Introduction. Keywords Chronic postsurgical pain Thoracic surgery TKA Risk factor

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1 CLINICAL REPORT Prevalence of chronic postsurgical pain after thoracotomy and total knee arthroplasty: a retrospective multicenter study in Japan (Japanese Study Group of Subacute Postoperative Pain) Yoko Sugiyama 1 Hiroki Iida 1 Fumimasa Amaya 2 Kanako Matsuo 2 Yutaka Matsuoka 2 Keiko Kojima 3 Fumitaka Matsuno 3 Takayuki Hamaguchi 3 Masako Iseki 4 Keisuke Yamaguchi 4 Yoshika Takahashi 4 Atsuko Hara 4 Yusuke Sugasawa 4 Mikito Kawamata 5 Satoshi Tanaka 5 Yoshimi Inagaki 6 Akihiro Otsuki 6 Mitsuaki Yamazaki 7 Hisakatsu Ito 7 Received: 1 September 2017 / Accepted: 1 March 2018 / Published online: 9 March 2018 Japanese Society of Anesthesiologists 2018 Abstract We performed a multicenter observational study to assess the prevalence and risk factors of persistent pain after lung cancer surgery and total knee arthroplasty (TKA) in the Japanese population. After receiving Ethics Committee approval, a retrospective chart review was performed for patients who underwent surgery at seven university hospitals in Japan in A total of 511 patients who underwent lung cancer surgery and 298 patients who underwent TKA were included. The prevalence of chronic postsurgical pain (CPSP) at 3 and 6 months was 18 and 12% after lung surgery and 49 and 33% after TKA, respectively. The prevalence of analgesic use at 3 and 6 months was 16 and 9% after lung surgery and 34 and 22% after TKA, respectively. In both groups, preoperative analgesic use was associated with CPSP. Anesthetic methods or techniques during both types of surgery did not significantly affect the prevalence of CPSP. This is the first study in which the prevalence of CPSP after lung surgery and TKA in Japanese population was extensively evaluated in a multicenter trial. Further prospective studies are needed to confirm the prevalence of CPSP in the Japanese population and to identify risk factors and prevention methods. Keywords Chronic postsurgical pain Thoracic surgery TKA Risk factor * Yoko Sugiyama yoko_sg@gifu u.ac.jp 1 Department of Anesthesiology and Pain Medicine, Gifu University Graduate School of Medicine, 1 1 Yanagido, Gifu, Gifu , Japan 2 Department of Anesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan 3 Clinical Pain Service, The Jikei University Hospital, Tokyo, Japan 4 Department of Anesthesiology and Pain Medicine, Juntendo University School of Medicine, Tokyo, Japan Department of Anesthesiology and Resuscitology, Shinshu University School of Medicine, Matsumoto, Japan Department of Anesthesiology and Critical Care Medicine, Faculty of Medicine, Tottori University, Tottori, Japan Department of Anesthesiology, University of Toyama Graduate School of Medicine and Pharmaceutical Sciences for Research, Toyama, Japan Introduction Chronic postsurgical pain (CPSP) is defined as pain that develops after surgical procedures and persists for at least 3 months after surgery [1]. CPSP that persists beyond normal wound healing periods has a serious impact on patients quality of life and has significant economic consequences. Since the incidence of surgery has greatly increased in recent years globally, CPSP has become widely recognized as an important clinical problem. Numerous studies from Europe and the United States have indicated that the prevalence of CPSP is quite high, at between 5 and 85% depending on the surgery and study [2]. Some reports have suggested that sensitivity to both clinical and experimental pain differs among ethnic groups [3]; however, ethnic differences in CPSP remain unclear. Although several small studies have been reported, the epidemiological characteristics of CPSP have not been extensively evaluated in Japan. In particular, Vol:.( )

2 there have been no multicenter studies of the prevalence of CPSP in the Japanese population. The aim of this multicenter trial was to preliminarily determine the prevalence and associated factors of CPSP in Japanese patients after lung cancer surgery and total knee arthroplasty (TKA), which are both regarded as high-risk surgeries for CPSP [2, 4]. Case report This study was a multicenter, retrospective medical chart review involving seven university hospitals in Japan: Gifu University Hospital in Gifu, Kyoto Prefectural University Hospital in Kyoto, the Jikei University Hospital in Tokyo, Juntendo University Hospital in Tokyo, Shinshu University Hospital in Matsumoto, Tottori University Hospital in Yonago, and Toyama University Hospital in Toyama. The study protocol was approved by each institutional review board and registered with the University Hospital Medical Information Network Clinical Trials Registry (registered ID: UMIN ). Adult patients who underwent elective lung cancer surgery (the lung group) or TKA (the knee group) between January 1 and December 31, 2013 were identified from medical records. Written consent for the study was waived, because no clinical interventions were performed and all protected health information was removed after data abstraction. The exclusion criteria were as follows: bilateral surgery, additional surgical procedures within 6 months, resection of the chest wall, presence of recurrence or infection at the surgical site, and follow-up for less than 6 months after surgery. The following data were collected: age, gender, type of surgery, type of anesthesia, preoperative analgesic use, postoperative radiation therapy or chemotherapy (lung group), description of surgical site pain at 3 and 6 months after surgery, prescription of analgesics for the surgical site pain at 3 and 6 months after surgery, and referrals to pain clinics. Perioperative management was performed in accordance with each institutional protocol. Statistical analyses were performed using the JMP software program, and p < 0.05 was considered significant. The characteristics of patients with or without surgical site pain at 3 and 6 months after surgery were compared using the Mann Whitney U test for continuous variables and the Chisquared or Fisher s exact test when appropriate for categorical variables. A multivariate logistic regression analysis was used to identify risk factors. Overall, complete study data were available for 511 patients in the lung group and 298 patients in the knee group during the study period. The individual and combined study site demographics are displayed in Table 1. A total of 18 and 12% of patients reported pain, and 16 and 9% of patients received analgesics at 3 and 6 months after surgery 435 in the lung group, respectively. Of 80 patients prescribed analgesics at 3 months after lung surgery, 80% received non-steroidal anti-inflammatory drugs (NSAIDs) or/and acetaminophen, 14% received opioids, and 23% received pregabalin (Table 1). Of the 44 patients prescribed analgesics at 6 months after lung surgery, 64% received NSAIDs or/ and acetaminophen, 9% received opioids, and 23% received pregabalin. A total of 49 and 33% of patients reported pain, and 34 and 21% of patients received analgesics at 3 and 6 months after surgery in the knee group, respectively. Of 100 patients prescribed analgesics at 3 months after TKA, 97% received NSAIDs or/and acetaminophen, 10% received opioids, and 11% received pregabalin (Table 1). Of the 64 patients prescribed analgesics at 6 months after TKA, 91% received NSAIDs or/and acetaminophen, 14% received opioids, and 13% received pregabalin. The referral rates to pain clinicians were quite low in both groups (Table 1). The potential risk factors for pain at 3 and 6 months after surgery are displayed in Table 2. The anesthetic methods and surgical procedures were not associated in either group. A logistic regression analysis was used to determine the risk factors for pain at 3 and 6 months after surgery from among age, gender, preoperative analgesics use, and anesthetic methods. Preoperative analgesics use was found to be associated with pain at 3 months (odds ratio (OR) = 3.9, 95% confidence interval (CI) ) in the lung group and pain at 3 months (OR = 2.4, 95% CI ) and 6 months (OR = 1.9, 95% CI ) in the knee group. Female gender was associated with pain at 6 months in the lung group (OR = 2.9, 95% CI ). Discussion The purpose of the present study was to determine the prevalence of CPSP after lung cancer surgery and TKA in Japanese patients. Seven university hospitals (two in Tokyo, five in other areas of Japan) participated in this study. The results showed that 18 and 48% of patients reported chronic pain 3 months after lung cancer surgery and TKA, respectively. This is comparable with the previous findings in other countries. Macrae found that the incidence of CPSP after thoracotomy was 5 65% [2]. Thomazeau et al. reported that the incidence of CPSP 3 and 6 months after TKA at a French hospital was 42 and 29% [5]. The previous studies have suggested ethnic differences in pain perception and pain management. Asians have demonstrated lower pain threshold and tolerance levels than non- Hispanic whites (NHWs) in the cold pain test [6]. Asian Americans also had significantly higher levels of clinical pain intensity than NHWs with knee osteoarthritis [7]. Genetic, psychological, or sociocultural factors may contribute to these differences [3]. Chan et al. demonstrated

3 436 Journal of Anesthesia (2018) 32: Table 1 Patients characteristics and outcomes by institutional site Group lung Jikei Juntendo KPUM Shinshu Tottori Toyama Gifu Combined N Age, mean (SD), years 67 (11) 66 (13) 67 (14) 67 (10) 68 (12) 69 (9) 66 (11) 67 (12) Gender; male:female, % 77:23 64:36 56:44 47:53 63:38 63:37 69:31 61:39 Preoperative analgesics, N (%) 3 (5) 4 (6) 12 (14) 7 (8) 7 (9) 5 (12) 1 (1) 39 (8) Procedure, N (%) Thoracotomy 1 (2) 71 (99) 10 (11) 27 (29) 28 (35) 10 (23) 70 (88) 217 (42) VATS 56 (98) 1 (1) 77 (89) 65 (71) 52 (65) 33 (77) 10 (13) 294 (58) Anesthesia type, N (%) General alone 1 (2) 2 (3) 87 (100) 12 (13) 12 (15) 0 (0) 0 (0) 114 (22) Epidural + general 54 (95) 70 (97) 0 (0) 80 (87) 67 (84) 43 (100) 69 (86) 383 (75) Regional nerve block + general 2 (4) 0 (0) 0 (0) 0 (0) 1 (1) 0 (0) 11 (14) 14 (3) Radiation therapy, N (%) 14 (25) 25 (35) 46 (53) 25 (27) 33 (41) 17 (40) 39 (49) 199 (39) Chemotherapy, N (%) 2 (4) 1 (1) 7 (8) 1 (1) 4 (5) 3 (7) 3 (4) 21 (4) Outcomes, N (%) 3M pain 2 (4) 6 (8) 16 (18) 28 (30) 13 (16) 12 (28) 14 (18) 91 (18) 3M analgesics 5 (9) 6 (8) 10 (11) 20 (22) 13 (16) 10 (23) 16 (20) 80 (16) AA/NSAIDs Opioids Pregabalin Others M pain 1 (2) 6 (8) 9 (10) 23 (25) 7 (9) 6 (14) 7 (9) 59 (12) 6M analgesics 1 (2) 3 (4) 5 (6) 16 (17) 6 (8) 4 (9) 9 (11) 44 (9) AA/NSAIDs Opioids Pregabalin Others Consultation with pain clinic 0 (0) 1 (1) 4 (5) 6 (7) 0 (0) 0 (0) 4 (5) 15 (3) Group knee N Age, mean (SD), years 71 (11) 72 (9) 73 (9) 70 (14) 76 (8) 71 (11) 74 (9) 72 (10) Gender; male:female, % 29:71 17:83 23:77 23:77 17:83 23:77 33:67 22:73 Preoperative analgesics, N (%) 1 (2) 40 (45) 35 (66) 15 (34) 9 (38) 16 (53) 10 (56) 126 (42) Anesthesia type, N (%) General alone 6 (14) 0 (0) 31 (58) 13 (30) 0 (0) 3 (10) 2 (11) 55 (19) Epidural + general 0 (0) 86 (98) 1 (2) 28 (65) 19 (79) 0 (0) 13 (72) 147 (49) Regional nerve block + general 33 (79) 2 (2) 20 (38) 2 (5) 5 (21) 27 (90) 3 (17) 92 (31) CSE 3 (7) 0 (0) 1 (2) 0 (0) 0 (0) 0 (0) 0 (0) 4 (1) Outcomes, N (%) 3M pain 5 (12) 57 (65) 23 (43) 24 (56) 10 (42) 20 (67) 8 (44) 147 (49) 3M analgesics 5 (12) 41 (47) 18 (34) 15 (35) 5 (21) 14 (47) 2 (11) 100 (34) AA/NSAIDs Opioids Pregabalin Others M pain 3 (7) 37 (42) 12 (23) 23 (53) 5 (21) 11 (37) 6 (33) 97 (33) 6M analgesics 4 (10) 27 (31) 11 (21) 11 (26) 2 (8) 7 (23) 2 (11) 64 (21) AA/NSAIDs Opioids Pregabalin Others Consultation with pain clinic 0 (0) 1 (1) 0 (0) 5 (12) 0 (0) 0 (0) 0 (0) 6 (2) Opioids include morphine, codeine, tramadol, tramadol/acetaminophen, and pentazocine VATS video-assisted thoracic surgery, CSE combined spinal epidural anesthesia, 3M 3 months after surgery, 6M 6 months after surgery, KPUM Kyoto Prefectural University of Medicine, AA acetaminophen, NSAIDs non-steroidal anti-inflammatory drugs

4 that ethnicity was not an independent risk factor for CPSP, although nitrous oxide used during surgery reduced the risk of CPSP in Asian patients compared to non-asian patients [8]. To elucidate the ethnic differences in the prevalence of CPSP, a large international prospective study is needed. In the present study, preoperative analgesic use was associated with CPSP in both surgeries, supporting the idea that patients with pre-existing pain may be at high risk of CPSP [9]. We defined CPSP as reports of surgical site pain 3 months after surgery in the medical charts recorded by surgeons. These data were wholly dependent on the surgeon s documentation, so we should consider that our results might underestimate the prevalence of CPSP. Our results indicated a higher incidence of CPSP after TKA than after lung cancer surgery. This might be because orthopedicians assessed pain more frequently using certain scoring systems [10] to measure the outcome of TKA and recorded slight to mild pain as well as moderate-to-severe pain. Conversely, thoracic surgeons might have recorded only moderate-to-severe pain, because mild pain may have affected the physical function of the patients to a lesser degree than more severe pain. The Tromsø Study, which was a cross-sectional survey performed in northern Norway, showed that persistent pain 437 in the area that underwent surgery was reported by 40.4% of the patients and moderate-to-severe pain by 18.3% [11]. Since this study was based on a retrospective chart review, the severity of pain was not quantitatively assessed. Pain rating data such as numerical rating scale and facial scale were missing in most of the medical records which were written by surgeons. However, prescription rates of analgesics at 3 and 6 months after surgery (Table 1) could be considered as the existence of uncontrolled, moderate-to-severe pain instead. A total of 16 and 34% of patients were prescribed analgesics at 3 months after lung cancer surgery and TKA, respectively. Most patients were treated with NSAIDs or/ and acetaminophen in both groups. Although a prospective study is needed to obtain further information about the types and pathophysiology of pain in each group, the necessity of enlightenment was suggested on how to use analgesics and adjuvant analgesics for each pathological condition of postoperative pain. Another limitation is that we were unable to distinguish all other causes of pain; however, we excluded the cases which postsurgical infection or recurrence at the surgical site was apparent in the medical records. Finally, we could not assess some potential predictors of CPSP due to the retrospective nature of the study. For example, the intensity of acute postoperative pain or psychological variables, Table 2 Comparison between patients with and without persistent pain 3M 6M Pain (+) Pain ( ) p value Pain (+) Pain ( ) p value Group lung N Age, mean (SD), years 67 (11) 67 (12) (10) 67 (12) 0.47 Gender; M:F, % 55:45 63: :61 64:36 < Preoperative analgesics, N (%) 16 (18) 23 (5) < (14) 31 (7) 0.07 Procedure, N (%) Thoracotomy 41 (45) 176 (42) 26 (44) 191 (42) VATS 50 (55) 244 (58) 33 (56) 261 (58) Anesthesia type, N (%) General alone 18 (20) 96 (23) 13 (22) 101 (22) Epidural + general 69 (76) 314 (75) 45 (76) 338 (75) Regional nerve block + general 4 (4) 10 (2) 1 (2) 13 (3) Group knee N Age, mean (SD), years 71 (11) 73 (10) (9) 73 (11) 0.21 Gender; M:F, % 19:81 25: :81 24: Preoperative analgesics, N (%) 77 (52) 49 (32) < (52) 76 (38) 0.03 Anesthesia type, N (%) General alone 16 (11) 13 (9) 9 (9) 20 (10) General + peri-articular morphine 11 (8) 15 (10) 6 (6) 20 (10) Epidural + general or spinal 83 (56) 68 (45) 59 (61) 92 (46) Regional nerve block + general 37 (25) 55 (36) 23 (24) 69 (34) SD standard deviation, VATS video-assisted thoracic surgery, CSE combined spinal epidural anesthesia, 3M 3 months after surgery, 6M 6 months after surgery

5 438 Journal of Anesthesia (2018) 32: such as anxiety and catastrophizing, may be associated with the development of CPSP [12, 13]. In conclusion, our preliminary study indicates that the prevalence of CPSP after lung cancer surgery and TKA among Japanese was comparable with the previous results in other countries. We are planning a prospective multicenter study to confirm the prevalence and predictors in Japanese patients. References 1. Treede RD, Winfried R, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavand homme P, Nicholas M, Perrot S, Scholz J, Schung S, Smith BH, Svensson P, Vlaeyen JWS, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015;156: Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth. 2008;101: Campbell CM, Edwards RR. Ethnic differences in pain and pain management. Pain Manag. 2012;2: Grosu I, Lavand homme P, Thienpont E. Pain after knee arthroplasty: an unresolved issue. Knee Surg Sports Traumatol Arthrosc. 2014;22: Thomazeau J, Rouquette A, Martinez V, Martinez V, Rabuel C, Prince N, Laplanche JL, Nizard R, Bergmann JF, Perrot S, Lloret-Linares C. Predictive factors of chronic post-surgical pain at 6 months following knee replacement: influence of postoperative pain trajectory and genetics. Pain Physician. 2016;19:E Rowell LN, Mechlin B, Ji E, Addamo M, Girdler SS. Asians differ from non-hispanic whites in experimental pain sensitivity. Eur J Pain. 2011;15: Ahn H, Weaver M, Lyon DE, Kim J, Choi E, Staud R, Fillingim RB. Differences in clinical pain and experimental pain sensitivity between Asian Americans and whites with knee osteoarthritis. Clin J Pain. 2017;33: Chan MTV, Peyton PJ, Myles PS, Leslie K, Buckley N, Kasza J, Paech MJ, Beattie WS, Sessler DI, Forbes A, Wallace S, Chen Y, Tian Y, Wu WKK, The Australian and New Zealand College of Anesthetists Clinical Trials Network for the ENIGMA-II investigators. Chronic postsurgical pain in evaluation of nitrous oxide in the gas mixture for anesthesia (ENIGMA)-II trial. Br J Anaesth. 2016;117: Fletcher D, Stamer UM, Pogatzki-Zahn E, Zaslansky R, Tanase VN, Perruchoud C, Kranke P, Komann M, Lehman T, eucpsp group for the Clinical Trial Network group of the European Society of Anaesthesiology and Winfried Meissner. Chronic postsurgical pain in Europe. Eur J Anaesthesiol. 2015;32: Davies AP. Rating systems for total knee replacement. Knee. 2002;9: Johansen A, Romundstad L, Nielsenm CS, Schirmer H, Stubhaug A. Persistent postsurgical pain in a general population: prevalence and predictors in the Tromø study. Pain. 2012;153: Kehlet H, Jensen T, Woolf C. Persistent postsurgical pain: risk factors and prevention. Lancet. 2006;367: Theunissen M, Peters ML, Bruce J, Gramke HF, Marcus MA. Preoperative anxiety and catastrophizing: a systematic review and meta-analysis of the association with chronic postsurgical pain. Clin J Pain. 2012;28: