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Vol. 25. Issue 6.
Pages 355-356 (November - December 2019)
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Vol. 25. Issue 6.
Pages 355-356 (November - December 2019)
Letter to the Editor
DOI: 10.1016/j.pulmoe.2019.07.008
Open Access
Debating pharmacological options for dyspnoea relief; the need for full, accurate and balanced critical appraisal of the evidence
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Joanna C. Grogono
Corresponding author
Joanna.Grogono@ouh.nhs.uk

Corresponding author.
Oxford University Hospitals NHS Trust, John Radcliffe Hospital, OX3 9DU, United Kingdom
Kyle T.S. Pattinson
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, OX3 9DU, United Kingdom
Shakeeb H. Moosavi
Department of Biological and Medical Sciences, Oxford Brookes University, OX3 0BP, United Kingdom
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To the editor,

We read with interest the review on strategies to relieve dyspnoea in patients with advanced chronic respiratory disease by Ambrosino and Fracchia.1 Given the clinical need for pharmacological options for dyspnoea relief, we would like to comment on some important aspects that we feel merit further clarification.

The review comments on inhaled furosemide as a potential drug for relieving dyspnoea and refers to our RCT in healthy volunteers2 which showed significant relief of experimentally-induced air hunger. The review stipulates that this was “a finding not confirmed later even at higher doses.”3 The comment is misleading, implying that higher-dose studies were completed subsequent to ours and that the findings were incongruous. Our study2 was published after the higher-dose studies. The controlled delivery of 80mg was associated with greater air hunger relief3 compared to what we found with uncontrolled delivery of 40mg (mean±SE: −17±3 versus −11±5%VAS). However, the greater relief in the higher-dose study was offset by a larger placebo effect (−13±4 versus −2.5±4%VAS). The enhanced placebo effect in the higher-dose study can be explained by differences in study design.

While there is high variability in dyspnoea relief in all published studies of inhaled furosemide, there is potential for it to form a viable treatment option for the most unpleasant form of dyspnoea if the sources of variability are unravelled. Potential sources of variability include, i) site of drug deposition in the lungs ii) rate of extinction from the lungs iii) lack of information on the quality of dyspnoea rated and iv) use of a dyspnoea model that is not focussed on ‘air hunger’. More research with inhaled furosemide is justified given that it is safe, inexpensive and underpinned by a defined physiological mechanism of action.

The discussion by Ambrosino and Fracchia on the use of opioids for dyspnoea relief is also misleading and fails to paint a balanced picture. The authors have ignored the opioid crisis that has killed over ¾ million Americans since 1999.4 They have not considered the absence of long-term studies of opioid efficacy or safety.5 In most people, opioid efficacy is high in the short term but diminishes over 6 weeks to 3 months. The resultant dose escalation increases risk of adverse events with no improvement in symptoms.5 We suggest extreme caution is necessary for prescription of opioid medication for breathlessness because, i) opioids increase risk for death in people with lung conditions,4 ii) people with anxiety/depression are more likely to have diminished opioid response to pain,5 and breathlessness,6 but also are more likely to have problems with dependency and failure to wean off opioids.

Finally the author's assertion that "Relief of dyspnoea […] is a human right" echoes sentiments expressed in the mid 1980′s that were used to justify using opioids for all kinds of pain,7 leading to the opioid crisis we are in today. It is preposterous to portray those who harbour legitimate concerns about opioid safety as human rights violators when the debate is not fuelled by a balanced appraisal of the evidence.

Statement of ethics

The authors have no ethical conflicts to disclose.

Funding

The authors have not received any funding specifically for this correspondence.

Author contributions

All authors contributed equally to this correspondence.

Conflict of interest

KP has acted as a consultant for Nektar Therapeutics. The work for Nektar has no bearing on the contents of this manuscript. KP is named as a co-inventor on a provisional UK patent application titled “Use of cerebral nitric oxide donors in the assessment of the extent of brain dysfunction following injury".

References
[1]
N. Ambrosino, C. Fracchia.
Strategies to relieve dyspnoea in patients with advanced chronic respiratory diseases. A narrative review.
Pulmonology, 25 (2019), pp. 289-298
[2]
J.C. Grogono, C. Butler, H. Izadi, S.H. Moosavi.
Inhaled furosemide for relief of air hunger versus sense of breathing effort: a randomized controlled trial.
Respir Res, 19 (2018), pp. 181
[3]
R.B. Banzett, R.M. Schwartzstein, R.W. Lansing, C.R. O’Donnell.
Aerosol furosemide for dyspnea: high-dose controlled delivery does not improve effectiveness.
Respir Physiol Neurobiol, 247 (2018), pp. 24-30
[4]
K.M. Babu, J. Brent, D.N. Juurlink.
Prevention of Opioid Overdose.
N Engl J Med, 380 (2019), pp. 2246-2255
[5]
K.T.S. Pattinson, M.J. Rowland, A.H. Nickol, J. Quinlan.
Adverse respiratory effects of opioids for chronic breathlessness: learning lessons from chronic pain.
Eur Respir J, 51 (2018),
[6]
S.J. Abdallah, O.K. Faull, V. Wanigasekera, S.L. Finnegan, D. Jensen, K. Pattinson.
Opioids for breathlessness: psychological and neural factors influencing response variability.
[7]
R.K. Portenoy, K.M. Foley.
Chronic use of opioid analgesics in non-malignant pain: report of 38 cases.
Pulmonology

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