Quantitative somatosensory assessments in patients with persistent pain following groin hernia repair: A systematic review with a meta-analytical approach

Objectives Quantitative sensory testing (QST) provides an assessment of cutaneous and deep tissue sensitivity and pain perception under normal and pathological settings. Approximately 2–4% of individuals undergoing groin hernia repair (GHR) develop severe persistent postsurgical pain (PPSP). The aims of this systematic review of PPSP-patients were (1) to retrieve and methodologically characterize the available QST literature and (2) to explore the role of QST in understanding mechanisms underlying PPSP following GHR. Methods A systematic literature search was conducted from JAN-1992 to SEP-2022 in PubMed, EMBASE, and Google Scholar. For inclusion, studies had to report at least one QST-modality in patients with PPSP. Risk of bias assessment of the studies was conducted utilizing the Newcastle Ottawa Scale and Cochrane’s Risk of Bias assessment tool 2.0. The review provided both a qualitative and quantitative analysis of the results. A random effects model was used for meta-analysis. Results Twenty-five studies were included (5 randomized controlled trials, 20 non-randomized controlled trials). Overall, risk of bias was low. Compared with the contralateral side or controls, there were significant alterations in somatosensory function of the surgical site in PPSP-patients. Following thresholds were significantly increased: mechanical detection thresholds for punctate stimuli (mean difference (95% CI) 3.3 (1.6, 6.9) mN (P = 0.002)), warmth detection thresholds (3.2 (1.6, 4.7) °C (P = 0.0001)), cool detection thresholds (-3.2 (-4.9, -1.6) °C (P = 0.0001)), and heat pain thresholds (1.9 (1.1, 2.7) °C (P = 0.00001)). However, the pressure pain thresholds were significantly decreased (-76 (-123, -30) kPa (P = 0.001)). Conclusion Our review demonstrates a plethora of methods used regarding outcome assessments, data processing, and data interpretation. From a pathophysiological perspective, the most consistent findings were postsurgical cutaneous deafferentation and development of a pain generator in deeper connective tissues. Trial registration CRD42022331750.


Background
1.1.1Persistent postsurgical pain following groin hernia repair.Groin hernia repair (GHR) is a common surgery performed in more than 20 million patients worldwide every year [1].Persistent postsurgical pain (PPSP) following GHR is a well-known medical complication [2] and efficacious management of patients with PPSP remains a major challenge for the healthcare profession [3].The IASP (the International Association for the Study of Pain ) criteria for chronic post-surgical or posttraumatic pain are "a chronic pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, i.e., at least three months after the surgery or tissue trauma" [4].More elaborate criteria have previously been proposed [5].The condition can significantly impair the physical and psychosocial functions of the individual, and a conservative estimate is that 2% of patients undergoing groin hernia repair will be affected by PPSP [6,7].The prevalence of PPSP is primarily contingent on the respective surgical procedure, whilst patient-related presurgical factors also affect the frequency and severity of PPSP [1,8,9].
The anatomical region in which the surgery is performed [10] is complex, with a high degree of vascularization, dense nerve fiber innervation, and several peripheral nerves traversing the region [10].Additionally, the region has a significant role in posture control, locomotion, as well as reproductive functions [10][11][12].The three primary causes of chronic pain after groin hernia repair are inflammatory processes caused by foreign materials, formation of a meshoma or the development of neuropathic pain, e.g., nerve injury, through nerve transection, compression or entrapment or devascularization [7].
One of the key investigative tools applicable in PPSP is QST (quantitative somatosensory testing), which has been used extensively in the research of pathophysiological mechanisms [7,13].A thorough examination of the somatosensory characteristics of patients, with the use of QST, could further decipher pathways underlying chronic pain, which might guide the therapeutic management of the condition [14].However, no systematic nor methodological review of the findings pertaining to the use of QST in patients suffering from PPSP following GHR has been published yet.
In relation to the treatment of PPSP following GHR, re-surgery, either in terms of meshectomy, or selective or triple neurectomy, is quite effective in treating a subset of patients [7,15,16], though the need for improvement of non-interventional treatment of PPSP is still an important factor to consider [17].

Quantitative sensory testing (QST).
QST is a standardized, non-invasive psychophysical testing procedure where the individual is exposed to various graded stimulation modalities (e.g., thermal and mechanical).The stimulus evoked responses are quantified by the individual in terms of sensory detection and pain thresholds.[18,19].An example of a thorough QST protocol is the standardized protocol provided by the DFNS (German Research Network on Neuropathic Pain).
Through performance of the QST procedure, it is possible to evaluate and quantify the somatosensory profile of individuals by assessing the function of different nerve fiber types in the somatosensory system [14].
1.1.3Aims of this study.The aims of this systematic review were: First, to retrieve and methodologically characterize the available literature related to QST in patients with PPSP following GHR.Second, to explore the role of QST in understanding mechanisms underlying PPSP following GHR.
From a pathophysiological perspective, the review may facilitate evaluation of the diagnostic efficiency of QST methods and, consequentially, improved treatment paradigms.

Materials and methods
The review was conducted in accordance with PRISMA guidelines [20] and was registered in the PROSPERO international register of systematic reviews (CRD42022331750).The PRISMA 2020 checklist is available as S1 Checklist.

Eligibility criteria
This review included studies concerning the use of QST on human subjects who had undergone GHR and were subsequently affected by PPSP.There were no exclusion criteria related to surgical technique; both open and laparoscopic surgeries were considered.QST was defined as an examination procedure of the groin using a quantifiable approach.Studies were eligible if a technique of somatosensory examination of the groin using QST had been used (cf.1.1.2.).Studies were included if at least one standard mechanical (MDT, MPT, PPT) or one thermal (WDT, CDT, HPT, CPT) modality related to QST was described in the study.No restriction regarding age was implemented in the literature search.Studies were included if the post-surgical assessment period was at least three months.Eligible studies were published in English or German language, during the period JAN-1992 to SEP-2022.

Systematic literature search
A systematic literature search was conducted using several online databases (PubMed, EMBASE, and Google Scholar).Furthermore, the authors searched PROSPERO and PubMed for published or ongoing reviews with the following search string: The final systematic search strategy and search paradigm, including citation tracking, were determined with the help of a research librarian.The search strategy was not limited to a specific study type.Randomized controlled trials (RCTs), cohort studies, and systematic reviews were included to secure as much of the relevant literature and data on the topic as possible.To further maximize the effectiveness of the search, manual searching was also performed in the reference lists of full-text studies to capture publications that might be overlooked in the online search.

Study selection process.
After conducting the search using the MeSH terms and Text Words, the initial screening was based on the titles.The subsequent selection of studies was determined by reviewing abstracts of these studies, followed by a final full-text screening.The respective studies obtained through the search were independently screened by three authors (AD, EKJ, MW) to identify the literature which met the eligibility criteria.In case of ambiguities, the senior author (MW) made the final decision.

Data extraction.
A data extraction sheet was produced with the purpose of systematizing relevant information extracted from each of the included studies.The extracted information included study design, number of eligible participants, demographics, QST protocol details, QST variables generated in the studies (e.g., thermal and mechanical detection and pain thresholds), and other relevant outcome measures.To establish a consistent and thorough data extraction, the three authors extracted and analyzed the data.No attempts were made to contact the respective study authors.

Assessing the risk of bias
The Newcastle Ottawa Scale (NOS) [21] and the Cochrane Risk of Bias Tool 2.0 (RoB 2.0) [22], were used to evaluate the methodological quality and risk of bias of non-RCT's and RCT's, respectively.The quality assessment was conducted independently and discussed by the three authors, and the senior author made the final decision in case of ambiguities.
The NOS is a tool with the purpose of assessing the risk of bias and overall qualities of non-RCTs.The tool utilizes a "star system" to delegate points based on three main perspectives: the selection of study groups, comparability of study groups, and the ascertainment of either the exposure or outcome of interest (depending on whether the study in question is a case-control study or cohort study, respectively).Each main domain contains further questions, totaling eight different assessment areas.A maximum of nine stars/points can be allotted to the study in question [21].
The RoB 2.0 is an instrument to assess risk of bias and quality of RCTs [22].The tool focuses on a set of domains related to multiple characteristics of trial design, conduct, and reporting.Each main domain is associated with a series of signaling questions aiming to report on specific features of the trials.The tool contains an algorithm providing a conclusive assessment of the risk of bias.Studies are categorized as being either "Low" or "High" in terms of risk of bias or that there are "Some concerns".

Strategy for data synthesis and data analysis
Data analysis was undertaken using Review Manager 5.4.1 [23] for the creation of forest plots.In total, data from 7 different QST modalities were used for analysis.For pooled analyses, data from 6 studies of punctate mechanical detection threshold (MDT) and mechanical pain threshold (MPT) [12,[24][25][26][27][28], data from 11 studies of warmth detection threshold (WDT) and heat pain threshold (HPT), data from 9 studies of cool detection threshold (CDT) [12,[24][25][26][27][28][29][30][31] and 6 studies of cold pain threshold (CPT) [12,24,[26][27][28]31], and data from 7 studies of blunt pressure pain threshold (PPT) [12,24,25,[27][28][29][30], were used.Outcome data were found qualified for analysis if the data were presented as continuous data (mean or median) and if the study included a comparison of data (surgical side vs. non-surgical side).Between the studies, the data for a specific modality would differ in presentation.For example, some studies presented MDT/MPT-values on a logarithmic scale, while other studies solely presented raw data, means, or medians.As such, to secure homogeneity between outcome data, all values were transformed to represent the same distribution.Data for MDT/MPT-values were log-transformed, while remaining forest plots contain raw data (WDT, CDT, HPT, CPT, PPT).For the data in intervention studies, only baseline values, i.e., pre-intervention values, were used for the analysis.The purpose of this was to avoid comparing outcome data affected by the respective interventions with data from non-interventional studies.In the forest plots, results on the left part of the abscissa, which represented a decrease in thresholds from the affected side to control side, were labeled "gain of sensory function".Correspondingly, the right part of the abscissa represented an increase in thresholds indicating a "loss of sensory function" [32].The analyses were conducted using a random effects model.Furthermore, standard tests of heterogeneity were performed.Data are, unless otherwise stated, indicated as mean (95% CI).For the interpretation of results in this review, a P-value of 0.01 was set to minimize the likelihood of a type 1 error due to multiple comparisons.

Literature search
A PRISMA flow diagram is presented in Fig 1 .The final search resulted in 1,105 records.After the subsequent exclusion of 11 duplicates, a total of 1,094 records were screened.After the initial screening of titles and abstracts, 1,046 records were excluded resulting in 47 reports assessed for eligibility.Further, 23 studies were excluded by full-text screening.A single study was identified through citation tracking, resulting in a total yield of 25 studies included in the review.
Interventions in the RCTs were purified capsaicin instillation [42], nerve conduction block with 1% and 2% lidocaine [8], use of 5% lidocaine patch [29], use of 8% capsaicin patch [30], and ultrasound-guided tender point blockade with 0.25% bupivacaine [9].A total of 11/25 studies [12,18,[24][25][26][27][28][29][30][31]33] were found qualified for statistical analysis.The authors used a pragmatic process to select the papers that presented extractable data for the analysis.For example, some studies only presented data as differences (delta-values), whilst the statistical analysis required absolute values.Another reason for a study not presenting data qualified for analysis could simply be that the QST-variables belonged to secondary or even tertiary outcomes.Of the 11 studies used for analysis, 2 were RCTs, and 9 non-RCTs.Raw data used for analysis from the 2 RCTs were not found in the studies, as data were only presented as differences across an intervention; however, one of the review authors (MW) was also one of the authors in the RCTs, and raw data were obtained, and used for analysis.The results from the statistical analyses are illustrated in the forest plots (Fig 2A -2G).

Demographics.
The demographics of included study participants are presented in Table 2.The mean age (SD) of all participants was 49.9 (10.3) yrs.One study [12] solely reported the range of age and was therefore not taken into consideration when calculating the mean age of study subjects.A single study stood out in terms of age since the study was conducted in children with the mean (range) age of 8 years (6 months-12 years) [37].Calculating age only from adult studies, the mean (SD) was 51.2 (10.1) yrs.The BMI of included participants was reported in 7/25 studies [9, 13, 28-30, 33, 35] with a mean (SD) of 26.5 (1.8) kg/m 2 .

Randomized controlled trials.
Thermal sensitivity evaluated by sensory mapping with a metal thermo-roller was assessed in all 5 RCTs.Mechanical hypersensitivity (allodynia) for brush and hypo-or hyperalgesia for punctate stimulation was additionally assessed with sensory mapping in one of these studies [42].
MDT and MPT were included as QST-modalities in one RCT [42] using 17 progressively rigid polyamide monofilaments ranging in bending force from 0.1 to 2941 mN.Thermal thresholds were assessed in all 5 RCTs.A suprathreshold heat pain stimulus (STHS) was used in the assessment of pain intensity.WDT, CDT, HPT, and CPT were assessed in one RCT [42], WDT, CDT, and HPT in 1/5 studies [8], whilst the thermal paradigms in the remaining 3/5 studies [9,29,30] were WDT, CDT, HPT, and STHS.The thermal examinations in all RCTs were performed using a Modular Sensory Analyzer (MSA).The active thermode area was 12.5 cm 2 and the temperature ramp rate ± 1˚C/s (Table 1).
The PPT was also measured in all RCTs using a pressure algometer, with a cut-off limit of 350 kPa (Table 1).
Assessment of temporal summation to brush and punctate stimulation was included in 1/5 RCTs [42].
Pain intensity assessments related to the QST were reported with the VAS (Visual Analog Scale) 0-10 in all studies.
Control-site examinations were performed in the contralateral groin in all 5 studies.
In the 15 studies examining MDT, there was no significant difference in MDTs between the surgical side vs. non-surgical side or control group in 6 studies [12,15,18,25,26,42].Four studies [13,24,27,28] reported a significantly increased MDT in the surgical groin compared to the contralateral side.Five studies [7,10,34,38,39] provided insufficient reporting of data regarding comparison of baseline MDT-values on the surgical side, contralateral groin, or other reference data (Table 3).
For the analysis of CPT, data from 6 studies [12,24,[26][27][28]31] were pooled (n = 160; Fig 2F).Compared to the control area, there were no significant differences in CPTs (mean difference 0.5 (95% CI = -0.7,1.6) ˚C (P = 0.44)).Heterogeneity was low (I 2 = 0, P = 0.67).In total, 3 studies [13,28,31] found a significant numerical increase in CPT in the surgical groin, compared to the control area.No significant differences were found in the remaining studies (Table 3).STHS was applied in 4 studies [8,9,30,33] (3 RCTs, 1 non-RCTs).A comprehensive analysis was not possible due to the format of data presentation in the studies.One study [29] found a statistically significant decreased STHS-induced pain intensity in the control group receiving 2% lidocaine blockade in the painful site.In the study by Wijaysinghe et al. [9], the intervention group had a significantly decreased STHS-induced pain intensity after bupivacaine tender point blockade.The remaining 2 studies [8,30] examining STHS did not find a significant difference in induced pain intensities when comparing the painful site with a reference area or a control group (Table 3).
In 2 of the RCTs [9,29], significant PPT increases in the surgical site were found following intervention with 5% lidocaine patch or 0.25% bupivacaine tender point block.There was no significant difference in PPT in the remaining RCTs [8,30,42].For the non-RCTs, 4 studies [12,18,26,27] found no significant difference in PPT.In 4 of the studies [24,25,35,37], there was a significant decrease in PPT, whilst 3 studies found a significant increase [13,15,28].The remaining 4 non-RCTs [7,10,38,39] showed insufficient reporting related to the outcome (Table 3).[8,9,29].The study by Aasvang et al [42] showed "some concerns" in domain 5 (bias in selection of the reported result), resulting in the overall judgement of "some concerns" of risk of bias.The study by Bischoff et al. [30] was assessed as having "high" risk of bias in domain 4 (bias in the measurement of the outcome), resulting in an overall judgment of "high" risk of bias.The assessment was justified by the fact that the blinding of investigators and study subjects would be problematic due to the pungent smell and stinging sensory properties of the capsaicin patch compared to the inert placebo patch.

Non-randomized controlled trials (Newcastle Ottawa Scale).
For the cross-sectional studies, a modified version of the NOS was used [45].A summary of the NOS bias assessments is provided in Table 4.A full overview of the quality gradings is available as S1 Table .Cross-sectional studies and S2 Table .Cohort studies.The NOS bias assessments summarized: Only 3 of the cohort studies [13,28,39] failed to meet the criteria related to "representativeness of the exposed cohort", as the cohorts consisted of highly selected study subjects.Additionally, 3 of the cohort studies [31,33,39] provided a "demonstration that outcome of interest was not present at the start of the study" [21].Not a single study was allocated a "star" under "assessment of the outcome" since every study either used self-reported questionnaires/interviews or because the outcomes related to QST were, in fact, self-reported by the study participant.Further comments regarding the NOS are provided in the discussion section below.

Short summary
The aims of this systematic review were, first, to identify and describe the available literature on the use of QST in patients with PPSP following GHR, and, second, to explore the role of QST in understanding mechanisms underlying PPSP following GHR.To the best of our knowledge, this is the first review to systematically assess the use of somatosensory testing in this cohort.The review, based on 25 studies (5 RCTs, 20 non-RCTs), delivers, a qualitative synthesis of the findings coupled with a meta-analysis of data obtained across eligible studies.
In 15/25 studies, mechanical assessments, MDT, and MPT were assessed.Thermal assessments WDT, CDT, HPT, CPT, or STHS, were included as QST-modalities in 21/25 studies and PPT in 20/25 studies.Analysis of pooled data from GHR patients with PPSP showed significant differences between the surgical side and reference sites in MDT   As mentioned, the RoB 2.0 was used for the methodological quality assessment of included RCTs and NOS for non-RCTs.For the quality assessments of the RCTs with RoB 2.0, we found the tool intuitive to use, and the Cochrane Collaboration has provided thorough guidance for the application of the tool.This resulted in less doubt when conducting the methodological quality assessments avoiding ambiguous interpretations of how to use the tool.It should be noted that RoB 2.0 is the gold standard for quality assessments of RCTs, whilst no such standard is set for non-RCTs as to the best of our knowledge.
4.2.2Newcastle-Ottawa Scale.Although the NOS is a validated tool for assessment of risk of bias in non-RCT studies, concerns have previously been raised regarding the use of this instrument [46,47].While a manual for the tool is provided [21], we found the available guidance on the application of the tool to be somewhat sparse.This lack of clear guidance and our limited experience with the tool led to repeated complex discussions regarding the obtained results between the present authors.

Mechanical assessments
4.3.1 Punctate mechanical thresholds.Methodological issues.Methodological concerns regarding the use of monofilaments for assessment of MDT and MPT, include regular calibration.Polyamide monofilaments are affected by the relative humidity [43,48] and usage [49].The calibration procedure entails measurement of bending force for each monofilament using a precision weight and recording of the relative humidity of the environment by an electronic hygrometer.Notably, one percent increase in relative humidity corresponds to a 1-4% relative decrease in numerical bending force, depending on the diameter of the monofilament [50].Seasonal variations in relative humidity are common, meaning that the bending force may fluctuate over the course of a study.Calibration curves across different relative humidities have been published [43].
In the included studies assessing MDT and MPT, the monofilaments used were handheld by the investigator, which could result in a variability in impact angle and contact area between the monofilament and skin [50][51][52].
Only five studies [13,26,28,34,39] specifically stated that the monofilaments were calibrated.A single study [18] mentioned that the monofilaments were calibrated at a specific relative humidity and temperature (35%, 23˚C).In the included studies assessing MDT and MPT, 8/15 [13, 15, 25-28, 33, 42] mentioned that the QST was performed in a room with a temperature of 20-24˚C.However, the bending force is not affected within a temperature range of 22-30˚C [43].
Outcomes-Mechanical detection threshold.Based on our analyses (Fig 2A ), MDT was significantly increased (P = 0.002) on the surgical site in patients with PPSP compared to the contralateral groin.As such, patients affected by PPSP following GHR experience hypoesthesia for punctate stimulation (loss of sensory function).A single study has been conducted to establish normative data on sensory function in pain-free post-herniotomy patients [27].The study included 40 patients, who had all undergone open surgery.A significant increase (hypoesthesia) in MDT, was demonstrated when comparing the surgical side with the contralateral side, corroborating our findings.
Outcomes-Mechanical pain threshold.Regarding MPT, our analyses indicated a near-significant difference in the surgical site compared to the contralateral groin (P = 0.02; Fig 2B).Two studies [13,25] showed a significant decrease in MPT (gain of sensory function), with one of them [13] being an outlier when compared to the other data.Five out of 13 patients included in the study had previously undergone remedial operations without meaningful improvement.The surgical interventions included "groin re-exploration, replacement or mesh-removal and unsuccessful neurectomy of the ilioinguinal and iliohypogastric nerves".Likely, this would indicate that the 5/13 patients experienced advanced neuropathic pain associated with mechanical hyperalgesia [13].This could explain the deviations, the gain of sensory function as well as the increase in data variance seen in this outlying cohort.Interestingly, prior to the triple neurectomy performed in the study, the patients had a VAS-score ranging from 5 at best to 9.5 at worst.Six months after the triple neurectomy, the VAS-scores were 1.5 and 5.5 respectively.4.3.2Blunt pressure pain threshold.Methodological issues.All 20 studies that included PPT as a QST-modality used a handheld pressure algometer for assessment of blunt pressure (Table 3).Several studies have demonstrated high reliability when assessing PPT with handheld pressure algometers in various anatomical regions [53][54][55][56].
However, differences across studies, related to the probes' contact areas could contribute to data variability (heterogeneity).Six of the 15 studies [12,15,18,24,26,27] assessing PPT used a probe with a surface area of 0.18 cm 2 , while the remaining 9 studies used a contact area of 1 cm 2 .It is important to consider the stimulation area, since differences in probe area size could influence results due to differences in stimulation of superficial and deeper situated nociceptors (skin vs. fascia) [1,57].If the same force was to be applied with a 0.18 cm 2 probe and a 1 cm 2 probe, the pressure would be reduced by a factor 5.6.This would result in a significant indentation when using the larger probe compared to the smaller probe.
As with the monofilaments, calibration can likewise potentially affect the equipment used for assessing PPT.This is however a mere speculation-no study has been conducted with the purpose of comparing calibrated vs non-calibrated handheld pressure algometers.None of the included studies mentioned whether the pressure algometers used were properly calibrated prior to assessments.
Outcomes.As a single modality, blunt PPT was most frequently included as part of the QST protocols in the studies.In total, 9/20 studies found significant differences in PPT.Five of these studies were intervention studies investigating the effects of a lidocaine patch [29], ultrasound-guided tender point blockade [9], and triple neurectomy [13,15,28].Based on the analysis, PPT was significantly decreased in the surgical site compared to the contralateral groin.

Thermal assessments
4.4.1 Methodological issues.An important aspect of thermal assessments is the active thermode area used for assessing thermal thresholds, i.e., spatial summation.Most of the studies used a rectangular thermode with a surface area of 12.5 cm 2 (Table 3), while three studies [13,28,39] used a quadratic size of 9 cm 2 .When comparing thermal thresholds considerable deviations may occur if differing active thermal areas are used uncritically, as shown in the study by Rasmussen et al. [58].Most noticeably, one study [31] stated the use of a thermode size of 30 mm 2 , while in the supplementary files for the study, an area of 9 cm 2 is mentioned.
None of the included studies commented on regular calibration procedures of the equipment used for thermal assessments.
4.4.2Detection thresholds.Our analyses of thermal detection thresholds showed significant increases in WDT and absolute values of CDT, indicating a loss of small fiber sensory function (cf.section 4.5.).

Pain thresholds.
Our analyses of thermal pain thresholds showed a significant increase in HPT, indicating a loss of small fiber sensory function, while no significant differences were found regarding CPT (cf.section 4.5.).

4.4.4
Outcome: Suprathreshold heat stimulus.Pain assessments with suprathreshold heat stimuli (STHS) were also included in 5 studies [8,9,18,30,33], with various results.As shown in Table 3, some studies found significant increases in pain intensities induced by STHS, which could indicate an involvement of central sensitization in patients with PPSP following GHR [10,59].

Cutaneous vs. deep mechanical thresholds
The surgical procedure and the type of mesh implant could also have an impact on the transition to chronic pain.Minimally invasive repair seems to be linked to a lower incidence of postoperative complications, e.g., hematoma, wound infection, a lower prevalence of persistent pain, and an earlier return to work/daily activities [1].Further research is, however, needed to minimize confounding variables obscuring the results [1,2].In addition to groin hernia repair, other surgical procedures such as breast implants, vascular grafts, and joint prosthetic material are also known to be associated with pathophysiologic events related to mesh implants [3].Iatrogenic nerve damage and the gradual onset of neuropathic pain may be brought on by surgical dissection or transection of the nerve or by fixation of the mesh (sutures, tacks).Additionally, the mesh implant is prone to dehiscence, dislocation, induration, invasion of nearby structures, or shrinkage, processes that may result in a 20-90% reduction in mesh area [4,5].
Studies have shown a loss of intraepidermal nerve fiber density (IENFD) on the surgical side in groin hernia repair patients when compared with the contralateral, healthy groin [29,30].This decrease in IENFD could serve as an explanation for the hyposensitivity ("loss of function") in WDT, CDT, HPT, and MDT.However, no significant differences in sensitivities were found for CPT and MPT, in spite of a loss of small fiber sensory function (theoretically resulting in increased thresholds).This paradoxical finding indicates the presence of a compensatory central sensitization phenomenon.
In the case of hyperalgesia ("gain of function") for blunt pressure stimulation, the issue likely resides in the deeper tissues.When assessing PPT, the pressure is applied on the point of maximum palpatory evoked pain, an area that relates to the superficial inguinal ring.The opening in the abdominal wall is associated with several important anatomical structures, including the vas deferens, vascular supply to the testicles, the ilioinguinal nerve, and the genital branch of the genitofemoral nerve [7].When performing blunt pressure algometry, pressure is applied to the superficial ring, compressing these deeper structures, including part of the implanted mesh [1].A severely inflamed mesh may develop into a pathological ''meshoma" [6].Histologically, a "meshoma" is a granulomatous process that mechanically or by inflammation may affect or compress adjacent tissues, e.g., the spermatic cord or nerves, developing into a "pain generator".Furthermore, peripheral nerves such as the ilioinguinal nerve and the genital branch of the genitofemoral nerve have been demonstrated to become embedded in mesh material leading to pain by mechanical and inflammatory reactions [1].
Two of the studies included in our review have specifically addressed the "pain generator" [8,9].The studies performed in patients with severe persistent pain following groin hernia repair were double-blind, crossover RCTs applying an ultrasound-guided blockade.In the first study (n = 12), the iliohypogastric and ilioinguinal nerves were targeted at the level of the anterior superior iliac spine [8].However, the blockades had no effect on the PPSP, possibly indicating that a block of the genitofemoral nerve instead was necessary to achieve pain reduction.In the second study (n = 14), blockades at the tender point located above the superficial inguinal ring were examined [9].A median decrease in pain was observed, i.e., 63% compared to 36% after placebo (P = 0.003) [9].Although the pain relief was found to be short lasting, the results suggested that peripheral afferent input from the tender point area has an essential role in the preservation of evoked and spontaneous pain in PPSP following groin hernia repair.In addition, several studies have found that a surgical approach, e.g., meshectomy, or, selective or triple neurectomy, may result in a significant reduction of pain compared to control groups [15,60].Furthermore, a recently published study [61] indicates that re-surgery in the form of meshectomy and selective neurectomy provides increases in thermal and punctate mechanical thresholds.The study importantly reports highly significant increases in PPT following re-surgery supporting that meshectomy and selective neurectomy may slow the "pain generator".
As such, the pathophysiology behind PPSP in GHR-patients could partially be explained by partial deafferentation of cutaneous nerve fibers in combination with the development of a "pain generator" in deeper layers, e.g., subepidermal structures and fascia layers.Re-innervation and neo-innervation in mesh implants and in indigenous tissue are well-known phenomena in herniorrhaphy patients.Interestingly, in patients where pain is the reason for meshexcision, the mesh neural innervation has been shown to be significantly higher in comparison to patients where the mesh was excised because of recurrence [4].

Limitations
4.6.1 Studies.Number of studies.One limitation of the review is the limited number of eligible studies.Whereas our comprehensive search strategy identified 25 studies, we were only able to pool data from 11 of the studies for quantitative analysis.
Level of heterogeneity.The studies differed regarding applied QST modalities, methodological quality, statistical processing, and data presentation.However, a caveat is that in most of the studies, QST variables were not part of the main outcome, which could explain the observed heterogeneity across studies.Although some of the studies cited the DFNS paradigm, comprising seven tests with 11 stimulation modalities and the assessment of 13 somatosensory variables, the complete paradigm was not used in any of the studies [14].Test durations of 27 ± 2.3 min per test area have been reported in healthy volunteers [14].Applying the complete testing paradigm on individuals in severe pain at two to three locations may cause individual distress and fatigue, and potentially affect the reliability of somatosensory testing.Definitions of "moderate" and "severe" pain also differed between studies, with discrepancies in the NRS score (0-10) corresponding to a particular intensity of pain.For example, some studies defined severe pain as NRS ranging from 8-10 [11, 26], whilst others defined it as NRS � 6 [29,42] or � 7 [38] (Table 1).Standardized definitions of pain intensities, as proposed by Collins et al [62], could be beneficial in reducing uncertainties in the literature regarding pain patients.
Test-retest reliability.Assessing the reliability of QST data is important for correct interpretation.The sensory perturbations caused by surgery are highly variable between individuals but also within individuals [61].Therefore, addressing the variability by test-retest analyses is necessary for evaluating validity of QST data.However, one study [63] reported test-retest reliability using secondary study data from healthy volunteers.Interestingly, thus, it does not seem that test-retest data are currently available in patients with persistent pain after groin hernia repair.
Healthy controls vs. contralateral side.The controlled studies used different methodological approaches when comparing the sensory abnormalities at the surgical site to a control site.Either an absolute approach, comparing with a normative healthy cohort, or a relative approach, comparing with the individual's contralateral homotopic site, or a combination of these approaches, were used.One of the advantages of the relative approach is that the within-subject variances often are significantly smaller than the between-subject variances.Using the individual's contralateral site as a control is thus expected to reduce data variability, making the data more robust and less susceptible to confounding factors such as age, gender, and random errors.On the other hand, mirror-image sensory dysfunction [64], a neural cross-talk between the sides, may influence the side-to-side difference in the relative approach.Very few studies have systematically examined the pros and cons of the absolute and relative approaches [65].
4.6.2Review methodology.Systematic vs. narrative approach.The limited number of studies available for quantitative analyses, 11/25, infers that a narrative analytical approach was necessary for the remaining studies.
Meta-analytical approach.Due to the limited data accessibility in the pooled analyses and the large general heterogeneity of the studies, the authors decided to designate the examination as a "meta-analytical approach".Nevertheless, the forest plots provide relevant and meaningful patterns of postsurgical sensory dysfunction (Fig 2A -2G).

Conclusions
This systematic review critically examined all published literature related to quantitative somatosensory testing in patients with persistent pain after groin hernia repair.Twenty-five studies were included; significant heterogeneity regarding methodology, outcome assessment, data synthesis, risk of bias, and overall quality was encountered.Based on a meta-analytical approach applied to 11/25 studies, quantitative analyses indicated significant sensory perturbations on the operated side, i.e., loss of sensory function regarding cutaneous thresholds and a gain of sensory function regarding deep tissue stimulation.These results indicate that hyperalgesia originating from deeper tissues is a potential key element in development of persistent pain after groin hernia repair.Cutaneous deafferentation may contribute to hyperalgesia either directly or indirectly by central sensitization.

Fig 1 .
Fig 1. PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources.*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.From: Page MJ, McKenzie JE.Bossuyt PM, Boutron l, Hoffmann TC, Mulrow CD, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.BMJ 2021; 372:n71.doi: 10.1136/bmj.n71.For more information, visit: http://www.prisma-statement.org/.https://doi.org/10.1371/journal.pone.0292800.g001

3. 5
Quality assessment 3.5.1 Randomized controlled trials (RoB 2.0).An overview of the assessments is provided in Fig 3. Three of the 5 studies were deemed "low" risk of bias