Persistent physical symptoms not explained by structural abnormalities or disease processes: a primary care approach to promote recovery

Abstract

Background: A substantial proportion of people consulting primary care practitioners have symptoms that persist even after structural problems and diseases have been excluded. They experience distressing somatic complaints – such as fatigue, pain, headaches, and brain fog – lasting months or longer which impair quality of life and workability. In this article, we refer to these as persistent physical symptoms (PPS). When diagnosis, advice and care are based solely on a biomedical interpretation of symptoms, patients may not improve. This can result in repeated and often frustrating consultations and investigations.

Aim: To outline contemporary theories around PPS for general practitioners, and offer practical, evidence-informed pathways to use in primary care.

Methods: Narrative literature review and consensus development with experienced practitioners.

Synopsis:Contemporary theories Contemporary theories of PPS provide a coherent framework for understanding symptom persistence and guide treatment. These theories propose that symptoms may arise from brain-based responses to perceived threat, influenced by expectations and learned associations. Such responses can become unhelpful when benign sensations are interpreted as dangerous. Biopsychosocial factors unique to each individual influence these mechanisms which need to be considered when assessing PPS and working towards symptom resolution with the patient.

Evidence-informed pathways Key strategies include validating patients’ symptoms and emotional experiences, providing clear explanations of symptom persistence, and developing personalised management plans that combine biological, psychological, and social approaches. Such strategies can reduce or resolve symptoms, foster hope and a sense of agency, and often lead to recovery.

Introduction

In this article, we define persistent physical symptoms (PPS) as bodily symptoms that last for several weeks or months and cannot be fully explained by any structural abnormality or disease process [1]. The use of PPS, a patient-centred term, in this context replaces the term medically unexplained symptoms (MUS). PPS is equivalent to bodily distress syndrome, a term used in Denmark and in the ICD 10 [2]. Recently, the Association for the Treatment of Neuroplastic Symptoms considers PPS/MUS to be ‘neuroplastic’ [3,4].

PPS include fatigue, exhaustion, pain, and sometimes digestive or specific functional neurological problems. Current diagnostic classifications do not correspond well with the contemporary scientific understanding of PPS, and this causes confusion. Groups of persistent symptoms may be labelled as conditions, and include myalgic encephalomyelitis/chronic fatigue syndrome, post-viral fatigue syndrome, post COVID-19 condition, fibromyalgia, irritable bowel syndrome, functional neurological disorders or environmental sensitivity. However, symptoms within these labels overlap and may evolve from one symptom profile to another over time [1,5–7]. A common element across all is the understanding that biological, psychological, and social factors influence these conditions.

PPS usually have predisposing, triggering, and sustaining factors [8]. Once structural causes that might account for symptom persistence have been treated appropriately, health practitioners can help a patient with PPS by using an explanatory model, incorporating patient-relevant biopsychosocial factors. The traditional dichotomy between structural or functional may be overly simplistic: functional symptoms may coexist with an organic illness, or persist after an initial injury or disease has healed [9]. We know that persistent physical symptoms are common also in patients with mental health disorders and other medical conditions [6]. However, in this article we are primarily concerned with PPS that cannot be explained by any structural abnormality or disease process, to help provide a framework for understanding and evidence based treatment in general practice [2].

We aim to present an overview of the theories and science behind PPS within this context to help understand them, explain them to patients, and to provide a basis for evidence-informed treatment options. We aim to offer practical examples of approaches for health care professionals to support recovery.

Overview of the science

The brain generates symptoms in response to perceived danger

Any perceived threat to well-being or survival will trigger biological and cognitive responses in the brain. These reactions are automatic, beyond our conscious control, and evolved to assure survival [10]. Sometimes, these physiological nervous system changes can lead to the brain misinterpreting harmless stimuli or bodily signals as threats. In response to these perceived threat signals, the central nervous system produces a protective response including symptoms such as fatigue, pain, dizziness, nausea, and many other symptoms [11].

When a patient develops one persistent symptom, other symptoms often occur over time. Neural networks creating fatigue, pain and other persistent symptoms overlap, and the mechanisms are similar [12]. This formulation explains how persistent symptoms can exist with or without tissue damage. PPS represent a response from the body’s internal warning system rather than persistent structural damage. Like all sensory experiences, symptoms arise from complex neural processes in the brain. While physical factors such as tissue damage or viral infections sometimes serve as initial triggers, that is, as the initial threat perceived by the brain, symptoms can occur or persist without any identifiable ongoing physical trigger [9].

Triggers may also include major life events, social rejection or chronic work stress. A person may then develop heightened bodily vigilance for perceived threats arising from interacting biological, psychological, and social influences. Predisposing factors include early-life adversity, such as childhood trauma, and individual biological vulnerability [13].

Once symptoms develop, they may be sustained by persistent worry, frustration, increased symptom monitoring, and avoidance behaviour. Stress from societal panic, such as lockdown during the COVID-19 pandemic, can increase vigilance and contribute to symptom persistence. Together, these processes keep the brain′s protective systems activated, as described in the cognitive activation theory of stress [14]. Unconscious protective mechanisms may persist and contribute to the persistence of symptoms even if the patient is not experiencing fear or anxiety.

Conscious and unconscious expectations influence brain predictive coding

The brain continuously processes information, using real-time predictions based on past experiences to interpret internal and external sensory data. This process, known as predictive coding, shapes our perception and responses to potential threats [15]. Conscious and unconscious expectations influence these predictions. For example, if a person believes they are drinking a high-calorie drink instead of a low-calorie one, they secrete less ghrelin, the gut hormone associated with hunger [16]. Similarly, if a person believes their symptoms are due to structural damage, the brain may misinterpret harmless sensory signals as threatening, thereby perpetuating the brain’s protective responses in a chronic vicious cycle [17].

Classical conditioning mechanisms at play

Classical conditioning mechanisms are part of the brain’s ability to learn, reorganise and adapt. The brain can associate a stimulus with an automatic physiological response, resulting in a conditioned reaction [10]. Although this adaptive mechanism evolved to help keep the organism safe, it can become problematic when the brain misattributes danger to harmless stimuli or continues the response after the original threat is no longer present. Once established, avoidance patterns driven by fear can persist through negative reinforcement, as consistently avoiding the adversely perceived stimulus reinforces the response [18]. Psychologically, responses can become automatically linked to specific internal or external cues, such as time, place, people, situations, or sensory stimuli (for example, smell, taste, noise), body position, or activities, triggering symptoms that persist long after the original danger has passed. This conceptual theory has been described in chronic fatigue, with empirical evidence [19,20].

This mechanism directs us to therapeutic approaches, such as exercise and cognitive behavioural therapy [21,22]. With support and guidance under safe circumstances, the patient can gradually be helped to reintroduce triggering stimuli (for example, physical or mental activity). This can help recalibrate the nervous system and reduce symptom persistence [23,24]. Interventions focusing on deliberate, small behavioural changes in daily situations, rather than direct symptom control, have shown promising results [25].

Suggested communication approaches

This section outlines principles to guide health care professionals managing patients with PPS.

Listen and evaluate

Sincere efforts to listen to and understand the patient are fundamental. In patients with PPS, it is particularly important from the outset to keep in frame the whole person in their life circumstances [26].

Evaluation of potential PPS can be assisted by taking a clinical history using the ‘F.I.T.’ criteria—functional, inconsistent, and triggered [4].

1. Functional: The symptom may have been initiated by an injury or event but is not maintained by ongoing structural pathology.

2. Inconsistent: Symptoms fluctuate in location or intensity and are not consistently explained by tissue damage or load, even when linked to physical or cognitive effort.

3. Triggered: Symptoms can be evoked by harmless stimuli such as light touch, weather changes, or even by thoughts about triggering situations.

Exploring any predisposing, triggering, and sustaining factors can help structure thinking and future management planning:

• Predisposing factors may include the person’s sex, familial trauma, adverse childhood experiences, personality traits such as perfectionism, and genetic vulnerabilities [27].

• Triggering factors may include an infection, illness, accident, or acute stress resulting from life events at work or home.

• Sustaining factors may consist of ongoing psychological stress, high levels of activation due to performance pressure at work or in sports, high personal expectations, illness beliefs, persistent searching for a biomedical cause and therapy, health-related anxiety, persistent challenges in daily life such as relational strain, social isolation or financial stress. Personality traits may contribute, such as people pleasing tendencies or persistent efforts to avoid disappointment or rejection [28].

Clinicians may also find it helpful to direct patients to online tools to help patients explore and identify with possible risk factors associated with PPS. We recommend the tool from the Association for the Treatment of Neuroplastic Symptoms [3].

Affirm the condition

When diagnostic test results reveal no structural disease, health care professionals may tell patients that ‘nothing is wrong’. This leaves patients uncertain and feeling that further investigations are needed. The practitioner should affirm that the symptoms are real and provide an explanation for why the patient is experiencing them. This provides clarity and enables a recovery-oriented treatment plan [29]. Language is important in this step: clinicians should both explain that the symptoms are real and common, as well as validate and reassure them that many people recover. Developing a portfolio of helpful phrases helps. Table 1 provides suggestions.

Table 1.

Examples of phrases that may be useful (adapted from abrahamsen et al. 2024 [30]).

1	Hope and direction	‘I have seen many people with these symptoms and people do get better. We first need to take some tests to exclude various conditions that have specific implications for treatment. Then I will see you again once we have these results back ‘.
	Validation	‘I want you to know that I believe you, and it’s not uncommon for health care professionals to be unable to determine the underlying cause of health issues through blood tests or other medical exams. For instance, after an infection, it’s typical to feel exhausted and sluggish, even after the infection has resolved’. ‘It is an explanation for your symptoms. They are real and valid, even if all your medical tests return normal’.
	Introducing a diagram	‘We’ve learned a lot about what might be causing your symptoms, and I have a visual model that can help us understand this together. Would you be okay with me showing it to you?’
	Making connections	‘To better assist you, I would like to get an overview of all the issues you feel are important…once we have a full picture, we can work together to address the issues at hand ‘.
	Joy and pleasure	‘I’d like to understand how these problems are affecting your life. Is there anything that typically brings you joy that you find challenging to do now?’ ‘Are there specific tasks or aspects of work that bring you joy or satisfaction?’

Explain and help patients make connections

Symptom understanding aids recovery. Practitioners may find the Explanatory Model for Persistent Physical Symptoms (Table 2) helpful in explaining the biopsychosocial underpinnings of PPS [30] or use of the F.I.T phenomenon explained above to help illustrate these symptoms are somehow different to a viral infection or injury.

Table 2.

Example of a step-by-step approach for persistent physical symptoms (from abrahamsen et al. 2024 [30]).

Principles: Move from problems to possibilities; shift from limitations to what is achievable; an integrated approach related to the cause and the solutions Consultation 1: The GP and the patient agree that biomedical pathology has been ruled out by reviewing tests and findings. Consultation 2: Use the ‘Explanatory Model for Persistent Physical Symptoms’ diagram to develop a shared understanding of their symptoms. In addition: Dialogue: Initiate a conversation about potential long-term stress triggers in their life, using a positive framing to encourage an open and supportive discussion. Allow reflection time: Don’t jump to solutions- let the patient start connecting their symptoms with stressors and an understanding of their experiences. Set positive expectations: Validate their feelings by stating, ‘The symptoms are not your fault; these are automatic processes in your body Build confidence: Encourage the patient to draw on the health care professionals’ confidence of recovery and avoid the perception that the health care professionals suggests that simple positive thinking will resolve their issues. Foster supportive relationship: Establish a safe atmosphere and optimism about their recovery. For example, you might say, ‘We will work together to find a path for your improvement ‘. Consultation 3: Using the explanatory model, develop a short, written activity plan with achievable goals by one of the lists (problem list, list of opportunities, or job list) depending on the patient’s problem.

People often need support in identifying factors that—both consciously and unconsciously—amplify the brain′s perception of threat. The aim is to clarify mechanisms, provide reassurance, reduce stigma, and relieve feelings of shame. For some people, understanding the mechanisms that resulting in the persistence of symptoms may bring immediate symptom relief. For others, this may be a gradual change.

Further, patient communication resources include the ‘Individual Challenge Inventory Tool (ICIT)’, part of a broader programme designed to alleviate symptoms and improve daily functioning [30,31]. A similar approach is used in the Norwegian Brief Outpatient Programme for post COVID-19 condition [24].

Recovery can progress once the patients gain understanding of their symptoms in their own life circumstances. Once biopsychosocial explanations are understood, treatment programmes supporting gradual and systematic behavioural change responses improve daily functioning and may lead to recovery. The aim is for the patients to learn how to respond differently to their symptoms.

Behavioural strategies aimed at extinguishing conditioned responses can play a central role in this process [32]. Approaches such as the Bergen micro-choices model and other brain-body retraining programmes such as the Lightning Process follow this rationale [25,33].

Stages of change

The stages of self-change, often used in smoking cessation, can help the general practitioners. Patients may move between the stages of behaviour change—from pre-contemplation (the patient does not see the need to change), to contemplation (acknowledging the problem but not taking action), preparation (actively making plans to implement the change), action, and subsequently, maintenance [34].

Precontemplation

Patients often initially resist the idea that the brain generates their symptoms. They may feel it implies that they are imagining them, that the symptoms are ‘psychological’ or that there is no treatment. It is important to understand what the patient believes is the cause of their PPS early in the consultation. There is a value in ‘planting a seed’. With validation and consistent explanations, many patients gradually accept that the brain is part of the explanation

Contemplation

To encourage contemplation, patient recovery narratives, available online, often resonate with patients and raise hope of recovery. YouTube channels include dialogues between patients and therapists, and some include scientists explaining the symptoms. Table 3 provides suggested resources.

Table 3.

Illustrative list of resources that may help patients.

Change stage	Type of content	Organization/author	website
Contemplation	Patient narratives	Recovery Norway	https://www.recoverynorway.org/
		Living Proof	https://www.livingproof.org.uk/
	Patients talking with therapists	Raelan Agle YouTube	https://www.youtube.com/c/RaelanAgle
		COFFI1 scientists with patients	https://www.youtube.com/@fatiguesciencetalks
Preparation	Self-administered quiz	The ATNS2	https://www.symptomatic.me/
	Terms	Research output	https://bodysymptoms.org/
Action & maintenance	APPS	FreeMe	https://freemehealth.com/
		Curable	https://www.curablehealth.com/
	Books	Alan Gordon	Gordon A, Ziv A. The way out : the revolutionary, scientifically-proven approach to heal chronic pain. London: Penguin; 2021
		Kasia Kozlowska et al.	Kozlowska KSS, Helgeland H. Functional Somatic Symptoms in Children and Adolescents: a stress-system approach to assessment and treatment. Switzerland: Palgrave Macmillan; 2020 2020.
		Jan Rothney	Rothney J. Breaking Free: a guide to recovering from Chronic Fatigue Syndrome and Long Covid Symptoms. Glasgow: Arkbound Foundaton; 2022. 1–253 p.
		Howard Schubiner et al.	Schubiner H, Betzold, M. Unlearn your pain: a 28-day process to reprogram your brain. Pleasant Ridge, MI: Mind Body Publishing; 2022.
	Structured brain retraining programmes3	DNRS	https://retrainingthebrain.com/
		Gupta Programme	https://guptaprogram.com/
		Lightning Process	https://lightningprocess.com/

1 Collaborative on Fatigue and related symptoms Following Infection.

2 Association for Treatment of Neuroplastic Symptoms.

3 The authors note that their patients have reported these resources as helpful to them. Listing is not exhaustive and we are aware there are many other useful resources; and listing does not imply specific endorsement of these particular programmes.

Preparation

In preparing for change, the self-administered questionnaire from the Association for Treatment of Neuroplastic symptoms can be useful, and a point of discussion with the doctor. The resources associated with contemplation (Table 3) have many details to help with preparation.

Action

In actioning a programme of change, there are dedicated apps such as FreeME© and Curable © have been used by many with PPS. Some patients find value in books, online resources, and their own thinking to ‘connect the dots’ regarding their own symptom pattern in their personal circumstances. Table 3 lists a few resources that are widely used.

Some patients benefit from specific brain retraining programmes; the Lightning Process has been evaluated in a small trial, and several trials in other packages are currently ongoing [33]. Some of these programmes offer one-to-one support from a trained practitioner as part of follow-up care. Case reports and case series, for example as documented on Recovery Norway, suggest some dramatic results of people with severe ME/CFS – bedbound and tube fed – who improved within a short period after participating in structured brain re-training programmes. More rigorous qualitative and quantitative evaluations are needed to inform policy and provide evidence-based guidance.

There are many practitioners and coaches with specific programmes to help people with PPS, often organized by people who have suffered these conditions themselves and found conventional medical care inadequate. The coaching used by these groups include a variety of explanations of how the brain and body work together. It’s a form of supportive coaching and procedural learning.

Maintenance

Recovery is a personal process that is about re-engaging with activities, reducing symptoms, rebuilding, slowly regaining and retaining previous capacity; and often realising the need to change old patterns of living; the latter emerging later in treatment [35].

Including the family, friends or carers in the explanation and connections can be helpful. Other health professionals, such as physiotherapists or psychologists with this special competence, are also often highly effective in supporting patients. This creates a community of support and validation for the patient.

Complexity and comorbidities

Some patients face complex barriers to recovery, such as severe early-life trauma, multiple comorbidities, or a strictly biomedical understanding shaped by prior healthcare experiences. Managing fatigue and pain may be part of a comprehensive strategy to support these individuals through interconnected social, psychological, and medical approaches. Social and environmental determinants, such as workplace stressors, job insecurity, or relational burdens may contribute to symptom development and persistence. In cases where workplace factors play a major role, collaboration between the patient, employer, and occupational health services is recommended.

Even if full recovery is not achieved in the short term, ongoing support and care can improve functioning and quality of life. Consistent, empathetic engagement remains valuable, whereas believing that strict regulated activity and eventually just staying in bed is the only option is unhelpful [36].

We emphasise the importance of making a positive affirmation of PPS (described in ‘suggested communication approaches’ above). This is to avoid repeated referrals and biomedical tests, as these can reinforce the patient’s state of hypervigilance and perpetuate symptoms. Nevertheless, comorbidities may emerge, and the patient may need to be reassessed, considering any symptomatic and clinical changes for any potential emerging disease. The clinician should remain observant and follow up as needed.

Conclusion

PPS are underpinned by science and can be treated. A biopsychosocial approach to diagnosis and management helps health professionals and patients understand these symptoms, their relationship to patients’ personal circumstances, and how to identify pathways to recovery.

Funding Statement

No funding was received for this project.

Consumer involvement

The Consumer Advisory Group of the Collaborative of Fatigue and Related Symptoms Following Infection advised on this document’s outline and final draft, and we thank Fiona Symington for her advice. Four of the authors have experienced PPS and recovered.

Disclosure statement

No potential conflict of interest was reported by the author(s).