Patients with multiple somatic symptoms which are not attributable to conventionally defined disease are prevalent in all medical settings. Such symptoms can inflict suffering and reduce both quality of life and work ability in the most severely affected patients. Furthermore, such patients require substantial socioeconomic expenditure because of the high use of health care services and social benefits.1, 2
For clinicians, these patients pose a major diagnostic and therapeutic challenge. Depending on the primary complaint and the specialist consulted, patients receive diagnoses such as chronic fatigue syndrome, irritable bowel syndrome, fibromyalgia, other functional somatic syndromes, or diagnoses of somatoform disorders. Some of these conditions are well defined, albeit by clinical features rather than biomarkers. Often, patients receive two or more syndrome diagnoses at the same time, and even more fulfil diagnostic criteria for multiple syndromes.3 In cases of multiple functional somatic syndromes, it is unclear which functional somatic syndrome should guide the treatment choice. Meta-analyses and high quality trials have given rise to pharmacological treatment guidelines in some functional somatic syndromes, but these are lacking for multiple functional somatic syndromes.4, 5, 6, 7 An effective intervention for patients with multiple functional somatic syndromes can potentially have a large public health impact.
Research in context
Evidence before this study
Patients with multiple functional somatic syndromes have conditions such as chronic fatigue syndrome, fibromyalgia, and irritable bowel syndrome concomitantly. We searched for evidence of antidepressant treatment of patients with multiple functional somatic syndromes using PubMed and Cochrane Library Databases up to July, 2011, and repeated the search on Nov 14, 2016, using the following terms: neurasthenia, somatoform disorders, functional somatic syndrome/symptoms, irritable bowel syndrome, fibromyalgia, multiple chemical sensitivity, low back pain, chronic fatigue syndrome, idiopathic pain syndrome, medically unexplained symptom/physical symptom, whiplash, WAD, somatisation disorder, recurrent abdominal pain, myalgic encephalomyelitis, chronic benign pain, dissociative disorder, non-epileptic seizures, pseudo seizures, non-cardiac chest pain, functional dyspepsia, somatic symptom disorder, bodily distress syndrome, chronic tension-type headache, and functional bowel disorder in combination with antidepressants, placebo, and randomised trials (no language restrictions). Previous interventions have focused primarily on study populations with single functional somatic syndromes or somatoform disorders with generally supportive evidence for efficacy of antidepressants, including tricyclic antidepressants. However, recommendations differ depending on the syndrome studied. The search did not identify other trials of patients with multiple functional somatic syndromes.
Added value of this study
This study shows that low-dose imipramine significantly improves overall health compared with placebo. The side-effects are tolerable albeit frequent. The diagnostic criteria used in this trial facilitate identification of the patient group. On the basis of our results, we suggest that patients with multiple functional somatic syndromes benefit from treatment with low-dose imipramine.
Implications of all available evidence
Patients with multiple functional somatic syndromes have often been considered treatment resistant. In our study, low-dose imipramine was an effective, tolerable, and easily delivered treatment. Low-dose imipramine can be of clinical value in patients with multiple functional somatic syndromes, where treatment choice is often ambiguous. We urge future research to address the generalisability of the results, identify predictors of treatment response, and assess the long-term effect of imipramine.
Pharmacological treatment recommendations in single functional somatic syndromes focus mainly on centrally acting drugs, especially antidepressants.1 While the evidence differs across diagnoses, antidepressants are generally found to be effective and are therefore among first-line treatments in fibromyalgia and irritable bowel syndrome.1, 4, 6, 8, 9 Newer drugs such as serotonin-norepinephrine reuptake inhibitors (SNRIs) are increasingly used in fibromyalgia, but despite the abundance of trials showing effects in selected aspects of fibromyalgia, a large-scale, longitudinal study showed no evidence of a clinical benefit compared with prior treatment with non-steroid anti-inflammatory drugs (NSAIDs) and the older and cheaper tricyclic antidepressants.10 Tricyclic antidepressant treatment has also proven beneficial in treatment of other functional somatic syndromes, but the use of tricyclic antidepressants is primarily supported by decades of clinical experience rather than by solid evidence or newer efficacy trials.4, 6, 8, 9, 11
Imipramine is a tricyclic antidepressant most commonly used to treat depressive illness. Like other tricyclic antidepressants, imipramine possesses pain-modulating properties unrelated to its antidepressant effect. Pain relief is commonly noted earlier and at doses of 25–75 mg, well below the effective antidepressant doses (100–200 mg), as shown especially in studies of neuropathic pain.12 After uptake, imipramine is partly converted to an active metabolite, desipramine. Together, imipramine and desipramine cause a balanced inhibition of serotonin and noradrenaline reuptake. Adverse events are common, but the registered frequency of sedation and weight gain is lower than for amitriptyline, the most commonly used tricyclic antidepressant. Owing to its balanced inhibition and the safety profile, imipramine could represent an easily available, affordable, and possibly beneficial treatment option for patients with multiple functional somatic syndromes. Besides pain relief, it could also relieve other somatic symptoms.
An evaluation of treatment across specific functional somatic syndromes diagnoses is facilitated by a joint diagnostic approach to the group of patients with multiple functional somatic symptoms. The recently introduced unifying research diagnosis of bodily distress syndrome embodies this broader concept of classification because it encompasses most of the functional somatic syndromes and somatoform disorders, though recognising a number of subtypes.13, 14 The diagnosis of bodily distress syndrome offers a set of precise and reproducible diagnostic criteria, which have been included in the current draft of the WHO's International Classification of Diseases (ICD) 11th revision for primary health care.15 Multiorgan bodily distress syndrome, the most severe subtype, is characterised by multiple, persistent bodily symptoms from several organ systems, and this subtype captures patients with multiple functional somatic syndromes (panel).13, 14, 16, 17, 18
We hypothesised that low-dose imipramine could improve overall health as well as physical, mental, and social health in patients with multiple functional somatic syndromes as defined by the criteria for multiorgan bodily distress syndrome.