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Widespread Mechanical Pain Hypersensitivity as a Sign of Central Sensitization after Breast Cancer Surgery: Comparison between Mastectomy and Lumpectomy

Carolina Fernández-Lao PT, MSc, Irene Cantarero-Villanueva PT, MSc, César Fernández-de-las-Peñas PT, MSc, PhD, Rosario Del-Moral-Ávila MD, PhD, Salomón Menjón-Beltrán MD, PhD, Manuel Arroyo-Morales MD, PT, PhD
DOI: http://dx.doi.org/10.1111/j.1526-4637.2010.01027.x 72-78 First published online: 1 January 2011

Abstract

Objective. To investigate the differences in widespread pressure pain hypersensitivity after two surgery approaches for breast cancer: mastectomy or lumpectomy.

Design. A cross-sectional blinded study.

Setting. Widespread pressure pain hypersensitivity has been suggested as a sign of central sensitization. No study has previously investigated the presence of widespread pain pressure hypersensitivity after breast cancer surgery.

Patients. Twenty-one women (age: 52 ± 9 years old) who had received lumpectomy after breast cancer, 21 women (mean age: 50 ± 10 years old) who had received mastectomy surgery after breast cancer, and 21 healthy women (age: 51 ± 10 years old) participated.

Outcome Measures. Pressure pain thresholds (PPT) were bilaterally assessed over C5-C6 zygapophyseal joint, deltoid muscle, second metacarpal, and the tibialis anterior muscle.

Results. Women with mastectomy had greater intensity of neck (t = −2.897; P = 0.006) and shoulder/axillary (t = −2.609; P = 0.013) pain as compared with those who received lumpectomy. The results showed that PPT were significantly decreased bilaterally over the C5–C6 zygapophyseal joint, deltoid muscle, second metacarpal, and tibialis anterior muscle in both lumpectomy and mastectomy groups as compared with healthy women in all points (P < 0.001), without differences between both breast cancer groups (P = 0.954). No significant differences in the magnitude of PPT levels between both breast cancer groups were found (all, P > 0.450). PPT levels over some areas were negatively associated with the intensity of pain in the mastectomy, but not lumpectomy, group.

Conclusion. The current study found widespread pressure pain hyperalgesia in women who received breast cancer surgery suggesting central spreading sensitization. The degree of central sensitization was similar between lumpectomy and mastectomy surgery.

  • Mastectomy
  • Lumpectomy
  • Pressure Pain
  • Sensitization

Introduction

Breast cancer is the most common form of cancer among women [1]. A recent study found that since 1980, the breast cancer incidence rate has increased by 2.9% per year in Spain [2]. In the United States, the National Cancer Institute has estimated that 1.09% (95% confidence interval [CI] 0.95–1.24%) of women aged 30 to 84 years had a lifetime absolute breast cancer risk of ≥20% which translates to 880,063 U.S. women [3]. Screening programs and advances in therapeutic and diagnostic approaches have raised survivor rate in last years close to 70% at 5 years of diagnosis [4]. There has been an increasing interest for improving surgical treatments for breast cancer, with two current different surgical options: mastectomy (whole breast removed) or lumpectomy (tumor and surrounding tissue removed). In fact, lumpectomy surgery is preferred in younger patients with smaller breasts, as it is less cosmetically mutilating [5]. Additionally, the incidence of postoperative complications has been found to be higher with mastectomy (35%) than with lumpectomy (24%) procedures [6].

Pain is the most frequent impairment after breast cancer treatment (20–65%) [7,8] with a strong relationship to higher self-perceived disability and lower quality of life [9]. In addition, preoperative pre-incisional paravertebral block seems to reduce the prevalence of chronic pain after breast cancer surgery [10]. The presence of persistent pain beyond the period of “normal” healing after breast cancer surgery is called “postmastectomy pain” and it is attributed to the damage of peripheral nerves during the operative procedure [11]. Nevertheless, there is an increasing evidence suggesting that postmastectomy pain may be also related to changes in nociceptive pain gain. Indeed, Andrykowski et al. found that mastectomy may enhance the experience of pain at distant sites via alterations in neuro-endocrine profiles or by sensitizing the central nervous system [12]. Gottrup et al. found in 15 women with postmastectomy pain and abnormal sensitivity that ongoing C-fiber inputs can induce a central sensitization state similar to that seen in other pain patient populations [13].

Several quantitative sensory tests are proposed for investigating the presence of sensitization mechanisms in chronic conditions [14]. One of the most common procedures used for evaluating the hyperexcitability of the central nervous system is calculating the pressure pain thresholds (PPT). In fact, several studies have investigated the nociceptive system in different chronic conditions by assessing widespread mechanical pain hypersensitivity, e.g., whiplash [15], fibromyalgia [16], repetitive strain injury [17], tension type headache [18], low back pain [19], lateral epicondylalgia [20], carpal tunnel syndrome [21], or knee osteoarthritis [22]. These studies found widespread pressure pain hypersensitivity as a sign of central sensitization in these chronic pain conditions. Nevertheless, to the best of the authors' knowledge, there are no previous studies investigating the presence of widespread pressure hypersensitivity after breast cancer surgery. Therefore, the aim of this study was to investigate the differences in the presence of widespread pressure pain hypersensitivity after two approaches for breast cancer: mastectomy or lumpectomy. We hypothesized that women receiving a total removal of the breast (mastectomy) would have greater widespread pressure pain hypersensitivity than those receiving a partial removal of the breast (lumpectomy).

Materials and Methods

Participants

Patients were recruited from the Department of Breast Oncology at the University Hospital Virgen de las Nieves, Granada, Spain. To be eligible for the study, participants had to meet the following criteria: 1) first time with a primary diagnosis of breast cancer (grades I–IIIA); 2) women who had received a simple mastectomy with breast reconstruction or women who had received lumpectomy; 3) those who received the surgery for at least 6 months and since surgery without sign recurrence; 4) receiving post-primary adjuvant treatment (radiation, cytotoxic chemotherapy) at least 3 months before the study; and 5) adults at least 18 years of age.

Exclusion criteria were: 1) breast surgery for cosmetic reasons or prophylactic mastectomy; 2) other medical conditions (i.e., arthritis); 3) presence of lymphoedema; 4) recurrent cancer; or 5) previous diagnosis of fibromyalgia syndrome [23].

Additionally, age-matched right-handed controls were recruited from volunteers who responded to a local announcement and were excluded if they exhibited a history of neck, shoulder or arm pain, history of trauma, or diagnosis of any systemic disease. The study protocol was approved by the local Ethics Committee (FIS 08-ETES-PI0890418) and conducted following the Helsinki Declaration. All participants signed an informed consent prior to their inclusion.

PPT

4Pressure pain threshold is defined as the minimal amount of pressure where a sensation of pressure first changes to pain [24]. An electronic algometer (Somedic AB, Farsta, Sweden) was used to measure PPT levels (kilopascal [kPa]). The pressure was applied at approximately rate of 30 kPa/second by a 1 cm2 probe. Participants were instructed to press the switch when the sensation first changed from pressure to pain. The mean of three trials (intraexaminer reliability) was calculated and used for the main analysis. A 30-second resting period was allowed between each trial. The reliability of pressure algometry has been found to be high the same day (intraclass correlation coefficient [ICC] = 0.91 [95% CI 0.82–0.97]) [25,26].

Sample Size Determination

The sample size determination and power calculations were performed with appropriate software (Tamaño de la Muestra1.1©, Madrid, Spain). The calculations were based on detecting, at least, significant clinically differences of 20% on PPT levels between both breast cancer groups [27] with an alpha level of 0.05, and a desired power of 80% and an estimated interindividual coefficient of variation for PPT measures of 20%. This generated a sample size of at least 16 participants per group.

Study Protocol

The study protocol was the same for both group of patients and controls. An 11-point numerical point rate scale [28] (0 = no pain; 10 = maximum pain) was used to assess the intensity of spontaneous neck pain and shoulder/axillary pain. Patients were asked to draw the distribution of their pain symptoms on an anatomical body map. Participants were asked to avoid any analgesic or muscle relaxant 24 hours prior to the examination. PPT levels were bilaterally assessed over the C5-C6 zygapophyseal joint, the deltoid muscle, the second metacarpal, and the tibialis anterior muscle. The order of point assessment was randomized between participants.

Pressure pain threshold exploration was done by an assessor who was blinded to the participants' condition. Due to the nature of breast cancer surgery and in order to satisfactorily blind assessor, PPT examination was performed with subjects lying supine with a sheet over their chest.

PPT Data Management

In the current study, the magnitude of sensitization was investigated assessing the differences of absolute and relative PPT values between both groups. For relative values, we calculated a “PPT index” dividing PPT of each patient at each point by the mean of PPT score of the control group at the same point. A greater PPT index (%) indicates lower degree of sensitization.

Statistical Analysis

Data were analyzed with the SPSS statistical package (16.0 version). Results are expressed as mean, standard deviation (SD), or 95% CI. The Kolmogorov–Smirnov test was used to analyze the normal distribution of the variables (P > 0.05). As PPT showed normal distribution, parametric tests were used. A two-way analysis of variance (anova) test was used to investigate the differences in PPT assessed over each point (C5-C6 zygapophyseal cervical joint, deltoid muscle, second metacarpal, and tibialis anterior) with side (affected/non-affected within patients or dominant/non-dominant controls) as within-subject factor and group (mastectomy, lumpectomy, or controls) as between-subject factor. A three-way anova test was used for assessing differences in PPT indices with side (affected or non-affected) and point (C5-C6 zygapophyseal joint, middle deltoid muscle, second metacarpal, and tibialis anterior) as within-patient factors and group (lumpectomy or mastectomy) as between-patient factor. The Bonferroni test was used as post hoc analysis in all the multiple comparisons. Differences in neck and shoulder/axillary pain mean intensity between both patients groups were assessed with the unpaired student t-test. The Pearson correlation test (r) was used to investigate the association between neck and shoulder/ axillary pain intensity and PPT over each point with each patient group. The statistical analysis was conducted at 95% confidence level. A P < 0.05 was considered statistically significant.

Results

Demographic and Clinical Data of the Patients

Twenty-one women, aged 30–70 years old (mean ± SD: 52 ± 9 years) who had received lumpectomy surgery after breast cancer; 21 women, aged 30–69 years old (mean ± SD: 50 ± 10 years) who had received mastectomy surgery after breast cancer; and 21 healthy women, aged 30–69 years old (mean ± SD: 51 ± 10 years) participated (F = 0.541; P = 0.791).

Within the lumpectomy group, 10 (48%) had the right breast affected whereas the remaining 11 (52%) had the left breast affected. Within the mastectomy group, eight (47%) had the right breast affected and the remaining nine (53%) had the right side (χ2 = 0.973; P = 0.615). Further, in the lumpectomy group, eight (38%) patients had breast cancer grade I, 11 (52%) had grade II and the remaining two (10%) had breast cancer grade IIIA, whereas in the mastectomy group, two (18%) patients had breast cancer grade I, 11 (65%) had grade II, and the remaining three (27%) had cancer grade IIIA (χ2 = 4.428; P = 0.219). All patients underwent axillary lymph node dissection during the operative procedure and received both radiotherapy and chemotherapy treatment after the surgery. The mean time from breast surgery intervention was 11 ± 3 months in the lumpectomy group and 14 ± 6 months within the mastectomy group (t = −1.725; P = 0.125).

Within the lumpectomy group, 13 (62%) women reported spontaneous neck pain (mean intensity: 4.0 ± 3.5) whereas eight (38%) had shoulder/axillary pain (mean intensity: 2.4 ± 3.5). Within the mastectomy group, 16 (95%) women reported spontaneous neck pain (mean intensity: 7.1 ± 2.7), whereas 13 (77%) had shoulder/axillary pain (mean intensity: 5.6 ± 3.8). Therefore, women who received mastectomy surgery had greater intensity of neck (t = −2.897; P = 0.006) and shoulder/axillary (t = −2.609; P = 0.013) pain than those who had received lumpectomy.

A significant positive correlation (rs = 0.469; P = 0.032) between neck pain and shoulder/axillary pain intensity was found within the lumpectomy group, but not in the mastectomy group (rs = 0.209; P = 0.421). Eight women (38%) in the lumpectomy group and six women (35%) in the mastectomy group were receiving tamoxifen, whereas eight (38%) women within the lumpectomy group, and seven women (41%) in the mastectomy group were taking aromatase inhibitors (χ2 = 0.096; P = 0.953). Finally, two women (10%) in the lumpectomy group and three (17%) in the mastectomy group were taking trastuzumab (χ2 = 0.543; P = 0.640).

PPT Levels

The anova revealed significant differences between groups, but not between sides, for PPT levels over the C5-C6 zygapophyseal joint (group: F = 48.456; P < 0.001; side: F = 0.327; P = 0.568), deltoid muscle (group: F = 45.024; P < 0.001; side: F = 1.891; P = 0.172), second metacarpal (group: F = 39.554; P < 0.001; side: F = 0.434; P = 0.511), and tibialis anterior muscle (group: F = 55.838; P < 0.001; side: F = 1.396; P = 0.240). No significant interaction between group * side was found: C5-C6 zygapophyseal joint (F = 0.004; P = 0.996), deltoid muscle (F = 2.038; P = 0.135), second metacarpal (F = 0.558; P = 0.574), and tibialis anterior muscle (F = 0.887; P = 0.415). The post hoc analysis revealed that both lumpectomy and mastectomy groups showed bilateral lower PPT than healthy women in all points (P < 0.001), without differences between both breast cancer groups (all, P > 0.952). Table 1 summarizes PPT levels assessed over the C5-C6 zygapophyseal, deltoid muscle, second metacarpal, and tibialis anterior muscle for both sides within each study group.

View this table:
Table 1

Pressure pain thresholds (kilopascal) in breast cancer survivors and healthy controls

C5-C6 Zygapophyseal Joint*Deltoid Muscle*Second Metacarpal*Tibialis Anterior*
Breast cancer treated with lumpectomy
    Affected171.8 ± 58.0 (146.4–197.4)198.9 ± 83.2 (164.4–233.3)224.3 ± 73.8 (194.1–254.5)304.1 ± 63.4 (257.4–350.9)
    Non-affected177.6 ± 58.2 (152.1–203.1)237.4 ± 71.2 (203.0–271.9)224.9 ± 51.4 (194.7–255.2)351.3 ± 44.4 (304.5–398.1)
Breast cancer treated with mastectomy
    Affected179.0 ± 65.8 (150.6–207.3)195.1 ± 51.1 (156.7–232.5)209.5 ± 97.0 (175.9–243.1)312.3 ± 60.2 (260.3–364.2)
    Non-affected184.4 ± 61.7 (156.0–212.7)238.4 ± 62.8 (200.1–276.6)237.7 ± 87.3 (204.3–271.5)348.4 ± 43.7 (296.4–400.4)
Healthy control subjects
    Dominant285.5 ± 28.5 (260.0–310.9)373.4 ± 48.2 (338.9–407.9)345.5 ± 59.8 (315.2–375.7)554.8 ± 60.7 (508.1–601.6)
    Non-dominant293.1 ± 73.4 (267.6–318.6)352.4 ± 34.5 (317.9–386.8)342.0 ± 45.3 (311.8–372.2)542.4 ± 64.4 (495.7–589.2)
  • * Significant differences between both breast cancer groups and controls (two-way analysis of variance test).

  • Values are mean ± SD (95% confidence interval for the mean).

Pressure Pain Indices

The three-way anova revealed significant effects for side (F = 7.237; P = 0.008), but not for groups or points for PPT indices (group: F = 0.043; P = 0.836; point: F = 0.819; P = 0.484). Additionally, no significant interactions between group * side (F = 0.111; P = 0.739), group * point (F = 0.058; P = 0.982), side * point (F = 1.308; P = 0.272), or group * side * point (F = 0.167; P = 0.918) were found (Figure 1).

Figure 1

Pressure pain threshold indices. The boxes represent the mean and the 25 and 75 percentile scores and the error bars represent the two standard deviations.

PPT and Current Level of Pain

Within the lumpectomy group, no significant association between either neck or shoulder/axillary pain intensity and PPTs in any point (P > 0.347) was found. On the contrary, in the mastectomy group, neck pain intensity was negatively associated with PPT levels over the affected deltoid (rs = −0.619; P = 0.008) and both tibialis anterior (affected: rs = −0.511; P = 0.036; non-affected: rs = −0.659; P = 0.004) muscles; whereas shoulder/axillary pain intensity was negatively associated with PPT levels over both C5-C6 zygapophyseal joints (affected: rs = −0.531; P = 0.028; non-affected: rs = −0.587; P = 0.013), over the affected deltoid (rs = −0.526; P = 0.030) and the affected tibialis anterior (rs = −0.567; P = 0.018) muscle. In summary, the greater the neck or shoulder/axillary intensity, the lower the PPT levels over these points.

Discussion

The main finding of the current study was a bilaterally and widespread pressure pain hypersensitivity in women who had received breast cancer surgery as compared with healthy women. In fact, widespread mechanical hypersensitivity was similar in women who received either lumpectomy or mastectomy, suggesting that central sensitization is present independently of the type of breast cancer surgery received. Additionally, PPT levels over some areas were negatively associated with the intensity of pain, suggesting a role of peripheral nociception after breast cancer surgery.

Bilateral and widespread pressure hypersensitivity found in the current study suggests central sensitization in women who had received either type of breast cancer surgery. The fact that lower PPT levels were found in pain-free distant areas, i.e., second metacarpal and tibialis anterior muscle, support the presence of second order neuron (or higher) sensitization mechanisms. In fact, the magnitude of sensitization, represented by pressure pain indices, was similar between symptomatic (C5-C6 zygapophyseal joint: 60–63%; deltoid muscle: 53–67%) and non-symptomatic (second metacarpal: 60–69%); tibialis anterior muscle: 54–69%) areas in both lumpectomy and mastectomy groups. Our findings supporting a central sensitization in women who had received breast cancer surgery agree with the results previously reported for women with postmastectomy pain where increased evoked pain intensity following repetitive pinprick stimulation in the vicinity of a breast scar was found [13]. This study showed that patients with postmastectomy pain and abnormal sensitivity had central sensitization [13]. Our study suggests that central sensitization is also present in women with breast cancer who had received lumpectomy or mastectomy. In fact, the hypothesis of hyperexcitability of the central nervous system after breast cancer surgery is clinically supported by the fact that many patients suffer from widespread diffuse persistent pain after surgery [29].

A relevant finding from the current study is that central sensitization was similar after either surgery, independently of partial (lumpectomy) or total (mastectomy) breast removal. In addition, a greater degree of sensitization in the affected deltoid muscle was found in both breast cancer groups, suggesting a greater sensitization in the surgical area. Gottrup et al. suggested that peripheral sensitization contributes to clinical pain and sensory disturbances in postmastectomy pain due to nociception from damaged small nerve fibers during the operative procedure [13]. One possible reason for our findings is that nerve injury may be similar in both surgical approaches, although this is unlikely as lumpectomy is considered less aggressive than mastectomy. Another reason for similar sensitization in both groups may be because all women received chemotherapy after the surgery which can influence sensitization processes. Chemotherapy can cause peripheral neuropathy and changes in afferent vagal activity leading to widespread changes in pain sensitivity [30]. Therefore, it would be interesting to compare the degree of sensitization with a control group that received similar chemotherapy without surgery as control group.

In fact, an important difference between lumpectomy and mastectomy groups was the number of women reporting neck and shoulder/axillary pain and the intensity of the pain which was greater in the mastectomy group. Further, the intensity of perceived neck and shoulder/axillary pain was associated with a greater sensitization (lower PPT over tibialis anterior muscles) within the mastectomy, but not the lumpectomy group. These findings support that lumpectomy, when indicated, would be preferred instead mastectomy for avoiding pain.

Conclusion

The current study found widespread pressure pain hyperalgesia in women who had received breast cancer surgery, suggesting central sensitization. In fact the degree of central sensitization was similar between lumpectomy and mastectomy. Nevertheless, the number of women reporting neck and shoulder/axillary pain, and the intensity of the pain which was greater in the mastectomy group Finally, PPTs over some areas were negatively associated with the intensity of pain in the mastectomy group suggesting a role of peripheral nociception in this surgical procedure.

Acknowledgments

The study was funded by a project grant from the Carlos III Health Institute, Ministry of Science, Spanish Government (FIS 08-ETES-PI0890418).

Footnotes

  • Conflict of interest/Competing interests: None to declare.

References

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