The effectiveness of a combined exercise and psychological treatment programme on measures of nervous system sensitisation in adults with chronic musculoskeletal pain - a systematic review and meta-analysis.

Background Quantitative sensory testing (QST) offers information regarding underlying mechanisms contributing to chronic pain (CP) in adults with musculoskeletal disorders. This review examined the use of QST measures in adults with CP following participation in a combined exercise and psychological intervention. Methods The review was conducted in accordance with the PRISMA guidelines. Five databases were searched from inception to November 2022. All study designs which evaluated the effects of a combined exercise and psychological treatment on measures of nervous system sensitivity in adults with chronic musculoskeletal pain were included. Results A total of 13 studies met the selection criteria, 10 of which were included in a meta-analysis. Local pressure pain thresholds were the most frequently used measure (n = 12 studies). Meta-analysis revealed statistically significantly improvements in favour of the combined exercise and psychological intervention group, compared to a control group, for local pressure pain threshold measures [SMD = 0.44, 95% CI 0.08–0.81, I2 = 84%], pain intensity scores [SMD=-0.89, 95% CI -1.66- -0.13, I2 = 94%] and the Central Sensitisation Inventory [SMD=-0.69, 95% CI -1.37- -0.02, I2 = 87%]. There were no significant differences found between groups for remote pressure pain thresholds, temporal summation or conditioned pain modulation. Conclusions The results suggest that a combined exercise and psychological intervention may lead to greater improvements in local pressure pain threshold, pain intensity and Central Sensitisation Inventory scores when compared to a control intervention in adults with CP, however these findings must be interpreted with caution as a large degree of heterogeneity was present in these results (I2: 84–94%). Further large, longitudinal studies are required using standardised QST measurement procedures and patient reported outcome measures to explore changes in nervous system sensitisation. Trial registration This systematic review is registered with PROSPERO, ID Number CRD42022380464. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-024-07274-8.

The effectiveness of a combined exercise and psychological treatment programme on measures of nervous system sensitisation in adults with chronic musculoskeletal paina systematic review and meta-analysis.

Background
Chronic pain (CP) is postulated to be augmented by changes in modulation of sensory inputs by the peripheral and central nervous system [1][2][3][4].It has been suggested that evaluation of different pain mechanisms may help to individualise and tailor pain management strategies, targeting individuals specific pain mechanisms [5].
Quantitative sensory testing (QST) may be useful for assessing pathology in pain processing.QST assessments are psychophysical methods of testing the perception of touch, vibration, proprioception, pinprick/blunt pressure sensitivity or sensitivity to cold or heat stimuli using stimuli applied under standardised testing protocols, and the participants' self-reported sensory experience is quantified [6].QST can offer information about the potential underlying mechanisms contributing to pain in musculoskeletal disorders and can explore mechanisms responsible for the development or maintenance of local and widespread pain [7,8].QST can be subdivided into static and dynamic measures [9,10].Static QST, for example pressure pain thresholds (PPT), typically refers to the measurement of the threshold of pain that primarily reflects states of the peripheral nervous system [9].PPTs can be measured local to the primary pain area or at a remote site.PPTs measured at remote sites while also measuring static mechanical allodynia, when decreased are thought to reflect mechanisms of central sensitisation (CS) [11].Dynamic QST measure mechanisms of pain processing in the central nervous system [9].For example, conditioned pain modulation (CPM) is thought to be a measure of the brain's capacity for activating endogenous analgesia, via the descending inhibitory tracts in the central nervous system [12] and temporal summation (TS) measures the state of hyperactivity in the dorsal horn of the pain facilitation pathways.
Information regarding individuals possible underlying pain mechanisms can also be inferred using a number of patient reported outcome measures (e.g.Pain-Detect for neuropathic pain or Central Sensitisation Inventory (CSI) for CS).
The biopsychosocial treatment model which acknowledges and addresses the biological, psychological and social contributions to CP and disability is currently seen as the most efficacious approach to the management of CP [13].Psychological treatments designed to target potential pain mechanisms contributing to CP [14] have been utilised in pain treatment programmes [15].In addition, physical activity is considered important for the promotion of biopsychosocial health [16] and is an important health management and disease prevention strategy for adults with CP, recommended for its neuromodulatory benefits, and is suggested for a variety of CP conditions such as arthritis [17,18], fibromyalgia [19], and dysmenorrhoea [20].A number of QST studies investigating the effects of exercise in populations of pain free adults have demonstrated exercise has an effect on a number of measures of nervous system sensitivity; showing lower central excitability (measured using TS), increased pain thresholds (PPT) and enhanced CPM [21][22][23].More variable results have been found in QST measures following exercise in clinical populations.Oosterwijck and colleagues [24] examined 22 women with chronic whiplash associated disorder and 22 healthy controls who performed a self-paced exercise test on a cycle ergometer and found PPT decreased following submaximal exercise in the individuals with whiplash and increased in healthy subjects.Furthermore, Meeus and colleagues [25] examined the change in mean PPT in response to exercise in 26 patients with chronic fatigue syndrome with CP, 21 patients with chronic low back pain and 31 healthy subjects.After submaximal aerobic exercise, mean pain thresholds decreased in patients with chronic fatigue syndrome, and increased in the chronic low back pain and healthy subjects.
This review aims to examine the use of QST as measures of pain sensitisation in adults with chronic musculoskeletal pain who have taken part in a combined exercise and psychological intervention.The review will further investigate changes in QST measures in adults with chronic musculoskeletal pain following participation in interventions combining exercise and psychological interventions.A greater understanding of the role of QST in measuring change following participation in these programmes may help to quantify the benefits of this type of pain management programme.

Study design and registration
The systematic review and meta-analyses were conducted in accordance with the Cochrane Handbook for Systematic Reviews [26] and the results are reported according to the guidelines included in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [27].The systematic review was registered on the Prospero database (CRD42022380464 ).A protocol was not published for the current review.

Literature search and identification of studies
To identify the relevant literature, electronic searches were conducted in the following databases: Medline (OVID), Embase (OVID), SportsDiscus (EBSCO), Scopus (Elsevier) and Cinahl (EBSCO) from their inception to 14th Nov 2022.A comprehensive search strategy was designed with the assistance of an experienced medical librarian.The search strategy was adjusted to account for differences in indexing across databases and developed using medical subject headings (MeSH) where available.The search strategy (Supplementary Material; S1) included relevant keywords which encompass terms for the three domains of interest: chronic pain, nervous system sensitization and combined exercise and psychological treatment.The focus of the review was chronic musculoskeletal pain as defined by ICD 11 for 'Chronic Primary Musculoskeletal Pain' and 'Chronic Secondary Musculoskeletal Pain' .As such the review did not include TMJ disorders or chronic headache specifically.References lists of identified systematic studies were also screened.Articles obtained following the systematic search were exported and saved into an online review management platform (Rayyan) where duplicates were removed.Following removal of duplicate papers, studies titles and abstracts were screened independently for inclusion and exclusion criteria by two reviewers (OD and CD).Full texts of the remaining studies were reviewed independently by the two reviewers for their eligibility.Any disagreements arising between the reviewers were resolved by discussion and consensus and the assistance of a third reviewer was not required.

Eligibility criteria
Only articles published as full text in the English language in peer-reviewed journals were included.Studies including adults (≥18 years) with chronic musculoskeletal pain (defined as pain persisting for ≥12 weeks) were eligible.Studies were included which investigated changes in nervous system sensitisation following interventions that included a combined exercise and psychological intervention.Studies had to be of an experimental design with an intervention and comparison control group.Studies were excluded if participants in both the intervention and control groups had pain due to serious pathologies; including fractures, neoplasm, infection, or specific conditions; rheumatoid arthritis, pregnancy, postpartum pain, or fibromyalgia.Participants who had undergone a surgical intervention in the three months prior to study participation were also excluded.Studies were excluded if surgical, injection, electro-acupuncture or oral analgesic treatments were used in the intervention or control group.The main nervous system sensitisation outcomes of interest were QST measures as well as patient reported outcome measures (questionnaires which primarily focused on measurement of nervous system sensitization).
In this review, the term QST included both static and dynamic measures of nervous system sensitization (e.g.pressure pain threshold (PPT), temporal summation (TS), conditioned pain modulation (CPM) pain tolerance threshold, thermal threshold).Questionnaires investigating nervous system sensitization were also included i.e. the CSI.All study designs were included if they utilized these measures pre and post a combined exercise and psychological treatment intervention in adults with CP.Exercise was defined as 'a series of specific movements with the aim of training or developing the body by a routine practice or as physical training to promote good physical health' [28].An exercise intervention encompasses a heterogeneous set of treatments prescribed by a health professional that include conducting specific activities, postures and/or movements.The psychological intervention for the experimental group included treatment with a definable psychotherapeutic content (e.g., Cognitive Behavioural Therapy, Pain Neuroscience Education, Mindfulness-Based Stress Reduction and excluded other types of general education) delivered by a health professional.

Evaluation of methodological quality
The methodological quality of each of the randomised control trials (RCT) in the review were assessed using the PEDro scale [29] scored by two independent reviewers.The PEDro scale's score depends on the presence or absence of the 11 criteria related to randomization, blinding, and data treatment.Studies are rated from 0 to 3 (poor quality), 4-5 (fair quality), 6-8 (good quality) and 9-11 (excellent quality) [30,31].The modified Newcastle Ottawa Scale (NOS) [32] was used for other study designs e.g., case-control and cross-sectional studies.The NOS assigns up to a maximum of eight points for the least risk of bias in three domains: (1) selection of study groups (four points); (2) comparability of groups (one point); and (3) ascertainment of exposure and outcomes (three points).Studies are rated from 0 to 9, with those studies rating 0-2 (poor quality), 3-5 (fair quality), 6-9 (good/high quality) [33].Survey questions were developed based on the NOS questions covering all three domains so that authors could provide detailed information about their studies.Studies rated as 'fair quality' or above were included in the review.

Data extraction
Data from each study were extracted by two reviewers (O.D. and C.D.) independently using a customized data extraction tool in the form of an MS Excel spreadsheet.The following data were extracted: (1) study characteristics: number of participants, sex, age, duration of pain symptoms, area of pain, study inclusion criteria; (2) characteristics of the interventions for both exercise and psychological intervention: type of intervention (group vs. individual), dosage, and description of content of interventions; (3) outcome measures: type of QST measure; data per group/time-point, description of QST area, type of patient reported outcome measure; data per group/ time-point, and (4) summary of findings.Studies with similar outcome measures allowed a meta-analysis to be performed.QST data were extracted in the unit presented in each paper (kPA, kg/cm 2 ).All scores were then converted to kg/cm 2 for analysis using a converter application, applying the following formula: 1 kg-force/Square Centimeter (kg/cm 2 ) = 98.0665Kilopascal (kPa).Completed data collection forms including data used in the meta-analysis are available upon request from the lead researcher (O.D.).

Data analysis
The QST measures were sub-classified as 'static' and 'dynamic' , with static modalities including PPTs, and dynamic modalities including CPM and TS.PPT measures were divided into local and remote measures, with local measures defined as those acquired from sites identified as the primary area of pain in the studied population and remote measures were defined as those acquired from sites which were not local to the primary area of pain [34].In the event that studies performed QST at multiple local and remote sites, data were pooled according to local and remote site for meta-analysis, as recommended [35].
Pain intensity was extracted where available from the included studies.If more than one measure of pain intensity was used in a study, then the one considered to be the primary outcome or the one considered most similar to outcome measures used in other included studies was chosen for inclusion in the meta-analysis (e.g., Numerical Rating Scale and Visual Analog Scale were considered similar outcome measures as they both require the rating on an 11-point severity scale).
Group means, standard deviations (SD), and sample sizes were extracted and analysed for each follow-up timepoint.If outcomes were incompletely reported or unclear, authors were contacted via e-mail.Where data were presented in graph format only the authors were contacted via e-mail with a request to provide the raw data.In cases where authors were uncontactable, a webbased tool was used to extract the data from the graphs (https://automeris.io/WebPlotDigitizer/).A number of studies reported median and interquartile range scores.Under the assumption of normality of the underlying distribution, the median was substituted for the mean and the width of the interquartile range was used as an approximation of 1.35 times the SD [36].If the SD was not given, it was calculated from the SE or confidence intervals when these were available.If no estimate was possible, the data were not used in the meta-analysis [36].Where data were presented as pre-intervention mean (SD) and mean (SD) change with intervention only, the pre intervention SD was utilised for the post-intervention mean based on Cochrane guidelines [36].
Meta-analyses of study outcomes were performed where possible using RevMan (The Nordic Cochrane Centre, Copenhagen, Denmark) using a random effects model.The standard mean difference (SMD) was calculated using the scores at post-intervention for each group.Statistical heterogeneity was assessed by calculating I 2 , which represents the percentage of total variation across studies that is due to heterogeneity rather than chance [37,38].An I 2 value of 25% represents a small, 50% a moderate, and 75% a large degree of heterogeneity [37].Pooled findings for each outcome were reported as SMD and 95% CI.The SMD is more generalisable than the mean difference (MD), and has similar statistical power as the MD [39].Effect size was interpreted using Cohen's criteria for pooled estimates [40].Cohen described 0.2 as small, 0.5 as moderate, and 0.8 as large effect sizes.Statistical significance was set at a level of 0.05.

Study selection
The trial identification process is summarized in Fig. 1.The electronic database search yielded 5308 records.After removal of duplicates, 3725 were screened independently by two reviewers based on title and abstracts.A further 3707 records were excluded, leaving 18 to be screened by full text.Of these, five studies did not fit the eligibility criteria for this review.The reasons for exclusion were; the subjects included in the study were not ≥18 years old, the article reviewed was an abstract from a previously included paper, the study had no appropriate psychological intervention and the studies did not have an appropriate control group comparison.A final total of 13 records met the selection criteria [41][42][43][44][45][46][47][48][49][50][51][52][53].A number of study designs were identified in the included studies; randomised controlled trials (n = 10) [41][42][43][44][45][46][47][48][49][50], case control study (n = 1) [53], non-randomised controlled trial (n = 1) [52], and prospective cohort study (n = 1) [51].
Four trials studied the effect of a combined exercise and psychological intervention on CPM [43,45,46,51].The study populations in which CPM was performed were chronic low back pain [46], chronic neck pain [51], knee osteoarthritis [45] and chronic Achilles tendinopathy [43].Two studies utilised cuff inflation on the contralateral limb as the conditioning stimulus [45,51] and two studies used cold water bath immersion of the contralateral limb as the conditioning stimulus [43,46].
Three trials studied the effect of a combined exercise and psychological intervention on TS measures [43][44][45] in the following study populations; knee osteoarthritis [45], chronic neck pain [51] and chronic Achilles tendinopathy [43].Georgopoulos et al. [51] reported measuring TS using of a single punctate stimulus applied to the dominant forearm using a retractable blunt needle, followed by 10 repetitive stimuli at a rate of 1/s to the forearm.Holm et al. [45] measured TS by utilising an inflating cuff on the index leg.The participant was then subjected to ten short-lasting pressure stimuli (1-s each), using the previously recorded pain tolerance threshold cuff pressure, with 1-s breaks between each stimuli.The

Table 1 (continued)
TS technique was not described in detail in the study by Chimenti et al. [43] The CSI scores were recorded in three of the included trials [41,44,46] in participants with chronic low back pain [41,44,46].
A number of additional QST measures were recorded in the following studies; Polaski et al. [48] measured cutaneous mechanical sensitivity, cutaneous mechanical pain, constant heat pain intensity, constant heat pain unpleasantness, constant pressure pain intensity, constant pressure pain unpleasantness) and Holm et al. [45] measured pain tolerance threshold.
Studies compared the experimental group to; a waiting list control [42], exercise only [41,47], pain education only [49], 'usual physiotherapy' [44], a leaflet with general advice [50], listening to an audio-book followed by 30 min resting [48], combined pathoanatomical education and exercise [43], and traditional back school with a biomedical approach combined with a pain contingent exercise programme [46].One RCT [52] was not included in the meta-analysis as both the experimental group and the comparator group included a combined exercise and psychological intervention.

Methodological quality
The 10 RCTs were assessed using the PEDRO scale (Table 2).The scores ranged from four to 10 out of a total possible score of 11.The most common biases present was failure to blind the therapist in all 10 included studies and failure to blind the participants in seven out of ten studies.The methodological quality of the remaining three studies was assessed using the Newcastle-Ottawa scale (Tables 3 and 4).This scale has three main criteria; the selection of the study groups, the comparability of the study groups, and the ascertainment of the outcome [32].The total scores of the included studies ranged from five to seven out of a possible maximum of nine.

PPT local
In terms of local PPT scores, five individual studies [41,42,44,46,49] showed significant increases in local PPT scores in a combined exercise and psychological intervention group compared to a control group.Four of these studies investigated low back pain [41,42] or spinal pain [46] and one investigated cervical pain [49].A further four studies, investigating knee [50], low back [48], Achilles tendon [43] and neck [47] pain, showed no between group differences post intervention.
Meta-analysis of all nine trials (n = 839 participants) post-intervention showed significantly higher PPT scores in favour of the exercise and psychological intervention group, with small effect sizes [SMD = 0.44; 95% CI 0.08-0.81;P = 0.02].The results appear to have high levels of heterogeneity I 2 = 84%.Visual analysis of the funnel plot demonstrated relative funnel plot symmetry suggesting that there was no significant publication bias (Fig. 2).

Subgroup analysis (PPT local) according to area of pain
A sub-group analysis of local PPT scores was carried where two or more studies were available, grouping studies according to the primary area of CP of the study participants [41,42,[46][47][48][49].The areas of CP included were all spinal pain; lumbar spine (n = 4 studies) and cervical spine (n = 2 studies).For participants with lumbar spine pain, where PPT scores were measured locally in the lumbar spine, the analysis revealed a significantly higher local PPT score in favour of the exercise and psychological intervention group with a large effect size [SMD = 0.80; 95% CI 0.27-1.33;P = 0.006] with the results appearing to have high levels of heterogeneity; I 2 = 76% (Fig. 3).The participants in the sub-group analysis investigating the lumbar spine presented with non-specific chronic low back pain for > 3 months [42,46] or > 6 months [41,48].There were no significant between group differences found in local PPT scores when the primary area of pain was the cervical spine (n = 2), with a low effect size [SMD=-0.03;95% CI 0.28 − 0.22; P = 0.79] and the results showing low levels of heterogeneity; I 2 = 0%.

PPT remote
In terms of remote PPT scores, one study [49] showed a significant increase in remote PPT scores in the exercise plus psychological intervention group compared to control group post intervention.This study [49] investigated remote PPTs scores in individuals with cervical pain.A further five studies [41,43,46,48,50] showed no between group differences post intervention.In these five studies, remote PPT scores were investigated in individuals with a number of different pain areas; knee [50], low back [41,46,48] and Achilles tendon [43].

Conditioned pain modulation
Two studies [43,46] investigated changes in CPM following a psychological and exercise intervention, in individuals with Achilles tendinopathy [43] and low back pain [46].Individually neither study found significant between group differences between experimental and control groups post intervention.Meta-analysis of these two trials (n = 185 participants) post-intervention revealed significantly higher CPM scores in favour of the control group with a moderate effect size [SMD = 0.67; 95% CI -0.77-2.11;P = 0.36].The results have high levels of heterogeneity I 2 = 95% (Fig. 5).

Temporal summation
Two studies [43,45] investigated changes in TS following a psychological and exercise intervention in individuals with Achilles tendinopathy [43] and knee osteoarthritis [45].Meta-analysis of the two trials [39,41] (n = 142   Legend Each item in the table gets a maximum of 1 point, if it meets the evaluation criteria, which is recorded as "*"

Non
'Comparability on the basis of design or analysis' has a maximum of 2 points available "-" denotes that the study did not meet the evaluation criteria There are 8 evaluation items in total, with a full score of 9 points A higher score means the least risk of bias NOS: Newcastle Ottawa Quality Assessment Scale
In terms of pain scores, four of these studies showed significant differences between the experimental group and comparator group post intervention [41,44,[48][49][50].Meta-analysis of the seven studies (n = 571 participants) demonstrated statistically significant differences in pain intensity were found in favour of the combined exercise and psychological intervention group [SMD=-0.89;95% CI -1.66--0.13;P = 0.02] with high heterogeneity (I 2 = 94%) noted in the included studies (Fig. 7).

Central sensitisation inventory
Two RCTs investigated changes in CSI scores following a psychological and exercise intervention in individuals with low back pain [46] and spinal pain [44].Meta-analysis of the two studies (n = 277 participants) showed statistically significant differences in CSI score in favour of the combined exercise and psychological intervention group (n = 2 studies), [SMD=-0.69;95% CI -1.37--0.02;P = 0.006] with high heterogeneity I 2 = 87% noted in the included studies (Fig. 8).Both studies experimental interventions included pain neuroscience education (PNE), with Malfliet et al. [46] combining PNE with one-on-one exercises sessions over 12 weeks and Galan-Martin et al. [44] combining PNE with group exercise over six weeks.

Discussion
To our knowledge this is the first systematic review and meta-analysis that has specifically investigated the effects of combined exercise and psychological interventions on measures of nervous system sensitisation in adults with chronic musculoskeletal pain.The current review found combined exercise and psychological interventions compared to a control group demonstrated improvements post-intervention in local PPT scores, patient reported pain scores and CSI scores in adults with chronic musculoskeletal pain and no significant differences in the dynamic QST measures (CPM and TS) or remote PPT scores, It is notable that there was evidence of large heterogeneity in the results for local PPT scores, patient reported pain scores and CSI scores which necessitates caution in interpreting these results.
In nine [41,43,45,46,[48][49][50][51][52] of those 12 studies, remote PPTs were measured in addition to local PPTs.In the literature, PPT appears to be the most frequently assessed  QST parameter [54].A recent meta-analysis [55] compared PPTs in a pooled sample of individuals with CP (n = 1280) and healthy controls (n = 1463) and found those with CP had significantly lower PPTs compared with healthy controls (pooled PPT mean difference was − 1.17, 95%CI = − 1.45 to − 0.90).Meta-analysis of the trials in the current review suggests that following a combined exercise and psychological intervention, local PPTs were significantly increased in adults with mixed chronic musculoskeletal conditions [SMD = 0.44; 95% CI 0.08-0.81;P = 0.02] and in a low back pain subgroup [SMD = 0.80; 95% CI 0.27-1.33;P = 0.006], when compared to a control intervention.No significant between group differences were found in the remote PPT measures [SMD = 0.04; 95% CI -0.17-0.24;P = 0.73].It is important to observe that high heterogeneity (I 2 ) was present in the local PPT score results (I 2 = 84%).This heterogeneity was anticipated following review of a previous meta-analysis investigating PPT scores [34].In addition, on investigation of the methodology described in the included studies measuring PPT, and the variable descriptions of the areas measured in both local and remote PPTs, it is notable that variation exists in the testing procedures which may impact the consistency of the results.The random-effects model was utilised in analysis of the data, due to the identified heterogeneity of the studies.As PPTs preferentially activate deep afferent fibres, they are considered an appropriate measure of the local pain areas response to blunt mechanical stimuli, thought to reflect local sensitisation of Aδ and C fibres [56].Furthermore, when considering remote PPTs, static mechanical allodynia of remote areas assessed by remote PPTs is thought to reflect mechanisms of CS found in nociplastic pain [11].As CS may be one of the key mechanisms associated with nociplastic pain, the effects of the combined interventions appeared to preferentially affect peripheral pain mechanisms, as measured by hyperalgesia (PPTs).It is notable that a greater number of trials (n = 9 studies), with a larger sample size (n = 839 participants) were used in the meta-analysis of local PPTs compared to remote PPTs which may contribute to this outcome.
Previous reviews investigating exercise interventions only in individuals with CP have reported some differing results to the current review.A review by Hall et al. [57] investigated the effects of both short-and longerterm exercise interventions on PPTs in individuals with knee osteoarthritis (n = 16 studies).Following a single bout of exercise, only local PPTs increased significantly [SMD 0.26, 95% CI 0.02-0.51,P = 0.04, I 2 = 46%].Following a longer exercise programme (5-12 weeks) no statistically significant changes were found in local [SMD 0.23, 95% CI -0.01-0.47,P = 0.06, I 2 = 64%] or remote PPTs [57].In the current review, only local PPTs were found to improve following participation in a longer-term (4-18 weeks) exercise intervention combined with a psychological intervention.While no reviews to date have examined the effects of combined exercise and psychological intervention on QST, a recent systematic review [58] investigated the potential benefits of combining exercise with Cognitive Behavioural Therapy (CBT) for adults with chronic diseases.This review [58] highlighted that CBT combined with exercise significantly decreased depression and anxiety with small effect sizes and fatigue with a large effect size, when compared to usual care or waitlist, however no QST measures were reported in the studies included in the review.Considering changes in depression and anxiety may reflect changes in central processing mechanisms, QST measures could be considered as a further investigation of these central nervous system changes.

CPM and TS
In the current review, CPM was investigated in four of the included studies [43,45,46,51] and TS was investigated in three of the included studies [43,45,51].The meta-analysis of dynamic QST measures in the current review, showed no significant between group differences for TS measures [SMD=-0.05;95% CI 0.48 − 0.39; P = 0.84], and for CPM [SMD = 0.67; 95% CI -0.77-2.11;P = 0.36].Variable outcomes have been shown when CPM has been previously investigated, with reviews reporting mixed results on the CPM effect in pain and control groups [59,60].The clinical value of CPM is thought to be in being a measure of the brain's capacity for activating endogenous analgesia, via the descending tracts [12], which is important to consider in relation to the effects of both exercise and psychological interventions in CP.A number of the psychological interventions of the studies included in the current review included elements of pain neuroscience education [41,43,44,46,47].Previous research investigating pain education alone shows that educating individuals with CP about pain mechanisms and challenging maladaptive pain cognitions/behaviours can also alter central pain processing [61,62].In individuals with CP, an increased understanding of pain using the "explain pain" [63] concept has been shown to correspond to an improvement in CPM [61].
Due to the small numbers of studies (n = 2) included in the meta-analysis investigating CPM in the current review, it is difficult to draw conclusions regarding the findings of the effects of combined exercise and psychological interventions on this QST measure.A number of previous studies investigating TS and CPM focused on exploring the measures as predictors of outcome [64][65][66].The studies included in the current meta-analysis utilised these dynamic QST measures as markers of treatment outcome, following participation in combined exercise and psychological interventions.Utilising dynamic QST as markers of treatment outcome has been a more common strategy in studies investigating the central modulatory effects of drug interventions [67,68], however future research could investigate changes in the central nervous system following participation in combined exercise and psychological interventions.

Pain and CSI
In the current review, meta-analysis of post intervention pain severity scores improved significantly [SMD=-0.89;CI -1.66--0.13;P = 0.02] in the combined exercise and psychology group compared to the control group for different groups of individuals with CP, i.e. low back pain [41,46,48], knee osteoarthritis [50], neck pain [47], spinal pain [44] and Achilles tendinopathy [43].The average change in mean pain score of the combined studies was 2.7 (SD2.9) in the combined exercise and psychological intervention group and 1.4 (SD2.4) in the control group.This finding is interesting as research highlights that the primary aims of pain management programmes are to reduce emotional distress and improve physical function rather than focusing on eliminating pain [69,70].Moreover, for CSI scores, the current meta-analysis showed significant differences post intervention, in favour of the combined exercise and psychological intervention group [SMD=-0.69;CI -1.37--0.02;P = 0.006].Similar to the findings for local PPT scores, high levels of heterogeneity were found in the CSI score results, and in addition, only two of the studies in this review were included in the meta-analysis.Considering no changes were found in favour of a combined exercise and psychological intervention in the meta-analysis investigating QST measures proposed to investigate the mechanisms involved in central sensitisation (TS, CPM, remote PPT), conflicting results are found in the meta-analysis of the post-intervention CSI scores.This finding may not be unique, as a recent systematic review (n = 69 studies) [71] investigated if questionnaires exploring central sensitisation reflected measures of nociceptive sensitisation.In this review the authors investigated the degrees to which the CSI and the Pain Sensitivity Questionnaire assessed nociceptive sensitisation or emotional sensitisation.When the CSI was examined for its correlation with QST measures, the results found no or weak correlations with a number of QST measures; PPTs, TS, and CPM (r < 0.3).The CSI was found however to be strongly correlated with psychological measures (anxiety, depression, pain catastrophising, stress, sleep, and kinesiophobia) with the review concluding that the CSI seemed to identify people with a psychological vulnerability that is associated with pain, rather than central sensitisation itself [71].With the current review examining interventions that were composed in part of psychological components, it may be possible that the changes identified in CSI scores in the meta-analysis, reflected changes in some psychological constructs in the intervention participants.Furthermore, the effects of exercise on psychological outcomes has been outlined in previous studies.A recent review of Cochrane systematic reviews (n = 21 systematic reviews) evaluated exercise for individuals with CP [72] highlighting five reviews that assessed psychological function [73][74][75][76][77] and found exercise interventions had significant effects on measures of mental health [75], depression scores [73] and anxiety [77].
In the current meta-analysis, two studies investigated CSI scores.A study investigating the effect of pain neuroscience education combined with cognition-targeted motor control training on chronic spinal pain [46], reported mean baseline scores of 40.02(1.47)were found in the combined exercise and psychology group and 39.88 (1.47) in the control group.A second study [44] investigating pain neuroscience education and physical therapeutic exercise for participants with chronic spinal pain, also was found to have high mean CSI baseline scores; 43.4(12.5) in the combined exercise and psychology group and 38.6 (11.7) in the control group.The baseline CSI scores in these two studies suggest that the cohorts included in these studies consisted of centrally sensitised individuals, with cut off scores of > 40 on the CSI indicating the presence of CS [78].

Strengths and limitations
It is a strength of the current review that the majority of included studies examined the QST measure, PPT, allowing a large sample for meta-analysis.In terms of limitations, a smaller number of studies examined CPM, TS and the CSI.The eligibility criteria for patients in this study outlined that studies that investigated individuals with chronic musculoskeletal pain would be included with the classification of chronic musculoskeletal pain guided by the ICD-11 classification for chronic pain.A wide range of different types of musculoskeletal pain conditions were reported in the studies, which may have condition specific implications for the effects of interventions on measures of nervous system sensitisation.However, associations in the heterogeneous sample found in the current review may also point to underlying factors related to pain mechanisms common to multiple chronic musculoskeletal pain conditions.Furthermore, a limitation of this review was the variability found in the comparison groups of the included studies included in the meta-analysis.A large number of studies included in this review used active comparison groups.This is important to consider when combining the effect of the interventions compared to the comparators in this review and is considered a limitation.In addition, it is notable that variation in testing procedures were described in testing PPT, CPM and TS which may have contributed to the heterogeneity found in resulting scores.

Conclusions
When considering the future of personalised pain treatment, research to date has identified QST measures to be useful to phenotype CP patient subgroups based on different underlying pain mechanisms [79][80][81], and to predict response to treatment based on mechanistic phenotype [82,83].Further research is required to quantify changes in nervous system sensitisation, using QST, following interventions utilising combined exercise and psychological approaches.In order to effectively investigate and pool the data from future research utilising QST measures, it would be helpful if both QST testing procedures and sites of testing were standardised.The ability to quantify change using QST may help measure the effects of such programmes on pain sensitisation measures and facilitate identification of individuals who may benefit from participation in these programmes.Including further longitudinal prospective studies with larger cohorts of individuals with CP in studies to investigate longer term effects of combined exercise and psychological interventions on static and dynamic QST measures could contribute to understanding the effects of this type of intervention on nervous system sensitisation.

Fig. 2
Fig. 2 Effect of combined exercise and psychological intervention on post intervention PPT local scores Legend: Forest plot for post-intervention analysis comparing combined exercise and psychological intervention with control group for local PPT scores (left) Funnel plot demonstrating publication bias (right)

Fig. 5 Fig. 4 Fig. 3
Fig. 5 Effect of combined exercise and psychological intervention on post intervention CPM scores Legend: Forest plot for post-intervention analysis comparing combined exercise and psychological intervention with control group for CPM scores

Fig. 8 Fig. 7
Fig. 8 Effect of combined exercise and psychological intervention on post intervention CSI scores Legend: Forest plot for post-intervention analysis comparing combined exercise and psychological intervention with control group for CSI scores

Fig. 6
Fig. 6 Effect of combined exercise and psychological intervention on post intervention TS scores Legend: Forest plot for post-intervention analysis comparing combined exercise and psychological intervention with control group for TS scores

Table 3
Quality of included cohort studies (Newcastle Ottawa Scale NOS)

Table 4
Quality of included case-control studies (Newcastle Ottawa Scale NOS)