Pain mechanisms in complex regional pain syndrome: a systematic review and meta-analysis of quantitative sensory testing outcomes

Background Complex regional pain syndrome (CRPS) is a chronic condition following inciting events such as fractures or surgeries with sensorimotor and autonomic manifestations and poor prognosis. This review aimed to provide conclusive evidence about the sensory phenotype of CRPS based on quantitative sensory testing (QST) to understand the underlying pain mechanisms and guide treatment strategies. Databases Eight databases were searched based on a previously published protocol. Forty studies comparing QST outcomes (thermal, mechanical, vibration, and electric detection thresholds, thermal, mechanical, pressure, and electric pain thresholds, wind-up ratio, mechanical pain sensitivity, allodynia, flare area, area after pinprick hyperalgesia, pleasantness after C-tactile stimulation, and pain ratings) in chronic CRPS (adults and children) versus healthy controls were included. Results From 37 studies (14 of low quality, 22 of fair quality, and 1 of good quality), adults with CRPS showed: (i) significant loss of thermal, mechanical, and vibration sensations, significant gain of thermal and mechanical pain thresholds, significant elevation of pain ratings, and no difference in wind-up ratio; (ii) significant reduction of pleasantness levels and increased area of pinprick hyperalgesia, in the affected limb. From three fair-quality studies, adolescents and children with CRPS showed loss of cold detection with cold hyperalgesia in the affected limb. There was moderate to substantial overall heterogeneity. Conclusion Diffuse thermal and mechanical hypoesthesia with primary and secondary hyperalgesia, enhanced pain facilitation evidenced by increased area of pinprick hyperalgesia, and elevated pain ratings are dominant in adults with CRPS. Adolescents and children with CRPS showed less severe sensory abnormalities. Supplementary Information The online version contains supplementary material available at 10.1186/s13018-022-03461-2.


Introduction
Complex regional pain syndrome (CRPS) is a chronic debilitating pain condition of the limbs following trauma or surgery with an incidence rate of 26.2 per 100,000 person-years [1,2]. CRPS occurs commonly in elderly people, in females more than males, and the upper extremity more than in the lower extremity [2]. Two main types of Page 2 of 42 Sobeeh et al. Journal of Orthopaedic Surgery and Research (2023) 18:2 CRPS were identified: CRPS types 1 and 2 [3]. CRPS type 1 or reflex sympathetic dystrophy is characterized by sensory, motor, and autonomic abnormalities without electrophysiological evidence of nerve lesion. On contrary, CRPS type 2 is characterized by identifiable nerve lesions that can be detected through electrophysiological findings and it is considered typical neuropathic pain [1]. CRPS is, usually, associated with poor outcomes, long-term complaints, and comorbidities (e.g., depression and photophobia) [4][5][6]; however, the pain mechanisms involved in CRPS are not fully understood. [7]. Neurogenic inflammation, peripheral sensitization (PS), central sensitization (CS), small nerve fiber pathology, autonomic dysregulation, and psychological states represent the shared model of the underlying pathophysiology of CRPS [8][9][10][11][12]. Neurogenic inflammation is caused by neuropeptides released from the primary afferents resulting in axon reflex vasodilatation and protein extravasation [8]. PS is defined as enhanced responsiveness and decreased threshold of nociceptive neurons within the afflicted receptive field, and it was demonstrated in CRPS by the presence of primary hyperalgesia in the affected regions [13]. Signs of PS in CRPS can include gain of thermal and mechanical pain thresholds at the affected sites [14][15][16].
In CRPS, secondary hyperalgesia in distant locations away from the affected area was found to be indicative of CS, which is an increased response of nociceptive neurons in the central nervous system to normal or subthreshold afferent input [17]. Signs of CS in CRPS can include widespread gain of thermal and mechanical pain thresholds, enhanced pain facilitation as evidenced by elevated pain ratings, and/or impaired pain inhibition [14,18].
It has been demonstrated that CRPS patients have a bilateral reduction in intraepidermal small nerve fiber density, and these fibers are responsible for nociception and perceiving temperature [19]. Conceivably, reduction of the small nerve fiber density would be responsible for altered perception of these sensations. Autonomic dysregulation could result in enhanced pain perception as evidenced by increased expression of α1-adrenergic receptors [11]. Also, post-traumatic stress disorder and pain catastrophizing seem to increase pain response in CRPS [12].
A valid and standardized tool to assess pain mechanisms involved in different chronic pain conditions (inflammatory, neuropathic, and mixed chronic pain conditions) is quantitative sensory testing (QST) [20]. As far as we are aware, this is the first review to consolidate and evaluate the QST data of affected areas and remote areas away from the affected site in adults and children with CRPS type 1 compared to healthy controls. Additionally, we analyzed a broad range of variables including flare area after induction of noxious stimulus, pain area after pinprick induced hyperalgesia, pain ratings after noxious thermal stimulus, electric pain threshold, current perception thresholds, and pleasantness levels after C-tactile perception in an attempt to reach more conclusive results on the sensory profile and pain mechanisms of CRPS type 1.

Protocol registration
The review protocol was registered as an a priori study at the International Prospective Register of Systematic Reviews (PROSPERO) (registration number: CRD42021237157) and we used PRISMA guidelines (www. prisma-state ment. org) to report this review.

Eligibility criteria
Studies were included if they (1) compared adults (age ≥ 18 years) or adolescents and children (age < 18 years) with CRPS type 1 (symptoms duration ≥ 8 weeks) to healthy controls, (2) diagnosed CRPS type 1 (unilateral or bilateral) through clinical assessment and the International Association for the Study of Pain (IASP) or the Budapest criteria, (3) investigated any modality of QST, flare areas after noxious stimulus, conditioned pain modulation, pain rating after noxious stimulus, and pain area after induced pinprick hyperalgesia, and (4) were written in English. We excluded studies that combined results of sensory testing of CRPS with other neuropathic conditions and studies that used the unaffected side as the control site. Additionally, we focused on the QST outcomes for CRPS type 1 only, which is a deviation from the previously published protocol. The protocol stated that both the QST outcomes for CRPS type 1 and type 2 would be included. However, a metaanalysis requires at least two studies, and we found one study only on CRPS type 2 that met the eligibility criteria [15]. Also, there is an identifiable nerve lesion in CRPS type 2 but not in CRPS type 1, which precludes including studies on CRPS type 2 and 1 in the same meta-analysis as that would prevent us from reaching a comprehensive understanding of the sensory profile and type of pain present in such a complex syndrome.

Risk of bias assessment
Two researchers (M.G.S. and K.A.H) independently used the Newcastle-Ottawa quality assessment scale (NOS) for case-control and cohort studies to perform the risk of bias assessment. Three aspects were evaluated through the NOS using a star rating system: the selection of the study groups, the comparability of the groups, and the ascertainment of the exposure or outcome of interest. Each aspect contains several items that can be scored

Levels of pleasantness
The pleasantness level after application of stroking of velocity commonly ranged from 1 to 10 cm/s with C-tactile fibers are responsible for affective touch processing with one star, except for comparability, which can score up to two stars (Table 3) [25]. The highest possible NOS score is 9. According to Agency for Health Research and Quality (AHRQ) standards, studies were deemed to be of good quality if they received three or four stars in the selection domain, one or two stars in the comparability domain, and two or three stars in the outcome/exposure domain. Studies were deemed to be of fair quality if they received two stars in the selection domain, one or two stars in the comparability domain, and two or three stars in the outcome/exposure domain. Studies were deemed to be of low quality if they received a score of zero or one in the selection domain, zero star in the comparability domain, or zero or one star in the outcome/exposure domain. Researchers were blind to the study authors when performing the risk of bias assessment. Inter-rater agreement between the two researchers was calculated using non-weighted Kappa statistics and respective 95% confidence interval (CI). A third researcher (A.G.S) was contacted if consensus was not reached.

Data extraction
Data extracted from the included articles were: authors, year of publication, number of participants, diagnostic criteria for CRPS, type, and raw data of measurements (CPT, HPT, PPT, CDT, WDT, TSL, VDT, MDT, MPS, MPT, DMA, WUR, pain area after pinprick hyperalgesia, pain ratings, and CPM), body site where measurements were taken, pain intensity, and details of QST parameters and measurement procedures (including method, number of trials, and devices used) ( Table 4). Data extraction was performed by one researcher (M.G.S.) and revised by another researcher (A.G.S.) to confirm the data were correctly gathered. Corresponding authors of the included studies were contacted if there were missing data.

Data management and meta-analysis
The raw data from individual articles were extracted (Table 4), grouped based on the applied measurements  (CPT, HPT, PPT, CDT, WDT, TSL, VDT, MDT, MPS,  MPT, DMA, WUR, pain area after pinprick hyperalgesia, pain ratings, and CPM), and further clustered according to age into: (1) patients with chronic CRPS type 1 ≥ 18 years and (2) patients with CRPS type 1 < 18 years. For each age group, the outcomes were clustered according to body location into (1) affected area and (2) remote areas away from the affected site. If a cluster of specific measurements contained at least two studies reporting means and standard deviations for patients with CRPS and healthy controls, a meta-analysis was performed [26]. Meta-analysis was conducted using the Review Manager computer program (RevMan 5.4) by Cochrane collaboration. The standardized mean difference (SMD) and the corresponding 95% CI were calculated based on inverse variance weighting [27]. SMD effect size values between 0.2 and 0.5 are regarded as small, 0.5 to 0.8 as medium, and values higher than 0.8 as large [28]. Egger's regression test was conducted when there were 10 or more effect sizes to assess publication bias [29,30] and represented graphically by Begg's funnel plot [31]. If the p value of Egger's regression test was less than 0.10, it is considered significant. Whenever publication bias was found, we applied the trim and fill method of Duvall and Tweedie to enhance the symmetry through adding the studies supposed to be missed [32]. To assess the heterogeneity, I2 was measured and classified into: 0%-40%: no heterogeneity, 30%-60%: moderate, 50%-90%:

Database Search keywords Number of records
PubMed (( "Central Sensitization" OR "Central Nervous System Sensitization" OR "sensitization" OR "CS" OR "pain sensitization" OR "hyperalges*" OR "hypesthes*" OR "hypoesthes*" OR "mechanical hyperalges*" OR "thermal hyperalges*" OR "mechanical allodyn*" OR "thermal allodyn*" OR "thermal threshold" OR "thermal detection threshold" OR "allodyn*" OR "temporal summation" OR "wind up" OR "wind-up ratio" OR "WUR" OR "pain threshold" OR "sensory threshold" OR "QST" OR "quantitative thermal testing" OR "quantitative sensory testing*" OR "sensation" OR "conditioned pain modulation" OR "CPM" OR "endogenous pain" OR "pressure pain threshold" OR "vibration detection threshold" OR "heat detection threshold" OR "WDT" OR "hot sensitiv*" OR "cold sensitiv*" OR "heat pain threshold" OR "HPT" OR "cold detection threshold" OR "CDT" OR "cold pain threshold" OR "CPT" OR "warm detection threshold" OR "mechanical pain threshold" OR "mechanical detection threshold" OR "mechanical pain sensitiv*" OR "PPT" OR "Pressure-pain threshold" OR "pain threshold" OR "sensory profile" OR "pain perception" OR "current perception threshold" OR "electric pain threshold" OR "pain tolerance threshold" OR "flare area" OR "laser doppler imaging")) AND (( "complex regional pain syndrome*" OR "complex regional pain syndrome type I" OR "complex regional pain syndrome type II" OR "causalgia" OR "reflex sympathetic dystroph*" OR "Type II Complex Regional Pain Syndrome" OR "CRPS Type II" OR "Sudeck's Atrophy*" OR "CRPS Type I*" OR "Shoulder Hand Syndrome*" OR "Algodystroph*" OR "CRPS" OR "CRPS-1" OR "CRPS-2")) Filters applied: Full text, English, Humans substantial, and 75%-100%: considerable [33]. We determined the borderline I2 values based on the magnitude and direction of effects and the strength of evidence for heterogeneity. So, if there is 50% heterogeneity with a narrower confidence interval and a large effect size, the amount of heterogeneity becomes moderate, whereas heterogeneity is substantial with a wide confidence interval and a small effect size. [33].  In affected and non-affected limbs of CRPS, it was 63 (27/100) and 54 (18) In the control group, it was 37 (27/100) and 36 (22)           PPT of the contralateral arm of CRPS was 3.6 (2.7-5.4), while in the control group, it was 6.2 (4.9-7.5) PPT of the ipsilateral leg of CRPS was 4.6 (3.4-7.1), while in the control group, it was 6.9 (5.7-8.6) PPT of the contralateral leg of CRPS was 4.6 (3.6-6), while in the control group, it was 6.6 (5. All data reported as median and IQR while transformed into mean and SD using Wan's method           was assessed at tongue In CRPS, TSL in the foot of affected side was 18(10.7) while in the control group was 9.5 (7.5) In CRPS, TSL in the foot contralateral to the affected side was 13 (9.2) while in the control group was 7 (3) In CRPS, TSL in the hand of affected side was 12.2 (10.1) while in the control group, it was 3.9 (2) In CRPS, TSL in the hand contralateral to the affected side was 8.2 (8) while in the control group, it was 3.7 (2.6) In CRPS, TSL in the maxilla of affected side was 6.5 (7.2) while in the control group, it was 1.8 (1.4) In CRPS, TSL in the maxilla contralateral to the affected side was 4 (5.5) while in the control group, it was 1.7 (1.3) In CRPS, TSL in the ophthalmic area of affected side was 11.8 (9.5) while in the control group, it was 3.2 (2.7) In CRPS, TSL in the ophthalmic area contralateral to the affected side was 5.5 (6.5) while in the control group, it was 3.8 (5.6) In CRPS, pain rating to suprathreshold stimulus in the tongue of the affected side was 163.5 (87)       In the control group, pleasantness levels were 3.7 (2) In this study, the data were represented in figure two as mean (95% CI), while we used Cochrane guideline to transform data into mean (SD) CRPS complex regional pain syndrome, CDT cold detection threshold, CPT cold pain threshold, DMA dynamic mechanical allodynia, HPT heat pain threshold, MDT mechanical detection threshold, MPS mechanical pain sensitivity, MPT mechanical pain threshold, PHS paradoxical heat sensation, PPT pressure pain threshold, QST quantitative sensory testing, TSL thermal sensory limen, VDT vibration detection threshold, PDT pressure detection threshold, LTT light touch threshold, WDT warm detection threshold, WUR wind-up ratio, EDT electric detection threshold, EPT electric pain threshold, SD standard deviation, CI confidence interval The overall effect was significant if the p value was less than 0.05. Studies not included in the meta-analysis were reported separately. Sensitivity analyses were performed to account for the studies with high risk of bias based on the NOS assessment.
GRADE assessment was conducted to check for the certainty of obtained results [34,35]. One author checked the quality of the evidence considering five domains: (i) risk of bias, (ii) inconsistency of results, (iii) indirectness, (iv) imprecision, and (v) publication bias. At the baseline rating, the studies were considered "low-quality" evidence, due to the observational study design, and then, the rating was upgraded or downgraded the ratings based on the judgment for each of the five domains listed above. The overall quality rating of the evidence was classified as high, moderate, low, or very low evidence [34,35].
A few studies included median and interquartile ranges, and Wan's method was used to convert this data into mean and SD [36]. Cochrane guidelines formula was used to convert CI and standard error of mean into SD to be added in the meta-analysis [37].

Study selection
The search yielded 4918 articles identified through different databases, with 4 additional studies identified through manual search [38][39][40][41]. The flowchart of the systematic review is shown in Fig. 1. The titles and abstracts of the remaining articles after removing duplicates were screened (n = 4001), and the full texts of 116 articles were read. Forty articles were included in this review [14-16, 18, 38-73, 76] articles were excluded. Reasons for exclusion were: use of animal models (e.g., Ohmichi et al. 's study [74]), different experimental design (e.g., Drummond et al. study [75]), absence of a control group or of a group of individuals with CRPS (e.g., Vaneker et al. study [76]), or inability to obtain the full text (eight studies). The corresponding authors of five publications were contacted requesting data for the meta-analysis [39,66,69,71,72]. Three authors replied and sent the required information [15,39,69].

Study characteristics
Ten studies were included in the qualitative analysis based on z-scores [14,39,40,53,61,66,68,[71][72][73], and the frequencies of gain and loss of sensations in CRPS were mentioned in six studies (Table 5) [14,15,44,53,65,69]. Twenty-six studies were included in the quantitative analysis. Two studies investigated the sensory profile of patients with CRPS accompanied by dystonia [50,70], and we included these results in the meta-analysis as we aimed to summarize the sensory profile and underlying pain mechanisms in individuals with CRPS in general. Two studies assessed the level of pleasantness after c-tactile touch perception in CRPS, and we included these results in the meta-analysis to illustrate the functionality of this specific type of C-fibers in CRPS [71,72].
Rooijen et al. reported the QST results for two groups of individuals with CRPS: one group with dystonia and one group without dystonia [50]. We included the results of both groups in our review. Huge et al. investigated the results of QST in acute and chronic CRPS, but we included only the results of the chronic group in our review [47]. Gierthmühlen et al. described the results of QST for two groups of CRPS (a group with type 1 and the other group with type 2), comparing them to the control group, while we added only the results of QST of CRPS type 1 to the quantitative analysis and after contacting the authors we got the reference values based on Magerl et al. [15,77]. Kemler et al. reported the results of QST for two groups of individuals with CRPS (one group with upper extremity CRPS and one group with lower extremity CRPS) [44]. We included the results of both groups in our metaanalysis. Thimineur et al. investigated pain ratings after the application of diluted ethanol on the tongue [57]. The results of this study were not included in the metaanalysis of pain ratings after noxious stimulus, because the methods used were very different from the methods used in the other studies. Mainka et al. and Terkelsen et al. [18,49] assessed both joint and muscle PPTs, which were included in a separate meta-analysis, one related to the muscle and the other to the joint PPTs, respectively.
Uçeyler et al. and Enax-krumova et al. [16,66] used the same cohort of patients with CRPS and controls. Thus, we added only the results of Uçeyler et al. in the quantitative analysis.
König et al. [40] investigated a subgroup of patients with CRPS that was previously investigated in König et al. [39]. Thus, only the results of König et al. [39] were used in our review. Two studies investigated the pleasantness level after C-tactile touch perception using brush stroking with a velocity of 3 cm/s both at the affected and contralateral sides. This variable was included in our review, despite addressing a variable not reported in the study protocol, as pleasantness levels could expand our knowledge about the sensory profile and the underlying pain mechanisms in CRPS [71,72].
Studies that investigated endogenous pain modulation could not be used in the meta-analysis because of different methodological approaches [45,53]. One study used repetitive electrical stimuli [45], while the other study used a restricted CPM paradigm [53].

Risk of bias
Quality assessment of the included studies is represented in Table 3, and Kappa statistics for agreement between the two reviewers was 0.76 (95% CI, 0.56-0.95), which is considered substantial agreement [78]. None of the 41 articles included in this review had a score above 7 points out of a maximum score of 9.
Most of the included studies were of fair quality as the mean quality score was greater than 4. Only one study reported the non-response rate [18], and all studies had the same ascertainment for cases and controls.

Sensory profile of adult patients with CRPS Cold detection threshold
Seven studies (one with low quality and six with fair quality), including a total of 505 patients with CRPS, investigated CDT on the affected area [15,43,44,47,50,67,70] and showed a significant loss of cold detection sensation with moderate heterogeneity (Additional file 1: Fig. S1) ( Table 6). Furthermore, there was symmetry in the funnel plot of included effect sizes (Additional file 2: Fig. S2).
Six studies (one with low quality and five with fair quality), including a total of 245 patients with CRPS, investigated CDT [43,44,47,51,67,70] in areas remote from the affected area showing a significant loss of cold  (Table 6). Also, there was no significant publication bias (p = 0.9) (Additional file 4: Fig. S4). Seven studies (two with low quality and five with fair quality) using z-scores to investigate CDT showed loss of cold sensation on the affected side [39,47,66,68,[71][72][73], and two studies (one with low quality and one with fair quality) showed loss of cold sensation on the contralateral limb [39,47]. One study of fair quality showed no between-group difference [14].
According to the GRADE assessment, there was lowquality evidence suggesting loss of the cold sensation in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).

Warm detection threshold
The meta-analysis of seven studies (one with low quality and six with fair quality) including a total of 505 CRPS patients (Additional file 5: Fig. S5) (Table 6) [15,43,44,47,50,67,70] showed a significant loss of warm sensation on the affected site, with moderate heterogeneity. Furthermore, there was symmetry in the funnel plot of included effect sizes (Additional file 6: Fig. S6).
The meta-analysis of six studies (one with low quality and five with fair quality) including a total of 245 CRPS patients for areas remote from the affected area (Additional file 7: Fig. S7) (Table 6) [43,44,47,51,67,70] showed a significant loss of warm sensation, with moderate heterogeneity. Also, there was no significant publication bias (p = 0.14) (Additional file 8: Fig. S8).
Nine studies (two with low quality and seven with fair quality) using z-scores showed loss of warm sensation at the affected side [14,39,47,53,66,68,[71][72][73], and two studies (one with low quality and one with fair quality) showed loss of warm sensation on the contralateral limb [39,47].
According to the GRADE assessment, there was lowquality evidence suggesting loss warm sensations in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).

Thermal sensory limen
Four studies (one with low quality and three with fair quality) with a total of 659 patients with CRPS showed a significant loss of thermal sensations on the affected regions, with moderate heterogeneity (I2 = 65%; p = 0.02) (Additional file 9: Fig. S9) (Table 6) [15,47,57,67].
A meta-analysis of three studies (one with low quality and two with fair quality) with a total of 894 patients with CRPS for areas remote from the affected area showed a significant loss of thermal sensation, with moderate heterogeneity (Additional file 10: Fig. S10) (Table 6) [47,57,67].
Eight studies (two with low quality and six with fair quality) using z-scores showed loss of thermal sensations at the affected side [39,47,53,66,68,[71][72][73], and two studies (one with low quality and one with fair quality) showed loss of thermal sensations on the contralateral limb [39,47].
According to the GRADE assessment, there was lowquality evidence suggesting loss of thermal sensations in patients with CRPS, either at the affected site or the remote areas away from the affected side (Table 6). Table 5 Frequencies of sensory gain and loss in CRPS based on QST CRPS complex regional pain syndrome, CDT cold detection threshold, CPT cold pain threshold, DMA dynamic mechanical allodynia, HPT heat pain threshold, MDT mechanical detection threshold, MPS mechanical pain sensitivity, MPT mechanical pain threshold; PHS, paradoxical heat sensation, PPT pressure pain threshold, QST quantitative sensory testing; TSL, thermal sensory limen, VDT, vibration detection threshold; WDT, warm detection threshold; WUR, wind-up ratio

Mechanical detection threshold
A meta-analysis of five studies (three with low quality and two with fair quality) including a total of 513 patients with CRPS showed a significant loss of mechanical detection sensation on the affected regions, without heterogeneity (Additional file 11: Fig. S11) ( Table 6) [15,44,45,52,57].
A meta-analysis of four studies (three with low quality and one with fair quality) with a total of 292 patients with CRPS showed a significant loss of mechanical detection sensation on the remote areas, without significant heterogeneity (Additional file 12: Fig. S12) ( Table 6) [44,45,52,57].
Four studies (one with low quality and three with fair quality) using z-scores showed loss of mechanical detection sensation in patients with CRPS [14,39,47,72], and three studies (one with low quality and two with fair quality) showed no between-group differences [66,68,73]. Two studies (one with low quality and one with fair quality) showed loss of mechanical detection sensation in the contralateral limb [39,47].
According to the GRADE assessment, there was lowquality evidence suggesting loss of mechanical detection sensations in patients either at the affected site or the remote areas away from the affected site (Table 6).

Vibration detection threshold
A meta-analysis of four studies of fair quality including a total of a total of 385 patients with CRPS showed a significant loss of vibration detection sensation on the affected regions, without significant heterogeneity (Additional file 13: Fig. S13) (Table 6) [15,38,50,67].
A meta-analysis of three studies of fair quality including a total of 163 patients with CRPS reported a significant loss of vibration sensation on areas remote from the affected area, without significant heterogeneity (Additional file 14: Fig. S14) (Table 6) [38,51,67].
Six studies (two with low quality and four with fair quality) using z-scores showed loss of vibration sensation on the affected side [39,47,66,68,72,73], one study of fair quality showed no between-group difference [14], and two studies (one with low quality and one with fair quality) showed loss of vibration sensation on the contralateral side [39,47].
According to the GRADE assessment, there was moderate-quality evidence suggesting loss of vibration sensations in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).

Cold pain threshold
Seven studies (one with low quality, five with fair quality, and one with good quality) investigated CPT on the affected areas in 481 patients with CRPS showing CI confidence interval, SMD standardized mean difference  (Table 6) [15,18,43,44,47,50,67]. Furthermore, there was asymmetry in the funnel plot of included effect sizes (Additional file 16: Fig. S16). Meta-analysis of six studies (one with low quality, four with fair quality, and one with good quality) including a total of 240 patients with CRPS investigated CPT in areas remote from the affected area and showed a significant gain of CPT in CRPS compared to healthy controls, without significant heterogeneity (Additional file 17: Fig. S17) ( Table 6) [18,43,44,47,51,67]. There was also no publication bias (p = 0.5) (Additional file 18: Fig. S18).
Six studies (one with low quality and five with fair quality) showed a sensory gain of CPT based on z-scores at the affected site of CRPS [39,47,53,68,71,72], while three studies (one with low quality and two with fair quality) showed no between-group differences [14,66,73] and two studies (one with low quality and one with fair quality) showed a gain of cold pain sensation on the contralateral side [39,47].
According to the GRADE assessment, there was lowquality evidence suggesting gain of cold pain thresholds in patients with CRPS at the affected site, but at remote areas, there was moderate-quality evidence ( Table 6).

Heat pain threshold
A meta-analysis of nine studies (one with low quality, seven with fair quality, and one with good quality) including a total of 548 patients with CRPS showed a significant gain of HPT on the affected area of patients with CRPS, with moderate heterogeneity (Additional file 19: Fig. S19) ( Table 6) [15,18,43,44,47,50,62,67,70]. Furthermore, there was no significant publication bias (p = 0.60) (Additional file 20: Fig. S20).
A meta-analysis of eight studies (one with low quality, six with fair quality, and one with good quality) including a total of 288 patients with CRPS reported a significant gain of HPT in areas remote from the affected area, without significant heterogeneity (Additional file 21: Fig. S21) ( Table 6) [18,43,44,47,51,62,67,70]. Also, there was no significant publication bias (p = 0.4) (Additional file 22: Fig. S22).
Six studies (one with low quality and five with fair quality) showed a sensory gain of HPT on the affected site using z-scores [14,39,47,68,71,72], while two studies (one with low quality and one with fair quality) showed no differences [66,73] and two studies (one with low quality and one with fair quality) showed a gain of heat pain sensation on the contralateral side [39,47].
According to the GRADE assessment, there was moderate-quality evidence suggesting gain of heat pain thresholds in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).

Mechanical pain threshold
On the affected side, a meta-analysis of four studies (two with low quality and two with fair quality) including a total of 375 patients with CRPS reported a significant gain of MPT in patients with CRPS, with considerable heterogeneity (Additional file 23: Fig. S23) (Table 6) [15,45,56,67].
On the remote areas, a meta-analysis of two studies (one with low quality and one with fair quality) with a total of 47 patients with CRPS and 34 healthy controls showed no group difference, without heterogeneity (Additional file 24: Fig. S24) (Table 6) [45,67].
Based on z-scores, five studies (two of low quality and three of fair quality) showed a sensory gain of MPT on the affected site in patients with CRPS [39,47,68,72,73], while three studies of fair quality showed no betweengroup differences [14,66,71] and two studies (one of low quality and one of fair quality) showed a gain of MPT on the contralateral side [39,47].
According to the GRADE assessment, there was very low-quality evidence suggesting gain of mechanical pain thresholds in patients with CRPS at the affected site, but at remote areas, there was low-quality evidence suggesting that there was no difference (Table 6).

Pressure pain threshold
The meta-analysis of nine studies (three with low quality, five with fair quality, and one with good quality) with a total of 507 patients with CRPS showed a significant gain of muscle PPT on the affected site in CRPS, with moderate heterogeneity (Additional file 25: Fig. S25) ( Table 6) [15, 18, 38, 48-50, 52, 63, 67]. There was also no significant publication bias (p = 0.12) (Additional file 26: Fig. S26).
Eight studies (three with low quality and five with fair quality) using z-scores showed a gain of muscle PPT at the affected site of patients with CRPS [14,39,47,66,68,[71][72][73], while at the contralateral side, one study of fair quality showed a gain of PPT in CRPS [47] and another one of low quality showed no difference [39]. Moreover, one study of fair quality showed a significant gain of PPT on the affected side and remote areas including face, chest, abdomen, and back [55]. According to the GRADE assessment, there was lowquality evidence suggesting gain of pressure pain thresholds of the affected muscles in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).
A meta-analysis of two studies (one with low quality and one with good quality) investigating PPT on affected joints reported a significant gain of PPT in CRPS, without significant heterogeneity (Additional file 29: Fig. S29) ( Table 6) [18,49].
In the remote joints, a meta-analysis of two studies (one with low quality and one with good quality) reported no difference of PPT in CRPS, with considerable heterogeneity (Additional file 30: Fig. S30) (Table 6) [18,49].
According to the GRADE assessment, there was moderate-quality evidence suggesting gain of pressure pain thresholds of the affected joints in patients with CRPS, but at remote joints, there was low-quality evidence suggesting that there was no difference (Table 6).

Mechanical pain sensitivity
The meta-analysis of five studies (two with low quality and three with fair quality) including a total of 396 patients with CRPS showed a significant elevation of MPS in CRPS, with moderate heterogeneity (Additional file 31: Fig. S31) (Table 6) [15,56,62,63,67].
In the remote areas, a meta-analysis of three studies (one with low quality and two with fair quality) showed no difference, with substantial heterogeneity (Additional file 32: Fig. S32) (Table 6) [62,63,67].
Five studies (one with low quality and four with fair quality) showed an elevated MPS on the affected site of patients with CRPS based on z-scores [39,47,68,71,72], while three studies (one with low quality and two with fair quality) showed no differences [14,66,73] and two studies (one with low quality and one with fair quality) showed elevated MPS on the contralateral side of CRPS [39,47].
According to the GRADE assessment, there was moderate-quality evidence suggesting enhanced mechanical pain sensitivity of the affected site in patients with CRPS, but at remote areas, there was very low-quality evidence suggesting that there was no difference (Table 6).

Wind-up ratio
A meta-analysis of five studies (one with low quality and four with fair quality) including a total of 374 patients with CRPS found no difference of WUR at the affected area, with moderate heterogeneity (Additional file 33: Fig. S33) (Table 6) [15,50,56,62,67].
On the remote areas, a meta-analysis of two studies with fair quality investigated WUR in 37 patients with CRPS showed no difference, with moderate heterogeneity (Additional file 34: Fig. S34) ( Table 6) [62,67].
Based on z-scores, four studies (two with low quality and two with fair quality) showed no differences in WUR on the affected site [14,39,66,73] and one study of fair quality showed elevated WUR on the affected area in patients with CRPS [72].
According to the GRADE assessment, there was lowquality evidence suggesting that there was no difference between the levels of wind-up ratio, either at the affected site or the remote areas away from the affected site (Table 6).

Pain ratings after the noxious stimulus
A meta-analysis of five studies (three with low quality, one with fair quality, and one with good quality) reported a significant elevation of pain ratings in CRPS on the affected site, with substantial heterogeneity (Additional file 35: Fig. S35) (Table 6) [18,42,43,45,56].
In the remote areas, a meta-analysis of four studies (two with low quality, one with fair quality, and one with good quality) reported a significant elevation of pain ratings in CRPS, without significant heterogeneity (Additional file 36: Fig. S36) (Table 6) [18,42,43,45].
According to the GRADE assessment, there was low-quality evidence suggesting elevated pain ratings in patients with CRPS, either at the affected site or the remote areas away from the affected site (Table 6).

Area after pinprick hyperalgesia
Meta-analysis of two low-quality studies including a total of 47 patients with CRPS showed a significant increase in the area of hyperalgesia on the affected site of patients with CRPS, with moderate heterogeneity (Additional file 37: Fig. S37) (Table 6) [45,56].
According to the GRADE assessment, there was lowquality evidence suggesting a significant increase in the area of hyperalgesia on the affected site of patients with CRPS (Table 6).

Flare area after electric stimulus
Two studies (one with low quality and one with fair quality) investigated flare areas using laser Doppler imaging [45,58]. Weber et al. showed a significant increase in

Electric pain threshold and current detection threshold
Two low-quality studies investigated the sensory profile after the application of electric current [45,59]. Seifert et al. used a 1 Hz electric current to measure both pain and detection thresholds and found no differences between CRPS patients (affected and contralateral sides) and healthy controls [45]. Raj et al. used electric current of different frequencies and showed that 64% of patients with CRPS had abnormal electric pain threshold, while a percentage of 33% showed abnormal current detection threshold on the affected side, with some abnormalities on the contralateral side [59]. Thus, there were inconsistent findings regarding both electric pain and detection thresholds in CRPS, which need further investigations.

Endogenous pain modulation
Two studies (one with low quality and one with fair quality) investigated endogenous pain modulation in CRPS [45,53]. One study used conditioned pain modulation and found comparable descending pain modulation in patients with CRPS and controls [53]. Seifert et al. showed enhanced pain facilitation in CRPS after using repetitive electric pulse stimulation [45].

Level of pleasantness in CRPS
Two fair-quality studies looked at the pleasantness level following c-tactile touch perception on the affected side, and their meta-analysis revealed that CRPS patients had significantly lower pleasantness levels than healthy controls, without heterogeneity (Additional file 38: Fig. S38) (Table 6) [71,72].
On the contralateral side, the meta-analysis of two studies of fair quality investigating the pleasantness level after c-tactile touch perception showed no difference in pleasantness level on the contralateral limb of CRPS compared with healthy controls, with moderate heterogeneity (Additional file 39: Fig. S39) (Table 6) [71,72].
According to the GRADE assessment, there was moderate-quality evidence suggesting a significant reduction of pleasantness levels at the affected site in patients with CRPS, but at remote joints, there was low-quality evidence suggesting that there was no difference (Table 6).

Sensory profile of children with CRPS Cold detection threshold
The meta-analysis of two fair-quality studies including a total of 76 children with CRPS showed a significant loss of cold sensation on the affected areas of CRPS, with substantial heterogeneity (Additional file 40: Fig. S40) ( Table 6) [46,64].
On the contralateral side, a meta-analysis of two fairquality studies including a total of 76 children with CRPS showed no difference in CDT between patients with CRPS and controls, with considerable heterogeneity (Additional file 41: Fig. S41) (Table 6) [46,64].
According to the GRADE assessment, there was lowquality evidence suggesting loss of cold sensations of the affected site in patients with CRPS, but at the contralateral side, there was low-quality evidence suggesting that there was no difference (Table 6).

Warm detection threshold
The meta-analysis of two studies with fair quality including a total of 76 children with CRPS reported no difference in warm sensation on the affected areas between patients with CRPS and controls, with considerable heterogeneity (Additional file 42: Fig. S42) ( Table 6) [46,64].
On the contralateral side, a meta-analysis of two fairquality studies including a total of 76 children with CRPS reported no difference in WDT between patients with CRPS and controls, with considerable heterogeneity (Additional file 43: Fig. S43) (Table 6) [46,64].
According to the GRADE assessment, there was lowquality evidence suggesting that there was no difference of warm sensations in patients with CRPS, either at the affected site or the contralateral side (Table 6).

Cold pain threshold
A meta-analysis of three fair-quality studies including a total of 102 children with CRPS showed a significant  Fig. 44) (Table 6) [41,46,64]. On the contralateral side, a meta-analysis of two fairquality studies including a total of 76 children with CRPS reported no difference in CPT between patients with CRPS and controls, without significant heterogeneity (Additional file 45: Fig. S45) (Table 6) [46,64].
According to the GRADE assessment, there was lowquality evidence suggesting gain of cold pain thresholds of the affected site in patients with CRPS, but at the contralateral side, there was low-quality evidence suggesting that there was no difference (Table 6).

Heat pain threshold
On the affected side, a meta-analysis of three fair-quality studies including a total of 102 children with CRPS reported no difference in HPT between patients with CRPS and controls, with considerable heterogeneity (Additional file 46: Fig. 46) (Table 6) [41,46,64].
On the contralateral side, a meta-analysis of two fairquality studies including a total of 76 children with CRPS reported no difference in HPT between patients with CRPS and controls, with considerable heterogeneity (Additional file 47: Fig. S47) (Table 6) [46,64].
According to the GRADE assessment, there was lowquality evidence suggesting that there was no difference of heat pain thresholds in patients with CRPS, either at the affected site or the contralateral side ( Table 6).

Frequencies of sensory abnormalities in adult with CRPS
Regarding the percentage of sensory loss and hyperalgesia, 25% to 33% of patients with CRPS showed a thermal and mechanical sensory loss, between 60 to 100% of patients showed pressure pain hyperalgesia, and 30% to 40% of patients showed thermal hyperalgesia (Table 5) [14,15,69].

Sensitivity analysis
A sensitivity analysis was carried out, and studies with a high risk of bias were omitted. As a result, p values of the effect sizes were not significantly impacted for all outcomes except TSL of remote areas and MPT of the afflicted site, which showed a non-significant difference. Levels of heterogeneity were also not significantly impacted except for CDT of the affected site, WUR of the affected site, pain rating of the affected site, MPT of the affected site, and MPS of the affected site and the remote areas, which showed a significant reduction. However, after adjusting for low-quality studies, levels of heterogeneity of MDT of the affected site and TSL of the remote areas were significantly increased.

Discussion
This systematic review aimed to summarize the current literature on QST measurements, pain ratings after noxious stimulus, area of pinprick hyperalgesia, and flare area in patients with CRPS to examine the sensory profile and underlying pain mechanisms.
Adult patients with CRPS showed loss of all detection thresholds (CDT, WDT, MDT, VDT, and TSL) compared to controls, both in the affected and contralateral sides. Also, there was a significant gain in CPT, HPT, and PPT both in the affected and remote areas. Furthermore, pain ratings after noxious stimulus showed significant elevation in the affected and contralateral areas, while MPS was elevated in the affected area only. The area of pinprick hyperalgesia was larger in CRPS compared to healthy controls, while the results for flare area were contradictory. The sensory profile of children with CRPS showed loss of cold sensation and cold hyperalgesia in the affected region without apparent sensory deficits at the remote areas away from the affected site.
Interestingly, adult patients with CRPS showed both sensory loss and primary and secondary hyperalgesia for all pain stimuli in the affected and remote areas, which strongly suggests the involvement of central nervous system and central sensitization [79][80][81]. This has also been supported by investigations in CRPS patients, which revealed bilateral structural and functional abnormalities in brain areas important for pain processing, cognition, and motor behavior [79,81,82]. Thus, central sensitization can be initiated by the enhanced peripheral sensitization (enhanced local hyperalgesia) [47,83], or neuroplasticity at the spinal and brain levels (hemisensory abnormalities and increased area after pinprick hyperalgesia) [45,63,70,84,85], or the release of inflammatory mediators after tissue injury as substance p, bradykinin, calcitonin gene-related peptide, interleukin-1β, -2, -6, and tumor necrosis factor-α [8,86,87]. The diffuse sensory loss discovered in this meta-analysis could be attributed to decreased neurite density in both affected and unaffected sides of CRPS patients, or it could have a central origin [19,43,72,88]. Finally, the reduced pleasantness level in CRPS could indicate loss of small nerve fibers and central nervous system remodeling as the pleasantness levels reduced more in patients with CRPS accompanied with depression and allodynia than those without allodynia and depression [71,72].
Comparing the sensory phenotype in CRPS with neuropathic pain conditions reveals distinct sensory patterns. In carpal tunnel syndrome, recent study revealed dominant sensory loss localized only to the affected hand area with inconclusive evidence about central sensitization [89]. Also, in different radiculopathies, the sensory loss was localized to maximum pain area and dermatomal area with inconclusive picture about the presence of hyperalgesia [90][91][92]. Even in migraine, the impaired pain processing was localized to the affected area [93].
Recently, a new study suggested contralateral spread of sensory loss in painful and painless unilateral neuropathy with slightly limited spread of hyperalgesia [94]. In contrast, the sensory loss and thermal and mechanical hyperalgesia in CRPS were diffuse as evidenced by bilateral sensory loss and bilateral reduction of neurite density. Comparing CRPS to other chronic conditions as tendinitis and arthritis, CRPS showed more prominent thermal and mechanical hyperalgesia [95][96][97]. Comparing CRPS to chronic conditions with unknown etiology such as fibromyalgia shows comparable results both at the level of diffuse sensory loss or hyperalgesia or reduced level of pleasantness after C-tactile perception [52,98,99], which could suggest shared pain mechanisms and etiologies. Such findings could support classifying CRPS as a nociplastic pain type instead of neuropathic pain type [100], in agreement with the recent definition and grading system of neuropathic pain and IASP recent classification which excluded CRPS [100][101][102]. Interestingly, there was evidence of the presence of different comorbidities in CRPS such as sleep disturbances, post-traumatic stress disorder, and increased sensitivity to light and auditory stimuli [6,12,[103][104][105] that strongly suggest a nociplastic mechanism for CRPS. Also, the frequency of sensory abnormalities in CRPS is more consistent than the frequencies found in previous studies for neuropathic pain conditions. In carpal tunnel syndrome, the percentage of patients with sensory loss was found to range from 22 to 33%, thermal hyperalgesia from 1 to 45%, and mechanical hyperalgesia from 20 to 45% [92,106,107]. Regarding CPM in CRPS, there were two studies discussing endogenous pain modulation in CRPS. One study showed enhanced pain facilitation rather than impaired descending pain inhibition after using repetitive noxious electrical stimuli [45]. The other study showed unimpaired descending pain inhibition when using the restricted CPM paradigm (heat was used as a test stimulus and cold as a conditioning stimulus) [53]. These contradictory results might be explained by the different disease duration (mean duration was 22 months in the study of Seifert et al., while the maximum disease duration was 12 months in the study of Kumowski et al.) and/ or by the different procedures of assessment of endogenous pain modulation. Fortunately, offset analgesia is a paradigm which can also assess endogenous pain modulation that showed impaired pain inhibition in patients with CRPS [108].
No difference was found for temporal summation, represented by WUR, between individuals with CRPS and controls both in the affected and the contralateral limb. This might be due to the small cohort of patients with CRPS in the included studies that investigated WUR, except for Gierthmühlen et al. [15], who showed elevated WUR in a large cohort of patients with CRPS. Importantly, the diffuse loss of small nerve fibers bilaterally can cause the absence of WUR both in the affected and the contralateral regions [43]. Interestingly, WUR of CRPS type II (with evidence of nerve injury) showed no difference when compared to the control group [15], similar to the findings of WUR in CTS (median nerve injury) which showed no difference also [89].
Sensory profile of children and adolescents with CRPS showed loss of cold sensation and cold hyperalgesia at the affected region only, indicating less severe form of CRPS in this age group. Interestingly, children and adolescent with CRPS showed better prognosis and improvement than adults with CRPS, which might be related to the less severe sensory abnormalities [109]. Importantly, the findings of sensory profile of children and adolescents with CRPS are based on three studies only, which prevents us from drawing a comprehensive sensory profile.

Limitations of the review
Since the overall level of certainty ranged from very low to moderate based on the GRADE assessment [34,35], the results should be regarded with caution. There were various issues that decreased the general level of certainty. At first, the included studies were observational studies with poor to good quality ratings. Second, there was moderate to substantial heterogeneity across the obtained results. Finally, the meta-analysis of several QST outcomes was based on a small number of studies, and the effect sizes occasionally appear small with large confidence intervals.
It is important to highlight that the sensitivity analysis controlling for low-quality studies (meta-analyses were repeated while excluding studies with high risk of bias) showed a non-significant effect either at the levels of heterogeneity or the obtained effect sizes and corresponding p values of most outcomes. Therefore, the degree of heterogeneity seen in the results might not be explained by the risk of bias of the included studies.
Possible causes of heterogeneity might include the different disease duration of CRPS across the included studies (ranging from six months to five years). Disease duration seems to result in different sensory profiles in patients with CRPS [14,47,70]. Thus, future studies might consider comparing sensory profiles of patients with CRPS of different durations. This heterogeneity may be also explained by several factors, starting with the diagnostic criteria for CRPS, which were modified to rely on the Budapest criteria [1] rather than the previous IASP standards [110]. Second, based on the predominant pathophysiology, a recent categorization is better able to distinguish between three clusters of individuals with CRPS type 1 and type 2: CRPS of central phenotype, CRPS of peripheral phenotype, and CRPS of mixed phenotype [111]. As a result, limiting the classification of CRPS to type 1 and type 2 may produce inconsistent results. It is interesting to note that the outcomes of this review are comparable to the findings of the one study that looked at the QST outcomes in CRPS type 2 [15]. This could provide credibility to the current division into three phenotypes. It is noteworthy to mention that some of the included studies recruited a mix of CRPS type 1 and type 2 which might represent a potential cause of heterogeneity. However, the number patients with CRPS type 2 included in these studies was very small. For example, Terkelsen et al. recruited 2 patients with CRPS type 2 and 18 patients with CRPS type 1 [18].
The results of the quantitative sensory testing outcomes of adolescents and children with CRPS were only examined in three studies, which limited the conclusions. Therefore, additional research is required to support the findings of the present review.

Conclusion
A mix of diffuse thermal and mechanical sensory loss and hyperalgesias in the affected and remote areas is the dominant sensory phenotype in CRPS indicating the dominant peripheral and central sensitization as key underlying pain mechanisms. There is some evidence regarding the enhanced pain facilitation more than impaired descending pain inhibition as evident by elevated thermal and mechanical pain ratings and increased areas of pinprick hyperalgesia. Such results could indicate the involvement of small nerve fibers both at the affected and remote areas. Adolescents and children with CRPS showed less severe form of sensory abnormalities as evident with loss of cold detection sensation and cold hyperalgesia at the affected site.

Future implications of the review
Further research is needed investigating the efficacy of the descending pain inhibition in patients with CRPS, as well as the widespread sensory loss and hyperalgesia, the pleasantness level after C-tactile stimulation, the electric pain and detection thresholds, and the area of pinprick hyperalgesia of the affected site and remote areas.
As evident from this review, there was a diffuse loss of sensation in patients with CRPS. Thus, the previous studies which compared the QST outcomes of the affected area to that of the contralateral healthy side might result in inconsistent findings as well as might hinder the progress in providing better treatment options. We suggest comparing the affected or contralateral side with reference values of healthy subjects or control group, to avoid any bias.
Previous research revealed that the sensory deficits extended from the affected area to the ipsilateral body sites more compared to the contralateral side [84,85]. Thus, such studies lacked the presence of control group, while we suggest comparing the results of QST in affected areas, areas in the ipsilateral side away from the affected region, and control group. It is noteworthy that Rooijen et al. investigated the sensory deficits in CRPS affected area, contralateral area, and ipsilateral areas away from the affected region but this study included both patients with CRPS with dystonia and without dystonia [51]. Moreover, face area showed specific sensory abnormalities in patients with CRPS [51,63] which indeed needs further investigations.
A group of CRPS patients had elevated WUR, whereas another group had no difference when compared to healthy controls. Future research will therefore be required to determine the relationship between the decline in small fiber density and the change in WUR, as it is possible that the decline in small fiber density could prevent the change of the WUR.
Finally, in order to inform better treatment options, it is crucial to compare the new classification of CRPS into three phenotypes (central, peripheral, and mixed) with the existing classification into type 1 and 2. The first step is to investigate the sensory profile of CRPS type 2 and compare it to the results of our review. This could indicate the same sensory profiles and the same underlying pain mechanisms. Thus, the necessity to switch over to the new classification would then likely be of vital importance.