How should we manage adults with persistent unexplained physical symptoms?

What is the evidence of uncertainty?

There is a lack of evidence to conclude whether pharmacological, psychological, or physical therapy, or enhanced general practitioner care was effective. Table 1⇓ summarises the evidence we found in Cochrane systematic reviews, excluding those related to specific functional syndromes such as irritable bowel syndrome. Studies included patients with a diagnosis of somatoform disorders as well as persistent unexplained physical symptoms. Many studies were of poor quality, included few patients, and followed them for just a few weeks (typically 2-12 weeks).

For pharmacological treatments there was no clear evidence of efficacy of tricyclic antidepressants. There was very low quality evidence for new generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) being effective in treating symptoms compared with placebo (standardised mean difference −0.91 (95% confidence interval −1.36 to −0.46); 3 studies, 243 participants; I²=63%) with no clear difference in efficacy between different drug classes. A combination of SSRIs and antipsychotics is more effective than SSRIs alone, though evidence is of low quality (standardised mean difference 0.77 (0.32 to 1.22); 2 studies, 107 participants; I²=23%).11 The review found low quality evidence favouring natural products such as St John’s wort compared with placebo (standardised mean difference −0.74 (−0.97 to −0.51); 2 studies, 322 participants; I²=0%).

The quality of studies was rated low because of a high risk of bias in many domains, strong heterogeneity in symptoms and study design, small sample sizes, and short follow-up (2-12 weeks). The small beneficial effect of drugs should be weighed against side effects (such as dry mouth, nausea) that were reported in these studies. However, discontinuation rates were similar between the intervention and comparison groups.

A Cochrane review examined different forms of psychological therapy (21 randomised controlled trials (RCTs), 2658 participants) including cognitive behavioural therapy, behaviour therapies, third-wave cognitive behavioural therapy (mindfulness), psychodynamic therapy, and integrative therapy in patients with somatoform disorders or persistent physical symptoms.12 Taken altogether, psychological therapies were effective in reducing symptom severity compared with usual care or waiting list, but effect sizes were small and psychological therapies had higher dropout rates than usual care. No harms or side effects were reported. The overall quality of evidence is low due to a high risk of bias with lack of blinding of the participants, therapists, and outcome assessors.

No studies addressed physical therapy.

Enhanced care by general practitioners comprises reattribution—where symptoms are reframed, making the link to presumed underlying psychological problems—and cognitive behavioural therapy. A Cochrane review on enhanced care (6 RCTs, 1787 participants) found no significant effect on quality of life in terms of physical and mental health and severity of physical symptoms.13 A Cochrane review on effectiveness of consultation letters from psychiatrists to provide general practitioners with a diagnosis and treatment advice for patients (6 RCTs, 449 participants) was also inconclusive.14

Overall, the quality of evidence is poor with significant heterogeneity, variations in diagnostic criteria, delivery of interventions, and outcome measures, and a short follow-up.

Is ongoing research likely to provide relevant evidence?

Overall the ongoing studies we identified will answer only some of the current questions. We recommend that future research focuses on different populations, interventions, and outcomes (see box 2)

We searched clinical trial registers (clinicaltrials.gov, controlled-trials.com, who.int/trialsearch, September 2015) for studies in patients with unexplained physical symptoms or somatoform disorders. We identified 10 ongoing randomised controlled trials evaluating non-pharmacological interventions including psychotherapy, a multidisciplinary intervention (by a neurologist, a psychologist and a physical therapist), and walking. There is one ongoing trial evaluating treatments with dalumin, a herb extract. A trial is planned to evaluate integrated care in general practice for these patients; more details on the intervention are not available. We did not find any ongoing trials on antidepressants in this patient group.

What should we do in the light of the uncertainty?

Several countries have developed guidelines for the management of patients with persistent unexplained symptoms.161718 Based on Dutch guidelines,1718 we encourage clinicians to explore all symptom dimensions (somatic, cognitive, emotional, behavioural, and social). For example, if a patient presents with unexplained muscular pain, explore

• The characteristics of the pain, such as location, severity, duration, and associated symptoms

• The patient’s thoughts and expectations about the pain

• How it affects the patient emotionally

• Behavioural consequences, such as avoiding exercise, absenteeism

• Impact on social life (relationships, work, and social activities).

Perform a thorough but focused physical examination and if necessary refer for relevant investigations. Screen for an undiagnosed mental health problem such as depression or anxiety and if screening is positive consider referral to a psychiatrist.

Share your findings based on the examination and investigations with the patient and explain that no underlying medical condition has been identified and is unlikely to exist. Where possible, provide an explanation for the persistence of symptoms—for example, by using the vicious circle theory, where pain can lead to less exercise and less exercise can lead to more pain. Treatment for symptomatic relief such as for pain may be offered for a limited time if the patient requests, but explain the pros and cons of treatment.

We consider cognitive behavioural therapy worth offering but do not advise pharmacological therapy. If the patient has a preference for medication, share uncertainty in evidence of any benefit and potential side effects. If a specific functional somatic syndrome is identified—such as chronic pain, fibromyalgia, or irritable bowel syndrome—follow guidelines for management of these syndromes. Not being able to identify an underlying condition does not completely exclude there being one. Ask the patient to report changing or worsening of symptoms, or new symptoms which may require reassessment.