Medication as a treatment for long-term medically unexplained physical symptoms (somatoform disorders): a review of the evidence

Who may be interested in this review?

- People with long-term unexplained physical symptoms (somatoform disorders) and their family and friends.

- Professionals working with people with somatoform disorders.

- Professionals working in chronic pain services.

- General practitioners.

Why is this review important?

Around 6 in 100 people are affected by long-term physical symptoms that have no clear medical cause (somatoform disorders). Symptoms can include pain, digestive problems, sexual or menstrual problems, breathing problems, and symptoms that mimic brain or nerve damage such as memory loss or sensory problems. Somatoform disorders often cause considerable distress and mean that people spend a lot of time consulting doctors and health professionals to try to find the cause of their symptoms and the correct treatment.

Guidelines for the treatment of somatoform disorders recommend that people receive talking therapies alongside medication. In current practice many people are treated 'off label' with medications that are intended for the treatment of anxiety, depression, and other mental health problems. However, it is unclear why medications such as antidepressants help to reduce the severity of medically unexplained physical symptoms.

What questions does this review aim to answer?

- What is the quality of current research on medication as a treatment for somatoform disorders?

- Is medication an effective treatment for physical symptoms in somatoform disorders compared with placebo (dummy pill)?

- Which types of medication are most effective?

- Are natural products such as St. John's wort an effective treatment for somatoform disorders compared with placebo?

- How well do people with somatoform disorders tolerate medication or natural products?

Which studies did we include in the review?

We searched databases to find all studies of medication for somatoform disorders published until January 2014. To be included in the review, studies had to compare medication with either placebo, usual treatment, another medication, or a combination of medication and include adults with a clear diagnosis of somatoform disorders. We included 26 studies in the review with 2159 participants aged between 18 and 77 years.

What does the evidence from the review tell us?

Although we identified 26 studies, each comparison only contained a few studies and a relatively small number of participants and so the findings must be interpreted with caution. We rated the quality of current research as low or very low and the risks of bias were high in many of the studies.

There was not sufficient evidence in order to make a statement about the efficacy of tricyclic antidepressants for the treatment of somatoform disorders.

New-generation antidepressants were moderately effective treatments for physical symptoms, anxiety, and depression in somatoform disorders.

There was no difference found between the effectiveness of tricyclic antidepressants and new-generation antidepressants for the treatment of physical symptoms. There was some evidence that a combination of antidepressants and antipsychotics was more effective than antidepressants alone.

Natural products, such as St. John's wort, significantly reduced the severity of physical symptoms compared with placebo.

High numbers of people dropped out of treatment due to side effects or lack of effects with antidepressant medication, and low numbers dropped out with natural products.

What should happen next?

The review authors suggest that future high-quality research should be carried out to look at the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly and to follow up participants over longer periods (the longest follow-up was just 12 weeks). The review authors also suggest that future research should measure changes in people's quality of life and daily functioning as well as physical symptoms and depression/anxiety symptoms.

Authors' conclusions: 

The current review found very low-quality evidence for NGAs and low-quality evidence for NPs being effective in treating somatoform symptoms in adults when compared with placebo. There was some evidence that different classes of antidepressants did not differ in efficacy; however, this was limited and of low to very low quality. These results had serious shortcomings such as the high risk of bias, strong heterogeneity in the data, and small sample sizes. Furthermore, the significant effects of antidepressant treatment have to be balanced against the relatively high rates of adverse effects. Adverse effects produced by medication can have amplifying effects on symptom perceptions, particularly in people focusing on somatic symptoms without medical causes. We can only draw conclusions about short-term efficacy of the pharmacological interventions because no trial included follow-up assessments. For each of the comparisons where there were available data on acceptability rates (NGAs versus placebo, NPs versus placebo, TCAs versus other medication, and antidepressants versus a combination of an antidepressant and an antipsychotic), no clear differences between the intervention and comparator were found.

Future high-quality research should be carried out to determine the effectiveness of medications other than antidepressants, to compare antidepressants more thoroughly, and to follow-up participants over longer periods (the longest follow up was just 12 weeks). Another idea for future research would be to include other outcomes such as functional impairment or dysfunctional behaviours and cognitions as well as the classical outcomes such as symptom severity, depression, or anxiety.

Read the full abstract...
Background: 

Somatoform disorders are characterised by chronic, medically unexplained physical symptoms (MUPS). Although different medications are part of treatment routines for people with somatoform disorders in clinics and private practices, there exists no systematic review or meta-analysis on the efficacy and tolerability of these medications. We aimed to synthesise to improve optimal treatment decisions.

Objectives: 

To assess the effects of pharmacological interventions for somatoform disorders (specifically somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, and pain disorder) in adults.

Search strategy: 

We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR) (to 17 January 2014). This register includes relevant randomised controlled trials (RCTs) from The Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). To identify ongoing trials, we searched ClinicalTrials.gov, Current Controlled Trials metaRegister, the World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry. For grey literature, we searched ProQuest Dissertation & Theses Database, OpenGrey, and BIOSIS Previews. We handsearched conference proceedings and reference lists of potentially relevant papers and systematic reviews and contacted experts in the field.

Selection criteria: 

We selected RCTs or cluster RCTs of pharmacological interventions versus placebo, treatment as usual, another medication, or a combination of different medications for somatoform disorders in adults. We included people fulfilling standardised diagnostic criteria for somatisation disorder, undifferentiated somatoform disorder, somatoform autonomic dysfunction, or somatoform pain disorder.

Data collection and analysis: 

One review author and one research assistant independently extracted data and assessed risk of bias. Primary outcomes included the severity of MUPS on a continuous measure, and acceptability of treatment.

Main results: 

We included 26 RCTs (33 reports), with 2159 participants, in the review. They examined the efficacy of different types of antidepressants, the combination of an antidepressant and an antipsychotic, antipsychotics alone, or natural products (NPs). The duration of the studies ranged between two and 12 weeks.

One meta-analysis of placebo-controlled studies showed no clear evidence of a significant difference between tricyclic antidepressants (TCAs) and placebo for the outcome severity of MUPS (SMD -0.13; 95% CI -0.39 to 0.13; 2 studies, 239 participants; I2 = 2%; low-quality evidence). For new-generation antidepressants (NGAs), there was very low-quality evidence showing they were effective in reducing the severity of MUPS (SMD -0.91; 95% CI -1.36 to -0.46; 3 studies, 243 participants; I2 = 63%). For NPs there was low-quality evidence that they were effective in reducing the severity of MUPS (SMD -0.74; 95% CI -0.97 to -0.51; 2 studies, 322 participants; I2 = 0%).

One meta-analysis showed no clear evidence of a difference between TCAs and NGAs for severity of MUPS (SMD -0.16; 95% CI -0.55 to 0.23; 3 studies, 177 participants; I2 = 42%; low-quality evidence). There was also no difference between NGAs and other NGAs for severity of MUPS (SMD -0.16; 95% CI -0.45 to 0.14; 4 studies, 182 participants; I2 = 0%).

Finally, one meta-analysis comparing selective serotonin reuptake inhibitors (SSRIs) with a combination of SSRIs and antipsychotics showed low-quality evidence in favour of combined treatment for severity of MUPS (SMD 0.77; 95% CI 0.32 to 1.22; 2 studies, 107 participants; I2 = 23%).

Differences regarding the acceptability of the treatment (rate of all-cause drop-outs) were neither found between NGAs and placebo (RR 1.01, 95% CI 0.64 to 1.61; 2 studies, 163 participants; I2 = 0%; low-quality evidence) or NPs and placebo (RR 0.85, 95% CI 0.40 to 1.78; 3 studies, 506 participants; I2 = 0%; low-quality evidence); nor between TCAs and other medication (RR 1.48, 95% CI 0.59 to 3.72; 8 studies, 556 participants; I2 =14%; low-quality evidence); nor between antidepressants and the combination of an antidepressant and an antipsychotic (RR 0.80, 95% CI 0.25 to 2.52; 2 studies, 118 participants; I2 = 0%; low-quality evidence). Percental attrition rates due to adverse effects were high in all antidepressant treatments (0% to 32%), but low for NPs (0% to 1.7%).

The risk of bias was high in many domains across studies. Seventeen trials (65.4%) gave no information about random sequence generation and only two (7.7%) provided information about allocation concealment. Eighteen studies (69.2%) revealed a high or unclear risk in blinding participants and study personnel; 23 studies had high risk of bias relating to blinding assessors. For the comparison NGA versus placebo, there was relatively high imprecision and heterogeneity due to one outlier study. Although we identified 26 studies, each comparison only contained a few studies and small numbers of participants so the results were imprecise.

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