The fatigue enigma: towards an integrative theoretical framework across clinical conditions, 2026, Davies et al

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Research Article

The fatigue enigma: towards an integrative theoretical framework across clinical conditions​

Jennifer L. Davies
,
Helen Dawes
,
Ezio Preatoni
,
Deborah Edwards
,
Bethan Thomas
,
Rhiannon Jones
,
Brittany Nocivelli
,
Rhys Denton
,
Caroline Dalton
Monica Busse Morris
&on behalf of the GW4 Fatigue Community show less
Received 13 Nov 2025, Accepted 28 Apr 2026, Published online: 19 May 2026





ABSTRACT​

Background​

Fatigue is a complex phenomenon that presents persistent challenges for research and clinical care across multiple conditions.

Objective​

To explore development of an integrative theoretical framework linking lived experience, underlying mechanisms, and the design and evaluation of interventions.

Methods​

We conducted systematic scoping reviews to identify (i) systematic and narrative reviews of mechanisms or pathways of fatigue across clinical conditions, and (ii) systematic reviews and recent randomised controlled trials of interventions addressing fatigue. These reviews informed four consensus workshops with researchers, clinicians, and individuals with lived experience of fatigue that examined: (1) the meaning and evaluation of fatigue across conditions; (2) mechanisms and pathways; (3) evidence for outcomes and novel interventions; and (4) consensus development and program theory generation.

Key findings​

We present a summary of the discussions across the workshops and highlight the challenges that remain in evaluating the utility of an integrative theoretical framework. Substantial conceptual ambiguity was identified in how fatigue is defined and how mechanisms, pathways, and interventions are categorised. Inconsistent terminology, measurement approaches, and theoretical specification limit synthesis across conditions, and the current evidence base remains insufficiently articulated to support a coherent cross-condition account.

Conclusion​

Critical gaps remain in the use of common language, outcome measures, and theory-informed approaches to intervention development. Addressing these foundational limitations is necessary to determine whether an integrative framework for fatigue can be constructed, and whether this may support knowledge translation across diagnostic boundaries and hypothesis-driven research that is responsive to stakeholder priorities and delivers meaningful clinical benefit.
KEYWORDS:

 

Acknowledgements​

The GW4 Fatigue community consisted of researchers, clinicians, and individuals with lived experience of fatigue who attended one or more or four online workshops held between November 2023 and March 2024. Those who consented to be named are listed in Supplementary Material 3.

Supplementary Material 3. Members of the GW4 fatigue community who participated in one or more of the four workshops as an attendee and agreed to be named in this report.





Aaron Greenhouse-Tucknott, Cognitive Neuroimaging Unit, Institut National de la Santé et de la Recherche Médicale, Commissariat à l'Energie Atomique et aux énergies alternatives, Centre national de la recherche scientifique, Université Paris-Saclay, France

Bethan Thomas, School of Healthcare Sciences, Cardiff University, UK

Brittany Nocivelli,, Centre for Trials Research, School of Medicine, Cardiff University, UK

Christopher Russell, Vivisco Limited, UK

Caroline Dalton, Advanced Wellbeing Research Centre, Sheffield Hallam University, UK

Claire Nollett, Centre for Trials Research, Cardiff University, UK

Deborah Edwards, The Wales Centre for Evidence Based Care, School of Healthcare Sciences, Cardiff University, UK

Diana Robinson

Ezio Preatoni, Department for Health, University of Bath, UK

Fiona Leggat, School of Health and Medical Sciences, City St Georges, University of London, UK

Gemma Brownbill, School of Sport, Exercise and Health Sciences, Loughborough University, UK

Helen Dawes, NIHR Exeter Biomedical Research Centre, Medical School, University of Exeter, UK

Jennifer L Davies, School of Healthcare Sciences, Cardiff University, UK

Joanna Rutkowska-Wheeldon, Cardiff and Vale University Health Board, Cardiff, UK.

John Derek Franklin, Kleijnen Systematic Reviews Limited, UK

Kate Button, School of Healthcare Sciences, Cardiff University, UK

Katrina Burchell, Pernicious Anaemia Society, UK

Monica Busse Morris, Faculty of Nursing, Midwifery and Palliative Care, Kings College London, UK; and Centre for Trials Research, School of Medicine, Cardiff University, UK

Nick Courtier, School of Healthcare Sciences, Cardiff University, UK

Paulo C. R. Santos, IDOR / Pioneer Science Initiative, Rio de Janeiro, Rio de Janeiro, Brazil; Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel; and Center of Advanced Technologies in Rehabilitation, Sheba Medical Center, Ramat Gan, Israel.

Pavlos E. Evangelidis, Public Health and Sport Science, University of Exeter, UK

Rachael Pattinson, School of Dentistry, Cardiff University, UK

Rhiannon Jones, School of Medicine, Cardiff University, UK

Rhys Denton, Centre for Trials Research, School of Medicine, Cardiff University, UK



Samit Chakrabarty, School of Biomedical Sciences, University of Leeds, UK

Timothy Pickles, Centre for Trials Research, Cardiff University, UK

Willow Holloway, Disability Wales, UK; Autistic UK; Fair Treatment for the Women of Wales, UK; and The Autistic Women’s Empowerment Project, UK

Funding​

This work was funded by a Building Communities award from GW4 to JD, HD, DE and MBM (https://gw4.ac.uk/community/gw4-com...in-people-with-multiple-long-term-conditions/).

Notes on contributors​

Jennifer L. Davies​

Jennifer Davies is a Senior Lecturer at the School of Healthcare Sciences, Cardiff University. Her research focuses on the neural and muscular control of human movement, with particular interest in how sensory information, motor coordination, and muscle activity are affected by factors such as stress, anxiety, and fatigue. She leads interdisciplinary work exploring the mechanisms underlying physical fatigue in both health and disease, integrating approaches from movement neuroscience and rehabilitation science.

Helen Dawes​

Helen Dawes is a rehabilitation scientist and physiotherapist at the University of Exeter and Co-Director of the Rehabilitation Theme within the NIHR Exeter Biomedical Research Centre. Her research investigates the mechanisms and management of fatigue and its cognitive and physical correlates across neurological, post-viral, and chronic conditions. She leads translational research aimed at improving rehabilitation outcomes and interventions for individuals experiencing fatigue.

Ezio Preatoni​

Ezio Preatoni is Senior Lecturer in Biomechanics at the University of Bath. His research lies at the intersection of human movement science, biomechanics, and sensor technology, with a focus on understanding how fatigue influences coordination, variability, and performance in sport and health contexts. His work contributes to developing novel approaches to quantify fatigue and to optimise recovery and performance in physically demanding settings.

Deborah Edwards​

Deborah Edwards is Principal Research Fellow at the Wales Centre for Evidence Based Care, Cardiff University. Her expertise lies in evidence synthesis and methodological development to support the design and implementation of complex healthcare interventions. She contributes to advancing understanding of fatigue through systematic evaluation of evidence.

Bethan Thomas​

Bethan Thomas was a doctoral researcher at Cardiff University at the time of this work, and is now a postdoctoral researcher. Her work focuses on the mechanisms underlying fatigue in long-term health conditions and explores physiological, sensory, and cognitive aspects of fatigue, with the aim of contributing to a better understanding of how fatigue develops and persists, and how it may be mitigated through targeted interventions. She worked as a research assistant within the GW4 network studying fatigue in people with multiple long-term conditions, from which is work is based.

Rhiannon Jones​

Rhiannon Jones was a student at the School of Medicine, Cardiff University at the time of this work and is now a foundation doctor within Hywel Dda Health Board. She worked as a research assistant within the GW4 network studying fatigue in people with multiple long-term conditions, from which is work is based.

Brittany Nocivelli​

Brittany Nocivelli was a doctoral researcher at the time of this work and is currently a Research Associate in the Centre for Adult Social Care and DECIPHer centres in the School of Social Sciences at Cardiff University. She works to improve research inclusivity of underserved, vulnerable populations and the development of interventions to empower underrepresented populations to participate in research. She worked as a research assistant within the GW4 network studying fatigue in people with multiple long-term conditions, from which is work is based.

Rhys Denton​

Rhys Denton is a Research Manager at Centre for Trials Research in the School of Medicine at Cardiff University. He worked as a research assistant within the GW4 network studying fatigue in people with multiple long-term conditions, from which this work is based. His interests lie in research accessibility, and he contributes his lived experience of fatigue as a researcher and as a public contributor.

Caroline Dalton​

Caroline Dalton is Reader in Neuroscience and Genetics and Theme Lead for Living Well with Chronic Disease at the Advanced Wellbeing Research Centre at Sheffield Hallam University. Her research spans Long COVID and ME/CFS, physical-activity interventions, symptom monitoring, wearable devices and fatigue. She has authored intensive-longitudinal studies exploring within-person predictors of physical activity and fatigue in Long COVID, advancing understanding of symptom-activity dynamics.

Monica Busse Morris​

Monica Busse Morris is a physiotherapist and clinical trials methodologist, specialising in mobility, lifestyle interventions and rehabilitation in complex chronic disease. She led major interventional trials in Long COVID, including a self-management support intervention (LISTEN trial) that reported significant reductions in fatigue impact. Her work bridges mechanism, mobility and rehabilitation strategy in fatigue-bearing conditions.
 
Is there any more detail anyone knows about the initiative behind getting this group together for this?

I see some names I recognise and note it being important that eg how ambiguously the term is used and issues all over the place with regard to this including measures.

I'd be interested in who is behind this as a momentum (so to speak) and what the aims are - and whether this is eg the first of something that might be/become (incrementally starting with one step and going from where that leads) a bigger plan?
 
I am 100% here for this. We need whole university departments studying the various fatigues, their biological correlates and their opposites.

- lack of energy substrate. (how does lack of phospocreatine compare to lack of glycogen compare to sugar compare to lipids, etc),
- having done too much exertion (aerobic, anaerobic, and overtraining syndrome),
- malfunctoining metabolism (fatigue is present in metabolic diseases),
- circadian ( we sleep, some sleep longer than others. but why?),
- immune (sickness behaviour - how many types are there? what controls them?)
- dauer
- hibernation
- not to mention the concept of a 'social battery' or the feeling of having done too much cognitive effort.
- others? There's a case for investigating manias too. Sometimes people feel spontaneously full of energy and decide to barely sleep. How does that work?

It's not that there's no research on this but it's isolated. We should be synthesising little islands of immunology, sleep science and exercise science that are thinking about fatigue.
 
The descriptions of the research participants interests seem to point more towards rehabilitation strategies rather than trying to investigate underlying physiology of fatigue.

For example the last 2 described in the list of participants Dolphin posted above describe behavioural interventions for LC and ME/CFS.

I need to read the whole paper and their published research to find out more. I'm not impressed by the abstract which seems to me to be focused on assuming fatigue can be addressed with behavioural interventions across all fatiguing conditions.
 
The paper said:
Fatigue is a complex phenomenon
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It's not. It's actually pretty simple. Not knowing how it works isn't the same thing as being complex. Neither is having many possible sources. It's a hard problem, not a complex one.
However, the current evidence base remains fragmented and is insufficient to support a fully theoretically grounded account
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Who needs theories when you can just make up models, fail to confirm any single part of them, and just indefinitely go with it anyway? This is why we still know nothing about fatigue, because it's effectively encouraged to just make stuff up and ignore reality.
The process of intervention development should be transparent and theory-driven and importantly informed by the views of those with lived experience of fatigue
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You can't have a theory-driven process without theory. Especially not when it's 1000x easier to just make up a fake model that entirely ignores the lived reality of those experiencing it, with all their pesky disagreements over facts and adherence to concepts like the linear passage of time, and asking questions such as "what the hell are you talking about??!"
We found that interventions that targeted fatigue were not sufficiently described to be able to understand the clinical contexts in which they were most suited or effective.
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We have literally been through decades of baseless assertions of chronic fatigue being mainly an issue of deconditioning and avoidance behavior, neither of which had any truth to them, the deconditioning was debunked years ago, and nothing matters, still going strong. This is why zero progress has been made. It's not because of the problem itself, it's that those working on the problem are actively avoiding the problem in favor of made-up models that ignore reality. It's considered a trivial problem and it doesn't even have a trivial level of minimal effort. If you don't do the work, you don't get the results of having done the work.
Mechanistic rationales for how interventions are expected to influence fatigue are also seldom articulated within intervention studies.
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Why would they? Almost no one cares. The whole industry is a bullshit factory for endless masses of identical nonsense. It can be as nonsensical as "you had things happen in your life", the most generic baseless bullshit imaginable.
 
Hello - I haven't been here for a while, but I contributed to this work.

The hope was that by looking across conditions, mechanisms, and interventions in one project, we might find some commonalities that could be addressed in later research that may be missed by looking at those areas individually. We were particularly hopeful for something rooted in a physiological or biological mechanism that could be targeted by an intervention across those various conditions and be measured. The project allowed us to bring together researchers from lots of different areas outside our own specialisms, too, including immunology, physiology, neurology etc which was a strength of the community approach.

As it panned out, the findings are probably as familiar to you as they were to me as someone with ME - interventions often not linked to appropriate (or any) mechanisms, use of certain types of intervention (psych, exercise) featuring heavily across the conditions studied, lack of clarity about what types of fatigue are even being targeted (where a distinction was made, anyway, which was rare - speaks to some of the terminology/specificity points in the paper). It's not where we'd hoped to get to, but it is what we found.

On a personal level, as familiar as I am with ME stuff (and admittedly I was not as familiar with other conditions, so I've learnt a lot through this), it was more than a bit disappointing to see fatigue - using the term broadly - being addressed in similar ways across other conditions, too.
 
Thank you for explaining how it came about and why it ended up with stuff about behavioural interventions, @ItsMERJjD. I'm thinking about whether its worthwhile to read the whole paper.
Was any interesting biology revealed?
 
Trish said:
Thank you for explaining how it came about and why it ended up with stuff about behavioural interventions, @ItsMERJjD. I'm thinking about whether its worthwhile to read the whole paper.
Was any interesting biology revealed?
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This paper likely doesn't provide much of that, given the place it ended up in, which was more a critique of existing RCTs (and reviews of). Immune, inflammatory and stress response factors were things we found most studied in other fields (outside the things mentioned above, psych etc). This is probably reflective of the fact cancer studies featured heavily in our search and tended to have more biological underpinnings, as there's a lot more investment around cancer and more expensive biological approaches, certainly than there is for ME.

This paper would be great to get in front of trialists as I suspect that link (mechanisms underpinning interventions) is likely missing across other fields too, as protocols don't often focus in on the biological underpinnings. Something for me to think about in the day job!
 
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