Pain sensitivity and shoulder function among breast cancer survivors compared to matched controls: a case-control study

Participants

Forty-two women participated in this case-control study, equally distributed in two groups: BCS (N = 21, mean (CI: 95%); age (years) = 57.4 (54;60.8), height (cm) = 167.9 (165.5;170.2), body mass index (kg/m2) = 27.6 (25.3;29.8)), and CON (N = 21, mean (CI: 95%); age (years) = 60 (55.5;64.5), height (cm) = 165.5 (162.8;168.2), body mass index (kg/m2) = 27.1 (24.9;29.2)). The same BCS group participated in a separate reliability study assessing absolute and relative reliability of pressure pain threshold (PPT), maximal isokinetic muscle strength (MIMS), and active ROM [16]. Participants for BCS were recruited by means of a database letter through the national database managed by the Danish Breast Cancer corporate Group. Women were eligible for inclusion in the BCS group if they were as follows: (i) diagnosed with primary unilateral breast cancer (grades I–IIIA); (ii) adult women at least 18 years of age; (iii) treated for breast cancer (i.e., surgery and possible adjuvant chemo and/or radiotherapy) at least 18 months before the start of the study; (iv) experiencing pain (self-reported) in the areas of the breast, shoulder, axilla, arm, and/or side of body with an intensity of ≥3 on a numeric rating scale (0 = no pain, 10 = worst pain imaginable); (v) women without signs of cancer recurrence; and (vi) reading, writing, and speaking Danish. Reasons for ineligibility were as follows: (i) breast surgery for cosmetic reasons or prophylactic mastectomy; (ii) bilateral breast cancer; (iii) recurrence of cancer; (iv) lymphedema; (v) other adverse medical conditions with potential influence on the study, or (vi) previous diagnosis of fibromyalgia syndrome. Controls were asymptomatic (pain-free) female volunteers with no previous history of cancer matched to the BCS group as well possible for age (mean difference, range: 2.6, 0–7 years) and body mass index (mean difference, range: 0.5, 0.0–2.2 kg/m2). Women were eligible for inclusion in the control group if they were as follows: (i) adult women at least 18 years of age and (ii) reading, writing, and speaking Danish. Reasons for ineligibility were as follows: (i) pregnancy; (ii) drug addiction, e.g., continued use of cannabis, opioids, or other substances taken for a non-medical purpose; (iii) presence of signs or symptoms of musculoskeletal pain; (iv) history of persistent pain or trauma in the upper body; (v) adverse medical conditions with potential influence on the study (e.g., chronic fatigue syndrome); (or vi) participation in other pain trials throughout the study period. All the participants were instructed to avoid physical activity and consumption of alcohol, caffeine, nicotine, or analgesics (e.g., paracetamol, ibuprofen, or codeine) in the last 24 h prior to the experiments. The study was conducted in accordance with STROBE guidelines [17]. The study protocol was approved by the local Ethics Committee (N-20180090) and conducted according to the Declaration of Helsinki. Following a detailed written and verbal explanation of the experimental risks, the participants gave their written informed consent prior to participating in the study.

Study design

Each participant completed a familiarization session (FS), and an experimental session (ES) separated by 1 week (Fig. 1). Baseline characteristics (anthropometrics, demographics, physical, health, surgical, medical, and pain profile) and physical activity level (IPAQ) [18] were collected during FS only, while PPT, active ROM, and MIMS were measured during both FS and ES (Fig. 1). PPT, active ROM, and MIMS were collected during FS for familiarization purposes only and not included in the further analysis. To avoid a confounding influence of excessive fatigue during the experimental sessions, measurements were performed unilaterally on the operated side for BCS and the left/right distribution were matched for CON. The resulting no. of assessments performed on the dominant side were 9 (34%) and 8 (38%) for BCS and CON, respectively. The participants were blinded to the measures of PPT, active ROM, and MIMS, and all assessments were performed by the same researcher who had received weekly training in the three months leading up to the study (GHFR, not blinded).

Fig. 1figure 1

Pressure pain threshold grids. Schematic representation of the dorsal (a) and ventral (b) grids for pressure pain threshold (PPT) assessments. The PPTs of the dorsal region were measured over 6 points located on the trapezius muscle (P1-P2), infraspinatus (P3), posterior deltoid (P4), latissimus dorsi (P5), and lateral deltoid (P6). The PPTs of the ventral region were measured over 11 points located on the anterior deltoid (P7-P10) and pectoralis major (P11-P17). d = distance between the seventh cervical vertebra (C7) and acromion (ACR), e = distance between the sternoclavicular joint (SCJ) and acromion (ACR), and C = the summed distance between P11 and P12, P12 and P14, and P14, and P16 on the x-axis

Outcomes

Movement evoked pain (MEP) intensity was rated after each series of MIMS on a 0–10 Numeric Pain Rating Scale (NPRS), where 0 corresponded to “no pain” and 10 to “worst pain imaginable” [19]. The cut-off scores used as reference were as follows: 0 = no pain; 1–3 = mild; 4–6 = moderate; 7–10 = severe pain [20].

Pressure pain thresholds are a reliable measure of mechanical pain sensitivity in BCS with intra class correlation coefficients (ICC) ranging from 0.88 to 0.97 [16], and were obtained in agreement with Rasmussen et al. [16]. Hence, PPTs were measured unilaterally across 17 points, located on the dorsal (6 points) and ventral (11 points) parts of the chest, shoulder, and neck region (Fig. 1). In addition, a distant reference point was located on the ipsilateral tibialis anterior muscle to assess the potential presence of generalized hyperalgesia [21]. All PPT measurements were collected using a pressure algometer (Somedic AB, Farsta, Sweden) with a 1 cm2 probe and a constant incremental pressure rate of 30 kPa/s. The participants were instructed to press a handheld button immediately when the sensation changed from pressure to pain. The measurements were performed twice in predefined order (P1-18), and a third time if the coefficient of variance was ≥20%. There were approx. 6 min between measurements made over the same point to avoid temporal summation of pain. Pressure pain threshold map of the dorsal and ventral regions was constructed from the mean PPT values of the points located on the dorsal and ventral muscles respectively by measuring the distance d between C7 and acromion, and the distance e between acromion and the sternoclavicular joint for each participant and computing the inter-distance between points. Inverse distance–weighted interpolation was then applied to obtain a map of the spatial pressure pain distribution of each region [22].

Body mass index (kg/m2) was calculated from height and body mass measured at the familiarization session. The fat-free mass (FFM), body fat mass (BFM), skeletal muscle mass (SMM), and body fat percentage (BF%) of each participant were computed using direct segmental multifrequency (DSM) bioelectrical impedance analysis (BIA) (InBody 370, Biospace, Seoul, Korea), in agreement with the manufacturer’s recommendations. DSM-BIA is considered valid and reliable for body composition measures in the general population when compared to dual-energy x-ray absorptiometry (DXA) [23].

Active ROM was measured with a universal goniometer for six movement directions: (1) supine shoulder flexion, (2) supine horizontal shoulder flexion, (3) horizontal shoulder extension, (4) seated upright shoulder abduction, (5) supine internal shoulder rotation, and (6) supine external shoulder rotation in agreement with the protocol of Rasmussen et al. [16]. Supine measurements were performed with the knees flexed to flatten the lumbar spine, and with manual stabilization of the scapulae during assessment of inter/external shoulder rotation. For the seated upright measurements, participants were positioned seated firmly against the back of the chair to ensure trunk stabilization, and instructed to maintain a neutral head position. For further details on anatomical starting positions of the shoulder and arm, see Rasmussen et al. [16]. Goniometric measurements of active ROM are reliable in BCS (ICCs: 0.66–0.97) [16], and were performed by the same researcher by aligning the goniometer arms between bony landmarks (e.g., olecranon process and ulnar styloid of the forearm, and medial epicondyle of the humerus) and positioning the fulcrum of the goniometer above the approximate projection of the given joint center on the movement plane. Similar to PPT, the assessments were performed twice over two rounds in systematic order and a third time if the measurements had a coefficient of variance ≥20%. The mean ROM values were calculated for each movement direction.

Maximal isokinetic muscle strength (MIMS) can also be measured reliably in BCS (ICCs: 0.62–0.92) [16], and was collected for eight movement directions: (1) supine shoulder flexion, (2) supine shoulder extension, (3) supine horizontal shoulder extension, (4) supine horizontal shoulder flexion, (5) seated shoulder abduction, (6) seated shoulder adduction, (7) supine internal shoulder rotation, and (8) supine external shoulder rotation. All measurements were performed using an isokinetic dynamometer (Humac Norm, model 770, Computer Sports Medicine Inc., Stoughton, USA). Each participant was familiarized with the protocol during FS, and performed a brief (approx. 10 min) general warm up of various stretching exercises for the prime movers prior to testing. This was followed by a series of 10 consecutive contractions with submaximal progressive effort followed by a series of five consecutive contractions at maximal effort for each muscle group with a 2-min rest period between series. Rest between measurements for each movement direction consisted of the time required for readjustment of the dynamometer (approximately 5 min). All isokinetic strength testing was conducted at a speed of 600/s through the ROM previously measured for each movement direction. The first repetition of each maximal trial was discarded, and mean peak torque was computed for the remaining four at a fixed joint angle. Mean peak torque was then normalized to FFM and expressed as Nm/kg FFM. Gravity correction was performed for each participant prior to the series of assessments. For a more detailed description about strength measurements, see Rasmussen et al. [16].

Statistical analysis

The minimum required sample size to detect a significant difference in PPT between groups, assuming an alpha level of 0.05, a beta level of 0.80 and a large effect size of 0.52 estimated from the pectoral PPTs reported by Caro-Moran et al. [6], was determined to be at least 32 (16 per group). To account for a potential drop out of 20–30%, 42 participants were enrolled in the study. Independent samples t tests were used to compare age and BMI between groups. A two-way analysis of variance (ANOVA) was performed to investigate potential differences between groups. PPT was used as dependent factor with anatomical location (P1-18, mean dorsal, & mean ventral) and group (BCS, CON) as independent factors. Similarly, active ROM and MIMS were used as dependent factors with movement direction (1–6 & 1–8) and group (BCS, CON) as independent factors. In the case of a significant interaction effect, simple main effects were analyzed within each combination of the other effects through univariate tests based on linearly independent pairwise comparisons among the estimated marginal using the overall error term of the two-way ANOVA. If no significant interaction effect was found, main effects were reported. Post hoc analyses were performed as univariate analyses with Bonferroni correction for multiple comparisons = α/n. The Shapiro-Wilks test of normality was applied to test the assumption of normal distribution and homogeneity of variance was tested through Levene’s Test of Equality of Error Variances. If the assumptions of normality and equal variance were violated, a Mann-Whitney U rank based nonparametric test with Holm-Bonferroni sequential correction for multiple comparisons was applied to assess between group differences for each outcome measure = α / (n – rank +1). Associations between PPTs and MEP assessments were explored through a Pearson's product-moment correlation analysis or Spearman’s rank order correlation. Assumptions of linearity and outliers were determined from visual inspection and the Shapiro-Wilks test of normality was applied to test the assumption of normal distribution. Since the afore-mentioned assumptions were violated, only Spearman’s rank order correlation was applied. All statistical procedures were conducted in IBM SPPS Statistics (26.0 version; IBM Corp., Armonk, NY, USA). A P value less than 0.05 was considered statistically significant. Differences are expressed as mean (confidence interval (CI) 95%) and median (25–75th percentile) for parametric and non-parametric tests, respectively. Effect size estimates are reported as partial eta squared (partial η2), and interpreted according to Cohen [24] in which ≥0.01 to < 0.06, ≥ 0.06 to < 0.14 and ≥ 0.14 correspond to small, medium, and large effect sizes, respectively. Similarly, correlation coefficients were interpreted in accordance with the guidelines of Cohen, where >0.1 to < 0.3, 0.3 to <0.5 and > 0.5 denote a small, moderate, or large correlational effects, respectively. Missing data points were omitted from the above analyses.

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