Observational Study Medicine ® OPEN Incidence of contralateral neurosensitive changes and persistent postoperative pain 6 months after mastectomy A prospective, observational investigation ∗ Paula Masgoret, MDa, , Inés de Soto, MDb, Ángel Caballero, MDa, José Ríos, MScc, Carmen Gomar, MD, PhDa Abstract Mirror image sensory dysfunction (MISD) after breast surgery has not yet been studied. This prospective observational study aimed to determine the incidence of MISD, persistent postoperative pain (PPP) and mirror image pain (MIP) during 6 months after total unilateral mastectomy. Visual analogue scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), Hospital Anxiety and Depression Scale (HADS), Life orientation test (LOT) and Quantitative Sensory Testing (QST) (in ipsi and contralateral breast, axilla and thigh) were recorded. VAS > 3 at 1, 3, and 6 postoperative months was considered PPP. Contralateral changes of QST at any time was considered indicative of MISD and spontaneous contralateral VAS ≥ 1 as MIP. Sixty-four patients were included. PPP at 1, 3 and 6 months was 18.8%, 56.2%, and 21.3%, respectively Ten patients presented MIP. MISD was detected in 79.7% patients in contralateral breast and 62.5% in contralateral axilla. Furthermore, changes in QST were present in 39.1% of patients in thigh. Electronic Von Frey (EVF) changes in both contralateral breast and axilla, and in thigh significantly diminished at all postoperative times. Changes of postoperative EVF ≥ 20% in contralateral breast were associated to higher VAS values. NPSI scores were significantly higher at all postoperative times. At 1 month, PCS, depression HADS subscale and LOT scores were significantly worse than all the other periods. MISD incidence was almost 80%, and 15.6% of patients showed spontaneous contralateral VAS ≥ 1. At 6 months 21.3% of patients manifested PPP. The worst alteration of factors related to PPP occurred at 1 postoperative month. Most consistent QST was EVF. Abbreviations: ASA = American Association of Anesthesiology status, BIS = bispectral index, DNIC = diffuse noxious inhibitory control, EVF = Electronic Von Frey, HADS = Hospital Anxiety and Depression Scale, HADSA = Hospital Anxiety and Depression Scale, anxiety subscale, HADSD = Hospital Anxiety and Depression Scale, depression subscale, LOT = Life Orientation Test, MIP = Mirror Image Pain, MISD = Mirror Image Sensory Dysfunction, NPSI = Neuropathic Pain Symptom Inventory, PCS = Pain Catastrophizing Scale, PPP = Persistent Postoperative Pain, QST = Quantitative Sensory Testing, VAS = Visual Analogue Scale, VFM = Von Frey Monofilaments. Keywords: Electronic Von Frey, mirror image pain, mirror image sensory dysfunction, persistent postoperative pain, quantitative sensory testing 1. Introduction Editor: Helen Gharaei. The authors have no funding and conflicts of interests to disclose. The mammalian nervous system shows a high degree of Supplemental Digital Content is available for this article. symmetry. Studies in rodents describe sensory changes in the a Department of Anesthesiology, Hospital Clinic, University of Barcelona, homonymous contralateral zone[1] after unilateral injuries.[2–6] b Department of Anesthesiology, Consorci Sanitari Parc Taulí de Sabadell, These changes are referred to as “mirror image sensory c Laboratory of Biostatistics and Epidemiology, Universitat Autonoma de dysfunction” (MISD).[2,5] There are reports of MISD cases in Barcelona, Biostatistics and Data Management Platform, IDIBAPS, Hospital humans,[7] and its spontaneous painful expression is called Clinic, Barcelona, Spain. ∗ “mirror image pain” (MIP).[1,5,8–12] Mechanisms engaged in Correspondence: Paula Masgoret, Department of Anesthesiology, Hospital MISD have not been completely elucidated,[1–4,6] although Clínic de Barcelona, Villarroel 170, 08036 Barcelona, Spain (e-mail: pmasgoret@gmail.com). nervous (at peripheral,[3] spinal,[6] thalamic or cortical[4] level) Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. or humoral[1,13] factors have been considered, involving This is an open access article distributed under the terms of the Creative neurons,[4,13] neural growth factors,[13] glia, microglia,[13] and Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is cytokines.[9] Studying mechanisms implicated in MISD and MIP permissible to download, share, remix, transform, and buildup the work provided may be useful in understanding chronic pain aethiopathogenesis, it is properly cited. The work cannot be used commercially without permission especially persistent postoperative pain (PPP),[11,14] which is from the journal. considered a potentially preventable major clinical problem. How to cite this article: Masgoret P, de Soto I, Caballero Á, Ríos J, Gomar C. Incidence of contralateral neurosensitive changes and persistent postoperative Moreover, it could provide a methodological advance in the pain 6 months after mastectomy: A prospective, observational investigation. design of pain studies.[2,11,15] Medicine 2020;99:11(e19101). When reported, MISD and MIP occurred in patients with Received: 1 October 2019 / Received in final form: 15 December 2019 / severe ipsilateral allodynia.[1,7–10] In addition, contralateral Accepted: 10 January 2020 neurosensitive changes are reported as being less intense and http://dx.doi.org/10.1097/MD.0000000000019101 of delayed onset with respect to ipsilateral responses.[2,9] 1 Masgoret et al. Medicine (2020) 99:11 Medicine Perceptive attention of patients focusing on the aching side could Exclusion criteria included allergy to protocol medication, any mean that contralateral sensory changes may go unnoticed. A previous thoracic surgery or mastectomy, chronic pain, opioid semi-objective exploration with quantitative sensory testing use in the last three months, neuropathy of different origin other (QST) would allow detection of MISD.[5] Simplified QST than chemotherapy or radiotherapy; drug or enol abuse, mental protocols, such as the one previously used by our group[16–18] illness requiring anti-psychotic medication; central neurological would permit repeated explorations in postoperative patients. disorder, cognitive alterations, emergency surgery, language The surgical injury model presents a unique opportunity to barriers and prediction of impossibility of immediate extubation study pain mechanisms as it allows QST explorations before the after surgery. Those patients who previously received chemo or lesion and eventual PPP initiation. This model also gives radiotherapy and presented, as a result, peripheral neuropathy information on the injury nervous distribution, limiting interpre- were not excluded from the study since this neuropathy was one tation variability and detecting posterior sensory changes. of the factors considered in the study. Moreover, factors which favor PPP[19] have been identified as During the pre-op visit, one or 2 weeks before surgery, eligible well as the correlation between degree of allodynia/hyperalgesia patients were informed about the study. The day before surgery area around the wound (secondary hyperalgesia) and develop- the investigation was explained in detail and informed consent ment of PPP.[19,20] was achieved. Features of mastectomies make a good model for PPP research The day before surgery, general variables were recorded and as they have a high PPP incidence (up to 60%)[21–25] and affect a patients were instructed about the Visual Analogical Scale (VAS well-defined nervous territory allowing contralateral assessment. 0–10) and how to report on their sensations in the Quantitative QST has been used for PPP exploration after mastectomy in the Sensory Testing (QST). Patients had to report as “painful” any operated side and also at distant zones for demonstrating “change in perceived stimulation that was disturbing enough to influence of central mechanisms such as neural sensitization or make him/her want it to stop” (QST positive alteration: lack of diffuse noxious inhibitory control (DNIC).[21–25] hyperalgesia/allodynia), and “absence” or “reduction” of their Contralateral side has also been used as control zone to detect sensation if they did not perceive the stimuli or felt it less in postmastectomy neurosensitive changes[23] or to assess test-retest comparison to the other side (QST negative alteration: hypo/ agreement of QST.[15] However, up to now, there have been few anesthesia). Patients were also asked about the presence of studies specifically focused on MISD[5] and none have been previous pain or paresthesia. In addition, the following assess- expressly designed to assess MISD after mastectomy using QST ments were carried out: subjective pain scales, psychological tests before surgery and until 6 months postoperative. and neurosensitive exploration with QST (See section “Varia- The primary endpoint was to determine the incidence of MISD, bles” and Table 1). PPP, and MIP during 6 months after total unilateral mastectomy For all patients we used our own anesthetic/analgesic protocol. and secondary endopoints were to establish possible relationship Sublingual diazepam 5 to 10 mg and thrombotic prophylaxis between them and with factors previously associated with PPP. with enoxaparin was given the previous night. On arrival to the surgery room midazolam 0.025 to 0.05 mg.kg 1 and antibiotic prophylaxis with cefminox and anti-emetic medication with 4 mg 2. Patients and methods dexamethasone were administered. Monitoring consisted of The study was approved by the research committee of the pulse oximeter, Electrocardiogram, non-invasive arterial pres- Institution as a prospective cohort study without therapeutic sure, capnography, esophageal temperature and bispectral index intervention (Registered HCB/2014/0548). (BIS, Dublin, Ireland). Anesthesia was induced with fentanyl (1–2 Between January 2012 and December 2016, patients of both ug.kg 1), propofol (1–2 mg.kg 1) and rocuronium (0.6 mg.kg 1) sexes older than 18 years who underwent a total unilateral and maintained with desfluorane 4% to 6% in O2/Air 60% (to mastectomy in the center, (simple, or radical modified) with or maintain BIS between 40 and 50). Fentanyl (2 ug.kg 1) and without axillary lymphadenectomy and/or removal of sentinel rocuronium bolus were used intraoperatively if needed. At the ganglion due to neoplasia or suspicion of it, were included in the end of surgery ondansetron 4 mg and dexketoprofen 50 mg were study. administered. In case of residual neuromuscular blocking, Table 1 Variables registered in the different times during 6 months. -24 h 2h 24 h 48 h 5d Month 1 Month 3 Month 6 General Variables x VAS x x x x x x x x NPSI and PCS x x x x x X HADS and LOT x x x x Presence of “glove-and-stocking” paraesthesia x x x x Analgesics intake x x x X Need of analgesic rescue with methadone x x x X QST x x x x X Treatment variables x x x X Adverse effects and complications x x x x x x x x HADS = Hospital anxiety and Depression Scale, LOT = Life orientation test, NPSI = Neuropathic Pain Symptom Inventory Scale, PCS = Pain Catastophizing Scale, QST = Quantitative Sensory Tests, VAS = Visual Analogue Scale. 2 Masgoret et al. Medicine (2020) 99:11 www.md-journal.com sugammadex was given previous to extubation in the surgical part of the middle third portion of the contralateral thigh was room. No nerve blocking was performed. also explored. Positive changes (allodynia/hyperalgesia) and Patients remained in the postsurgery care unit during 2 to 3 negative ones (hypo/anesthesia) were also recorded as described hours. Postoperative analgesia consisted of dexketoprofen 50 mg below and paracetamol 1 g intravenous alternating every 8 hours and if Electronic Von Frey (EVF) was analyzed for its quantitative VAS > 3 methadone 3 to 5 mg/8 hour subcutaneous was used as results. The remainder QST used, Von Frey Monofilaments rescue analgesia. (VFM), and temperature and vibratory tests were analyzed according to the presence of response to the stimulus and, since 2.1. Variables the systematics of the exploration and data collection were the same, these were grouped as “Binary QST”. In addition, the sizes Variables were collected on the day previous to surgery and in the of the response areas to any binary QST in breast and axilla after postoperative period as described in Table 1. surgery were registered as continuous variables analyzing their After operation, variables were recorded face to face up to evolution throughout the study. postoperative 5th day and at 1 and 6 months post-surgery. A Furthermore, “absolute changes”, defined as the emergence of follow-up was done by telephone 3 months after surgery applying alterations or the disappearance of responses previously detected the subjective scales of pain and psychological tests. with any of the binary QST, whether positive or negative, were If at 3 or 6 months any patient presented clinical symptoms of registered. PPP, oral paracetamol with or without codeine was prescribed and the possibility to be transferred to the Pain Clinic of the  Mechanical sensibility was assessed by VFM of 0.1, 0.6, 10, hospital for follow-up and treatment was offered. and 60 g (Bioseb, Vitrolles, France). VFM were applied as General variables (gender, age, body mass index); ocupational, isolated stimuli as described by Stubhaug,[32] starting at 10 cm smoking and American Association of Anesthesiology (ASA) from the surgical incision and at a 5 cm distance until status and benzodiazepine and antidepressant intake were completing the radial area around the wound. The procedure assessed. Treatment variables were evaluated the day before continued towards the incision marking the point where the surgery and at 1, 3, and 6 postoperative months. Characteristics patient expressed a change in his/her perception. The process of chemotherapy, hormone therapy, biological treatments and was repeated with the 4 tested VFM outlining an area of radiotherapy were recorded. The duration and type of surgery response on the skin for each VFM. As in previous studies from performed (simple or radical modified mastectomy), axillary our group[16,17] this information was transferred to planimetry node resection (without resection, extraction of sentinel ganglion paper in order to calculate the size of the area. On the or radical lymphadenectomy) and reconstruction (insertion or contralateral breast a line simulating the surgical incision was not of expander/prosthesis) were also registered. Hospital length defined and measurements were done in the same manner. The of stay was recorded. During admission emergence of nausea or areas with positive and negative changes to VFM stimuli in the vomiting, hemodynamic, cognitive or visual alterations, sedation, contralateral side (considered as MISD) were registered transfusion or vasoactive drugs requirements were assessed. according to each case. The day before surgery, as the surgical Surgical complications such as seroma, hematoma, or surgical incision was not yet defined as reference, the measurements wound infection were recorded. were taken in the zone of dermatome T4 in the anterior thoracic wall and in the axilla of both sides. Only the presence or 2.1.1. Pain assessment and psychological tests. In all the absence of positive or negative alterations were registered. The evaluated periods the patients were asked to refer VAS in the same exploration was done on the thigh at all times. ipsilateral and the contralateral side of surgery, in the following  Vibratory testing was done using an electronic toothbrush zones: breast, lateral thoracic wall, axilla and arm. Values of VAS following the same exploration described for VFM in thorax, > 3 were considered as non-controlled pain in the immediate axilla and thigh. postoperative period and as PPP at month 1 and 6. Based on the  Thermal sensibility was tested with 2 probes at 24°C and 40°C criteria used in previous studies,[16,18,26] VAS ≥ 1 values in the (Rolltemp, Sösdala, Sweden) applied following the same ipsilateral side after 1, 3, and 6 months in the above mentioned methodology for VFM. zones were recorded. Contralateral spontaneous pain (Mirror  EVF (Electronic Von Frey Aesthesiometer, Woodland Hills, image pain), which has been reported as less intense[1] was Canada): The day before surgery, as there was no surgical defined as VAS ≥ 1 referred in the same zones but in the incision, a 10  10 cm area in dermatome T4 and axilla in contralateral side of the surgery at any moment of the follow-up. both sides was defined. Measurements on the internal, In order to detect a neuropathic component of pain the external, superior, and inferior limits of that area were Neuropathic Pain Symptom Inventory (NPSI)[27] was applied. carried out. After surgery, the exploration was done at 2, 4, The presence and intensity of glove-and-stocking paraesthe- and 6 cm over and under the surgical incision in three different sia,[28] use of analgesics in the preoperative period and after areas of the wound (internal and external edge and middle of hospital discharge up to 6 months, and the need for methadone incision). A total of 18 measurements was completed in each rescue during admission were recorded. zone and their average was recorded. In the contralateral Pain Catastrophizing Scale (PCS),[29] Hospital anxiety depres- breast a line was defined simulating the surgical incision and sion scale (HADS)[30]: with its subscales anxiety (HADSA) and the measurements were done in the same way. A 10  10 cm depression (HADSD), and Life Orientation Test (LOT)[1,31] were area on the middle third portion of the anterior part of the applied. thigh was defined for all times and the measurements were 2.1.2. Quantitative sensory testing (QST). QST were applied in done. The frequency of EVF changes higher or lower than the ipsilateral side around the incision, in the contralateral breast 20% in all the zones during the postoperative period were also and in both axillae (anatomical axillary hollow). The anterior registered. 3 Masgoret et al. Medicine (2020) 99:11 Medicine 2.1.3. Statistical analysis. Given the observational character- quantitative results (VAS, EVF, areas of VFM, vibratory and istics of the general evaluation of this type of casuistic, and temperature tests, NPSI, PCS, HADS, and LOT), as well as for considering that among our primary endpoints, MISD was the the binary QST (EVF changes superior to 20%, VAS ≥ 1, VAS > most important since there is no report of MISD or MIP after 3, presence or absence of response to VFM, vibratory and mastectomies, the sample size was not formally defined. The size temperature tests. The statistical analyses were stratified by of the sample was fixed by feasibility retrieved from the different explored zones: ipsilateral, contralateral breast, axilla, systematic recording of the clinical activity in a third level and thigh. hospital during the 5 years of the study. The description of the results was done based on the The binary QST in the preoperative explorations in all the characteristics of each variable and how they were obtained. zones and in the thigh at all times were analyzed in a binary Categorical variables are shown as absolute frequency and manner (“yes” or “not”) to the presence of areas of positive or percentage, and quantitative variables as mean or median and negative changes or alterations. For each binary QST, the mean their dispersion by standard deviation or interquartile range. The areas size showing positive or negative changes with respect to the kappa concordance index was calculated between the presence of preoperative exploration was calculated. The differences in the EVF changes superior or inferior to 20% and the rest of QST areas size through time in comparison with the size of the areas at evaluated in a binary manner in terms of their interpretation. In 6 months adjusted by presence or absence of areas of change in all analysis a bilateral type I error of 5% was considered. Given the preoperative period were estimated. The presence of the observational nature of the present study and the hypothesis contralateral changes of the binary QST at any time was formulated, no correction strategy for multiplicity was per- considered indicative of MISD. formed. SPSS Statistical program v. 20 (IBM) was used for all the The differential characteristics of patients that presented statistical analyses. neurosensitive changes in the contralateral side at any time of the study and the association with the appearance of PPP were 3. Results analyzed. The inferential analyses of longitudinal results was per- During the inclusion period, 290 patients underwent total formed using Generalized Estimating Equation models using an mastectomy in the institution. Eighty-three patients fulfilled the intra-subject correlation matrix of type AR(1). These models inclusion criteria and a total of 64 patients were included. Three have the particularity that they can be applied to different types patients were evaluated only at 3 months while 61 completed a 6 of dependent variables. In this study these were used for months follow-up. (Fig. 1). The time for each face-to-face 290 patients had elective mastectomy 83 met inclusion criteria 207 excluded 87 previous surgery in anterior chest region 10 withdrawn by organizative issues 70 bilateral surgery 11 cognitive impairment 10 central nervous system impairment 9 refusals to participate 10 antipsycothic drugs intake 64 included 5 peripheric neuropathy (due to other causes than chemotherapy) 61 completed 3 lost to follow 4 chronic pain due to surgical or traumatic causes follow up up at 3 months 4 Idiomatic barrier 3 opioids intake 2 alcoholism 1 non-inmediate extubation prevision Figure 1. Patients Flow chart. Patients included and excluded and reasons for exclusion. 4 Masgoret et al. Medicine (2020) 99:11 www.md-journal.com assessment was approximately 40 minutes. No patient had to be Table 2 transferred to the Pain Clinic. Preoperative surgical and treatment variables during follow up. Preoperative general, pain and psychological status varia- Preoperative variables Median and interquartile bles, and surgical and treatment variables during follow-up range or N (%) are shown in Table 2. All patients were female except 2 males. During the preoperative evaluation about one third of patients Age 56 [45;68] manifested VAS≥1 and about one sixth VAS > 3 in the Women 62 (96.9%) BMI 24 [23;28] affected breast. The percentage of patients taking analgesics Occupationally active 36 (56.2%) preoperatively was similar to that of VAS > 3. About half the Smoking 22 (34.4%) patients were consuming benzodiazepines or antidepressants ASA and glove-and-stocking paresthesias we present in 37.5% of I 14 (21.9%) patients. The psychological tests did not present clinically II 47 (73.4%) significant alterations. Intraoperative Fentanyl consumption III 3 (4.7%) did not differ between patients and did exceed in any case Benzodiazepines intake 29 (45.3%) 8 ug.kg 1. Antidepressants intake 10 (15.6%) Malignancy confirmed 62 (96.9%) VAS ≥ 1 20 (31.2%) 3.1. Pain assessment and psychological tests VAS > 3 10 (15.6%) Preoperative analgesic intake 9 (14.1%) VAS values in each postoperative period and their differences NPSI score 0 [0;1.5] with respect to preoperative VAS (–24 hours) and VAS at 6 PCS score 0 [0;3.5] months are shown in Table 3. VAS mean values during the whole HADSA score 4 [2;8] study was <3.5 except at month 1 when VAS obtained the HADSD score 3 [1;5] highest values (4.08 ± 2.67). At 6 months VAS was significantly LOT score 20 [18;22] higher than in the preoperative assessment. Glove-and-stocking paraesthesia 24 (37.5%) VAS > 3 was present in 18.8%, 56.2%, and 21.3% at 1, 3, and Treatment variables Median and interquartile 6 months, respectively.; VAS ≥ 1 was present in 76.6%, 85.9%, range or N (%) and 57.4% of patients at 1, 3, and 6 months, respectively. (Table 3). The use of analgesics was present in 67.2%, 45.3%, Neoadjuvant chemotherapy 36 (56.2%) and 28.3% of patients at 1, 3, and 6 postoperative months, Neoadjuvant hormone or biological therapies 23 (35.9%) Adjuvant chemotherapy 9 (14.1%) respectively. Adjuvant hormone or biological therapies 47 (73.4%) Ten patients (15.62%) expressed contralateral spontaneous Adjuvant radiotherapy 34 (53.1%) pain with VAS values between 1 and 3 in some of the postoperative periods starting at 1 month until the end of the Surgical variables Median and interquartile range or N (%) study. No patient mentioned contralateral spontaneous pain during the first 5 postoperative days. Simple mastectomy 28 (43.8%) Postoperative glove-and-stocking paresthesias were present in Radical modified mastectomy 36 (56.2%) 29 (45.3%), 30 (46.9%) and 26 (41.9%) of patients at 1, 3, and 6 Reconstruction with expander/prosthesis 13 (20.3%) months, respectively. Twenty-one patients (32.8%) required Radical lymphadenectomy 31 (48.4%) Sentinel Ganglion extraction 30 (46.9%) subcutaneous methadone as analgesic rescue during admission. Surgery duration (min) 135 [118;153] The NPSI and psychological tests values are shown in Table 4. Hospital stay (days) 6 [5;7] NPSI scores were significantly higher in all the postoperative ASA = American Association of Anesthesiologists classification, BMI = body mass index, HADSA = times in comparison with the preoperative ones. At month 1, the Hospital Anxiety subscale, HADSD = Hospital Depression Subscale, LOT = Life Orientation Test, N = PCS, HADSD subscale, and LOT scores presented significantly number of patients, NPSI = Neuropathic Pain Symptom Inventory Scale, PCS = Pain Catastrophizing worse values than in the rest of times, expressing a higher degree scale, VAS = Visual Analogue Scale. of catastrophism, depression and pessimism, respectively. The 3.2. QST assessment HADSA subscale at 3 and 6 months showed significantly lower scores than in the preoperative, pointing out a lower level of For each QST, the preoperative examination ( 24 hours) was used anxiety. as baseline reference in order to evaluate postoperative changes. Table 3 VAS values in each postoperative period and their differences with respect to preoperative VAS (-24 hours) and VAS at 6 months. Number and percentage of patients presenting with VAS ≥ 1 and VAS > 3 at all times are presented. 24 h 2h 24 h 48 h 5d Month 1 Month 3 Month 6 VAS (X ± DS) 1.33 ± 2.25 3.11 ± 2.19 3.42 ± 2.33 3.06 ± 2.17 2.14 ± 2.07 4.08 ± 2.67 2.62 ± 2.26 2.1 ± 2.32 ∗ ∗ ∗ ∗ ∗ ∗ ∗ (difference with VAS at -24 h) (N/A) (+1.78) (+2.09) (+1.73) (+0.81) (+2.75) (+1.29) (+0.72) ∗ ∗ ∗ ∗ ∗ ∗ (difference with VAS at month 6) ( 0.72) (+1.05) (+1.36) (+1.01) (+0.085) (+2.02) (+0.57) (N/A) VAS ≥ 1 N (%) 20 (31.2%) 20 (31.2%) 56 (87.5 56 (87.5%) 49 (76.6%) 49 (76.6%) 55 (85.9%) 35 (57.4%) VAS > 3 N (%) 10 (15.6%) 10 (15.6%) 22 (34.4%) 22 (34.4%) 12 (18.8%) 12 (18.8%) 36 (56.2%) 13 (21.3%) NA = Not applicable, VAS = Visual Analogue Scale. ∗ P < .05 Statistical significant difference. N = number of patients, VAS = Visual Analogue Scale, X ± SD = mean ± standard deviation. 5 Masgoret et al. Medicine (2020) 99:11 Medicine Table 4 NPSI and psychological tests applied at all times of the study and their differences with respect to preoperative ( 24 hours) scoring. 24 h 48 h 5d Month 1 Month 3 Month 6 NPSI 2.33 ± 5.12 7.09 ± 8.51 7.11 ± 8.39 13.89 ± 11.6 11.67 ± 10.66 9.54 ± 9.85 ∗ ∗ ∗ ∗ ∗ (+4.77) (+4.78) (+11.56) (+9.34) (+7.12) PCS 3.42 ± 6.39 3.17 ± 5.7 2.83 ± 5.25 5 ± .74 4.13 ± 6.54 3.95 ± 7.17 ∗ (-0.25) (-0.59) (+1.58) (+0.70) (+0.42) HADSA 5.08 ± 3.81 — — 4.55 ± 3.72 4.12 ± 3.36 4.07 ± 3.22 ∗ ∗ (-0.53) (-0.95) (-1) HADSD 3.37 ± 3.2 — — 3.93 ± 3.43 3.5 ± 3.49 3.03 ± 3.37 ∗ (+0.59) (+0.13) (-0.38) LOT 19.42 ± 3.16 — — 18.52 ± 3.64 19.34 ± 3.23 20.05 ± 3.09 ∗ (-0.90) (-0.08) (-0.61) Values are expressed as x ± SD (mean ± standard deviation). In brackets the magnitude and sense of the changes with respect to 24 h values. HADSA = Hospital Anxiety and Depression scale, anxiety subscale, HADSD = Hospital Anxiety and Depression scale, depression subscale, LOT = Life orientation test, NPSI = Neuropathic Pain Inventory Scale, PCS = Pain Catastrophizing Scale. ∗ P < .05 statistically significant differences respect 24 h scoring. Absolute positive or negative changes with any of the “binary”  In the ipsilateral axilla the areas were 22 cm2 (range 1–22 QST in some of the postoperative periods were detected in 51 cm2). The areas with positive changes with 10 g and 60 g VFM, patients (79.7%) in contralateral breast, in 40 patients (62.5%) vibratory and 40° T probe tests were significantly larger at 6 in contralateral axilla and in 25 patients (39.1%) in thigh. In the months than at 48 hours and 5 days. The area of negative operated side, these changes were registered in 61 patients changes was significantly larger at 1 month than at 6 months (95.3%) in the breast and in 53 patients (82.8%) in the axilla. with all the QST except vibratory test. The percentage of patients presenting positive and negative Regarding EVF, Figure 3 shows EVF threshold values in the changes with respect to the preoperative period with each explored zones during the study periods and the comparison with “binary” QST through time in the five zoness explored is shown preoperative values and at 6 months. It can be observed that the in Figure 2. changes evolution in contralateral breast, axilla and thigh is The size of the areas with changes in the QST (X ± SD) at 6 similar although of different magnitude. In these three zones the months were compared with those at 48 hours, 5 days and 1 EVF values significantly decreased in all the postoperative times month adjusted depending on the presence or absence of changes with respect to the preoperative ones indicating hyperalgesia/ in the preoperative exploration for all the zones, except thigh. allodynia, being this decrease highest at 1 month. The table with results of area sizes for each explored zone and In the ipsilateral breast, the EVF values significantly increased type of QST in all studied periods and the differences with respect at 48 hours and 5 days with regard to the preoperative period to month 6 for each time can be consulted in Supplemental Digital indicating hypoesthesia/anesthesia. In contralateral breast and Content 1, http://links.lww.com/MD/D763, http://links.lww. axilla as in the ipsilateral breast the EVF values at 6 months were com/MD/D764. significantly lower than those found in the preoperative, 48 hours The areas with positive or negative changes in the binary QST and 5 days. In the thigh there was a significant decrease in the that reached statistically significant differences during the study EVF at 6 months with respect to the preoperative. are as follows: The frequency of EVF changes over and under 20% with  In the contralateral breast, the areas were 30 cm2 (range 0–30 respect to preoperative values in the different zones and times are cm2). The areas with negative changes with 0.1 g, 0.6 g, and 10 shown in Table 5. g VFM and positive changes with 0,6 g, 10 g, 60 g VFM and In general, a good concordance between patients that positive changes with vibratory and 40° T probe tests, were presented changes of EVF above or below 20% and positive significantly larger at 6 months than at 48 hours and 5 days. or negative changes with the rest of QST was not observed. The The area with positive changes with 60 g VFM and 40° T probe highest values of Kappa index were found in breast and ipsilateral were significantly larger at 1 month than at 6 months. axilla, however, in no case did the Kappa index show values  In the contralateral axilla the areas were 12 cm2 (range 0–12 higher than 0.5. cm2). The areas of negative changes with 0.1 g and 0.6 g VFM and positive changes with 10 g and 60 g VFM, vibratory and 3.3. Characteristics of patients with contralateral temperature test were significantly higher at month 6 than at 48 alterations hours and 5 days. The areas of negative changes with 0,1 g VFM and 40° T probe and positive with 10 g and 60 g VFM Table 6 shows relationship of ipsilateral VAS mean values, VAS ≥ were significantly larger at 1 month than at 6 months. 1, VAS > 3 and EVF threshold values in contralateral axilla,  In the ipsilateral breast the areas were 91 cm2 (range 2–91 ipsilateral breast, ipsilateral axilla and thigh with presence or cm2). The areas with negative changes with 0,1 g, 0,6 g, and 10 absence of EVF changes above or below 20% in contralateral g VFM and 40°C T probe and with positive changes with 10 g breast at some period of the study with respect to preoperative and 60 g VFM, vibratory and 40° T probe tests were exploration. significantly larger at 6 months than at 48 hours and 5 days. Patients with a 20% decrease of EVF in contralateral breast The area with negative changes with all the tests was with respect to the preoperative values at some period manifested significantly larger at 1 month than at 6 months. VAS values significantly higher at 6 months. No significant 6 Masgoret et al. Medicine (2020) 99:11 www.md-journal.com Patients with a 20% increase of EVF in contralateral breast with respect to the preoperative values at some period showed average VAS values significantly higher at 48 hours and 1 month. A significant correlation existed between increases of 20% of EVF in contralateral breast and VAS ≥ 1 and VAS > 3 in ipsilateral breast up to month 1. Although there was a trend for patients with absolute “binary” QST changes in contralateral breast at some period to express, at some moment, higher VAS, the difference reached statistical significance only in the preoperative exploration (Fig. 4). Only 26.6% incidence of nausea and vomiting with an incidence of 26.6% was registered as adverse effect or complication. 4. Discussion The aim of this study was to assess presence of MISD, MIP, and PPP during the first 6 months after mastectomy. As far as we know, this is the first study which prospectively follows ipsilateral and contralateral neurosensitive changes looking for MISD, from the preoperative period throughout 6 months after mastectomy, including psychological aspects involved in PPP. Incidence of PPP, defined as VAS > 3 at 6 months was 21.23%, similar to previous studies[21,22]; 57.4% of patients reported VAS ≥ 1 at 6 months, a value that can be considered clinically irrelevant but has been used as threshold to define PPP in previous studies.[16–18,26] The most relevant finding of this study is the high incidence of MISD assessed by QST, which was present in almost 80% of patients. Furthermore, 15.6% of patients referred contralateral spontaneous pain (MIP). This study applied a brief QST protocol which had been previously used by our group[16,18] as original QST testing is cumbersome, time–consuming and difficult to apply repeatedly in postoperative patients and therefore seldom published after surgery. Reference values for QST around surgical area are scarce.[15,24] Furthermore, QST was designed specifically for neuropathic chronic pain and even in it, the neurological substrate of responses is still of difficult interpretation.[32] Despite those drawbacks, appearance of postoperative QST changes compared to preoperative exploration in the contralat- eral zone to the surgery (not been injured at all) can be clearly interpreted as MISD. MISD has been demonstrated in some chronic pain patients[7,8,10–12] but only 2 papers[5,9] have described it in surgical patients, and with already established PPP. Since in these studies preoperative QST assessment had not been made, comparison with baseline pattern is lacking, which limits the definitive attribution of QST alterations to surgery. In our study, contralateral QST changes can be clearly attributed to the surgical process since we had preoperative exploration for each patient as baseline reference. Figure 2. Percentage of patients presenting areas with positive and negative Information available on MISD development mechanisms is changes with respect to the preoperative period with each “binary” QST scarce and confusing, and we can only speculate in the through time in the 5 zones explored. Order of zone display: 1. Contralateral breast; 2. Contralateral axilla; 3. Ipsilateral breast; 4. Ipsilateral axilla; 5. Thigh. interpretation of our findings. Furthermore, the contralateral VFM = Von Frey Monofilament. side to mastectomy, and a distant zone, the thigh, was also explored to assess if neurosensitive changes extended beyond spinal innervation symmetry, suggesting the involvement of correlation of EVF changes with VAS ≥ 1 or VAS >3 values in supraspinal mechanisms in MISD.[15,24] Interestingly, the inci- ipsilateral breast at any time was found. The EVF thresholds in dence of postoperative QST changes at thigh was 39.1%. QST these patients were lower in the contralateral axilla, ipsilateral changes in zones distant from each other supports the implication breast and axilla, and thigh reaching statistically significant of extensive changes at central nervous level in postoperative values in both axillae at 1 and 6 months. pain[15,24,33] and alterations in DNIC has been suggested.[19] It is 7 Masgoret et al. Medicine (2020) 99:11 Medicine Figure 3. Electronic Von ∗ Frey threshold values in the explored zones during the study periods and comparison with preoperative values and at 6 months. Values expressed as x ± DS. Statistically significant difference with preoperative values (P < .05). ̈Statistically significant difference with 6 months values (P < .05). of note that 15.6% of patients (10 patients) referred MIP reduce QST protocols to make them applicable in the clinical evaluated by VAS, starting 1 month after surgery and coinciding setting.[1,28] In light of our results, in the surgical patient the with the highest ipsilateral VAS value. This late appearance, with complex protocols can be replaced by a single QST, EVF. By an intensity curve parallel to the contralateral side and thigh QST doing so, EVF will detect neurosensitive changes easily and alert coincides with previous experimental studies.[2,9] It is believed about those patients with a higher risk of PPP. that MIP is rarely reported by patients since it corresponds in time There are no references about what magnitude of EFV change with intense ipsilateral pain that focuses attention and “masks” has a neurophysiological meaning but we considered empirically contralateral manifestations.[1] Interrogation specifically directed that a 20% change had clinical significance in order to detect towards MIP allowed us to detect its incidence in the period of changes. More than 1/3 of patients showed 20% changes of EVF maximum pain in the surgical side. in the contralateral side postoperatively, being highest at 1 Any significance of the different QST in the perioperative month. Decrease of 20% contralateral EVF, which means higher period is not clear[17,23] and we could not corroborate sensibility, was more frequent than increase. Contralateral EVF consistency among the different QST and their evolution except changes ≥20% were associated with changes in the same for one of them, EVF. It is thought that EVF explores mechanical direction in the other zones explored confirming consistency of sensitivity,[34] and is the easiest QST to apply and provides a this QST. numeric value, which allows reliable analysis. In this study, EVF We assessed the size of the area that presented neurosensitive showed a concordant evolution between the different explored changes around the surgical incision (secondary hyperalgesia) zones and allowed doing a quantitative follow-up of mechanical since it has been associated with PPP onset.[14,20] There are no sensitivity changes in the postoperative period comparing them reference values for the size of these areas. In thoracic and hepatic with the preoperative evaluation. it has recently been proposed to surgery, our group found areas with changes less frequent and Table 5 Frequency of Electronic Von Frey changes over and under 20% with respect to preoperative values ( 24 hours) in the different zones explored. 48 h 5d 1 mo 6 mo Increase Decrease Increase Decrease Increase Decrease Increase Decrease Contralateral breast 9 (14.1%) 18 (28.1%) 10 (15.6%) 27 (42.2%) 7 (10.9%) 39 (60.9%) 7 (11.5%) 30 (49.2%) Contralateral axilla 4 (6.2%) 18 (28.1%) 8 (12.5%) 23 (35.9%) 5 (7.8%) 35 (54.7%) 8 (13.1%) 28 (45.9%) Ipsilateral breast 24 (37.5%) 14 (21.9%) 29 (45.3%) 17 (26.6%) 22 (34.4%) 25 (39.1%) 20 (32.8%) 23 (37.7%) Ipsilateral axilla 10 15.6%) 18 (28.1%) 16 (25%) 20 (31.2%) 16 (25%) 35 (54.7%) 14 (23%) 26 (42.6%) Thigh 9 (14.1%) 19 (29.7%) 7 (10.9%) 21 (32.8%) 5 (7.8%) 31 (48.4%) 8 (13.1%) 23 (37.7%) Values expressed as N (number of patients) and (%). 8 Table 6 Relationship of ipsilateral VAS scores, VAS > 1, VAS > 3 and Electronic Von Frey threshold values in contralateral axilla, ipsilateral breast, ipsilateral axilla and thigh with the presence or absence of Electronic Von Frey changes above or below 20% in contralateral breast at some period of the study with respect to preoperative exploration. Masgoret et al. Medicine (2020) 99:11 24 h 2h 24 h 48 h 5d Month 1 Month 3 Month 6 DECREASE >20% OF EVF IN CONTRALATERAL BREAST AT SOME TIME Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No ∗ VAS 1.25 ± 2.14 1.5 ± 2.54 3.18 ± 2.43 2.95 ± 1.57 3.36 ± 2.43 3.55 ± 2.14 3.14 ± 2.31 2.9 ± 1.89 2.34 ± 2.24 1.7 ± 1.59 4.18 ± 2.68 3.85 ± 2.72 2.91 ± 2.37 2 ± 1.93 2.45 ± 2.53 1.32 ± 1.57 X ± DS VAS≥1 14 (31.8) 30 (68.2) 38 (86.4) 6 (13.6) 38 (86.4) 6 (3.6) 38 (86.4) 6 (13.6) 35 (79.5) 9 (20.5) 37 (84.1) 7 (15.9) 34 (77.3) 10 (22.7) 26 (61.9) 16 (38.1) N (%) VAS>3 6 (13.3) 38 (86.4) 15 (34.1) 29 (65.9) 18 (40.9) 26 (59.1) 15 (34.1) 29 (65.9) 9 (20.5) 35 (79.5) 27 (61.4) 17 (38.6) 16 (36.4) 28 (63.4) 12 (28.6) 30 (71.4) N (%) ∗ ∗ ∗ EVF contralateral axilla 191 ± 74 155 ± 55 N/A N/A N/A N/A 164 ± 70 172 ± 57 154 ± 69 177 ± 59 119 ± 51 180 ± 79 N/A N/A 127 ± 50 192 ± 68 EVF Ipsilateral breast 180 ± 75 168 ± 81 N/A N/A N/A N/A 219 ± 115 229 ± 113 220 ± 124 233 ± 121 191 ± 131 225 ± 163 N/A N/A 176 ± 105 222 ± 140 ∗ ∗ ∗ EVF ipsilateral axilla 178 ± 71 165 ± 59 N/A N/A N/A N/A 165 ± 83 199 ± 89 157 ± 84 212 ± 106 147 ± 97 203 ± 122 N/A N/A 135 ± 66 215 ± 107 9 EVF thigh 267 ± 109 232 ± 76 N/A N/A N/A N/A 239 ± 110 240 ± 85 225 ± 101 237 ± 82 201 ± 116 236 ± 96 N/A N/A 220 ± 117 230 ± 80 Increase >20% of EVF in contralateral breast at some time Yes No Yes No Yes No Yes No Yes No Yes No Yes No Yes No ∗ ∗ ∗ VAS 1.33 ± 2.53 1.33 ± 2.19 3.6 ± 1.3 2.96 ± 2.39 4.47 ± 1.81 3.1 ± 2.39 3.93 ± 1.94 2.8 ± 2.19 2.33 ± 1.4 2.08 ± 2.24 5.2 ± 2.6 3.73 ± 2.63 2.67 ± 1.88 2.61 ± 2.39 1.38 ± 1.71 2.29 ± 2.44 X ± DS ∗ ∗ ∗ ∗ VAS≥1 4 (26.7) 11 (73.3) 15 (100) 0 15 (100) 0 15 (100) 0 14 (93.3) 1 (6.7) 15 (100) 0 12 (80) 3 (20) 6 (46.2) 7 (53.8) N (%) ∗ VAS>3 2 (13.3) 13 (86.7) 7 (46.7) 8 (53.3) 11 (73.3) 4 (26.7) 8 (53.3) 7 (46.7) 3 (20) 12 (80) 10 (66.7) 5 (33.3) 4 (26.7) 11 (73.3) 1 (7.7) 12 (92.3) N (%) ∗ ∗ ∗ EVF contralateral axilla 147 ± 49 190 ± 73 N/A N/A N/A N/A 173 ± 62 165 ± 68 179 ± 69 156 ± 65 175 ± 92 126 (53) N/A N/A 199 ± 76 133 ± 52 ∗ EVF Ipsilateral breast 164 ± 70 180 ± 79 N/A N/A N/A N/A 257 ± 99 211 ± 116 263 ± 104 213 ± 126 231 ± 169 193 ± 132 N/A N/A 262 ± 141 171 ± 104 ∗ ∗ ∗ ∗ EVF ipsilateral axilla 161 ± 53 178 ± 72 N/A N/A N/A N/A 224 ± 87 160 ± 80 245 ± 107 153 ± 80 213 ± 139 149 ± 93 N/A N/A 250 ± 108 136 ± 65 EVF thigh 244 ± 86 259 ± 105 N/A N/A N/A N/A 252 ± 92 235 ± 106 254 ± 85 221 ± 98 228 ± 87 207 ± 118 N/A N/A 246 ± 88 217 ± 111 EVF = Electronic Von Frey, N/A = not applicable, N = number of patients, VAS = visual analogue scale, X ± DS = mean ± standard deviation. ∗ P < .05. www.md-journal.com Masgoret et al. Medicine (2020) 99:11 Medicine Figure 4. VAS values (X ± SD) in patients with and without absolute ∗ “binary” QST changes in the contralateral breast at some period thought the study. VAS is represented in 0-5 scale since no patient showed VAS > 5. : P < .05; QST = Quantitative Sensory Tests, VAS = Visual Analogue Scale. smaller than those found in the present study in mastecto- patients met them in a tertiary hospital during a 5-year mies.[16,18] The area affected by mastectomy has a more extensive period with almost 300 patients submitted to mastectomy. To and complex innervation than thoracotomy or hepatectomy and extend the period would entail risk of changes in treatment this fact may explain larger areas with neurosensitive changes. protocols and to wide inclusion criteria would reduce sample We were not able to correlate extension of those areas with PPP. homogeneity. We looked for association of QST changes in the contralateral Strengths of this study are its prospective condition, homoge- side with the other explored zones and with PPP development, neous sample of patients, almost complete follow up and since there is evidence about their direct relationship.[14,19,20] The exhaustive subjective and semi-objective evaluation of changes amount of data obtained have made their analysis and related with PPP and MISD during 6 postoperative months interpretation difficult, but we can state that, in this study having as control the preoperative exploration in each patient. intensity of postoperative pain correlated with MISD. Decrease of In conclusion, after mastectomy, MISD incidence was high, EVF values ≥20% at any time was associated to higher VAS almost 80%, with MIP in 15.6% of patients. PPP incidence at 6 values at 6 months and increases of EVF ≥20% were associated months was 21.3%. The greatest alteration in all factors that with higher VAS values at 1 month. This confirms certain have been associated with PPP after mastectomy appeared at relationship between intensity of ipsilateral postoperative pain month 1. EVF is the QST that provides an easier applicability and and PPP with neurophysiological changes that affect those zones consistency in order to show contralateral changes after far from the surgical lesion. mastectomy. One important contribution of this study is the analysis of psychological tests that influence pain chronification. Applied Acknowledgments tests worsened postoperatively, especially at 1 month coinciding with the highest VAS values and with the lowest EVF values in the The author thanks the contribution of Dr. Pinar De Santos, the contralateral side and thigh. members of Breast Surgery Section and of the Oncology Patients were at their worst at month 1, in which the highest Department, the nurses of the postanesthetic care unit and the VAS, the worst result of psychological tests and the greatest ward of Gynecology of the Hospital Clinic of Barcelona. The intensity of QST changes coincided. This finding is important in authors pay great recognition and admiration to the participating order to guide postoperative support for these patients. At month patients. 1 also chemotherapy or radiotherapy are frequently initiated and bandages are usually removed making patients aware of the Author contributions physical sequelae of mastectomy. Those factors, among others,[21,23,25,35] may influence negatively in their well-being. Conceptualization: Carmen Gomar, Paula Masgoret. The coincidence of the worsening of all the studied variables Data curation: Paula Masgoret, Inés de Soto, Ángel Caballero, supports that changes detected in this study are caused by the Carmen Gomar. surgical process. Formal analysis: José Ríos, Paula Masgoret, Carmen Gomar. The most important drawback of this study is the limited Methodology: Paula Masgoret, Carmen Gomar. sample size for one of the objectives of the study: PPP incidence. Supervision: Carmen Gomar. The strict inclusion criteria to limit as much as possible Writing: Paula Masgoret, Inés de Soto, Ángel Caballero, José confounding factors in MISD detection, made that only 64 Ríos, Carmen Gomar. 10 Masgoret et al. Medicine (2020) 99:11 www.md-journal.com References [19] Granot M. Can we predict persistent postoperative pain by testing preoperative experimental pain? 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