CURRENT OPINION

Opioids for Chronic Refractory Breathlessness: Right Patient,Right Route?

David C. Currow • Magnus Ekstrom •

Amy P. Abernethy

Published online: 11 December 2013

� Springer International Publishing Switzerland 2013

Abstract Chronic breathlessness at rest or on minimal

exertion despite optimal treatment of the underlying

chronic cause(s) is termed chronic refractory breathless-

ness. This is prevalent across the community and is an

independent indicator of poor prognosis. This narrative

review focuses on the palliation of chronic refractory

breathlessness in people predominantly with non-cancer

diagnoses. Breathlessness is a complex sensation with at

least three dimensions—intensity, distress/unpleasantness

and its impact on function. It is the conscious representa-

tion of a mismatch between central ventilatory drive (the

demand to breathe) and the responding respiratory output

(the ability to breathe). Measurement relies on subjective

reports by patients using a choice of uni- and multi-variable

tools; the minimal clinically important difference is the

smallest change conceived as clinically meaningful by the

patients. Exogenous and endogenous opioids work cen-

trally to reduce the sensation of breathlessness, with mor-

phine as a mu opioid receptor agonist the most widely

studied. Regular, low doses of sustained-release morphine

have been shown to safely reduce breathlessness in this

setting without evidence of respiratory depression nor

obtundation. Patients should be initiated at a dosage of

10 mg/24 h and titrated by 10 mg if there is no benefit

once in steady state. The highest dosage in the only dose-

ranging study published to date was only 30 mg/24 h.

Predictors of response to opioids for chronic refractory

breathlessness include younger people with more severe

breathlessness at baseline. Future research should address

whether upward titration delivers further clinical benefit

and whether all underlying aetiologies respond as predict-

ably to opioids.

1 Introduction

1.1 Definition of Chronic Refractory Breathlessness

A number of conditions leave people with chronic

breathlessness at rest or on minimal exertion despite opti-

mal treatment of the underlying chronic cause(s). This is

now termed chronic refractory breathlessness. Chronicity

has been operationalised in timeframes of 8 weeks [1] and

3 months [2] although in practice, once breathlessness

persists despite maximal treatment(s) of underlying chronic

causes and the cause is irreversible, it should be considered

‘chronic’. Underlying conditions include chronic obstruc-

tive pulmonary disease (COPD), interstitial lung disease,

cancer, chronic heart failure and advanced disease where

cachexia and muscle loss appear to cause breathlessness

even in the absence of underlying cardio-respiratory dis-

ease [3].

Across the community, the prevalence of chronic

breathlessness in resource-rich countries is surprisingly

high. A very small number of studies have looked at the

D. C. Currow � A. P. Abernethy

Discipline, Palliative and Supportive Services and Flinders

Centre for Clinical Change, Flinders University, Sturt Road,

Bedford Park, SA 5042, Australia

D. C. Currow (&)

Health Sciences Building, Repatriation General Hospital, Daws

Road, Daw Park, SA 5041, Australia

e-mail: david.currow@flinders.edu.au

M. Ekstrom

Lund University, Lund, Sweden

A. P. Abernethy

Center for Learning Health Care, Duke University, Durham, NC,

USA

Drugs (2014) 74:1–6

DOI 10.1007/s40265-013-0162-8

prevalence and reflect rates that, understandably, increase

with age. In one population-based survey, 1 in 12 people

had breathlessness that impacted on their day-to-day lives,

1 in 100 had breathlessness that impacted significantly on

their activities of daily living chronically and 1 in 300 were

housebound because of breathlessness [2]. As such,

breathlessness creates a massive symptom burden across

the community. Several studies have confirmed that the

presence of breathlessness is an indicator of a poor prog-

nosis with rates of subsequent death more than twice that of

the rest of the community [4, 5].

The aim of this narrative review is to define the evidence

underpinning treating chronic refractory breathlessness

with opioids, with a focus on people with COPD. It will

include consideration of patient selection, the choice of

opioid, dosing and route(s) of administration.

2 Measuring Breathlessness: Current Instruments

A thorough clinical examination is essential for evaluating

and managing the underlying disease. Physiological

parameters have very poor correlation with the experienced

severity of breathlessness [6, 7]. Given the subjective

nature of breathlessness, self-assessment by the patient is

considered the ‘‘gold standard’’ for rating the symptom and

its impact [8]. However, breathlessness is a complex sen-

sation with at least three dimensions—intensity, distress/

unpleasantness and its impact on function [8], which

patients can experience distinctly. This has been reflected

by in vivo studies in the laboratory setting [9–11]. Further

research is needed to elucidate the measurement, interplay

and impact of these different dimensions of breathlessness.

There is therefore no single measure that captures all

dimensions, and the choice of rating instrument is influ-

enced by factors including the main dimension of interest,

feasibility, study population and setting [8].

Studies of opioids in severe cardiopulmonary disease

have mainly measured the intensity of breathlessness using

unidimensional instruments: the Visual Analogue Scale

(VAS), Numerical Rating Scale (NRS), modified Borg

scale or Likert scale [8, 12–14]. The VAS is a continuous

100-mm scale anchored at 0 with ‘‘no breathlessness’’ and

at 100 for ‘‘worst possible breathlessness’’, which is valid

for measuring intensity changes within individuals, with

high sensitivity and reproducibility [15, 16]. Likewise,

anchors can reflect the affective component of breathless-

ness with ‘‘no unpleasantness’’ and ‘‘most unpleasant

breathlessness imaginable’’. The NRS is highly correlated

to VAS but is an ordinal scale between 0 and 10 [17]. The

modified Borg and the four category Likert scales are

categorical measures with a verbal description for each

category. Borg and Likert scales are also highly correlated

with VAS [18–20]. Timeframes for the measures can

include the last 12 or 24 h and may reflect ‘average’, ‘best’

or ‘worst’ sensations.

Application of more functional measures such as the

Medical Research Council (MRC) scale allows an under-

standing not only of the subjective rating of breathlessness,

but seeks to understand the level of exertion before breath-

lessness intervenes [21]. The widespread use of the MRC, for

example, in general practice in the UK, will allow a much

better understanding of breathlessness across the community

and help to evaluate outcomes in day-to-day practice.

Multidimensional instruments aim to capture several

dimensions of breathlessness but are more complicated and

less used in clinical trials of opioids to date. Examples

include the Baseline Dyspnea Index/Transitional Dyspnea

Index (BDI/TDI), which focus on the functional impact of

dyspnoea [22], the Dyspnea-12 scale, [23] the Cancer

Dyspnea Scale (CDS) [24] and measures included in health-

related quality-of-life instruments, such as the St George

Respiratory Questionnaire (SGRQ) and the Chronic Respi-

ratory Disease Questionnaire (CRDQ) [25, 26].

2.1 The Minimally Clinically Important Difference

in Chronic Breathlessness

The minimal clinically important difference (MCID) is the

smallest change in a parameter that is conceived as clini-

cally meaningful by patients [8, 27]. To date, most MCID

data for breathlessness have been developed in the setting

of acute breathlessness. The reduction required to be

clinically meaningful to patients in the acute setting, such

as an exacerbation of asthma, is of the order of 2 cm on a

NRS or 20 mm on a VAS [28, 29].

In the setting of chronic refractory breathlessness,

MCID was -9.2 mm (-15.8 to -2.1) on a 100-mm VAS

in patients with mainly severe COPD and chronic heart

failure [27]. Supported cut-offs for intensity changes were

-5.5 mm for small change, -11.3 for moderate and

-18.2 mm for large change [27]. Data on the MCID for

other dimensions of breathlessness are lacking; however,

information available to date suggests that, in the setting of

chronic refractory breathlessness, relatively small reduc-

tions in breathlessness will be perceived beneficially by

patients in this setting. Future trials should be powered to

detect a difference in breathlessness intensity correspond-

ing to at least 10 mm on a 100-mm VAS.

3 In Vivo Studies Contributing to the Understanding

of the Role of Opioids in Reducing Breathlessness

Laboratory studies underpinning the evidence now include

important data on the administration of opioid antagonists,

2 D. C. Currow et al.

which help define the role of endogenous opioids, labora-

tory exercise studies of opioid agonists in healthy volun-

teers, and, most recently, important changes demonstrated

through functional imaging.

3.1 Opioid Antagonists

Opioid antagonists have been administered to people with

moderate to severe COPD in the laboratory setting after

which they are asked to exercise on the treadmill [30].

Breathlessness increased with an opioid antagonist sug-

gesting that endogenous opioids help to modulate the

sensation of breathlessness. The regression slope of

breathlessness as a function of oxygen consumption was

higher with naloxone than placebo during exercise.

3.2 Opioid Agonists

The most widely studied opioid for the relief of breath-

lessness is morphine, the archetypal opioid agonist for the

mu opioid receptor. Discovered at the beginning of the 19th

century, morphine was commercialised within a quarter of

a century. Orally, bioavailability is between 20 % and

40 %, with similar rates of protein binding. Ninety percent

of morphine is metabolised in the liver, with more than

90 % excreted renally and the balance through the biliary

system. The pharmacokinetics of oral morphine vary

depending on which of the three most widely available

delivery systems are used: immediate-release oral mor-

phine solution, controlled-release morphine tablets, and

sustained release [31].

Central modulation of breathlessness appears to occur in

two distinct pathways: afferent sensations to the somato

sensory cortex reflect intensity; and afferent pathways to

the limbic system transmit unpleasantness. The latter is an

area with large numbers of opioid receptors [32].

The use of opioid agonists in healthy volunteers in the

laboratory suggests that exogenous opioids (morphine)

help to modulate breathlessness. Work is continuing to

define whether the combination of endogenous and exog-

enous opioids is of benefit, how they work, and whether

peripheral and central opioid receptors are equally impor-

tant in modulating breathlessness [33].

Other opioids are being studied to see if their net effects

are similar to morphine. The most promising study was of

fentanyl in the laboratory setting, showing a similar pattern

of reduced breathlessness with maintained work effort [34].

3.3 Functional Imaging

Breathlessness is the conscious representation of a mis-

match between central ventilatory drive (demand to

breathe) and the resulting respiratory output (ability to

breathe) [8]. Although much remains to be understood,

recent positron emission tomography and functional mag-

netic resonance imaging studies have shed light on

neurobiological pathways and mechanisms that contribute

to different qualities of breathlessness. Awareness of the

intensity of breathlessness is mediated by afferent projec-

tions from peripheral chemo-mechanical receptors, which

mostly remain uncharacterised, to the brainstem medulla,

ventro-posterior thalamic area and somatosensory cortex

structures [35]. Awareness of the unpleasantness of

breathlessness involves areas in the right anterior insula

and amygdala [35, 36]. These areas are also activated by

other unpleasant stimuli including hunger, nausea, thirst

and pain [37].

Endogenous opioids (endorphins) are, to date, the only

neurotransmitters that have been shown to modulate

breathlessness [38]. Endogenous opioids reduce both the

intensity and unpleasantness of laboratory-induced

breathlessness [30, 39, 40]. Increasing endogenous opi-

oids selectively in the blood did not affect breathless-

ness, suggesting that opioids modulate breathlessness

mainly through direct effects on the central nervous

system [33].

4 Clinical Care of People with Chronic Refractory

Breathlessness: Net Benefit of Therapy

Considering the net effects of opioids requires an under-

standing of both the benefits and harms. Benefits include

reduced breathlessness in a way that is safe, effective,

sustained and improves functioning. Harms include pre-

dictable problems such as constipation, and theoretical

concerns including respiratory depression, obtundation and

confusion extrapolated from the acute administration of

much higher doses of opioids. The net effects need to

balance all of these factors in considering the use of opioids

in this clinical setting.

4.1 Oral Opioids: Evidence of Effect

Low-dose sustained-release oral morphine has level I evi-

dence for the treatment of chronic refractory breathlessness

in advanced, progressive disease, irrespective of diagnosis

[12, 13, 41]. In a meta-analysis published in 2002 of nine

studies (102 patients), oral and parenteral opioids

decreased breathlessness by a mean standardised difference

(MSD) -0.40 (95 % confidence interval, -0.63 to -0.17),

corresponding to a mean decrease of 8 mm on a 100-mm

VAS [12]. A sub-analysis showed similar effects in

patients with COPD.

An adequately powered study in patients with chronic

refractory breathlessness was published by Abernethy and

Opioids for Chronic Refractory Breathlessness 3

colleagues in 2003 [13]. In this double-blind, placebo-

controlled, crossover, randomised trial, a daily dose of

20 mg sustained-release oral morphine decreased the mean

breathlessness in the morning (6.6 mm; 1.6–11.6;

p = 0.011) and evening (9.5 mm; 3.0–16.1; p = 0.006) on

a 100-mm VAS, compared with 4 days of placebo [13]. As

a secondary outcome, opioids also improved sleep quality

as a result of fewer dyspnoea-related sleep disturbances

(p = 0.039). The 48 included patients were elderly (mean

age 76 years), had severe breathlessness (mean 42 mm on

morning VAS), mostly had COPD as their underlying

cause of breathlessness (88 %) and mostly used long-term

oxygen therapy (71 %). This finding was consistent with

the findings of a meta-analysis that opioids reduced

breathlessness (MSD -1.3; -2.49 to -0.13) in patients

with cancer [42].

One disease-specific study in chronic heart failure failed

to demonstrate a net benefit in the short term for immedi-

ate-release oral morphine solution given at a dosage of

5 mg four times each day. The crossover, randomised,

controlled trial failed to show any significant difference in

breathlessness over 4 days compared with placebo [14].

However, a subsequent analysis indicated improvements

after 3 months treatment in those who continued therapy,

suggesting the need for a dose titration study in people with

chronic heart failure [43].

4.2 Titrating of Oral Opioids for Chronic Refractory

Breathlessness

In an observational phase-II dose-increment study of oral,

low-dose sustained-release morphine in 83 patients (54 %

COPD, 29 % cancer), 64 % of patients responded to opi-

oids, defined as receiving a C10 % decrease in breath-

lessness [41]. In this open-label, single-arm study, based on

the number of responses and adverse effects over baseline

among those participating, for every 1.6 people started on

sustained-release morphine for breathlessness, one person

derived a net clinical benefit. For every 4.6 people, one

person had to stop therapy because of adverse effects that

reversed. There were no episodes of respiratory depression

or obtundation. Among responders, 70 % needed only

10 mg morphine once daily to get a beneficial effect, and

30 % responded to doses up to 30 mg daily. As such, only

relatively small doses of the drug appear to have a clini-

cally significant therapeutic effect. Response to opioids

occurred mostly within 24 h after the successful dose

increase, with an additional decrease in breathlessness

during the subsequent week [44]. There was clear evidence

of net clinical benefit in this longitudinal study; research is

needed on whether increasing the opioid dose above the

lowest dose needed for response provides additional

benefit.

A clinical trial of regular, low-dose, sustained-release

morphine is recommended for patients with severe, ongo-

ing breathlessness that is refractory to treatment of the

underlying aetiology [13]. Opioid titration should be done

by initiating a low dose equivalent to 10 mg per 24 h

morphine with up-titration weekly or faster as needed.

Having achieved a response, it will be important to wait

1 week before further upward titration [44]. Prophylactic

treatment for constipation should be offered to all people as

they commence on opioids. Response is measured using a

VAS or NRS before and during the treatment, helping

clinicians to balance beneficial and adverse effects.

4.3 Predictors of Response to Oral Opioids

A recent pooled analysis of four clinical studies (178

patients with mostly severe COPD and chronic heart fail-

ure) demonstrated that the chance of responding to opioids

was higher in patients with more severe breathlessness at

baseline (p \ 0.001) and in younger patients (p = 0.025

for relative response). Response was defined as an absolute

or relative improvement of C10 % over the baseline

breathlessness [45], and was not predicted by functional

status, gender or the underlying disease aetiology [45].

Further work is needed to understand why younger, more

breathless patients derive more benefit from low-dose,

regular opioids.

4.4 Safety of Oral Opioids

Low-dose opioids are safe in opioid-naı̈ve patients with

severe cardiopulmonary disease. The main reported

adverse effects in pragmatic, prospective trials where tox-

icities were actively and routinely sought were constipation

and nausea/vomiting, and to a lesser degree dizziness and

drowsiness [12–14, 41]. Adverse effects were transient and

reversible when treated or upon opioid discontinuation and

did not cause any hospitalisations or deaths [12–14, 41,

46]. Respiratory depression and hypoventilation have not

been reported in any study of regular, low-dose opioids to

date [12–14, 41, 46, 47]. Research is needed on predictors

of adverse effects and on the safety of opioids in routine

clinical practice [48], particularly in expected high-risk

populations such as patients with respiratory failure,

especially central hypoventilation syndromes.

5 Other Routes of Administration: Nebulised Opioids

The bronchial tree is also richly innervated with opioid

receptors [49]. This has led to work to explore the possi-

bility that local delivery of nebulised opioids may also help

to ameliorate the sensation of breathlessness, without

4 D. C. Currow et al.

systemic absorption. The systematic review by Jennings

et al. [12] identified nine small studies that had used neb-

ulised opioids. The meta-analysis failed to demonstrate any

benefit, but this may well be a Type II error given the

studies available for analysis. Most notably, particle size

and delivery mechanisms have a major impact on where in

the bronchial tree the drug is ultimately delivered [49].

More recently, a double-blind, randomised trial dem-

onstrated that in people with severe, ongoing breathless-

ness, a single dose of nebulised morphine relieved

breathlessness [50]. It is not clear if there was any systemic

absorption. This relatively small, single-dose study needs

to be incorporated into the meta-analysis by Jennings et al.

[12].

6 Conclusions

Low-dose opioids have a key role to play in the safe

reduction of chronic refractory breathlessness, with the

majority of people in the study setting deriving symptom-

atic benefit. Systemic opioids are now supported by theo-

retical, laboratory and clinical evidence in the patient

populations for whom such medications should be pre-

scribed. Most recently, significant statements by the

American College of Chest Physicians [51], the American

Thoracic Society [8] and the Canadian Respiratory Society

[52] all endorse the use of opioids in the setting of

refractory breathlessness. Ensuring timely and appropriate

access to regular, low-dose oral morphine is a key chal-

lenge as the evidence for this therapy strengthens.

Future research needs to address two key issues: whe-

ther upward titration delivers a further net clinical benefit;

and whether all underlying aetiologies respond as predict-

ably to opioids and with the same magnitude of benefit.

This work is currently underway in blinded, randomised

trials.

Acknowledgements No funding was associated with this work.

Competing interest DC Currow, M Ekstrom and AP Abernethy

declare no competing interests.

References

1. Pratter MR, Abouzgheib W, Akers S, et al. An algorithmic

approach to chronic dyspnea. Respir Med. 2011;105(7):1014–21.

2. Currow DC, Plummer JL, Crockett A, et al. A community pop-

ulation survey of prevalence and severity of dyspnea in adults.

J Pain Symptom Manage. 2009;38(4):533–45.

3. Currow D, Smith J, Davidson P, et al. Do the trajectories of

dyspnea differ in prevalence and intensity by diagnosis at the end

of life? A consecutive cohort study. J Pain Symptom Manage.

2010;39(4):680–90.

4. Hammond EC. Some preliminary findings on physical complaints

from a prospective study of 1,064,004 men and women. Am J

Public Health Nations Health. 1964;54:11–23.

5. Frostad A, Soyseth V, Haldorsen T, et al. Respiratory symptoms

and 30 year mortality from obstructive lung disease and pneu-

monia. Thorax. 2006;61(11):951–6.

6. Gift AG, Plaut SM, Jacox A. Psychologic and physiologic factors

related to dyspnea in subjects with chronic obstructive pulmonary

disease. Heart Lung. 1986;15(6):595–601.

7. Hui D, Morgado M, Vidal M, et al. Dyspnea in hospitalized

advanced cancer patients: subjective and physiologic correlates.

J Palliat Med. 2013;16(3):274–80.

8. Parshall MB, Schwartzstein RM, Adams L, et al. An official

American Thoracic Society statement: update on the mecha-

nisms, assessment, and management of dyspnea. Am J Respir

Crit Care Med. 2012;185(4):435–52.

9. Banzett RB, Pedersen SH, Schwartzstein RM, et al. The affective

dimension of laboratory dyspnea: air hunger is more unpleasant

than work/effort. Am J Respir Crit Care Med. 2008;177(12):

1384–90.

10. Wan L, Van Diest I, De Peuter S, et al. Repeated breathlessness

experiences induced by hypercapnia: differential effects on

intensity and unpleasantness. Chest. 2009;135(2):455–61.

11. von Leupoldt A, Dahme B. Differentiation between the sensory

and affective dimension of dyspnea during resistive load

breathing in normal subjects. Chest. 2005;128(5):3345–9.

12. Jennings AL, Davies AN, Higgins JP, et al. A systematic review

of the use of opioids in the management of dyspnoea. Thorax.

2002;57(11):939–44.

13. 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. BMJ.

2003;327(7414):523–8.

14. 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(9):1006–12.

15. Mancini I, Body JJ. Assessment of dyspnea in advanced cancer

patients. Support Care Cancer. 1999;7(4):229–32.

16. Gift AG. Validation of a vertical visual analogue scale as a

measure of clinical dyspnea. Rehabil Nurs Off J Assoc Rehabil

Nurs. 1989;14(6):323–5.

17. Gift AG, Narsavage G. Validity of the numeric rating scale as a

measure of dyspnea. Am J Crit Care. 1998;7(3):200–4.

18. Reuben DB, Mor V. Dyspnea in terminally ill cancer patients.

Chest. 1986;89(2):234–6.

19. Lush MT, Janson-Bjerklie S, Carrieri VK, et al. Dyspnea in the

ventilator-assisted patient. Heart Lung. 1988;17(5):528–35.

20. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms,

lung hyperinflation, and endurance during exercise in chronic

obstructive pulmonary disease. Am J Respir Crit Care Med.

1998;158(5 Pt 1):1557–65.

21. Fletcher CM. The clinical diagnosis of pulmonary emphysema;

an experimental study. Proc R Soc Med. 1952;45(9):577–84.

22. Mahler DA, Weinberg DH, Wells CK, et al. The measurement of

dyspnea: contents, interobserver agreement, and physiologic

correlates of two new clinical indexes. Chest. 1984;85(6):751–8.

23. Yorke J, Moosavi SH, Shuldham C, et al. Quantification of

dyspnoea using descriptors: development and initial testing of the

Dyspnoea-12. Thorax. 2010;65(1):21–6.

24. Uronis HE, Shelby RA, Currow DC, et al. Assessment of the

psychometric properties of an English version of the cancer

dyspnea scale in people with advanced lung cancer. J Pain

Symptom Manage. 2012;44(5):741–9.

25. Guyatt GH, Berman LB, Townsend M, et al. A measure of quality

of life for clinical trials in chronic lung disease. Thorax.

1987;42(10):773–8.

Opioids for Chronic Refractory Breathlessness 5

26. Jones PW, Quirk FH, Baveystock CM. The St George’s Respi-

ratory Questionnaire. Respir Med. 1991;85 Suppl B:25–31 (dis-

cussion 3–7).

27. Johnson MJ, Bland JM, Oxberry SG, et al. Clinically important

differences in the intensity of chronic refractory breathlessness.

J Pain Symptom Manag. 2013;46(6):957–63.

28. Karras DJ, Sammon ME, Terregino CA, et al. Clinically mean-

ingful changes in quantitative measures of asthma severity. Acad

Emerg Med Off J Soc Acad Emerg Med. 2000;7(4):327–34.

29. Ander DS, Aisiku IP, Ratcliff JJ, et al. Measuring the dyspnea of

decompensated heart failure with a visual analog scale: how

much improvement is meaningful? Congest Heart Fail (Green-

wich, Conn). 2004;10(4):188–91.

30. Mahler DA, Murray JA, Waterman LA, et al. Endogenous opi-

oids modify dyspnoea during treadmill exercise in patients with

COPD. Eur Respir J. 2009;33(4):771–7.

31. Gourlay GK, Plummer J, Cherry DA, et al. A comparison of

Kapanol (a new sustained-release morphine formulation), MST

Continus, and morphine solution in cancer patients: pharmaco-

kinetic aspects of morphine and morphine metabolites. Seventh

World Pain Congress, 1994. p. 631–43.

32. Mahler DA. Understanding mechanisms and documenting plau-

sibility of palliative interventions for dyspnea. Curr Opin Support

Palliat Care. 2011;5(2):71–6.

33. Mahler DA, Gifford AH, Waterman LA, et al. Effect of increased

blood levels of beta-endorphin on perception of breathlessness.

Chest. 2013;143(5):1378–85.

34. Jensen D, Alsuhail A, Viola R, et al. Inhaled fentanyl citrate

improves exercise endurance during high-intensity constant work

rate cycle exercise in chronic obstructive pulmonary disease.

J Pain Symptom Manage. 2012;43(4):706–19.

35. Davenport PW, Vovk A. Cortical and subcortical central neural

pathways in respiratory sensations. Respir Physiol Neurobiol.

2009;167(1):72–86.

36. von Leupoldt A, Sommer T, Kegat S, et al. The unpleasantness of

perceived dyspnea is processed in the anterior insula and amyg-

dala. Am J Respir Crit Care Med. 2008;177(9):1026–32.

37. Evans KC, Banzett RB, Adams L, et al. BOLD fMRI identifies

limbic, paralimbic, and cerebellar activation during air hunger.

J Neurophysiol. 2002;88(3):1500–11.

38. Mahler DA. Opioids for refractory dyspnea. Expert Rev Respir

Med. 2013;7(2):123–35.

39. Bellofiore S, Di Maria GU, Privitera S, et al. Endogenous opioids

modulate the increase in ventilatory output and dyspnea during

severe acute bronchoconstriction. Am Rev Respir Dis.

1990;142(4):812–6.

40. Gifford AH, Mahler DA, Waterman LA, et al. Neuromodulatory

effect of endogenous opioids on the intensity and unpleasantness

of breathlessness during resistive load breathing in COPD.

COPD. 2011;8(3):160–6.

41. Currow DC, McDonald C, Oaten S, et al. Once-daily opioids for

chronic dyspnea: a dose increment and pharmacovigilance study.

J Pain Symptom Manag. 2011;42(3):388–99.

42. Ben-Aharon I, Gafter-Gvili A, Leibovici L, et al. Interventions

for alleviating cancer-related dyspnea: a systematic review and

meta-analysis. Acta Oncol. 2012;51(8):996–1008.

43. 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(3):250–5.

44. Currow DC, Quinn S, Greene A, et al. The longitudinal pattern of

response when morphine is used to treat chronic refractory

dyspnea. J Palliat Med. 2013;16(8):881–6.

45. Johnson MJ, Bland JM, Oxberry SG, et al. Opioids for chronic

refractory breathlessness: patient predictors of beneficial

response. Eur Respir J. 2013;42(3):758–66.

46. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in

advanced COPD: revisiting a role for opioids. Thorax.

2009;64(10):910–5.

47. Clemens KE, Quednau I, Klaschik E. Is there a higher risk of

respiratory depression in opioid-naive palliative care patients

during symptomatic therapy of dyspnea with strong opioids?

J Palliat Med. 2008;11(2):204–16.

48. Johnson MJ, Abernethy AP, Currow DC. The evidence base for

oxygen for chronic refractory breathlessness: issues, gaps, and a

future work plan. J Pain Symptom Manag. 45(4):763–75.

49. Krajnik M, Schafer M, Sobanski P, et al. Local pulmonary opioid

network in patients with lung cancer: a putative modulator of

respiratory function. Pharmacol Rep. 2010;62(1):139–49.

50. Shohrati M, Ghanei M, Harandi AA, et al. Effect of nebulized

morphine on dyspnea of mustard gas-exposed patients: a double-

blind randomized clinical trial study. Pulm Med. 2012;2012:

610921.

51. Mahler DA, Selecky PA, Harrod CG, et al. American College of

Chest Physicians consensus statement on the management of

dyspnea in patients with advanced lung or heart disease. Chest.

2010;137(3):674–91.

52. Marciniuk DD, Goodridge D, Hernandez P, et al. Managing

dyspnea in patients with advanced chronic obstructive pulmonary

disease: a Canadian Thoracic Society clinical practice guideline.

Can Respir J. 2011;18(2):69–78.

6 D. C. Currow et al.