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Pain as a moderator of treatment effect

Project title

Pain as a moderator of treatment effect

Project reference


Final report date

10 January 2014

Project start date

01 July 2010

Project end date

30 December 2013

Project keywords

Co-morbidity; Treatment interaction; Widespread pain; Musculoskeletal disorders; Pain; Function; Longitudinal analysis

Lead investigator(s)
  • Professor Elaine Hay, Primary Care Sciences, Keele University
NIHR School Collaborators
  • Professor Nadine Foster, Primary Care & Health Sciences, Keele University
  • Professor Paul Little, Medicine, University of Southampton
  • Dr Marta Buszewicz, Primary Care & Population Health, UCL
  • Professor Chris Salisbury, School of Social and Community Medicine, University of Bristol
  • Professor Catherine Sackley, Physiotherapy, King's College London
  • Professor Richard McManus, Nuffield Department of Primary Care Health Sciences, University of Oxford
  • Professor Elizabeth Murray, Primary Care & Population Health, UCL
  • Professor Irwin Nazareth, Primary Care & Population Health, UCL
  • Professor Andrew Farmer, Nuffield Department of Primary Care Health Sciences, University of Oxford

Project objectives

Aims and objectives

The overall aim of this proposal is to investigate the influence of comorbid pain, in relation to specified index musculoskeletal sites, on clinical outcome and to assess whether any impact is dependent on the intervention given. The specific objectives were:- 

  • to investigate the association between co-morbidity and severity of the index condition at baseline presentation in primary care
  • to descriptively examine the influences of co-morbidity on prognosis of the index condition
  • to statistically evaluate the interaction of co-morbidity on quality of life and disease specific outcomes of treatment of the index condition

Changes to project objectives


Brief summary


Patients in primary care often present with more than one medical complaint; it is hypothesised that treatment response in intervention studies of musculoskeletal pain at an index site may be influenced by the presence of co-morbid factors. 


Similar outcomes of recovery have been reported in many primary care trials investigating a range of treatments for musculoskeletal pain – namely a rapid initial response to therapy, but with little further improvement after 3-12 months follow up and, generally, little difference between treatment arms. A number of explanations for this observation have been proposed, including intervention response that is related to the symptom severity experienced by the individual, but one specific hypothesis is that treatment response in intervention studies may be influenced by the presence of comorbid pain. Individuals often experience pain at multiple sites or regions, and complex pain syndromes have been shown to influence prognosis and outcomes. The implication is that intervention trials might need to take comorbidity into account. 


We hypothesised that the presence of widespread pain will reduce the effectiveness of interventions, which typically target pain at the index site only. For example, patients with shoulder pain alone might be more likely to respond to specific treatments such as local steroid injections than patients whose shoulder pain is one manifestation of a widespread pain syndrome. 


A secondary analysis of five primary care trials of musculoskeletal pain disorders with a total sample of 1632 participants (back pain (Hay et al., 2005), neck pain (Dziedzic et al., 2005), shoulder pain (Hay et al., 2003), knee pain (Hay et al., 2006; Foster et al., 2007)). Participants in each trial were stratified into two groups (presence/absence of ‘widespread pain’ (WP or non-WP)) according to the ACR classification (Wolfe et al., 1990). Differences in treatment effect between the two groups were evaluated in respect of short (1 to 3 months) and long-term pain and disability outcomes (6 to 12 months). Longitudinal linear regression modelling including an interaction term for treatment and study group was used to estimate differences in treatment response across WP and non-WP subgroups. Datasets were not be pooled as the patient populations were heterogeneous and the outcome measures and assessment endpoints different. Univariate and multivariate approaches were adopted for the regression modelling; the latter including adjustment for potential baseline covariates.   


Interaction effects were recorded between WP and non-WP subgroups – notably for physiotherapy versus injection (shoulder trial) over long-term outcome: the WP subgroup performing relatively worse in respect of injection treatment.


Evidence is provided that a targeted approach to treatment on the basis of patient subgroups stratified according to widespread pain may yield more favourable clinical outcomes than a standard treatment across all patients. The clinical implication is that we might need to move the traditional focus away from site-specific pain treatment to a broader approach that encompasses multisite pain.

Plain English summary

This proposal covers the first two studies in a proposed programme of work to develop interventions to tackle multimorbidity in primary care.

The first study aims to investigate whether comorbidity influences clinical outcome in intervention trials in primary care and will use a set of five high quality musculoskeletal pain trials to investigate whether co-morbid pain in addition to index site pain influences clinical outcome. We will explore whether treatments are more or less effective in those with and without comorbid pain. The methods will incorporate individual patient data meta-analyses, drawing on existing data from trials completed in the Keele Centre and in other School departments. 

This exemplar work will be shared and expanded through up to three collaborative meetings with other National School members to:- 

  • verify the findings in other appropriate trial datasets and 
  • develop new multicentre, randomised clinical trials to assess the clinical and cost-effectiveness of different treatment approaches to co-morbidity. 

The second study is the development stage for the integration of a health status measure with consultation data as a clinical-decision support system in primary care for patients with comorbidity. The pilot study will identify a generic physical and psychological health measure that can be integrated into live primary care consultations (literature review and consensus study), and test the feasibility of integrating the generic health questionnaire as a “pop-up” template during primary care consultations. This study will form the basis for development as a proposal for the second phase of School funding of a trial in the use of routine health status measurement as an aid to managing comorbidity in practice.


To agree final paper and submit/publish in an international peer-reviewed journal with interest in musculoskeletal disorders/primary care

Public involvement

A GP is a co-applicant and member of the study team – involved in the design and inputting into the study as it is analysed and interpreted. No service users are involved directly in this study.


This study is important as another step in informing the applicability of stratified care for musculoskeletal conditions in primary care. This adds to the limited available evidence which indicates that such a non-uniform approach is more effective than a standard ‘one-size fits all’ approach to patient care in this clinical area. 

An NIHR programme grant has been awarded to the Centre which builds on this work and other Centre studies in evaluating a stratified care tool and its use in general practice for patients with musculoskeletal disorders. Hence, the current study has served as an important platform in aiding discussions and decisions to further investigate the potential benefit of a stratified care approach to management of musculoskeletal conditions in primary care. If the outcome of the new (NIHR funded) programme of work concords with the findings of the current study there is expected to be considerable (worldwide) impact on policy and practice.

This project was funded by the National Institute for Health Research School for Primary Care Research (project number 87)

Department of Health Disclaimer

The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR School for Primary Care Research, NIHR, NHS or the Department of Health.