Nociceptive Pain in Patients with Neuromuscular Disorders: A Cross-Sectional Clinical Study

INTRODUCTION

The estimated prevalence of pain and fatigue in patients with neuromuscular disorders (NMD) ranges from 30–90% but without differentiation, whether pain is directly associated with muscle disease or secondary due to muscular-skeletal problems [1]. Results of surveys indicate that pain, as a common secondary problem in patients with NMD, has a major impact on their quality of life [2–5]. In some neuromuscular diseases, musculoskeletal pain manifests as one of the initial symptoms, while in others, pain gradually develops as the disease progresses. Findings in pain research are often difficult to compare. The heterogeneity across clinical studies, methods, patient cohorts, and research objectives may explain the substantial variability in pain prevalence, intensity, characteristics, and factors influencing the pain.

Pain perception is individual, very heterogeneous, and based on a complex interaction of exogenous and endogenous influences. Some factors may exert a direct influence on pain. Our previous paper described a correlation between muscle pain and muscle weakness in patients with spinal muscular atrophy (SMA) type 3 [6]. We also found gender differences modifying the perception of pain, which is already described in literature [7, 8]. Surveys conducted by Solbakken et al. in late-onset Pompe disease (LOPD) patients [4] and Moris et al. in facio-scapulo-humeral muscle dystrophy (FSHD) patients [9] also corroborate gender disparities in pain perception within the context of neuromuscular diseases. Individual pain perception is additionally influenced by psychological processes, including cognitive setting, emotions (anxiety, depression, stress, positive feelings), and coping strategies (e.g. avoidant behavior) [10]. Enax-Krumova et al. [11] described a correlation between relevant depression and anxiety symptoms and the intensity of pain in LOPD patients. All these factors contribute to a complex pain perception system that is currently not fully understood.

The aim of this explorative, cross-sectional clinical pilot study was to observe possible differences in prevalence, localization, intensity and characteristics of muscle pain among the various examined neuromuscular diseases. The second objective was to determine whether the patients’ nociceptive pain (assessed by pressure pain threshold PPT) is influenced by gender, muscle strength and psychological factors. Further secondary objective was to examine whether muscle pain of the neck muscles is associated with alterations in muscle frequency, stiffness, relaxation, and creep (assessed by myotonometry).

MATERIAL AND METHODS

Adult patients (aged≥18 years) with genetically confirmed neuromuscular diseases and the ability to perform study-related functional tests were enrolled in this study. Patients with the following neuromuscular diseases were included in the study: spinal muscular atrophy type 3 (walkers), late-onset Pompe disease (LOPD), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), and facio-scapulo-humeral muscle dystrophy (FSHD). Healthy participants were examined as a control group. Because of possible interferences between major depression symptoms and pain, patients with a Beck depression inventory- fast screen score > 3 at screening were excluded from study participation. Other exclusion criteria were participation in another clinical study or the use of an investigational treatment. Also, patients unable to adhere to the requirements of the study, e.g., inability to complete questionnaires due to limited decision-making capacity, language barriers, or organizational difficulties were excluded from this study. All patients were enrolled during their ambulatory or stationary stay at the neuromuscular expert center Friedrich-Baur-Institute at the LMU Munich, Germany, or were invited online through the German patient organizations (Deutsche Gesellschaft für Muskelkranke e.V.). The study was approved by the ethics committee of the LMU Klinikum, Project No. 20-0980, and the protocol was registered on a public clinical trials registry (ClinicalTrials.gov Identifier NCT04907162). Written informed consent to participate in the study was obtained before any study-related procedure.

Detailed methods are described in our previous paper [6]. Summarized, patients' disease-related history and perceived pain, including quality-of-life-related information, was collected. Therefore, we used a battery of questionnaires consisting of the Brief Pain Inventory (BPI), the Fatigue severity scale (FSS) and the German Pain Questionnaire (GPQ), which included the Marburg Questionnaire (MFHW) and the Depression, Anxiety and Stress Scale (DASS). The short form of the BPI thematizes the distribution and intensity of pain as well as the functional limitation due to the pain in the past 24 hours [12]. To assess a possible contributing fatigue, we included the FSS, which measures the severity of fatigue and its effect on persons’ activities. A detailed description of pain was evaluated with the German Pain Questionnaire (GPQ), including pain sites, duration, intensity, pain-relieving and aggravating conditions, and subjective pain perception [13]. The GPQ includes the MFHW and the DASS. The MFHW was used to assess habitual well-being about perceived pain [14]. The DASS is a brief and reliable questionnaire to describe the likelihood of the presence of a depressive disorder, an anxiety disorder, or an increased stress load [15].

Musculoskeletal strength was assessed by the MRC scale (Medical Research Council scale) and dynamometry. A 6-minute walk test (6MWT) and a Quick Motor Function Test (QMFT) were performed to examine the patient’s physical function and muscular endurance. To quantify local nociceptive pain, we used a pressure algometer to measure the pressure pain threshold (PPT) in different muscles. For the non-invasive measurement of muscle fibers’ characteristics, myotonometry was performed using the commercially available MyotonPro^® [16]. The tip of the MyotonPro^® is placed perpendicular to the underlying muscle. Applying a slight preloaded pressure of 0.18 N initiates compression of the superficial subcutaneous tissue, causing oscillation. This oscillation leads to a brief deformation of the muscle underneath. An acceleration sensor now analyzes the vibration behavior of the muscle (see below). The device calculates the tone of the muscle (in Hz), the stiffness of the muscle (in N/m), the relaxation time after deformation (in ms), and the creep, which puts in relation the relaxation time to the total time of deformation [17].

We selected three body regions for which we created sum scores for nociceptive pain and muscle strength to better compare them between subgroups: the neck and shoulder region, the arm region and the leg region. For the assessment of nociceptive pain in each body region, a pressure pain threshold score was calculated by summarizing the PPT values [kg] of the included muscles (deltoid and biceps for the arm region, neck extensor, supraspinatus and trapezius for the neck and shoulder region and knee extensor, foot flexor and extensor for the leg region). To compare muscle strength in each region, MRC or dynamometer values were used. For the arm and leg region, we summarized dynamometer values [kg] for the legs (including hip flexor, knee flexor and extensor and foot flexor and extensor) and arm muscles (including biceps, triceps and deltoid muscle). For the neck region, MRC (Medical Research Council) scale was specified for the neck extensor muscles by assigning a value from 0 (complete paralysis) to 5 (normal strength).

We performed multiple linear regression analyses to show whether gender, muscle strength and psychological components have a significant influence on muscle pain. We chose PPT sum scores as the dependent variables to quantify muscle pain via the pressure pain threshold of the muscles in the three body regions. We chose QMFT, FSS points, and gender as the independent variables. One model was performed for the leg, one for the arm, and one for the shoulder/neck region. For the multiple regression analysis, we chose the inclusion method, in which all variables are inserted in the model simultaneously. This method examines which of the potential variables should ultimately be included in an explanatory model. Correlations were graphically checked for linearity. Because all variables were recorded only one time, the independence of the residuals is present. Because all observations belong to different patients, all observations are independent. To exclude any multicollinearity, absolute Pearson correlations between independent variables exceeding 0.7 were excluded (Table 2). For each independent variable we used at least 15 independent observations. So, at least 45 (3 * 15) observations were needed. Our sample size of 81 independent observations is sufficient for this analysis. Because of list-wise case exclusion because of some missing values, we sometimes worked with fewer cases (but at least 75 cases, which is still sufficient). The significance level (alpha) was set at ≤0.05. A Bonferroni correction was carried out to protect against type I errors. Cohen’s D was calculated for significant test results to estimate the effect size.

SPSS Statistics^® Version 27 and Microsoft Excel^® 2016 were used for statistical analysis. For the illustrations of the human body, BioRender^® was used.

RESULTS

Of 111 patients screened for eligibility, 81 patients were enrolled in the study. 5 patients declined to participate after the study information. 25 patients were not eligible due to BDI score of > 3 at screening.

Patients with the following neuromuscular disorders were included: 20 patients with genetically confirmed spinal muscular atrophy type 3 (walkers), 13 patients with genetically confirmed late-onset Pompe disease (LOPD), 12 patients with genetically confirmed myotonic dystrophy type 1 (DM1), 12 patients with genetically confirmed myotonic dystrophy type 2 (DM2), 12 patients with genetically confirmed facio-scapulo-humeral muscle dystrophy (FSHD), and 12 healthy participants.

Prevalence of pain and fatigue

Pain was distributed with a high variability of frequency and location among the subgroups. Results of perceived pain in the patients are shown in Figs. 1 and 2.

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Fig. 1

Pain frequency for all six subgroups in four different locations of the body Four body regions: the head, neck and shoulder region; the arm region (including upper arm, forearm and hands); the spine region (including thoracal and lumbar spine); the leg region (including gluteal region, thigh, knee, calf, shin and feet region); the unit of the scale is percentage of patients experiencing pain.

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Fig. 2

Pain body maps for the different subgroups DM1 (picture 1), DM2 (picture 2), LOPD (picture 3), SMA (picture 4), FSHD (picture 5) and the control group (picture 6) indicating the frequency of pain in different colors from a low frequency (blue) to a high frequency (red) in different locations.

Pain was especially reported by patients with FSHD and DM2 (Figs. 1 and 3). In FSHD patients, it was mainly the head, neck, and shoulder region (83,3%; N = 10) that was indicated as painful. We found an especially high prevalence of reported pain in the shoulders (75%) and in the neck (58,3%) (Fig. 2, picture 5). In DM2 patients, the leg region (100%; n = 12) was most affected by the pain: 83,3% of the patients reported pain in the thigh region, 50% in the calf region, and 33,3% in the gluteal region. Furthermore, DM2 patients also indicated pain in the shoulder region (58,3%), the lumbar spine (58,3%) and upper arm region (50%) (Fig. 2, picture 2). Back pain was present in 30 to 60 % of all participants.

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Fig. 3

Report of pain. Percentage of subjective pain prevalence in all examined patients and in all examined women. The report of pain was significantly (p = <0.01^**) higher in DM1, DM2, and FSHD patients compared to the control group.

MULTIPLE REGRESSION ANALYSIS

DISCUSSION

We examined differences in pain perception among different neuromuscular subgroups and investigated the impact on possible influencing factors on muscle pain by evaluating clinical assessments and patient-reported outcomes (PROMs). We also examined the association of muscle pain and parameters of a relatively new method by myotonometry.

For the leg and arm region (but not for the neck region), higher values in the QMFT (reflecting higher muscle strength) are associated with decreased muscular sensitivity to pressure. Other significant factors that lead to decreased muscular sensitivity to pressure are male gender and a low score in the FSS (low levels of fatigue). Findings of the myotonometry analysis collectively suggest that the intrinsic muscular tone and stiffness of the neck muscles may play an important role in their pain pressure sensitivity.

It is important to mention, that 22,5% of all screened patients were excluded from the study in advance due to high scores in the Beck Depression Inventory Fast Screen (BDI-FS), suggesting potential interference between manifest depression and pain perception. The prevalence of possible depression in this sample is higher than the prevalence of depression in the general German population (10,1%) [21). However rthe BDI-FS is not equivalent to a psychiatric diagnosis of depression rwhich is likely a contributing factor to this observed bias.

Regarding the first objective of the study rour results (Figs. 1 and 2) indicate differences in the subjective pain experience among patients with different neuromuscular diseases. Pain was especially reported by patients with FSHD and DM2 (Fig. 3). The impairment of pain in daily life (assessed by the MFHW) and fatigue levels were also significantly higher in DM2 patients than in the other subgroups and in the control group (supplements table 2).

To examine the impact of influencing factors on muscle pain rwe extended the analysis by performing a multiple regression analysis (Table 4 r1 r2 r3 r4 r5 r6 rgender and psychological component (represented by FSS). Results show rthat patients who are overall stronger (higher QMFT score) are less likely to experience pain in the muscles of the extremities (Tables 3 and 4). In contrast rthe multiple regression analysis suggests that rin the neck region rhigher muscle strength is associated with higher sensitivity to pressure (Table 5).

A further finding of this analysis is that gender influences PPT scores. Female gender is associated with lower PPT values and increased muscular pressure sensitivity. This result is consistent with the literature 7 r18 r19">21). However, the BDI-FS is not equivalent to a psychiatric diagnosis of depression, which is likely a contributing factor to this observed bias.

Regarding the first objective of the study, our results (Figs. 1 and 2) indicate differences in the subjective pain experience among patients with different neuromuscular diseases. Pain was especially reported by patients with FSHD and DM2 (Fig. 3). The impairment of pain in daily life (assessed by the MFHW) and fatigue levels were also significantly higher in DM2 patients than in the other subgroups and in the control group (supplements table 2).

To examine the impact of influencing factors on muscle pain, we extended the analysis by performing a multiple regression analysis (Table 4–6). We chose the three variables muscle strength (represented by QMFT), gender and psychological component (represented by FSS). Results show, that patients who are overall stronger (higher QMFT score) are less likely to experience pain in the muscles of the extremities (Tables 3 and 4). In contrast, the multiple regression analysis suggests that, in the neck region, higher muscle strength is associated with higher sensitivity to pressure (Table 5).

A further finding of this analysis is that gender influences PPT scores. Female gender is associated with lower PPT values and increased muscular pressure sensitivity. This result is consistent with the literature [7, 18, 19]: male participants were less sensitive to pain pressure threshold measures than women. In a 2009 study [22], Fillingim et al. showed that overall, women are more sensitive to mechanically induced pressure than to other noxious agents and are more likely to develop and maintain musculoskeletal pain conditions. In another study, women showed higher sensitivities to musculoskeletal pain [19]. Differences in the gender-specific perception of pain are frequently reported, but their cause is not yet fully understood. The influence of sex hormones and endogenous opioid structures, as well as psychosocial differences in coping strategies, early childhood stress or the influence of stereotypical gender roles and the associated social gender bias in dealing with pain are widely discussed [5, 19]. The influence of these factors needs to be further investigated in future studies to better understand and treat pain perception, especially in female patients.

Psychological components greatly influence the perception of pain [10]. The influence of the FSS was significant for the arms, neck, and shoulder regions, but not for the leg region. An increase of FSS points, reflecting higher levels of fatigue, resulted in lower PPT scores (and so in higher muscular sensitivity to pressure).

The analysis of the MyotonPro is shown in Table 6. Frequency is measured in Hz and characterizes the intrinsic tension of the neck muscles in a resting and not contracted state [17]. The positive correlation with frequency suggests that higher PPT values (decreased sensitivity to pressure) are associated with increased muscle tone of the neck muscles. Consequently, neck muscles with low intrinsic tension seem to be more likely to cause neck pain. Dynamic stiffness is measured in N/m and characterizes the resistance of the muscle to an external deformation [17]. The positive correlation we found in the analysis suggests that high resistance to the external force of deformation leads to less sensitivity to pressure-induced pain. Mechanical stress relaxation time is measured in ms and shows how fast a muscle can recover after deformation. The parameter of creep is the relaxation time to the total deformation time. The higher the frequency (tension) and the stiffness of a muscle, the shorter the recovery time (the relaxation), and the lower the creep [17]. The correlation was negative for relaxation time and the creep of the neck muscles indicating that PPT values are higher (pain sensitivity is decreased) when muscle recovery time is shorter. In conclusion, less pain seems to be experienced in neck muscles with a high muscle tone, high stiffness (resistance), high structural integrity and a short relaxation time. These factors significantly interacted with our cohort group’s perception of neck pain.

With regard to DM1 and DM2, the symptom of myotonia must also be addressed. This is characterized as involuntary muscle contraction with delayed relaxation and can therefore also influence the MyotonPro measurements. Due to the parallel presence of myotonia and pain, alternative treatment options are also available for myotonic dystrophies. Mexiletine, for example, is used both to treat myotonia and for pain therapy [23].

However, as shown in the multiple regression analysis, the interaction of factors is more complex, and the origin of neck pain must be investigated in further studies.

CONCLUSION

Patients with Myotonic Dystrophy type 2 had significantly higher levels of pain prevalence, fatigue, and impairment of quality of life compared to other examined NMD subgroups and the control group. In contrast, the PPT values of the different body regions were not significantly lower for DM2 patients than those of the other NMD.

We performed a multiple regression analysis to subsume most possible influences on the PPT values. Female gender, high fatigue levels (representing factors such as depression, anxiety, stress, and impairment of quality of life), and low QMFT scores (representing reduced muscle strength) showed an association with increased sensitivity to pressure pain in both the arm and leg regions. These factors should not be underestimated, especially when managing pain in female patients with neuromuscular conditions. Individualized therapeutic concepts including psychological and physical approaches in the pain management of patients with NMDs should be considered. Further research in this field is necessary to gain a more detailed insight into the perception of muscle pain.

The findings revealed that neck pain exhibited distinct characteristics compared to pain in the extremities. In contrast to limb pain, we observed stronger neck muscles correlated with heightened pressure sensitivity. The correlation between PPT values of the neck extensor muscles and corresponding MyotonPro values suggest that the intrinsic muscular tone and stiffness of the neck muscles play an important role in the pain pressure sensitivity of the neck.