Paradox pain sensitivity using cuff pressure or algometer testing in patients with hemophilia

1 Introduction

Hemophilia is a rare coagulation disorder with a deficiency of either clotting factor VIII (FVIII), known as hemophilia A or factor IX (FIX), which is referred to as hemophilia B. The factor deficiency leads to (spontaneous) bleeding into muscles and joints [1,2,3]. Most frequently, patients with hemophilia (PwH) are affected by joint bleeds (hemarthroses) in ankles, knees, and elbows [1,4]. The major consequence is that repeated joint bleeds can lead to chronic synovitis and progressive joint damage, known as hemophilic arthropathy, going along with severe joint pain, swelling, warmth, and decreased range of motion [3].

The assessment of pain is difficult since pain is a highly subjective and complex sensation usually measured using certain scales. Though, pain sensitivity, which refers to the degree to which an individual experiences pain in response to a stimulus that would typically produce pain, can be measured semi-objectively by applying, among others, mechanical pain stimuli [5]. Here, pressure pain thresholds employing algometry (PPT_a) are used to assess pain sensitivity, for instance at affected structures, i.e., ankle, knee, and elbow joints [2]. Prior research indicates that PwH suffers from hyperalgesia at the joints, as PPT_a are lower compared to healthy control subjects [6,7]. The results of local pain thresholds provide an insight into acute joint health and sensitivity. However, peripheral, central, and cognitive-affective influences can affect pain processing [8]. It is still a matter of research to investigate the precise pain processing mechanisms [9]. The relationship between joints, which are affected by hemophilic arthropathy and pain, is undisputed, though it is not possible to point to the origin of altered pain sensitization in PwH so far, emphasizing the complexity of pain processing [10,11].

Moreover, cuff pressure algometry (CPAR) is getting more attention in research of pain assessment (PPT_cuff), whereby single or double chamber cuff pressure is induced on peripheral structures such as the calf or arms. Equal to the handheld algometry, patients indicate the first painful stimulus and PPT are determined. This assessment tool is less prone to bias, as the whole measurement is computer-controlled and hence user independent [12]. It has been shown that patients, who suffer from knee osteoarthritis, have lower PPT_cuff values compared to healthy controls [13]. These findings agree with prior literature on other pain-associated musculoskeletal diseases [14]. Yet, findings on PPT_cuff in PwH do not exist so far. However, previous literature showed that PPT_a of the forehead does not differ in PwH compared to Con, which points toward a local joint-specific hyperalgesia only [6]. Thus, it is of interest to examine the pressure pain sensitivity of the calves, which are localized between affected structures though are not directly affected by degeneration. To bridge this gap, it is aimed to measure the PPT_a at the commonly affected joints in PwH, the knee and ankle, using a hand-held algometer. In addition, for a broader perspective on pain perception, it is aimed to assess PPT_cuff at the shank using the CPAR device. Including this non-joint site measurement, insights into whether pain sensitization patterns in PwH are joint specific or more generalized can be generated.

Based on these considerations, the following two hypotheses are stated: (1) The PPT_a at the knee and ankle joints in PwH will differ from that of a pain-free age- and BMI-matched control group, indicating specific pain sensitivities related to hemophilia. (2) The PPT_cuff at the shank will show differences between the two groups, suggesting that pain sensitization in PwH may extend beyond the joints typically affected.

2 Methods

3 Results

Due to regular analgetic intake, three PwH were excluded from further analysis as well as 10 Con due to a lack of compliance during the measurement or too high NRS (≥3) scores, indicating the presence of pain which influences pain assessment. Hence, data from 37 PwH and 35 Con were analyzed. Anthropometric data are presented in Table 1. PwH showed a significantly higher HJHS total score compared to Con (p < 0.001) as well as a higher HJHS score of the lower extremities (p < 0.001), indicating a significantly worse orthopedic joint situation in PwH. In PwH, total joint replacement was present in 9 PwH at 11 joints: ankle right (n = 1), knee left (n = 5), and knee right (n = 5). Besides, the subjective pain situation on both scales was significantly higher in PwH compared to Con (see Table 1). The presence of neuropathic pain based on the painDetect questionnaire was considered unlikely in all Con and in all but three PwH. These three PwH showed a score between 13 and 18 points revealing an unclear neuropathic pain component.

Results of the pain measurements are presented in Figure 1 and Table S1 (Supplementary Material) and reveal lower PPT_a values at the left ankle (p = 0.034) and both knee joints (left: p = 0.005, right: p = 0.017) in PwH compared to Con. The only exception is observed at the right ankle, where data do not show a significant difference (p = 0.076). PPT_a measured at the forehead showed no differences between the groups (p = 0.257). Results of the PPT_cuff measurements reveal higher values in PwH compared to Con at the left (p = 0.009) and right (p = 0.038) leg. Patients with viral comorbidities did not show any significant difference in any PPT_a or PPT_cuff outcomes. Differences in PPT_a were observed between major affected PwH, minor PwH, and Con at the left (p = 0.014) and right knee (p = 0.047). Post hoc analyses for the left knee revealed that minor PwH exert significantly lower values compared to Con (p = 0.020) while no significant post hoc differences were observed at the right knee. At the left (p = 0.105) and right (p = 0.199) ankle, no main effects were observed. Regarding PPT_cuff, a significant difference was observed between the groups (p = 0.015) at the left leg. Post hoc analyses revealed a significant difference between major PwH and Con (p = 0.012). No difference was observed at the right leg (p = 0.093) (see Figure 1).

Figure 1

Boxplots (a, c, and e) showing the comparison between patients with hemophilia (PwH; n = 37) and Con (n = 35) and (b, d, f) showing comparisons between PwH with major (left n = 19, right n = 17) affected lower extremities (based on the HJHS) to minor (left n = 17, right n = 18) affected PwH and Con (n = 35). Outliers are displayed; whiskers indicate 1.5 times the interquartile range, horizontal bars reflect the median, and the box reflects interquartile 1 and 3. * indicates a significant difference of p < 0.05; ** indicates a significant difference of p < 0.01. PwH = patients with hemophilia, Con = healthy controls, PPT_a = pressure pain threshold measured using the algometer, and PPT_cuff = pressure pain threshold measured using cuff pressure algometry.

Results of the correlation analyses between PPT_a of the right and left knee and ankle and respective PPT_cuff of each side are presented in Figure 2. Results reveal significant positive correlations between PPT_a and PPT_cuff in PwH except for the correlation between PPT_a of the right knee and PPT_cuff of the right leg (p = 0.100). In Con, significant positive correlations are observed except for the correlation between PPT_a of the right ankle and PPT_cuff of the right leg (p = 0.102).

Figure 2

Spearman correlation analyses between PPT_cuff and the respective PPT_a of the right (a) and left leg (b) of PwH as well as the right (c) and left leg (d) of Con. PwH = patients with hemophilia (n = 37), Con = healthy controls (n = 35), PPT_a = pressure pain threshold measured using the algometer, PPT_cuff = pressure pain threshold measured using cuff pressure algometry.

Results of the correlation analyses of both groups between PPT and HJHS scores as well as NRS values are presented in Table 2.

The results of the sensitivity analysis, considering total joint replacements can be found in Table S2 (Supplementary Material). It is shown that the results of the main analysis and the sensitivity analysis do not differ substantially.

4 Discussion

The main results obtained in this explorative study are (1) that PwH show a higher local pain sensitivity at affected structures measured via a handheld pressure algometer compared to healthy controls of similar age and (2) that PwH show a lower pain sensitivity at the calves with higher PPT_cuff values measured via CPAR.

PPT_a measurements were conducted at the usually affected joints of the lower extremities in PwH, i.e., the ankle and knee joints [4]. In PwH, these joints are prone to develop hemophilic arthropathy resulting from hemarthroses, which can also occur sub-clinically [23,24]. During these bleedings, blood enters the joint space and induces an inflammatory process, resulting in acute synovitis [1]. Repetitive hemarthroses result in a chronic inflammation and might consequently lead to cartilage and bone degeneration. This inflamed and degenerated joint state is associated with local hyperalgesia and higher overall subjective pain states [2,11]. Neuropathic pain components might also influence pain processing, but this is unlikely in the cohort observed in this study [20]. The PwH included in the present study possess a worse total orthopedic joint condition and a worse condition of the lower extremity joints compared to the Con. Besides, PwH report higher subjective pain states (currently and average over the last 4 weeks) compared to Con. The joint degeneration as well as inflammation might be the main explanatory factors for the higher pain sensitivity at the joints in PwH as observed in lower PPT_a values in PwH compared to Con. These results are in line with previous studies that revealed that PPT_a are lower in PwH compared to healthy control subjects at the joints, while no difference is observed at the forehead [2,25,26]. Furthermore, the correlation analyses reveal that the higher the orthopedic joint impairment is, the lower the PPT_a values are at the joints and that higher subjective pain states also go along with lower PPT_a values at the joints.

In both methods, experimental mechanical pain is tested as pressure increases constantly until the subject reports pain for the first time. Yet, some major differences in terms of the method of how experimental pain is evoked need to be considered as follows: during the PPT_a measurement at the joint space, the active nociceptors are mainly located at the periosteum of surrounding bones, at the joint capsule as well as the overlaying skin. More specifically, at the knee joints, the rubber tip of the algometer presses against the medial condyle of the femur and the tibia and to the tibial collateral ligament of the capsule making these structures most responsible for the sensory response [27,28]. At the ankle joints, pressure is also applied to the joint space between the fibula and the talus (fibulotalar joint) as well as to the anterior talofibular and in part to the anterior tibiofibular ligaments. Physical changes, such as joint effusion and tissue edema, which are observed in the context of hemophilic arthropathy as well as synovitis (induced by pro-inflammatory mediators released within the damaged tissue resulting from hemarthroses) sensitize articular nociceptive afferents and increase the pain sensitivity at the damaged joint [29,30]. This might be associated with silent nociceptors, which are insensitive to noxious stimuli unless inflammation is present [31].

In contrast to the results observed in PPT_a, PPT_cuff results reveal that PwH seem to be less sensitive to experimental cuff-based pressure pain compared to Con. The cuff pressure is mainly applied to the gastrocnemius, soleus, and fibularis longus muscles, as well as to the tibialis anterior muscle. These structures are most likely the structures responsible for the nociceptive response as within muscles, free nerve endings connecting to afferent fibers are found in the connective tissue of the muscle, in blood vessel walls, between muscle fibers, and in tendons [32]. Even though bleeding into muscles can happen in PwH these structures are not as frequently affected as the joints [23].

However, it can only be speculated why PwH show higher PPT_cuff values compared to Con and not similar ones. Pain research conducted in other musculoskeletal disorders reveals that patients with knee osteoarthritis show lower PPT_cuff values compared to healthy controls [13]. This was observed at both the affected and the contralateral knee. Besides, fibromyalgia patients also exerted lower PPT_cuff values compared to healthy controls [33]. Yet, fibromyalgia patients suffer mostly from muscle pain and not from joint pain as is the case in PwH and osteoarthritis patients. When interpreting the results observed in the present study, the different methods used at the affected and non-affected structures need to be considered. Yet, it was previously demonstrated that PPT_cuff and PPT_a are positively correlated [34]. Furthermore, it was recently evaluated whether PPT_cuff measured at the lower limbs and PPT_a measured at the tibialis anterior and the midportion of the gastrocnemius muscle correlate within healthy subjects. Results of this recent experiment reveal a high positive correlation between PPT_cuff and PPT_a measured at the beforementioned muscle structures as well as at the ankle joint space (r > 0.5) [35]. Interestingly, PPT_a and PPT_cuff are positively correlated (weak to moderate) in the present study in PwH and Con. The main difference is that Con shows lower PPT_cuff values, whereas PwH show lower PPT_a values. Reasons explaining this observation remain rather elusive but might be explained by the fact that PwH subjectively experience constant local pain resulting from hemophilic arthropathy, with an average pain over the last 4 weeks of 2.7 (±1.6). It might be possible that, during the PPT_cuff measurement, a certain threshold must be exceeded to be perceived as painful resulting in higher PPT_cuff values.

Moreover, a higher orthopedic impairment of the lower extremities seems to go along with lower pain sensitivity (higher PPT_cuff values), also at the non-affected structures. Considering previous literature, it can be assumed that individuals’ coping strategies lead to this phenomenon [2]. As pain is present in many PwH from young age on, they develop specific coping strategies. However, regions that are primarily affected by degenerative changes are exempt from coping [2,36], especially when mechanical pressure is applied. Here, the structural impairments and inflammation at the hemophilic joints lead to local mechanical hyperalgesia.

5 Strengths and limitations

The major strength of this study is that two experimental pain measurement methods are compared within a relevant large number of patients suffering from the rare disease hemophilia and reveal a different pain sensitivity regulation. However, some limitations are noteworthy to interpret the results obtained. First, this is a cross-sectional study and the cause-and-effect relationship of the disease and the observed results can only be partially established. Second, PPT_a was administered to affected structures, while PPT_cuff was administered to non-affected structures as it is not possible to employ the CPAR at joint landmarks. Therefore, it is difficult to gauge the exact effect of the device used on the pain responses of the respective structures. Third, physical activity was not investigated in this study, though it is known that regular exercising might impact pain processing as seen, e.g., in competitive athletes [37,38]. However, the included subjects did not perform any high-level exercising. Fourth, the presence of total joint replacement might influence pain outcomes. However, a sensitivity analysis showed that the exclusion of joints with replacement does not influence the results.

6 Conclusion

While PPT_a of the knee and ankle joints are lower in PwH, PPT_cuff is higher in PwH compared to Con. This reveals a paradox situation, which can, on the one hand, be pathophysiologically explained by the presence of hemophilic arthropathy influencing local joint pain sensitivity in PwH. On the other hand, explanations regarding the experimental cuff pressure observations on non-affected structures remain elusive. The results are different from results observed in patients of similar musculoskeletal disorders, e.g., osteoarthritis, and future investigations focusing on the different types of pain processing in PwH are needed to verify these results.