Illness Perceptions; Mediators and/or Moderators in Disabling Persistent Low Back Pain? A Multiple Baseline Single-Case Experimental Design

Illness Perceptions (IPs) may be important in the management of persistent low back pain. The mediation and/or moderation effect of IPs on primary outcomes in physiotherapy treatment is unknown. Methods A multiple single-case experimental design, using a matched care physiothetapy intervention, with 3 phases (phases A-B-A’) was used including a 3-month follow up (phase A’). Primary outcomes: pain intensity, physical functioning and pain interference in daily life. Analyzes: linear mixed models, adjusted for fear of movement, catastrophizing, avoidance, sombreness and sleep. Results Nine patients were included by six different primary care physiotherapists. Repeated measures on 196 data points showed that IPs Consequences, Personal control, Identity, Concern and Emotional response had a mediation effect on all three primary outcomes. The IP Personal control acted as a moderator for all primary outcomes, with clinically relevant improvements at 3-month follow up. This is the rst study to shed some light in the mediating effects of IPs on the outcome of a matched care physiotherapy treatment. At baseline, assessing Personal control is relevant to determine the outcome prognosis of successful physiotherapy management of persistent low back pain.


Introduction
For decades now, low back pain (LBP) has been recognized as the main cause of Years Lived with Disabilities 1 .
Managing the global impact of LBP on patients, the increase of economic costs and the impact on society are challenging issues and therefore The Lancet Series on Low Back Pain 2018 included a call for action [2][3][4][5] .
Management of persistent LBP has been proposed to shift from a unidimensional (focused on a pathoanatomical disorder) to a more holistic approach, making the transition from the biomedical model to a more biopsychosocial model [6][7][8] . Following this proposal, a physiotherapy treatment of LBP that incorporates biopsychosocial factors that play an important role in the patients' LBP has the potential to increase the positive effect of physiotherapy. Examples of such treatment strategies are described in a Cochrane review on behavioral therapy for LBP; operant, cognitive-. and respondent strategies 9 .
Most of the extensive body of knowledge on the management of LBP derives from systematic reviews and randomized controlled trials (RCTs). These designs represent the highest level of evidence in Evidence Based Medicine. In addition, the randomized n-of-1 trials are also recognized as level 1 evidence in the Oxford Center for Evidence-Based Medicine 2011 levels of evidence 10,11 . The use of evidence from systematic reviews and RCTs is a form of "reference class forecasting" and can be challenging for clinicians when making clinical relevant decisions for individual patients 12 . Does this patient t within the "reference class" that has been reported to progress well with the intervention?
Recently, the call for a more personalized approach for LBP was made 13 . Such an approach could be a 'matched-care' intervention, in which patients' individual prognostic factors for recovery are assessed, and a response guided treatment package can be designed. A response guided treatment means that the treatment is matched to the 'risk-pro le' of the patient and that the speci c content of the treatment is established before each intervention by assessing this 'risk-pro le'. Known factors in such risk-pro ls are psychological factors like fear of movement 14 , catastrophizing 15 , avoidance 16 , somberness 17 and sleep 18 . It is hypothesized that such 'matched-care' intervention may result in better treatment outcomes 19 . In this study we investigate the impact of taking into account another psychological factor in the risk-pro le, namely Illness Perceptions' (IPs), which is the core element of Leventhal's Common Sense Model of health and Illness Representations (CSM) 20 21 .
The CSM is a parallel processing model that describes both cognitive and emotional representations of perceived health threats, leading to patients' IPs resulting from these health threats. Higher IPs scores re ect a more threatening perception of illness and can be called 'dysfunctional IPs'. These dysfunctional IPs may mediate or moderate persistent pain and disability 22 . To personalize management of LBP, IPs might be addressed. Dysfunctional IPs have shown to attribute to higher pain intensity and lower physical functioning and quality of life in a variety of conditions 23 . It is not known how this attribution unfolds during treatment. For instance, whether IPs act as a mediator or moderator for LBP outcomes. This has not yet been researched in primary care physiotherapy, whilst physiotherapists are important primary care practitioners in our healthcare system.
It is hypothesized IPs can mediate and/or moderate the association between intervention and outcome. To research the possible mediation and/or moderation effect of IPs on pain and disability, a multiple baseline Single Case Experimental Design (SCED) can be used to screen and measure patients' individual prognostic factors for recovery before, during and after an intervention. In this study we use 'matched-care' physiotherapy as the intervention for patients with persistent LBP and dysfunctional levels of IPs. In order to analyze the results from our experiment in this study, we pose the following three research questions: Eligible patients for this study were enrolled from 6 different primary care physiotherapy practices in The Netherlands. Inclusion criteria were age 18 years or older, LBP for at least 3-months, experiencing a movement problem in daily life due to LBP and having dysfunctional levels of at least one out of eight IP dimensions. Dysfunctional levels of IPs were based on a secondary analysis of an earlier study on the associations of IPs with patient burden with musculoskeletal pain 22 . We choose the fourth quartile as threshold (box 1), expecting these high-level scores to represent dysfunctional IPs.
Exclusion criteria were speci c LBP and existing (and diagnosed) psychiatric illness. When matching the inclusion criteria, patients were invited to participate by their physiotherapist after reading the patient information letter. Their decision on participating in the study did not have consequences for their treatment.
After signing the informed consent, patients were included in the study.

'Matched-care' treatment package
We used the Dutch guideline for LBP, and added a treatment package which was based on three frequently applied strategies for persistent LBP 9 3.4 (Appendix A). The speci c aim of this response guided treatment package was to alter the dysfunctional levels of IPs by using cognitive, exposure and/or respondent strategies 9 . For instance, a cognitive strategy showed successful improvements in patient-relevant physical activities in patients with more than 1-year LBP 25 .
The treatment package offered the patient and physiotherapist the possibility to create a 'matched-care' intervention as advised in the Dutch Guideline for Low Back Pain. This means that patients' 'risk-pro le' scores were assessed before each intervention and consequently these scores were used to design the respons guided treatment, thereby providing 'matched-care' (see paragraph 2.4).

Measures
An online questionnaire was developed for assessing primary outcomes (pain intensity, physical function, and pain interference), secondary outcome (Illness Perceptions) and the co-variates (fear for damage/pain, pain anxiety, depressive mood, avoidance beliefs and sleep). Frequent administration allowed for monitoring the effect of the treatment package on all outcomes. These items are described below.

Primary outcome
Three outcome measures were chosen as primary outcome based on consensus recommendations from the literature; 1) pain intensity last 24-hours 26 . 2) limitation in patients' own selected physical function and 3) pain interference in daily activities 27 . All three primary outcome were assessed with a 11-point numeric rating scale (0-10). High scores for these three primary outcome measures mean respectively 1) higher levels of pain intensity, 2) stronger linitations in physical nction and 3) greater inference of pain in daily activities. The physical function measure was adjusted to patients' speci c limitation in physical function (i.e. bending forward).

Illness Perceptions secondary outcome
The Brief Illness Perception Questionnaire was used to assess patients' Illness Perceptions representation on LBP 28,29 . This questionnaire contains 9 questions, of which the questions IP1 -IP8 were used in this study. Each item represents a different dimension of IPs. In order to ensure that all higher scores signify stronger dysfunctional IPs, data of the IP3-4 and 7 were reversed before entering into the analyses.

Co-variates
The selection of co-variates was based on research showing these factors being associated with treatment outcome of LBP. They have also previously been used in a SCED study on persistent LBP 30 . The co-variates are: fear of movement 14 , catastrophizing 15 , avoidance 16 , somberness 17 and sleep 18 . For all these co-variates we hypothesized that the higher their scores, the more negative impact they will have on the primary outcome.

Statistical analysis
To investigate whether primary outcomes change during and after matched-care physiotherapy treatment, linear mixed model analyses were performed, including all repeated measurements as outcome, and 'phase' as independent variables. First a crude analysis was performed. In a next analysis we controlled for the covariates.
To investigate whether IPs mediate the effect of matched-care physiotherapy on primary outcomes, these adjusted analyses were performed including the IPs. Based on the change in the coe cient for treatment-phase (two dummies, with phase A as reference category) the mediating role of each IP was evaluated independently. The magnitude of the mediation effect, the Indirect Effect, was calculated by subtracting the Direct Effect from the Total Effect.
Finally, to investigate whether baseline IPs moderate the effect of matched-care physiotherapy on primary outcomes. For the effect size on the three primary outcome during the treatment-phase and post0treatment phase (two dummies, with phase A as reference category) the baseline IPs were added to the adjusted linear mixed models. The importance of the moderation was evaluated on signi cance (p<0.05) of the interaction terms. in addition to statistical signi cant effects, we evaluated the outcomes on their clinical meaningful effect using a threshold of 30% change in phase A' on primary outcome from baseline scores phase A 31 .
All analyses were performed with STATA ® (version 15). Table 1 presents the characteristics of participating physiotherapists. Six physiotherapists participated in the study, all working in different primary care physiotherapy practices across the Netherlands.    Table 3 shows which baseline IPs dimensions reached the threshold score, as one of the inclusion criteria, per patient.    Table 5 shows the results of the mediation analyses performed on the adjusted models.

Results
Five of the 8 IP dimensions substantially mediated the total effect on all three primary outcomes (    Table 6 shows the statistically signi cant results of the moderation analyses performed on the adjusted models. The IPs dimension Personal control moderated the treatment effects for all three primary outcomes.
There is a stronger treatment effect for patients with a low baseline score (

Discussion
In this matched-care physiotherapy treatment for patients with persistent LBP SCED-study, we showed a statistically signi cant and clinical meaningful improvement in decreasing pain intensity, increased physical function and lesser pain interference in daily life during and 3-months post-treatment. We did not observe a wash-out phenomenon during the post treatment phase. Furthermore, we found ve IP dimensions to substantially mediate the effect on all three primary outcomes; namely, Consequences (45. Control, Identity, Concern and Emotional response also acted as moderator.

Illness Perceptions as mediator
The search for causal mechanisms for non-speci c LBP has been a quest for decades now 32,33 . Identifying such mechanisms is useful, for instance, when designing a 'Magic Bullet' cure, for a condition that is primarily caused by a pathoanatomical impairment 34 . In the case of persistent musculoskeletal pain like LBP, such pathoanatomical impairment most likely cannot be identi ed. LBP is considered to be more a symptom of a complex condition with multiple contributors to both pain and associated limitations in physical function, including psychological factors, social factors, biophysical factors, comorbidities, and pain-processing mechanisms 4 . Models for management of complex conditions should incorporate these multiple contributers, including patients' beliefs about their condition 35,36 . IPs are thought of as one aspect of these beliefs 35 .
Through mediation analyses we identi ed 5 IP dimensions that mediated the total effect of our matched-care physiotherapy treatment package 17 . Intervention studies on how to alter IPs in LBP are scarce. We know of one RCT that looked at altering baseline IPs with cognitive treatment to improve patient relevant physical activities 25 . In this study IP dimensions Timeline cyclical, Consequences, Personal control and Coherence attributed 14.4% of the explained variance to physical activities. This partly overlaps with our results. We found IP dimensions Consequences and Personal control also signi cantly mediating the total effect on all three primary outcomes.
The effects in our study are found within a non-controlled design and should be further tested in a larger population and with a different design such as a randomized controlled trial.

Illness Perceptions as moderator
The course and prognosis of developing persistent LBP have been extensively researched 36 . The overall ndings are reported as; "Low to moderate levels of pain and disability were still present at one year, especially in the cohorts with persistent pain." In a Cochrane review on individual recovery expectations it is concluded: "Our ndings suggest that recovery expectations should be considered in future studies, to improve prognosis and management of low back pain" 37 . We found the IP dimension Personal control to be moderating the effect on all three primary outcomes. This IP dimension can be seen as re ecting patients' expectations about the effect of the treatment. We therefore would like to advise to include the IP Personal control in future research concerning treatment and prognosis of LBP.

Limitations & strengths
Several limitations need to be considered. First, there was no randomization. The effects in our study are found within a non-controlled design. We explicitly focused on a 'matched care intervention'. Meaning that the intervention was tailored on the patients' clinical presentation, and therefor randomization was not included in our design. Secondly, selection bias of patients. The patients were selected by the participating physiotherapists, therefore the generalizability of our results is somewhat limited. Thirdly, patients were required to complete a questionnaire, monitoring their progress on a weekly basis for several months. This may have given rise to the awareness of being studied. This possibly impacted behavior 38 , resulting in a Hawthorne effect.
Fourthly, there is a potential sampling bias of treating / participating physiotherapists due to the use of convenience sampling of physiotherapists via social media and within the network of the rst author. They were invited to our 2-day course to be informed on the design of the study. These physiotherapists might not be representative of the physiotherapy community in the Netherlands. Fifthly, we do not have data to analyze the treatment delity of participating physiotherapists on delivering the matched-care treatment package. The weight this has on the effects is not clear. We tried to minimize this limitation by including several implementation interventions addressing delity of the physiotherapists to participate in the study: a 2-days course, videos were assesible demonstrating how to apply treatment strategies and the use of repeated measures during the treatment phase.
Finally, due to the design of this study conclusions about causal relations between IPs and the primary Page 13/17 outcome cannot be drawn. Further studies on the temporal order of the associations between matched-care physiotherapy, IPs and treatment outcomes are recommended.
There are several strengths of this study to be considered. First, the use of repeated measures and a matchedcare intervention instead of a strict treatment protocol allowed the physiotherapists to adjust their interventions to the clinical status of the patient with each new appointment. This dynamic and cyclical process is commonly used by physiotherapists and is a re ection of their clinical reasoning process 39 , making this design representative for daily practice. For example, if the patient shows a su cient decrease of safety behaviors, than withdrawal of safety behavior strategy is justi ed 40 . Secondly, within the model of Illness Representations by Leventhal it is hypothesized that dysfunctional perceptions affect pain and limitations in physical functioning. The use of an IP threshold as an inclusion criterium implies good diagnostics for creating a window of opportunity to improve pain and physical functioning by altering IPs. Thirdly, this study is a good example of how to include physiotherapists' clinical relevant decisions for avoiding problems concerning "reference class forecasting". Such forecasting relies on prediction from past reference classes, a model wich may not be the most suitable because of the large variability in clinical signs and symptoms in patients with low back pain. In our study we explicitly incorporated psycho-social elements which were relevant for that patient as was shown in their 'risk-pro le'.

Practical implications
The use of a matched-care physiotherapy treatment is accompanied by a decrease of pain and physical function related health problems in patients with persistent low back pain. This type of research, looking at treaments that incorporate a dynamic and cyclical process is a reproduction of daily physiotherapy practice. We would like to encourage this way of working and researching the effectiveness of physiotherapy.
In earlier research, we concluded based on a longitudinal study with 2 timepoints that baseline IPs did not predict poor recovery on pain and/or physical function after 3-months (de Raaij et al., 2020).
The results of this study are not in line with these ndings. For instance, dysfunctional baseline IP Personal control scores (8-10) moderate the effect signi cantly, meaning that physiotherapists can be encouraged to use item 3 of the Brief IPQ-DLV for the baseline assessment of patients' perceptions on controllability of their condition. A speci c intervention targeting this dysfunctional perception can be adviced. Further, it can be adviced to evaluate the change in the IPs dimension Consequences, Personal control, Identity, Concern and Emotional response because our results show a mediating effect of change in these perceptions on the effect of the treatment. If one of these perceptions does not change during treatment there could still be room for improvement by speci cally targeting these perceptions with interventions. Thereby, applying the principles of 'matched-care' treatment.

Conclusion
This is the rst study shedding some light on how IPs may affect pain intensity, physical function and pain interference during primary care physiotherapy treatment. Our ndings indicate that the IP dimensions Consequences, Personal control, Identity, Concern and Emotional response, might be important to include in a matched-care treatment of LBP, because they enhance the positive mediation effect of all three primary outcomes. In addition, at baseline, assessing Personal control may be relevant to determine the outcome prognosis of successful physiotherapy management of persistent LBP. Availability of data and materialsT the datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. The datasets are stored in a repository of the University of applied sciences Utrecht, which can be accessed from a University account.
Competing interest:

Not applicable
Funding: This study is supported by a grant of the Dutch government; NWO-023.005.029