Paper under discussion
Haubner, A., Oluyase, A. O., & Higginson, I. J. (2026). Rapid Relief of Breathlessness With Fast-Acting Opioids and Benzodiazepines: A Systematic Review. Journal of pain and symptom management, S0885-3924(26)00756-6. Advance online publication. https://doi.org/10.1016/j.jpainsymman.2026.04.606

Having chanced across a recent systematic review on the utility of opioids in acute breathlessness by Haubner et al, I found myself, being forced, albeit hesitantly, to recount the reservations that my erstwhile pulmonary medicine colleagues, had hinted at – the slippery landscape of opioids in those with COPD (citing the possibility of carbon dioxide retention and possible worsening). I have also been surprised with the insistence of former colleagues to not touch upon the vexing issue of opioid induced respiratory depression, completely negating the possibility of such an event, with the intent to sanitize opioid prescribing and opening it up to those with limited experience in the specialist setting. That said, this post is intended to be more about understanding the limitations of opioid usage in this setting rather than OIRD, a subject which shall be reserved for another post.

The author’s rigorous and novel approach stands out for praise. Having a specific question – Efficacy of fast acting drugs with site of action within the Central Nervous System for relief of spontaneous breathlessness with responses measured with the time frame of less than 20 minutes, might place restrictions on the data available, but promises to be more rewarding.

Let’s address the implications of various terms used in this research question and extrapolate them to real world-practice
a. Fast acting drugs – identifies the setting as being that of acute breathlessness.
b. Site of action within the central nervous system – hints at the inclusion of both benzodiazepines and opioids on which it focuses, while leaving, anti-depressants out of its purview. c. Focuses on immediate release preparations only.
d. Measuring the response at less than 20 minutes also forces a reasonable time-frame, as well as a pharmacokinetic constraint. It seems prudent to assume that a patient with advanced illness and episodes of worsening breathlessness might be correct to expect reprieve within this somewhat generous time frame.

The review also characterizes episodes of acute exacerbations of breathlessness in a somewhat relatable and clinically-applicable manner. It attaches a mean duration of 10 minutes, while warning that these episodes might last 20 minutes or longer.

It also contains a mechanistically sound judgement which acknowledges that while this setting might not lend itself well to manipulation of peripheral afferent mechanisms, central mechanisms remain plausible targets.

The fact that pharmacotherapy is divided into three lines of treatment including fixed scheduled dosing, prophylactic treatment of exercise-induced breathlessness and fast-acting treatment of spontaneous breathlessness also hints at a novel approach aimed at prioritizing the patient’s experience.

Minimally Clinically Important Difference (MCID) – a difference of -1 on VAS (1-10), -1 on NRS (1-10) and Standard mean difference of -0.5 for measuring the effect size have been used.

Statistical insight – The paper uses Albatross plots in order to highlight the fact that there were two studies involving the use of intravenous and subcutaneous morphine where the results exceeded predetermined levels of significance graphically. The study uses the plot mainly as a visual exploratory tool rather than as a means of substantive statistical analysis. Heterogeneity in studies exists in the setting, comparator and the route of administration.

Results
Most studies were small crossover trials in the setting of advanced cancer or COPD. No studies involving the use of anti-psychotics or cannabinoids met the inclusion criteria.
Apart from the two studies that showed some benefit for the use of parenteral morphine in the setting of acute breathlessness and were able to cross the threshold of MCID, the following are the take-away findings:
Most opioid formulations did not show any benefit when compared to placebo.
No specific opioid formulation was found to be superior to the other.
Benzodiazepine formulations were not found to be unequivocally beneficial. Intranasal midazolam did not show any beneficial effect when compared to placebo and iv midazolam was also not found to be more effective than iv morphine.
Significantly, two important safety signals were identified, bringing the safety of rapid opioid infusion into question. Use of iv morphine was associated with more intubations in acute respiratory failure and more cardiovascular events in acute pulmonary edema.

Conclusion
Supports the use of non-pharmacological management in preference of parenteral (intravenous) opioids in acute breathlessness, though intravenous morphine may be suited for use in specific populations, however safety issues remain and limited efficacy, and that recommendations supporting their use cannot be made at this time. The lack of unequivocal efficacy of benzodiazepines also negatively impacts the theoretical framework governing the anxiety-breathlessness combination as a shared experience.

Editor’s take
The study centered on acute breathlessness, tries to position intravenous opioids in a manner similar to inhaled bronchodilators, but succeeds only to a very small extent in proving evidence for efficacy. However, it brings a hitherto hidden and long gestating fact into direct focus – despite a scientific rationale for their use, the real-world evidence supporting the use of opioids in breathlessness remains wanting. It is important to understand that the effects of opioids on breathlessness are not driven by a conventional receptor binding, signal transduction and downstream effect, but are more complex. While,these drugs act centrally and are expected to modulate response of the respiratory centre to changes in concentration of carbon dioxide, a phenomenon which is mu receptor driven, the other postulated mechanism of action – acting via corollary discharge and modifying the efferent output to an afferent signal does not involve a direct receptor-target interaction. Suffice to say that the mechanism of action is less well understood and influences that impact it, even more so.

The authors have used pre-existing cut-offs for MCID which have been developed in the setting of chronic breathlessness, in a different setting, which also deserves further justification.

There remains the need to identify specific population subsets in whom opioid use might prove to be most beneficial, while preventing their unregulated use in settings, where risk benefit ratio remains unfavourable. Till that time, the decision concerning their usage and heirarchy in the scheme of available treatments rests on the clinical judgement of the specialist prescriber.

Cite as
Arora, R. D. (2026). Research Radar (RR4) – Deciphering the codex- Opioids in breathlessness. Zenodo. https://doi.org/10.5281/zenodo.20827267

Disclaimer
Palliative medicine is a relatively young subspecialty whose intellectual and clinical boundaries continue to evolve. In the absence of definitive texts to address contemporary questions, artificial intelligence tools, primarily Claude (Anthropic), have been employed to challenge assumptions, support deeper conceptual exploration, and improve clarity of expression. They do not replace critical scholarship, clinical experience, or editorial judgment. Final responsibility for all interpretations, factual accuracy, originality of synthesis, and the quality of the published material rests entirely with the Founder and Editor.