Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study

2.1 Study population

All patients of 18 years of age or older were eligible for study participation if they met the following inclusion criteria: (1) Patient (had) suffered from abdominal complaints matching ACNES with a constant superficially located site of tenderness, a small (<2cm²) area of maximal tenderness, and increased tenderness by abdominal muscle tensing while palpating the trigger point [1, 2, 4] (Carnett’s test positive) [15]. (2) Patients had been treated for this condition with injection therapy or surgery at least 3 and at most 12 months before.

Exclusion criteria were: (1) a history of a chronic pain syndrome that possibly interfered with the interpretation of QST results, e.g. fibromyalgia, (2) pre-existing affected sensory input (e.g. neuropathy due to diabetes mellitus) and (3) pain localized in a surgical scar.

2.2 Allocation

The pain state before and after treatment was documented using the Visual Analogue Scale (VAS). Patients were asked to mark their pain on a 100 mm line, with the extreme left representing no pain and the extreme right the worst imaginable pain [16].

Patients were allocated to either the responsive or refractory treatment group based on their response to treatment. They were scored ‘responsive’ if they showed an improvement of the VAS score after treatment resulting in an absolute pain score of <40. As a VAS of 40 or higher indicates moderate to severe and clinically relevant pain, we chose this as our cut-off point [17, 18]. The satisfaction of treatment result was also evaluated.

Baseline characteristics comprised age, sex, aetiology, Body Mass Index (BMI), abdominal medical history, use of analgesics, duration of pain symptoms until diagnosis and local sensory dysfunction before treatment.

2.3 Study procedures

Quantitative Sensory Testing was performed according to the Nijmegen Aalborg QST Screening protocol (NASQ) [19, 20]. Mechanical, i.e. pressure, and electric stimuli were applied. All measurements were performed by the same investigator, in the same calm and climate controlled room, specifically equipped for QST measurements. The complete protocol took approximately 45 min.

After initial QST training, pressure pain detection thresholds (pPDT, stimulation just becomes painful) were obtained using a handheld pressure algometer with a 1.0 cm² probe (Wagner Instruments, Greenwich CT, USA). Pressure was increased at a rate of 5N/s. Each of the following areas on the non-dominant body side was stimulated: musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis, the thenar and bilaterally the paravertebral dermatome affected by ACNES.

Three electric thresholds were measured: electric sensation threshold (eST, stimulation just felt), electric pain detection threshold (ePDT, stimulation just becomes painful), and electric pain tolerance threshold (ePTT, painfulness of stimulation just becomes intolerable).

Thresholds to electric constant current skin stimulation (Digistim; Biometer A/S, Copenhagen, Denmark: titanic stimulation 100 Hz; square waves; self-adhesive electrodes, 3 cm apart) were measured on the musculus trapezius pars medialis, musculus rectus femoris and bilaterally on the abdominal dermatome of the ACNES-affected area.

The sum of the individual dermatomal non-ACNES thresholds was used as a measure of generalized hyperalgesia and the sum of the bilateral dermatomal ACNES thresholds as a measure of segmental hyperalgesia.

The ability to generate descending central inhibitory pain modulation was tested using a Conditioned Pain Modulation (CPM) paradigm, in which we measured the relative change (%) in pain thresholds (pPDT and ePTT) before and after a cold pressor task (CPT). The cold pressor task comprised the immersion of the subjects’ non-dominant hand in ice-chilled water during 2 min, or less if the pain was considered intolerable.

To ensure the validity and reproducibility of the threshold measures, patients were thoroughly instructed and trained. Every threshold was measured twice for pressure testing and three times for electric testing. For all elements of QST measurements VAS scores were documented to verify whether patients understood the instructions correctly and were consistent in indicating their thresholds. The CPM response was tested last, as it may influence the other measurements. All concomitant medication was continued.

2.4 Psychosocial assessment

To assess the psychosocial dimension of pain in ACNES, subjects were asked to complete three questionnaires before QST measurements. The Pain Anxiety Symptom Scale (PASS) measures four aspects of pain related anxiety: (1) fear of pain, (2) cognitive anxiety, (3) flight or avoidance behaviour and (4) physiological symptoms of pain. Higher scores reflect a higher degree of pain-related anxiety [21, 22]. The Pain Catastrophizing Scale (PCS) assesses pain-related ruminating, magnifying and helplessness, a score of more than 24 indicates a high level of catastrophizing [23]. The Hospital Anxiety and Depression Scale (HADS) is a screening instrument for possible signs of depression and anxiety. Scores for each subscale (anxiety and depression) can range from 0 to 21 with normal (0–7), mild (8–10), moderate (11–14), severe (15–21) [24, 25].

2.5 Statistical analysis

This was an exploratory study for which no sample size calculation was performed. We pragmatically chose a sample size of 50 subjects. The primary effect parameter for comparison between groups was the difference in sum of the individual dermatomal non-ACNES thresholds. Only the second measurements were compared to decrease bias due to unmodulated first responses, using a Mann–Whitney U test. Secondary outcome measures were differences in sum of electric thresholds, differences in individual dermatomal thresholds and differences in CPM response and questionnaire results. For determination of correlations we used Kendall’s Tau test. Data analysis was performed using the Statistical Package for the Social Sciences (SPSS version 20, SPSS Inc., Chicago, IL, USA), and all statistical tests were two-tailed. The chance for type one errors was set at 5%. Given the non-Gaussian data distribution purely non-parametric analysis was performed and all baseline characteristics and test results are presented as medians with interquartile ranges (IQR). Missing data were left out of analysis.

3.1 Pressure pain thresholds

Refractory ACNES patients showed a significantly lower sum of the non-ACNES as well as the ACNES dermatomal pressure pain thresholds compared to the responsive group as shown in Figs. 2 and 3. Pressure pain detection thresholds also differed according to individual site of measurement. In the refractory group significantly lower thresholds were found for the musculus trapezius, musculus abductor hallucis and both corresponding paravertebral ACNES dermatomes (Fig. 4).

Fig. 2

Sum of non-ACNES dermatomes pressure Pain Detection Thresholds (pPDT) in responsive (n = 15) and refractory (n = 34) ACNES patients, presented as medians with IQR.

Fig. 3

Sum of ACNES dermatomes pressure Pain Detection Thresholds (pPDT) in responsive (n = 15) and refractory (n = 34) ACNES patients, presented as medians with IQR.

Fig. 4

Individual pressure Pain Detection Thresholds (pPDT) in responsive (n = 15) and refractory (n = 34) ACNES patients, presented as medians with IQR.

3.2 Electric pain thresholds

Sums of electric non-ACNES and ACNES dermatomes thresholds did not differ between groups (Table 2). No differences in individual thresholds were found (data not shown)

3.3 Conditioned pain modulation

CPM response was similar in both groups for latency of cold pressor task (CPT), VAS score during CPT and percentage change in pressure and electric thresholds after CPT (Table 3).

3.4 Psychological assessments

Patients refractory to treatment scored significantly higher on the PASS and both subscales of the HADS questionnaire. For the PCS only a trend towards higher scores was seen in treatment-refractory patients (Table 4).

4.1 Findings

This is the first study investigating central pain processing in ACNES. The refractory group showed significantly lower pressure pain thresholds, sum and individual-dermatomal, compared to the responsive group, despite the use of more and stronger analgesics in the refractory group.

Lower pressure pain detection thresholds in the affected ACNES dermatome in refractory patients are to be expected, as these patients are currently experiencing pain. Interestingly, pressure pain thresholds are also decreased in areas remote from the ACNES dermatome, despite the very localized character of ACNES.

Based on our results, we hypothesize that the lower pressure pain detection thresholds in the ipsi- and contralateral ACNES dermatomes are a representation of segmental hyperalgesia. The higher sum and individual pain thresholds in the areas remote from the ACNES dermatomes may be a reflection of generalized hyperalgesia. In other words, sensitization of both spinal and supraspinal central pain processing might be present in some patients suffering from ACNES. Given the localized treatment, one could imagine poorer outcomes in these patients.

There was a significantly longer duration of complaints until diagnosis and treatment in the refractory group, which also correlated with treatment outcome. As persistent nociceptive input is associated with the development of spreading hyperalgesia and central sensitization, this finding is compatible with our hypothesis of altered central pain processing in ACNES.

The distribution of age and gender, which are known to influence thresholds, was equal between groups [26, 27]. Therefore, we assume they have not altered the results.

No differences were found in any of the electric thresholds. A possible explanation for this outcome can be found in the different targets of the different QST modalities. Electric testing is predominantly targeted at cutaneous Aβ-fibres and normally does not penetrate beyond cutaneous tissue [28, 29]. Pressure algometry is directed at the more deeply situated tissue, such as muscles and bones [29]. The absence of difference in electric testing could thus reflect the pathophysiology of ACNES, in which the problem is located in the more deeply situated tissues, i.e. at the level of the rectus abdominis muscle [3].

The CPM results were similar between groups. The used paradigm for testing met the methodological criteria advised in a recent review on CPM [30]. Based on these results we have no indications that impaired endogenous analgesia plays a role in persisting pain in ACNES, However, the lack of difference could be due to the small sample size.

Refractory patients scored higher on the psychological surveys, which is in line with a higher prevalence of depression and anxiety in chronic pain patients [31]. Whether these characteristics are determinants for, or consequences of persistent pain cannot be answered by the current study design. Given the bidirectional association between chronic pain and factors such as depression and anxiety described in literature, baseline and follow up measurements would be needed [32]. It would be very interesting to see whether the presence of these factors will fluctuate with intensity and duration of pain. Though refractory patients scored higher on the HADS questionnaire, their scores remained in the normal range.

4.2 Methodological aspects

A major limitation of this study is the retrospective data collection of patient demographics and pain scores, which has a considerable risk of recall bias. Considering treatment effects, recall bias often leads to an overestimation of the degree of effect [33, 34]. Group allocation was based on improvement after treatment resulting in a current VAS score of <40, but not on the degree of effect. Therefore we believe this has not significantly influenced the allocation procedure and consequently our results.

Although satisfaction is an important success parameter, we allocated two unsatisfied patients to the responsive group. Thirty-three to 50% or 11–30 mm improvements on a Visual Analogue Scale are generally accepted as clinically relevant changes in pain [35, 36, 37], and VAS scores of <40 indicate only mild pain [17, 18]. As both criteria applied to these two unsatisfied patients, we judge this allocation as correct.

Quantitative Sensory Testing is a validated and commonly used tool for exploring the central nociceptive processing of a group of patients [13]. Apart from pure diagnostic value, QST has shown to be able to monitor disease progression [38], predict treatment effects [11, 39] and contribute to choice of treatment [14].

These characteristics of QST could be particularly useful in ACNES, given the relatively high percentage of patients refractory to standard treatment.

Unfortunately, we only performed a single post-treatment QST measurement. Therefore, we do not know whether the differences in central pain processing between groups were present before treatment. Nor do we know whether treatment has influenced pain processing, in either direction. For instance, in osteoarthritis of the hip successful treatment has led to normalization of pain thresholds [40]. We find it less likely that the lower pain thresholds in refractory patients are a consequence of treatment, as both groups received equal treatment.

To validate the aforementioned utilities of QST in ACNES and our hypotheses that (1) altered central pain processing can play a role in ACNES and (2) local treatment failure may be related to these alterations, longitudinal research is needed. We suggest a prospective repeated measures cohort study, with thorough baseline measurements and multiple follow up moments during and after treatment, up to at least one year post-treatment [41, 42]. The good intra- and interobserver and test-retest reliability of QST makes it an appropriate tool for this study design [43, 44].

An additional weakness in the study design is the collection and analysis of data by the same investigator, who was not blinded to group allocation during measurements, which increased the risk of bias. Furthermore there is a chance of type II error given the relatively small sample size.

4.3 Clinical and scientific implications

The experimental protocol presented in this exploratory study provides a non-invasive technique to identify ACNES patients with abnormalities in central pain processing. Hypothethically, these patients suffer from an increased risk of failure of locally directed treatments or the development of chronic pain. In such patients, it would seem logical to consider treatment with drugs targeting central pain processing, e.g. gabapentinoids or tricyclic antidepressants, instead of instituting local deafferenting treatments such as local anaesthestic injection or neurectomy [45]. To validate these hypotheses additional research is needed.