuing barrier to their use in the wider clinical community. There is also a need to understand the optimal dosing of opioids when used for the relief of breathlessness, and whether long-term dosing can be maintained at a starting dose. The other pressing question is whether opioids whose predominant effect is not as a mu receptor agonist have similar effects on breathlessness.
For frusemide, there are now enough data to warrant well designed phase II studies leading to phase III studies, especially in populations who do not have a reversible component of airways disease. Such studies need to use a variance between the groups that is sufficient to be clinically meaningful and, as such, these are likely to be relatively small studies. Given the relatively short duration of benefit in at least one randomized controlled trial, dosing and dose scheduling will need to be considered very carefully as such studies are designed.
How should practice change as a result of new studies coming to light? There is a strong and strengthening case for the use of opioids for individuals with refractory breathlessness. Such use, however, should be in the context of careful phase IV postmarketing data collection to understand optimal use in the population with refractory breathlessness.
Frusemide is not yet supported by an evidence base to recommend use in routine clinical care. Dosing, frequency and degree of systemic absorption need to be rigorously resolved before there can be widespread use of nebulized frusemide. The issue of absorption is of concern if the medication requires frequent dosing in a population whose renal function may already be impaired.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 146).
1 Bredin M, Corner J, Krishnasamy M, et al
. Multicenter randomized controlled trial of nursing intervention for breathlessness in patients with lung cancer. Br Med J 1999; 318:901–904.
2 Corner J, Plant H, A'Hern R, Bailey C. Nonpharmacological intervention for breathlessness in lung cancer. Palliat Med 1996; 10:299–305.
3 Evans KC, Banzett RB, Adams L, et al
. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol 2002; 88:1500–1511.
4 Kallet RH. The role of inhaled opioids and furosemide for the treatment of dyspnea
. Resp Care 2007; 52:900–910.
5 Bailey PL, Lu JK, Pace NL, et al
. Effects of intrathecal morphine
on the ventilatory response to hypoxia. N Engl J Med 2000; 343:1228–1234.
6 Pattinson KTS. Opioids and the control of respiration. Br J Anaesth 2008; 100:747–758.
7 Jennings AL, Davies AN, Higgins JP, et al
. A systematic review of the use of opioids in the management of dyspnoea. Thorax 2002; 57:939–944.
8 Abernethy AP, Currow DC, Frith P, et al
. Randomised double-blind placebo-controlled crossover trial of sustained-release morphine
for the management of refractory dyspnoea. Br Med J 2003; 327:523–525.
9 Clemens KE, Klaschik E. Symptomatic therapy of dyspnoea with strong opioids and its effect on ventilation in palliative care
patients. J Pain Symptom Manage 2007; 33:473–481.
10 Global Initiative for Chronic Obstructive Lung Disease. 2006 Edition. www.goldcopd.org
. [Accessed 28 January 2008]
11 Kvale PA, Selecky PA, Prakash UBS. Palliative care
in lung cancer. Chest 2007; 132:368S–403S.
12• Ben-Aharon I, Gafter-Gvili A, Paul M, et al
. Interventions for alleviating cancer-related dyspnea
: a systematic review. J Clin Oncol 2008; 26:2396–2404. A comprehensive review of the current evidence for the treatment of dyspnoea in cancer.
13 Johnson MJ, McDonagh TA, Harkness A, et al
for the relief of breathlessness in patients with chronic heart failure: a pilot study. Eur J Heart Fail 2002; 4:753–756.
14 Currow DC, Plummer J, Frith P, Abernethy AP. Can we predict which patients with refractory dyspnea
will respond to opioids? J Pall Med 2007; 10:1031–1036.
15• Viola R, Kiteley C, Lloyd NS, et al
. The management of dyspnea
in cancer patients: a systematic review. Support Care Cancer 2008; 16:329–337. A useful overview of the approaches to breathlessness in people with cancer. The review includes pharmacological and nonpharmacological approaches.
16 Clemens KE, Klaschik E. Effect of hydromorphone on ventilation in palliative care
patients with dyspnoea. Support Care Cancer 2008; 16:93–99.
17 Estfan B, Mahmoud F, Shaheen P, et al
. Respiratory function during parenteral opioid titration for cancer pain. Pall Med 2007; 21:81–86.
18 Currow DC. The pharmacological management of dyspnoea. In: Booth S, Dudgeon D, editors. Dyspnoea. Oxford: Oxford University Press; 2005.
19 Coller JK, Christrup LL, Somogyi AA. Role of active metabolites in the use of opioids. Eur J Clin Pharmacol 2009; 65:121–139.
20• Moosavi SH, Binks AP, Lansing RW, et al
. Effect of inhaled furosemide on air hunger induced in healthy humans. Resp Phys Neurobiol 2007; 156:1–8. An overview of a subtype of breathlessness that can be created in the laboratory with significant clinical correlations.
21• Newton PJ, Davidson PM, Macdonald P, et al
. Nebulized furosemide for the management of dyspnea
: does the evidence support its use? J Pain Symptom Manage 2008; 36:424–441. An excellent overview of the uses of frusemide
beyond diuresis for breathlessness. Much of the paper reviews asthma, but six papers relate predominantly to breathlessness.
22 Bianco S, Pieroni MG, Refini RM, et al
. Protective effect of inhaled furosemide on allergen-induced early and late asthmatic reactions. N Eng J Med 1989; 321:1069–1073.
23 Ong KC, Kor AC, Chong WF, et al
. Effects of inhaled furosemide on exertional dyspnea
in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2004; 169:1028–1033.
24 Kohara H, Ueoka H, Aoe K, et al
. Effect of nebulized furosemide in terminally ill cancer patients with dyspnea
. J Pain Symptom Manage 2003; 26:962–967.
25 Shimoyama N, Shimoyama M. Nebulized furosemide as a novel treatment for dyspnea
in terminal cancer patients. J Pain Symptom Manage 2002; 23:73–76.
26 Stone P, Rix E, Kurowska A, Tookman A. Nebulized furosemide for dyspnea
in terminal cancer patients. J Pain Symptom Manage 2002; 24:274–275.
27 Nishino T, Ide T, Sudo T, Sato J. Inhaled furosemide greatly alleviates the sensation of experimentally induced dyspnea
. Am J Respir Crit Care Med 2000; 161:1963–1967.
28 Minowa Y, Ide T, Nishino T. Effects of inhaled furosemide on CO2 ventilatory responsiveness in humans. Pulm Pharmacol Ther 2002; 154:363–368.
29 Harver A, Mahler DA, Schwartzstein RM, Baird JC. Descriptors of breathlessness in healthy individuals: distinct and separable constructs. Chest 2000; 118:679–690.