Medically unexplained physical symptoms (MUPS), especially pain, dizziness, and fatigue are frequent in primary care, in fact 25%-50% of all symptoms presented during consultations cannot be adequately medically explained [1]. If there are physical complaints for which no medical condition can be found after adequate medical examination, they will be defined as MUPS [2,3].

MUPS can be regarded as a spectrum ranging from mild unexplained physical symptoms (low incidence, one or two domains, low impact), to moderate symptoms (more frequent, two or three domains, higher impact) and finally to persisting or chronic MUPS (high impact, more clusters involved, chronic; eg, fibromyalgia, chronic fatigue syndrome, or irritable bowel syndrome) [3,4]. In this spectrum, mild MUPS have an estimated prevalence of 70% to 80% [4,5]. These patients consult their general practitioner (GP) for a symptom that cannot be explained immediately, but the symptoms improve within 2 weeks [6]. Moderate MUPS have an estimated prevalence of approximately 15%, where patients still experience unexplained symptoms after three months without a diagnosis of a functional somatic syndrome [6]. Patients with chronic MUPS will have a symptom duration of at least six months, with the presence of a functional somatic syndrome, such as fibromyalgia, chronic fatigue syndrome or irritable bowel syndrome, or a somatic symptom disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [4,6,7]. Patients with chronic MUPS occur in approximately 2.5% in primary care, and 3% of the GP consultations are MUPS consultations [1,8].

Despite the low prevalence of chronic MUPS, the burden is substantial [1], with a high impact on patients’ quality of life and daily functioning. Compared with the general population, as well with other patient groups such as major depressive disorder and cancer patients, patients with chronic MUPS report a lower quality of life [9,10]. Moreover, patients with MUPS consult a GP more frequently, but GPs find adequate management of MUPS challenging [11].

GPs frequently focus on exclusion of a somatic disease by recommending somatic interventions such as drug prescriptions, an investigation or a referral to a specialist; while patients often do not request for somatic interventions [12]. Furthermore, GPs face difficulty in the timely recognition of patients with MUPS [13]. On average, it takes two years to obtain a diagnosis. During this time period patients have on average 15 GP consultations, 8 visits to a hospital specialist and 14 sessions with the physical therapist [10]. Almost 40% of patients with MUPS report absenteeism from work [10]. As a result, MUPS are associated with increased direct and indirect costs related to health care expenditure as well as work and insurance related costs [10,14].

Much research has been conducted on effective interventions for chronic MUPS. Neurosciences-based therapeutic education, cognitive behavioral therapy, and exercise therapy have been shown to be effective treatment modalities in patients with MUPS [15-18]. Overall, the vast majority of these studies included patients with chronic MUPS. So far little research has been conducted in patients with moderate MUPS, partly due to the fact that adequate methods for early identification are lacking. Early identification of patients with moderate MUPS would enable interventions directed at prevention of chronicity, which ultimately might decrease the burden of these symptoms for patients, health care professionals and society.

Recently, a screening method (PRESUME; preventive screening of medically unexplained physical symptoms) has been developed to identify patients with moderate MUPS using data from the electronic medical record of the patient’s GP as shown in Figure 1 [19]. The PRESUME screening method showed acceptable prognostic accuracy over a five-year follow-up [19]. For patients with moderate MUPS, we developed a proactive, blended, and integrated mental health and physical therapy care program to prevent chronicity. This is a 12-week program consisting of 4 face-to-face consultations with the mental health nurse and 5 physical therapy sessions, which are supplemented with a Web-based program (e-Exercise). Blended care has already proven to be effective in other studies [20,21] and it helps to promote self-management.

The primary objective of the present study is to investigate the effectiveness of the proactive, blended and integrated mental health and physical therapy care program (PARASOL) on impact of symptoms, as well as the physical and mental dimensions of quality of life in patients with moderate MUPS in comparison with usual care. Secondary objectives are to study the effect on severity of (psychosocial) symptoms, general health, physical behavior, illness perception, and self-efficacy in patients with moderate MUPS as well as to determine the cost-effectiveness of this program.

The components of this intervention are based on results of a literature search and focus groups with experts (general practitioners, physical therapists, mental health nurses, and psychologists) [46]. The content of the information, self-management, and exercise modules were specifically developed for the current study. The functionality of the online program used in this study is based on the blended exercise intervention for patients with hip or knee osteoarthritis (e-Exercise) [47].

Before the start of the intervention program, physical therapists and mental health nurses of the experimental health care centers received two days of training on the content of the blended PARASOL intervention. The training consisted of presentations on the study population, central sensitization, therapeutic neuroscience education, graded activity, and perpetuating factors for all professionals involved in the study. Furthermore, the training included discussion of the content of the online modules and instructions on their implementation. During the study, a follow-up training session for the therapists will be conducted to ensure adherence to the treatment protocol.

The recruitment of health care centers started in June 2016 and inclusion of patients began in March 2017. Follow-up assessments of patients are expected to be completed in March 2019.

In this randomized clinical trial, the effectiveness (including cost-effectiveness) of the PARASOL intervention, a proactive blended and integrated mental health and physical therapy intervention program, will be studied.

Although the study is well-planned and involves all relevant stakeholders, the conduction of the study will present several operational challenges. The first challenge has been identified as GPs motivation to actively participate in the recruitment of patients with moderate MUPS. Patients with MUPS are a difficult patient group for GPs and often the patient-doctor relationship is under pressure due to mismatches between the expectations of the patient and doctor [48]. To motivate GPs to recruit patients with moderate MUPS, information about the PARASOL study will be sent to them beforehand. During the study, GPs will be individually informed if one of their patients is participating in the PARASOL study. Furthermore, all participating GPs will be sent updates at 3-month intervals informing them about total patient inclusion in the study, as well as patient inclusion per GP.

A second challenge identified is the recruitment of adequate patient numbers to achieve the desired statistical power. Patients with moderate MUPS will be identified using the PRESUME screening method, following which they will be proactively approached by their GP. This proactive approach may lead to patients in a non-symptomatic phase or without a treatment demand being contacted. Consequently, these patients might be less motivated to follow the blended PARASOL intervention aiming to prevent chronicity of MUPS. To deal with this challenge, setting individual treatment goals has been identified as an important part of the intake session. It should be noted that the face-to-face sessions are not performed on a weekly basis to not only reduce the burden for patients, but more importantly to encourage self-management.

A third challenge is the potential drop-out rate in the control group since these patients will not be receiving the blended PARASOL intervention and therefore may be less motivated to participate in the study. To deal with this challenge, patients in the control group will be offered to follow the blended PARASOL intervention after the study ends.

A final identified challenge is the non-usage of the Web-based component of the blended PARASOL intervention. Previous studies have shown that patients in online interventions are less motivated and feel less pressure to continue with the intervention compared to face-to-face interventions [49]. To combat this, patients will receive email reminders for the eHealth modules weekly. Furthermore, the PARASOL intervention has been designed as a blended care program, and this is therefore expected to maximize adherence compared to self-guided internet interventions [50].

Besides these challenges, there are several strengths and limitations in the design of the study that should be noted. The first strength of this study is that physical therapists and mental health nurses will participate in two days of intensive training about the content of the blended PARASOL intervention. This will minimize the differences in the care offered by professionals at different health care centers during the health care program [51]. In addition, a meeting with the participating physical therapists and mental health nurses will be organized after 6 months to discuss the content of the blended PARASOL intervention as well as any possible difficulties faced. The 12-month follow-up measurement is another strength of this study as it will result in data being obtained about long-term effectiveness (and cost-effectiveness) of the program. The PARASOL intervention stimulates self-management by focusing on achieving a healthier lifestyle as well as the adoption and maintenance of exercise behavior. Since the process of adopting a change to maintaining a change takes at least six months, a long-term follow-up is of particular interest [52]. A third strength of this study is performing cluster randomization at the level of the health care centers as this ensures that a contamination-effect will be avoided [22]. Finally, this is the first study, to the best of our knowledge, that investigates the effectiveness of an intervention program for patients with moderate MUPS to prevent chronicity.

The first identified limitation of this study, is that it is unblinded. Patients, health care professionals, and the researchers are aware all of the group allocated to the blended PARASOL intervention. This may lead to bias mechanisms such as response bias or observer bias being present in the data [53]. One of the aims of the training provided to the healthcare professionals involved in the study is to avoid response bias from the health care professionals. Observer bias will be avoided by using a measurement protocol, well trained observers, and standardized outcome measures. A second limitation is that overtreatment may occur since not all patients with moderate MUPS will be prevented from developing chronic MUPS after completing the PARASOL intervention. This could lead to higher health care costs if patients are still consulting health care professionals after completing the PARASOL intervention. However, an early intervention for patients with moderate MUPS may lead to a decrease of direct and indirect costs on long term if chronic MUPS is prevented. Therefore, one of the secondary objectives is to determine the cost-effectiveness of the PARASOL intervention. A third limitation is complexity of the design of the study due to the use of cluster randomization. Cluster randomized trials are more complex, require more patients to obtain equivalent statistical power, and require more complex analysis [43]. However, in the sample size calculation and statistical analysis, this possible design effect has been taken into account.

This study is the first trial that investigates the effectiveness (including cost-effectiveness) of a blended care program in patients with moderate MUPS. Therefore, this study will provide relevant results regarding short- and long-term effectiveness of a multidisciplinary, blended care program to prevent chronic MUPS.