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Imipramine versus placebo for multiple functional somatic syndromes (STreSS-3): a double-blind, randomised study

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Summary

Background

Functional somatic syndromes, including chronic fatigue syndrome or irritable bowel syndrome, often co-exist. Treatment guidelines supported by high quality evidence exist for most functional somatic syndromes, but are lacking for multiple comorbid functional somatic syndromes. We aimed to assess the effect of the tricyclic antidepressant, imipramine, in patients with multiple functional somatic syndromes defined by the criteria for multiorgan bodily distress syndrome, a unifying diagnosis that encompasses most functional somatic syndromes and somatoform disorders.

Methods

In this single-centre, double-blind, randomised trial done in a Danish university hospital setting, participants were patients consecutively referred (age 20–50 years) fulfilling criteria for multiorgan bodily distress syndrome with no concurrent comorbid depression or anxiety disorder. Participants were randomly assigned (1:1) to receive either 10 weeks of low-dose imipramine or placebo (oral daily doses of 25–75 mg). The hospital pharmacy handled randomisation (computer-generated) and masking, providing sequentially numbered packs of study drug that were given serially to the participants. All others involved were masked to allocation. Primary outcome was patient-rated overall health improvement on a 5-point clinical global improvement scale. Improvement was defined as patients responding “better” or “much better” as opposed to “unchanged” and “worse” or “much worse” when rating their overall health status after 10 weeks of minimum 25 mg study drug. Analyses included patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01518634.

Findings

Between Jan 30, 2012, and Nov 24, 2014, 138 patients were randomly assigned; 70 to receive imipramine and 68 to receive placebo. The study was completed on May 1, 2015. 125 patients received at least one dose of study drug: 65 received imipramine and 60 received placebo. Treatment was terminated prematurely for eight (12%) patients receiving imipramine and seven (12%) patients receiving placebo. Data were missing for two (3%) patients receiving imipramine and three (5%) patients receiving placebo. Of the 120 patients (96%) who provided primary outcome data, 33 (53%) receiving imipramine reported their overall health status as “better” or “much better” compared with 14 patients (25%) receiving placebo. The improvement after imipramine was significantly greater than after placebo (odds ratio 3·3 [95% CI 1·6–6·8]; p=0·001). Number needed to treat was 3·6 (95% CI 2·3–8·9). Analysis of the worst-case scenario for patients with missing outcome did not change the interpretation of the results. 32 patients (49%) receiving imipramine and 10 patients (17%) receiving placebo had at least one adverse event of moderate intensity (p=0·0001); eight patients (12%) receiving imipramine and three patients (5%) receiving placebo had at least one adverse event of severe intensity (p=0·1496). One patient (1%) receiving placebo experienced a serious adverse event (a subdural haematoma sustained after an accident). Adverse events caused dropout in four patients (6%) receiving imipramine and three patients (5%) receiving placebo.

Interpretation

Imipramine treatment compared with placebo significantly improved overall health in patients with multiple functional somatic syndromes when both treatments were supported by regular contacts with clinicians. Adverse events were more common in the imipramine group, but only rarely led to discontinuation of treatment.

Funding

The Danish Foundation, Trygfonden.

Introduction

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.

Section snippets

Study design and participants

This single-centre, randomised, double-blind trial was done in a university hospital setting at the Research Clinic for Functional Disorders, Aarhus University Hospital, Aarhus, Denmark. This trial (Specialised Treatment for Severe Bodily Distress Syndrome-3 [STreSS-3]), is part of a group of studies with the shared aim to provide evidence-based treatment options for patients with multiorgan bodily distress syndrome. Long-term follow-up is being planned, including data for prescription

Results

Between Jan 30, 2012, and Nov 24, 2014, 551 consecutively referred patients were screened for inclusion (figure 1). 418 patients fulfilled diagnostic criteria for multiorgan bodily distress syndrome. Primary reasons for exclusion hereafter were psychiatric disorders demanding treatment or ongoing pain medication. The study was completed on May 1, 2015.

Discontinuation of antidepressants or pain-modulating drugs, besides paracetamol, was required for 51 patients (37%). 139 patients were included

Discussion

This single-centre, randomised, double-blind trial investigated the effect of low-dose imipramine in patients with multiple functional somatic syndromes defined by the criteria for the research diagnosis multiorgan bodily distress syndrome. This study shows that a minimum dose of imipramine taken for 10 weeks supported by regular contacts to clinicians results in an improvement in patient-rated overall health and a series of other parameters, including physical health, somatic symptom burden,

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