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A systematic review and meta‐analysis of pain neuroscience education for chronic low back pain: Short‐and long‐term outcomes of pain and disability

Pain neuroscience education (PNE) has shown promising ability in previous reviews to improve pain and disability in chronic low back pain (CLBP). This review aimed to evaluate randomized controlled trials comparing the effectiveness of PNE on pain and disability in CLBP.


| INTRODUCTION
Low back pain (LBP) is one of the most common musculoskeletal conditions worldwide (Hoy et al., 2014), and it is estimated that most people will at some point in their lifetime experience LBP. Recent guidelines for LBP advocate the use of education as a key component of LBP management (National Guideline Centre 2016; Wong et al., 2017). Education typically aims to reduce the risk for further symptoms by enhancing and improving the participant's knowledge to create a change in the participant's behaviour (Linton & van Tulder, 2001;Haines et al., 2009). Strong evidence has demonstrated the effectiveness of individual education in subacute LBP on short-term and long-term return to work in comparison to no intervention. Further, it is as effective as non-educational interventions on long-term pain and global improvement in subacute LBP. However, in chronic low back pain (CLBP), the effectiveness of individual education remains unclear (Engers et al., 2011).
In response to a growing body of research, a model of education called pain neuroscience education (PNE) has been developed (Butler & Moseley, 2003;Louw, Diener, & Puentedura, 2015;Moseley & Butler, 2015;Nijs, Paul van Wilgen, Van Oosterwijck, van Ittersum, & Meeus, 2011;Nijs, Roussel, Paul van Wilgen, Köke, & Smeets, 2013;Zimney, Louw, & Puentedura, 2014). PNE originates from educational psychology and aims to reconceptualize pain as "a marker of tissue damage" to being a representation of the threat or need to protect the body from harm (Moseley, 2003a;Moseley & Butler, 2015). PNE differs from traditional pain education by aiming to desensitise the neural system by focusing on the neurophysiology, neurobiology, representation of pain and meaning of pain, in place of using a traditional anatomical and biomedical model (e.g. what is broken and how do we fix it; Louw et al., 2015). Further, it aims to shift one's concept of pain as a portrayal of harm, to one of pain as a form of alarm system for protection of bodily tissue (Moseley & Butler, 2015). Geneen et al. (2015) describe education as a means for self-empowerment and self-management (Wong et al., 2017), but until recently, most traditional educational models have focussed on anatomical and biomedical models of pain as a representation of damage (Moseley, Nicholas, & Hodges, 2004) or traditional biopsychosocial approaches (Engel, 1980). Recent reviews have reported strong evidence for PNE to change pain intensity, knowledge of pain, disability, psychological function and pain behaviours (meta-analysis was not performed) in patients with musculoskeletal pain (Louw, Diener, Butler, & Puentedura, 2011;Louw, Zimney et al., 2016); however, they highlight that PNE alone was not sufficient to have an impact on reducing pain scores. Clarke, Ryan, and Martin (2011) similarly found a statistically but not clinically significant improvement for pain reduction in the short term (5 mm on the 100 mm VAS [95% CI 0, 10.0]), when PNE was added to a pain management programme and a clinically and statistically significant improvement at 1 year compared to the control group (27-point difference, 68% improvement). However, Clarke et al. (2011) were unable to pool the disability scores due to lack of homogeneity in outcome measures but did not report statistically or clinically significant improvements in this outcome. Although Clarke et al. (2011) found promising results to support the use of PNE on pain, physical-, social-and psychological function in CLBP, they highlight that this was very low quality evidence due to a high level of publication bias (both included studies were authored by a prominent author of PNE) and both included studies had small sample sizes (n = 122) increasing the risk of inadequate power to demonstrate a significant difference.
Since this review (Clarke et al., 2011), a number of studies on the use of PNE in the management of CLBP have been published (Pires, Cruz, & Caeiro, 2015;Téllez-García et al., 2015;Wälti, Kool, & Luomajoki, 2015) which warrants an updated review. Given the increasing popularity and clinical utility of PNE for CLBP, it is imperative to systematically evaluate the evidence for its effectiveness on pain and disability in CLBP.

| STUDY OBJECTIVES
This purpose of this systematic review was to evaluate the evidence for the effectiveness of PNE in isolation and in combination therapy in comparison to control groups on pain and disability outcomes in non-specific CLBP adult patients. This study also aims to summarize the results of included studies in a meta-analysis (where possible according to heterogeneity) for statistical significance and weighted mean differences of grouped outcomes to be derived.

| METHODS
3.1 | Inclusion and exclusion criteria 3.1.1 | Type of study RCTs published in English were searched from 2011 (01) to 2017 (12). The search was limited at 2011 given the most recent review on CLBP was performed at this point (Clarke et al., 2011). Secondary searching from before this time point was sourced from secondary searching of relevant reviews (Clarke et al., 2011;Louw et al., 2011). WOOD AND HENDRICK | 235 3.1.2 | Type of participants Trials involving adult populations (>18 years) were included. All participants were required to have chronic non-specific LBP of at least 3-month duration, with or without leg pain but excluding specific pathology such as spinal stenosis, lumbar instability, post-surgical pain, pregnancy-related low back pain etc. Trials of participants with specific diagnoses of serious pathologies (cauda equina, spinal tumours, spinal fractures, spondyloarthopathies etc.) and patients with widespread chronic pain or systemic pain conditions such as fibromyalgia, chronic fatigue, rheumatoid arthritis, polymyalgia rheumatica were also excluded.

| Type of intervention
Pain neuroscience education (PNE; Nijs et al., 2011), or therapeutic neuroscience education (Louw & Puentedura, 2013), or "explain pain" (Moseley & Butler, 2015) was required to be a component of the experimental group. The PNE could be delivered in isolation or in combination with other forms of physiotherapy treatment: including exercise, manual therapy, acupuncture or dry needling. Since there is no standardization for the delivery of PNE, all forms of delivery will be considered: such as group instruction, individual explanation, the use of presentations, books or leaflets to supplement the explanations.

| Type of comparator
All control groups were considered provided they did not include PNE. This may have included waitlist controls, physiotherapy, other educational methods or no treatment.

| Type of outcome
The outcome measures of pain and disability were included for this review. The principal summary method was mean difference between groups assessed at short-term (<12 weeks) and long (>1 year)-term follow-up. Adverse events were also captured where mentioned.

| Search strategy
The databases of CINAHL, Medline, Cochrane and Web of Science were searched from 2011 (01) to 2017 (12). The search terms were developed using the PICO format (Population, Intervention, Comparator and Outcome) which is advocated by the York Centre for Reviews and Dissemination team (Centre for Reviews and Dissemination & University of York 2008) and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (Liberati et al., 2009). Search terms utilized were: (("low* back" OR lumbar OR sciatic* OR "low back pain" OR "back pain" OR "back ache" OR backache OR spinal OR spine) AND (education OR "pain education" OR "neuroscience education" OR "pain biology education" OR "pain physiology education" OR "neurophysiology education")). Key authors in this field were also contacted to ensure no papers had been missed (G.L. Moseley, J. Nijs, A Louw). Secondary searching of systematic reviews of PNE in musculoskeletal pain occurred to ensure no papers were missed (Clarke et al., 2011;Louw et al., 2011;Moseley & Butler, 2015).

| Study selection
Search results were imported into Refworks for screening. All study titles and abstracts of search results were screened by the lead author for preliminary elimination. Screened titles and abstracts, and full-text studies were then reviewed independently by both authors. Disagreements were resolved with discussion. At this point, any articles which did not fulfil the inclusion criteria above were discarded, with reasons documented, and the remaining articles comprised the review and meta-analysis.

| Data collection
Data were collected from included studies by means of a data extraction spreadsheet in Microsoft Excel which included the headings: author, year, setting, population, intervention, comparator, follow-up periods, outcome measures and numerical values for each reported outcome measure by the lead author. This form was piloted in a literature review on the topic before being utilized for this study.

| Methodological quality assessment
Studies were rated using the Cochrane Risk of Bias tool (Ottawa Methods Centre, Clinical Epidemiology Program, 2015) to evaluate the risk of bias in each RCT by the lead author. These results were reviewed independently by the second author (PH) to ensure accuracy and agreement. Guidance to interpretation of the bias levels was scored in accordance with the Cochrane Back Review Group (CBRG), whereby RCT studies with a score >6 out of 12 are considered to have a low risk of bias (Furlan, Pennick, Bombardier, & van Tulder, 2009). Liddle, Gracey, and Baxter (2007) further assessed the quality scores into low, medium and high, risk of bias. This review is reported according to the PRISMA statement for reporting systematic reviews that evaluate health care interventions (Liberati et al., 2009).

| Unit of analysis issues
Pain scores, where reported on a 0-100 scale were converted to a 0-10 score where necessary for ease of metaanalysis. The NRS has been shown to be highly correlated with the VAS in patients with chronic pain of more than 6 months (r = 0.86 to 0.95), with test-retest reliability observed in both literate and illiterate patients (r = 0.96 and 0.95, respectively; Hawker, Mian, Kendzerska, & French, 2011). Disability scores were grouped according to outcome measure used and pooled where 2 or more trials utilized the same score for comparison with minimally clinical important change scores reported in the literature. Disability scores were not grouped across outcome measures due to poor correlation found between scores (Morris, Hee, Stallard, Underwood, & Patel, 2015). Grouped scores were entered into the Review Manager (RevMan 5.1) software for analysis. Where scores were unable to be grouped, narrative review occurred.

| Dealing with missing data
Authors were contacted for unpublished missing data for the purposes of meta-analysis.

| Data analysis
Reported outcomes were pooled where possible for metaanalysis using the RevMan 5.1 software. Statistical pooling of the overall effect (random effects model) compared to a comparison treatment with a 95% confidence interval was used in accordance with previously reported reviews (Clarke et al., 2011) and the CBRG (Furlan et al., 2009). Results for each of the primary outcome measures (pain and disability) were pooled according to outcome measure utilized. Mean difference for outcomes from baseline outcomes, standard deviation, 95% confidence intervals and total participants were input into RevMan 5.1, where possible, for meta-analyses. Weighted mean difference was then interpreted in relation to minimal detectable clinical change scores recommended in the literature for pain (NRS), Roland Morris Disability Questionnaire (RMDQ), Oswestry Disability Index (ODI) and Patient-specific functional scale (PSFS). The minimal clinically important change for the RMDQ was two points or 8%-12% (Furlan et al., 2009). The MCID for the ODI has been reported as eight, and the PSFS needs a change of more than two points to be considered clinically significant (Maughan & Lewis, 2010). The QBPDS has a minimal detectable change of 20 points or 30% (Smeets, Köke, Lin, Ferreira, & Demoulin, 2011), whilst the PDI-DV requires a clinically important change in score to decrease by 8.5-9.5 points (Soukup, Lönn, Glomsröd, Bö, & Larsen, 2001). The recommended minimal detection of clinical change for the NRS is two points or 30%, in a low back pain subgroup over a short-term (duration of one-month) follow-up (Hawker et al., 2011). In accordance with the CBRG, statistical pooling of the overall effect (random effects model) was compared to a comparison treatment with a 95% confidence interval (Furlan et al., 2009).

| GRADE assessment
The evidence for each outcome was further assessed in accordance with the GRADE system recommended by the CBRG guidelines (Furlan et al., 2009), namely: study design limitations, consistency between studies, directness (ability to generalize), precision (sufficient or precise data) of results and publication bias. Five levels of evidence may then be generated for each pooled outcome from this information: high, moderate, low, very low quality of evidence and no evidence. Please see Table S4 for details on the criteria used for assessment (Ryan & Hill, 2016).

| Included studies
A total of 6761 papers were found through the computeraided search strategy with 2110 duplicates removed. Title and abstract screening resulted in removal of 4630 results with 27 full-text articles reviewed, of which four trials were included. Six full-text papers were reviewed following secondary literature searching, of which three were included Moseley, 2002;Moseley et al., 2004). One paper was included further to correspondence with the authors (J.N; Malfliet et al., 2017). The details of trial selection are visually depicted in Figure 1. In total, eight RCTs were included (n = 615) and the study characteristics are detailed in Table 1.

| Excluded studies
Following full-text review, two records were excluded as they were poster presentations of the original RCTs (Luomajoki, Kool, & Wälti, 2016;Pires, Caeiro, & Cruz, 2016), pain mechanism education was given to both groups in Aasa et al. (2015) and (Moseley, 2003a). One study was excluded due to being unpublished and sourced from secondary referencing (Moseley, 2009), and another study was excluded as it had no control group (Demoulin et al., 2016). One study did not include the outcomes of pain and disability (Løchting, Storheim, Werner, Småstuen Cvancarova, & Grotle, 2017). The other fourteen papers were excluded did not use pain education (PNE) as described by Butler and Moseley (2003)

| Delivery and dosage
Please see Table S1 for details regarding PNE dosage and delivery methods amongst included trials.

| Outcomes
Five of the studies measured short-term pain (within the first 6 weeks), whereas Wälti et al. (2015) reported results at 12 weeks. Five studies utilized the Numeric Pain Rating Scale (NRS; 0-10; Moseley, 2002;Tellez-Garcia et al., 2015;Wälti et al., 2015;Werner et al., 2016), whilst Pires et al. (2015) utilized a 100 mm visual analogue scale (VAS). Six of the eight studies reported back-specific disability outcomes in the short term. Five studies used the Roland Morris Disability Questionnaire (RMDQ; 0-24; Moseley, 2002;Moseley et al., 2004;Tellez-Garcia et al., 2015;Wälti et al., 2015;Werner et al., 2016). Pires et al. (2015) utilized the Quebec Back Pain and Disability Scale (QBPDS; 0-20 points), Tellez-Garcia et al. (2015) also utilized the Oswestry Disability Index. Wälti et al. (2015) used the Patient-Specific Functional Scale, whilst Malfliet et al. (2017) utilized the Pain Disability Index (PDI-DV). Moseley (2002) and Werner et al. (2016) were the only trials to perform long-term follow-ups of participants at twelve months. Figure 2 demonstrates the results of the risks of bias assessment. Using the GRADE classification, one trial was of high quality (Malfliet et al., 2017;10;/12), with the F I G U R E 2 Risk of bias summary other seven studies of moderate quality (>6/12; Wälti et al., 2015;Louw, Farrell et al., 2016;Moseley et al., 2004;Moseley, 2002;Tellez-Garcia et al., 2015;Pires et al., 2015). All studies apart from Moseley et al. (2004) utilized random sequence generation. Adequate description of the allocation concealment was performed in Pires et al. (2015) and Werner et al. (2016). Blinding of care providers was not performed in all studies apart from Moseley et al. (2004). All trials were considered to have a low risk of bias, suggesting that although a degree of bias was present, the criteria that are unfulfilled are unlikely to change the results or conclusion of the study (Furlan et al., 2009). For detailed risk of bias assessment, please see Table S2.

| Pain
Six studies comprised of 428 participants provided data on short-term pain outcomes. Meta-analysis of the results demonstrated a weighted mean difference of 0.73 (95% CI −0.14, 1.61) on a 10-point scale of PNE in comparison to control groups at a mean of 31.8 days. This is not statistically significant (p = 0.10). There was significant heterogeneity with I 2 statistic of 95% and χ 2 = 109.57 (p < 0.000001; see Figure 3). There is low quality evidence that the use of PNE in isolation/combination with other treatment may improve pain relief in the short term.
Subgroup analysis of physiotherapy interventions combined with PNE (Louw, Farrell et al., 2016;Moseley, 2002;Pires et al., 2015;Tellez-Garcia et al., 2015;Wälti et al., 2015) demonstrates a statistically significant difference in favour of the addition of PNE (p < 0.00001), with a weighted mean difference of 1.32 (95% CI 1.08, 1.56) for 212 participants, which is clinically insignificant (Hawker et al., 2011). The heterogeneity was low I 2 = 0% and χ 2 = 3.55 (p = 0.47; please see Figure 4). There is moderate quality evidence that the addition of PNE to a physiotherapy intervention has a short-term improvement on pain.
Two studies captured data at a 12-month follow-up period (Moseley, 2002;Werner et al., 2016). The weighted mean difference for long-term effects of PNE on pain was 0.44 (95% CI −1.03, 1.91) for 254 participants which was not statistically significant (p = 0.56). Considerable heterogeneity was demonstrated between these two studies with I 2 = 99% and χ 2 = 80.40 (p < 0.00001; please see Figure 5). We are uncertain whether the use of PNE is effective in reducing pain in the long term, due to the domains of imprecision and indirectness not being met, as well as publication bias due to the small number of papers included (n = 2) and one of these being authored by a prominent PNE author (Moseley, 2002).

| Disability
Meta-analysis was performed with all five studies which used the RMDQ (n = 362) at a mean of 32.8 days F I G U R E 4 Forest plot of PNE with physiotherapy intervention versus PNE F I G U R E 3 Forest plot of PNE versus alternative intervention in short term WOOD AND HENDRICK (Moseley, 2002;Moseley et al., 2004;Tellez-Garcia et al., 2015;Wälti et al., 2015;Werner et al., 2016). The overall mean difference was 2.28 (95% CI 0.20, 4.25; p = 0.02) which is both clinically and statistically significant when compared to the minimal clinically important change of two points or 8%-12% (Furlan et al., 2009); however, due to the wide confidence interval, this should be interpreted with caution. Between-study variability demonstrated considerable heterogeneity (I 2 = 98%, χ 2 = 215.51, p < 0.00001; please see Figure 6). There is moderate quality evidence that the use of PNE either as stand-alone intervention or in combination with physiotherapy probably improves disability in the short term.
Subgroup analysis of PNE in addition to a physiotherapy intervention utilizing the RMDQ for disability demonstrates a weighted mean difference of 3.94 (95% CI 3.37, 4.52) for 88 participants (Moseley, 2002;Tellez-Garcia et al., 2015;Wälti et al., 2015) which is both clinically and statistically significant (p < 0.00001). Between-study variability was low I 2 = 0%, χ 2 = 0.86 (p = 0.65; please see Figure 7). There is moderate quality evidence that the addition of PNE to physiotherapy improves disability in the short term.
Subgroup analysis of the long-term effect of PNE on RMDQ disability demonstrated a weighted mean difference of 2.18 (95% CI −0.67, 5.02; p = 0.13) for 254 participants (Moseley, 2002;Werner et al., 2016) which was not statistically significant. This demonstrated significant between-study variability with I 2 = 95% and χ 2 = 21.80 (p < 0.00001; please see Figure 8). We are uncertain whether the intervention of PNE influences disability in the long term due to the very low quality of evidence. Werner et al. (2016) reported a between-group difference of 0.70 (−0.32, 1.72) in favour of PNE which was not statistically significant (p = 0.18) at 1 year. However, there was a statistically significant difference in favour of physiotherapist-delivered education in comparison to GP delivery (1.41 points, 95% CI 1.12, 1.70; p < 0.00001) at twelve-month follow-up.
In the results of PSFS, although the PNE group improved by a clinically significant 2.55 points (95% CI 1.3, 3.8), the between-group difference was not significant p p F I G U R E 5 Forest plot to depict PNE versus alternative intervention at 12 months p p F I G U R E 6 Forest Plot to depict combined RMDQ scores for PNE compared to alternative intervention in short term p p F I G U R E 7 Forest plot to depict combined RMDQ scores for PNE in addition to physiotherapy intervention compared to physiotherapy interventions alone at 1.42 points (95%CI −0.25,3.09; p = 0.09) in the short term (12 weeks; Wälti et al., 2015). Similarly, Malfliet et al. (2017) reported a between-group difference on the Pain Disability Index of 1.84 points (95% CI −2.80, 6.47) which was not statistically significant. Comparing PNE and aquatherapy against aquatherapy, both groups demonstrated a statistically non-significant improvement in their QBPDS score (3.40 difference; 95% CI −3.34, 10.14; p = 0.32; Pires et al., 2015). Tellez-Garcia et al. (2015), in the comparison of dry needling with PNE against dry needling alone, reported a non-significant difference in ODI scores between groups of −4.50 (95% CI −10.62, 1.61; p = 0.15).

| Psychological effects
Three studies reported on the short-term outcomes of fear of movement or kinesiophobia (Malfliet et al., 2017;Pires et al., 2015;Tellez-Garcia et al., 2015) utilizing the Tampa Scale of Kinesiophobia. The weighted mean group difference was 4.72 (95% CI 2.32, 7.13) in favour of PNE (p = 0.0001; please see Figure 9); however, this was clinically insignificant falling short of the required 5.5 points to demonstrate a minimal clinically important change in CLBP (Monticone, Ambrosini, Rocca, Foti, & Ferrante, 2016).
Two studies (n = 178) utilized the pain catastrophizing scale (PCS), and the weighted mean group difference was 2.54 points (95% CI −4.23, 9.31) in favour of the PNE group (p = 0.46; please see Figure 10). However, this difference was not statistically significant. However, very high scores of heterogeneity were present with I 2 of 99% and χ 2 = 195.85.

| Reported harmful effects
There were no adverse effects reported due to PNE. Tellez-Garcia et al. (2015) reported soreness in 83% of their participants after the trigger point dry needling treatment, but this resolved spontaneously within 32 hr for all participants. There were no adverse effects reported by Moseley (2002), Pires, Cruz, and Caeiro (2014) or Werner et al.

| GRADE analysis
Please see Figure 11 for the detailed GRADE assessment and Table S3 for the criterion used for assessment. When PNE is delivered in addition to a physiotherapy intervention, there is moderate quality evidence of benefit on pain scores in the short term, as the domain of imprecision was not met. However, when PNE is delivered either in isolation or in combination with physiotherapy, there is very low evidence for the effectiveness of PNE in reducing pain in the long term. In the long term, this was due to the domains of imprecision and indirectness not being met, as well as an additional risk of publication bias due to the small number of papers included (n = 2) and one of these being authored by a prominent PNE author (Moseley, 2002). For disability, there is moderate quality evidence that the use of PNE either as a stand-alone intervention or in combination with physiotherapy improves disability as measured with the RMDQ in the short term (both clinically and statistically significant improvement), as the domain of indirectness was not met. There is moderate quality evidence that the addition of PNE to physiotherapy provides a statistically and clinically significant improvement in disability in the short term, limited by the domain of imprecision not being met due to the small sample sizes. There was low quality evidence that the use of PNE as a standalone intervention improved disability in the long term due to the domains of indirectness, imprecision and publication bias not being met. This was due in part to the small number of papers included (n = 2) and one of these being a prominent PNE author (Moseley, 2002).

| Summary of main findings
This study aimed to evaluate the effectiveness of PNE on pain and disability in CLBP. The results of this review show that the use of PNE probably improves disability in the short term, irrespective of whether it is delivered in conjunction with physiotherapy or not. The minimal clinically detectable change for the RMDQ is two points on the 24-point scale and this review demonstrated a change of 2.28 (95% CI 0.20, 4.25; p = 0.02) and 2.18 (95% CI −0.67, 5.02) for the short-term and long-term effects. However, when PNE was added to a physiotherapy intervention, the between-group difference for disability was 3.94 (95% CI 3.37, 4.52) suggesting a greater clinical improvement in favour of the addition of PNE to physiotherapy treatment. When PNE in addition to physiotherapy interventions was analysed in a subgroup analysis, heterogeneity was found to be negligible (I 2 = 0%). Therefore, supporting the results that the addition of PNE to physiotherapy interventions is clinically significant in improving disability.
When PNE was added to usual physiotherapy interventions, there is moderate evidence that it probably slightly improves pain scores (weighted mean difference 1.32 (95% CI 1.08, 1.56; p < 0.0001). However, PNE as a stand-alone intervention or in combination with physiotherapy had little or no effect on pain scores in the short-term 0.73 (95% CI −0.14, 1.61; p = 0.10). Similarly, when PNE in addition to physiotherapy interventions was analysed in a subgroup analysis, heterogeneity was found to be negligible (I 2 = 0%). The small but clinically insignificant benefits on pain in the short term may also be considered robust.
The use of PNE either in conjunction with physiotherapy or in isolation created a statistically significant improvement in TSK scores (4.72 (95% CI 2.32, 7.13) p = 0.0001), in the short term. However, neither of these changes was clinically significant, and both these analyses demonstrated a high degree of heterogeneity (I 2 = 99% and 95%, respectively): thus, these results should be interpreted cautiously.
Considerable heterogeneity was found in a number of factors including age, with mean ages of 38 years  to 60 years ); duration of pain, with Werner et al. (2016)'s participants having an average of 6 weeks of pain, whereas Louw et al. (2015)'s participants had an average of 9 years of pain (see Table 1). Further, the delivery of the PNE was applied in a wide variety of formats, from one-to-one sessions, to webinars, group delivery; with variable prescriptions of reading to perform at home which may assist with improved outcomes. The comparator group also varied between trials, with only one trial utilizing a waiting list control (Moseley, 2002) whilst Wälti et al. (2015) compared multi-modal treatment group to a usual physiotherapy group. All other intervention groups compared the same intervention with or without PNE which can reduce the bias of co-interventions,

| Limitations of included studies
For the meta-analysis of pain and disability in the short and long term, there was a high degree of heterogeneity with I 2 statistics of 95% and 98%, respectively. This was possibly due to the variety of interventions assessed and reduces the robustness of the short-term and long-term results for all studies combined. Attempts to reduce the  (Moseley, 2002;Werner et al., 2016;Wälti et al., 2015;Pires et al., 2015;Tellez-Garcia et al., 2015; heterogeneity of trials was attempted by subgrouping trials into the intervention of PNE in addition to physiotherapy and as an educational stand-alone which successfully reduced the I 2 coefficient. A further limitation was the small sample sizes of some of the included studies (n = 12 (Tellez-Garcia et al., 2015), n = 28 (Wälti et al., 2015)), which reduces the ability of the trial to detect a significant difference, whilst also reducing the likelihood that any significant results found reflect a true effect (Button et al., 2013).
The trials included within this review all scored above 6/ 12 on the Cochrane Risk of Bias score, indicating a low level of bias. However, the most common source of bias was blinding of care providers, which was only performed by Moseley et al. (2004); followed by inadequate description of allocation concealment in 75% of trials. 50% of trials had inadequate blinding of participants and personnel, and 25% of included trials did not blind the outcome assessors. Only two studies followed up participants at twelve months (Moseley, 2002;Werner et al., 2016), of which Werner et al. (2016) had a higher rate of attrition bias due to an increased rate of dropout in the GP group (38%) in comparison to the physiotherapist-delivered intervention group (26%).
It is interesting to note the variation in delivery methods by Werner et al. (2016) whereby GPs and physiotherapists were used to deliver the intervention and control, as opposed to Moseley et al. (2004) who utilized physiotherapists only. Both trials found improvements in both groups, with the addition of PNE providing no extra benefit in Werner et al. (2016). However, Moseley et al. (2004) found improvement in physical performance and a normalization of pain attitudes and beliefs which favoured the PNE intervention group. Werner et al. (2016) noted the difficulty in recall across delivery agents of the content in sessions provided and postulated that patients may have received treatments more similar than intended. Further, the training received in the delivery of PNE may require standardization, as we know from previous studies the content and understanding of PNE by those delivering the intervention can potentially effect adequate reconceptualization in others (Moseley, 2003b;Moseley & Butler, 2015): health professionals may potentially underestimate patients' ability to understand PNE, and without specific training, health professionals themselves were found to be unlikely to demonstrate sufficient understanding of PNE on the pain neurophysiology knowledge test when compared to trained counterparts (Moseley, 2003b).

| Comparison with other reviews
The findings of this study are in keeping with Moseley and Butler's review of Explain Pain (2015) in which they reiterate the clinically intended use of PNE as an adjunct to biopsychosocial rehabilitation. These results are in contrast to the last review of PNE in CLBP whereby Clarke et al. (2011) reported non-significant improvements in favour of the PNE group in physical function but significant improvements in pain scores in the short term (a mean difference of 5 mm (95% CI 0, 10.0) on the 100mmVAS) and long term (27 point (68%) between-group difference). However, they had limited study inclusion (n = 2), with small sample sizes (n = 58; n = 64) which increases the risk of false positive results (Button et al., 2013). Similarly, the recent review by (Louw, Zimney, Puentedura, & Diener, 2016) included 13 studies evaluating PNE, and concluded strong evidence for the use of PNE in reducing pain ratings and disability in all musculoskeletal conditions.
The strength of evidence for the effect of PNE on pain in the short term is low to moderate, suggesting that further evidence may well alter the results of this review, although we are moderately confident that the results of this review reflect a positive effect of PNE on disability.
Despite the small mean differences shown for pain and disability, it is important to note that in all studies, both groups demonstrated an improvement from baseline, regardless of whether they received an intervention or not. Subgroup analysis provided moderate quality evidence for the support of PNE in addition to physiotherapy interventions on pain and disability in the short term, which is supported by existing literature Moseley & Butler, 2015). However, for pain outcomes, non-clinically significant changes were demonstrated, and small clinically significant changes were demonstrated in disability, suggesting that future research may play an important role in deciding the cost-benefit of including PNE alongside physiotherapy treatment.

| Limitations of this review
Although this study includes eight moderate quality RCT studies, the heterogeneity in primary outcomes selected and outcome measure utilized limited the ability to pool all results in meta-analysis and increased the indirectness of effect. As such the limited ability to group studies results in increased influence of imprecision, and publication bias with three of the included studies authored by prominent PNE authors receiving royalties from PNE's promotion.
The lack of a registered protocol for this review is also recognized as a methodological shortcoming.

| Implications for practice
There is moderate quality evidence that the use of PNE alongside physiotherapy interventions for CLBP probably reduce disability and pain in the short term. The variety of interventions included in this review is reassuring, ensuring treatments can be tailored to patient's individual goals and preferences. There is low evidence for the use of PNE to reduce fear avoidance and pain catastrophizing.
As GPs are seeing a large proportion of first-contact patients and managing CLBP patients possibly more frequently than physiotherapists, future research should include training of GPs in the delivery of PNE to assist with increasing their familiarity with the biopsychosocial and PNE approach, as well as to evaluate whether there are differences in patient outcomes.

| CONCLUSION
This study provides moderate quality evidence for the use of PNE as an adjunct to usual physiotherapy interventions in the improvement of disability and pain scores in CLBP in the short term. We are uncertain whether PNE may improve long-term pain and disability. Future research should evaluate the cost-effectiveness of the addition of PNE to usual care.