- Email: [email protected]
Chronic Pain After Lung Resection: Risk Factors, Neuropathic Pain, and Quality of Life
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Journal of Pain and Symptom Management
Vol. 60 No. 2 August 2020
Original Article
Chronic Pain After Lung Resection: Risk Factors, Neuropathic Pain, and Quality of Life Silvia Fiorelli, MD, Luigi Cioffi, MD, Cecilia Menna, MD, Mohsen Ibrahim, MD, PhD, Roberto A. De Blasi, MD, Erino A. Rendina, MD, Monica Rocco, MD, and Domenico Massullo, MD Department of Clinical and Surgical Translational Medicine (S.F., L.C., R.A.D.B., M.R., D.M.), Anesthesia and Intensive Care Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome; and Department of Clinical and Surgical Translational Medicine (C.M., M.I., E.A.R.), Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
Abstract Context. Chronic postsurgical pain (CPSP) can occur frequently after thoracic surgery. Objectives. This retrospective study aimed to determine CPSP prevalence, risk factors, neuropathic pain (NP) occurrence, and its impact on quality of life. Methods. About 200 patients who underwent lung resection via minithoracotomy or thoracoscopy between January 2017 and December 2017 were assessed 4e12 months postoperatively via phone interview for chronic pain by a 0e10 Numeric Rating Scale, for NP using the Douleur Neuropathique 4 test, and for quality of life using a Short Form-36 (SF-36) Health Survey (Italian version). Results. CPSP incidence was 35% (n ¼ 70 of 200; 95% CI 41e28) of which 31.5% (n ¼ 22 of 70; 95% CI 41e21) was with NP. Only 10% of patients with CPSP reported severe chronic pain. According to univariate analysis, CPSP was associated to moderate and severe acute postoperative pain (P < 0.001), open surgery (P ¼ 0.001), and female gender (P ¼ 0.044). According to multivariable analysis, independent risk factors for CPSP development included moderate-to-severe acute postoperative pain occurrence (odds ratio 32.61; 95% CI 13.37e79.54; P < 0.001) and open surgery (odds ratio 6.78; 95% CI, 2.18e21.03; P ¼ 0.001). NP incidence was higher in female patients (16% in women and 6% in men, respectively; P ¼ 0.040). A significant decrease in all SF-36 Health Survey domain scores was recorded for patients with CPSP and NP (P < 0.001). Conclusion. More than one of three patients who underwent lung resection could develop CPSP, frequently showing neuropathic component. Female gender reported a higher CPSP and NP incidence. Moderate-to-severe acute postoperative pain occurrence and open surgery seem to be independent risk factors for CPSP. Chronic pain and NP have a negative impact on quality of life, decreasing the SF-36 scores of all domains. J Pain Symptom Manage 2020;60:326e335. Ó 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Pain, chronic postsurgical pain, thoracic surgery, neuropathic pain, quality of life
Key Message
Introduction
This retrospective study describes chronic postsurgical pain (CPSP) prevalence after lung resection. The results indicate that more than one of three patients could develop CPSP, frequently showing neuropathic component, and affecting postoperative quality of life. Acute postoperative pain occurrence and open surgery resulted to be risk factors for CPSP.
Thoracotomy is considered one of the most painful surgical access1 not infrequently causing chronic postoperative pain and disability.2 Chronic postsurgical pain (CPSP) is defined as persistent pain for at least three months after thoracic surgery, pain is different from preoperative pain, and pain caused by other conditions, such as continuing malignancy or chronic infection
Address correspondence to: Silvia Fiorelli, MD, Department of Clinical and Surgical Translational Medicine, Anesthesia and Intensive Care Medicine, Sapienza University of Rome,
Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. E-mail: [email protected] Accepted for publication: March 15, 2020.
Ó 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2020.03.012
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Chronic Postsurgical Pain: A Retrospective Study
should be excluded.3 Previous studies have reported an extremely variable incidence of CPSP ranging from 25% to 75%.1,4e14 The wide variability of the reported incidence is due to differences in definitions and time of postoperative follow-up.4 Among patients affected by CPSP, only 3%e16% experience moderate-to-severe pain.5,6 The pain is typically pleuritic or aching and might be described by the patients as a continuous dysesthetic burning at the dermatomic level of thoracic incision. Moreover, symptoms can be aggravated by touch, changes in temperature, or shoulder girdle movements.1 Chronic pain is equally common after surgery for a benign disease or a malignant disease.5 Several known risk factors could be associated to the development of CPSP with variable results:6,7 severe acute post-thoracotomy pain, high consumption of analgesics, female sex, age, radiation/chemotherapy, tumor recurrence, psychosocial factor, and extensive surgery. It is not clear whether the surgical access (thoracotomy or thoracoscopy) could influence the incidence and severity of CPSP.7,8 Pathogenesis and specific changings occurring in neural circuits responsible for nociception are not fully known.7 The etiology of CPSP seems to be the result of several mechanisms involving both nociceptive and neuropathic pain (NP), central sensitization, and tumor recurrence.9 The direct damage of the intercostal nerves is a significative risk factor. Rib injury from the spreading of the intercostal space by the thoracic retractor, posterior rib fractures at the costovertebral junction, and costochondral separations anteriorly may also have a determining role.1 CPSP, especially when associated with a neuropathic component, can result in a significant negative impact on patients’ quality of life10 with higher morbidity.11 Although several studies investigated various treatments to attempt to reduce CPSP incidence, chronic pain after thoracic surgery is still the most common complication after thoracotomy7 and represent a major public health concern. Improvements in perioperative care have decreased the severity but not the incidence of CPSP.4 A better knowledge of the mechanisms underlying CPSP development can help to improve perioperative pain management and postoperative patients’ quality of life. Chronic pain with neuropathic component can be diagnosed by history and clinical examination. Among screening tools for NP, the Douleur Neuropathique 4 (DN4), it is a widely accepted and accurate test to identify the presence of a neuropathic component.12,13 Although NP-specific questionnaires may underestimate patients with clinician-diagnosed NP, reporting chronic pain co-occurrence with the sensory disturbance items of these questionnaire could allow identification of NP cases.14 The Medical Outcomes Study Short Form-36 (SF36) Health Survey, established by the International
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Quality of Life Assessment Project, is a well-validated and used tool15 to assess health-related quality of life for patients who suffer from chronic postoperative pain or NP. Although CPSP has been widely studied, few reports investigated pain occurrence with neuropathic component after thoracic surgery and the related impact on the quality of life. The first aim of this study was to investigate the CPSP prevalence after lung resection. Second aims were to assess neuropathic component of pain, identify potential protective or risk factors for chronic pain, and determine its effects on quality of life. A better knowledge of CPSP risk factors may help to reduce its incidence, ameliorate postoperative pain management, and ultimately improve patients’ qualify of life.
Methods This retrospective study, approved by the Bioethics Committee of Sapienza University of Rome (no. 5105_2018), conducted from January to April 2018 included 690 patients who underwent thoracic surgery in the period between January 2017 and December 2017 at our institution (Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy). Patients who underwent lung resection via minithoracotomy or video-assisted thoracic surgery (VATS) were included in the study. Exclusion criteria were extended surgery, emergency surgery, pregnancy, aged 18 years and younger, American Society of Anesthesiologists classification $IV, history of previous thoracic surgery or reinterventions, any pre-existent chronic pain, radiant therapies, neurological disease, and surgical site infection. All patients received a letter by electronic mail at the beginning of the study stating the purpose and methods of the study and asking them to participate. Patients were contacted at least four up to 12 months after surgery. Before proceeding to interview, informed consent was obtained. Patients were asked whether they were in pain because of the surgical procedure at the moment of interview. The degree of pain was assessed by a 0e10 Numeric Rating Scale (NRS) and classified in the absence of pain (NRS score 0), mild pain (NRS score 1e3), moderate pain (NRS score 4e6), and severe pain (NRS score 7e10). Zero usually represents no pain at all, whereas the upper limit represents the worst pain ever possible.16 Neuropathic component was also assessed using DN4 test. This questionnaire consists of 10 items, seven concerning the quality of pain and three items analyzing the presence or the absence of tactile hypesthesia and allodynia. A score of 1 is given to each positive item, and a score of 0 is given to each negative
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item. Scores $4 of 10 are considered indicative of NP. During the interview, patients were also submitted to an SF-36 Health Survey (Italian version). The SF-36 survey consists of eight scaled scores. The eight sections assessed by this survey are as follows: vitality, physical functioning (PF), bodily pain (BP), general health, role limitations because of physical problems (role physical), role limitations because of emotional problems (role emotional), social functioning, and mental health.15 Each subscale score was converted to a range from 0 to 100, with higher scores indicating better levels of functioning. Demographic data, medical history, comorbidities, surgical procedure, operative time, surgical approach (VATS or minithoracotomy), postoperative 24 hours NRS value, perioperative pain management, number of draining chest tubes, and duration of chest tube placement were collected from the electronic medical records system. Acute postoperative pain was classified in: absence of pain (NRS score 0), mild pain (NRS score 1e3), moderate pain (NRS score 4e6), and severe pain (NRS score 7e10).
Perioperative Management Before surgery, patients received premedication with ondansetron 8 mg, ketorolac tromethamine 30 mg, dexamethasone 4 mg, and pantoprazole 40 mg intravenously. Anesthesia was induced using propofol 1.5e2 mg/kg, fentanyl 2 mg/kg, ketamine 0.3 mg/kg, and rocuronium bromide 0.6 mg/kg. Maintenance of general anesthesia was achieved with desflurane (minimum alveolar concentration at 1 atmosphere) and continuous infusion of remifentanil, using a target-controlled infusion system in effect-site target mode with AlarisÒ PK Syringe Pump (Cardinal Health, Rolle, Switzerland). The target effect-site concentration of remifentanil was calculated by a Minto pharmacokinetic set. The surgical approach was based on minithoracotomy or VATS. Muscle-sparing minithoracotomy was performed through the fifth intercostal space, usually extended from the posterior to the anterior axillary line for a length ranging between 10 and 13 cm and applying limited rib retraction. At the moment of thoracotomy, an intrapleural intercostal nerve block from the fourth to the eighth space was performed by the surgeon using 20 mL of ropivacaine 0.75% (4 mL for each space). Injection of the local anesthetic in each intercostal space was performed approximately 2e3 cm from the spine. Video thoracoscopy was performed using an anterior approach and three surgical incisions. The first surgical access (1 cm) was performed at the seventh or the eighth intercostal space at the anterior axillary line and was used to insert an optic (10 mm) in the pleural
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cavity. A second incision (1 cm) was placed anteriorly from the first to the fifth intercostal space based on the tumor localization. The last incision (1 cm) was performed at the sixth intercostal space at the posterior axillary line. No rib or soft tissue retractors were used. All surgical access points were infiltrated with 10 mL of ropivacaine (7.5 mg/mL). The chest tube insertion point was also infiltrated with 10 mL of ropivacaine (7.5 mg/mL). Postoperative analgesia was delivered using a 24-hour continuous intravenous infusion of tramadol 0.1 mg/kg/hour and ketorolac 90 mg with an elastomeric pump. Paracetamol 1 g was administered four times a day.
Statistical Analysis Statistical analysis was performed using SPSS, Version 25.0 software (SPSS, Inc., Chicago, IL). The Shapiro-Wilk test was used to assess the normality of distributions. For the comparison of the parametric data, Student’s t-test and analysis of variance test were applied. Continuous nonparametric data were analyzed using Kruskal-Wallis test. Bonferroni correction was applied for multiple comparisons. Fisher’s exact test was applied for qualitative variables. Univariate analyses and multiple forward stepwise logistic regression analyses were performed to identify protective or risk factors for CPSP and its neuropathic component, considering age, gender, surgical access, number of drainages, duration of drainages, length of stay, and acute pain as potential covariates in the model. After univariate analyses, variables with P-value less than 0.05 were included in a multivariable logistic regression model to identify potential independent protective or risk factors for CPSP and NP. P-values less than 0.05 were considered statistically significant.
Results A total of 690 patients were contacted and evaluated for enrollment as shown in Fig. 1. After phone contact, 80 patients were excluded because they were either deceased (n ¼ 80), not answering phone calls (n ¼ 309), or not giving consent to participate (n ¼ 101). We were able to collect and analyze the data from the rest 200 patients, whose characteristics were summarized in Table 1. At the time of the telephone interview, the incidence of chronic post-thoracotomy pain was 35% (n ¼ 70 of 200; 95% CI 41e28). Only 7 of 70 (10%) patients experienced severe chronic pain (NRS score 7e10). Twenty-eight patients (40%) and 35 patients (50%), respectively, reported mild (NRS score 1e3) and moderate (NRS score 4e6) chronic pain. A statistically significant higher CPSP incidence in female
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TELEPHONE CONTACT, N=690
PATIENTS INTERVIEWED, N=200
CPSP, N=70
NP, N=22
Chronic Postsurgical Pain: A Retrospective Study
PATIENTS EXCLUDED, • N=80, deceased • N=309, not answering phone calls • N=101, refused to participate
NO-CPSP, N=130
NO NP, N=48
Fig. 1. Flow diagram of the study. CPSP ¼ chronic postsurgical pain; NP ¼ neuropathic pain.
gender and patients submitted to minithoracotomy approach was reported. About 31.5% of patients with CPSP (n ¼ 22 of 70; 95% CI 41e21) developed NP with a DN4 score greater than 4. Among all enrolled patients, NP incidence was statistically significantly higher in the female patients than male patients (16 patients [16%] and six patients [6%], respectively; P ¼ 0.040). All patients with NP underwent surgery through thoracotomy. Moderate and severe acute postoperative pain occurrences were significantly higher in patients who
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developed CPSP than in patients who did not develop CPSP; conversely, mild acute postoperative pain or the absence of pain occurrence was significantly higher in patients without CPSP than in patients with CPSP, as shown in Table 2. In the univariate analysis, thoracothomic access, female gender, and moderate to severe acute postoperative pain were associated with chronic pain (P ¼ 0.001, P ¼ 0.044, and P < 0.001, respectively). According to logistic regression analysis, risk factors for developing CPSP included moderate-to-severe acute postoperative pain occurrence and thoracotomy access (Table 3). Univariate analysis and logistic regression were also used to determine potential risk factors for NP occurrence in patients who developed CPSP after lung resection. Only moderate-to-severe acute postoperative pain occurrence was identified to positively correlate with NP according to logistic regression (Table 4). SF-36 domain scores of patients with no pain, acute pain, CPSP, and NP are shown in Fig. 2. Compared with patients with no CPSP, there was a significant decrease in the scores of all domains for CPSP patients (P < 0.001), as shown in Fig. 3. Compared with patients without neuropathic component pain, there was a more significant decrease in the scores of all domains for patients with NP (P < 0.001), as shown in Fig. 4.
Discussion This study showed an overall incidence of CPSP at the interview time (4e12 months postoperatively) of 35%. Only 10% of patients experienced severe
Table 1 Main Characteristics of All Patients, Patients With, or Patients Without CPSP After Thoracic Surgery Participants Gender, n (%) Male Female Age (yrs) Surgery, n (%) Minithoracotomy VATS Surgery duration (minutes) Malignancy, n (%) Smoking history, n (%) Length of postoperative stay four and/or more days, n (%) Chest tube drainage, number 1/2 Discharge with chest tube drainage, n (%) ASA I/II/III Moderate-to-severe acute postoperative pain
All Patients (n ¼ 200)
No CPSP (n ¼ 130)
CPSP (n ¼ 70)
100 (50) 100 (50) 63.43 10.48
73 (56) 57 (44) 63.45 10.85
27 (39) 43 (61) 63.39 9.82
0.965
155 (78) 70 (22) 62.5 28.3 188 (94) 125 (63) 64 (32)
91 (70) 39 (30) 60.58 27.65 119 (92) 84 (65) 42 (32)
64 (91) 6 (9) 64.71 30.41 69 (99) 41 (59) 22 (31)
0.001 0.104 0.060 0.445 1
118/82 47 (24)
81/49 30 (23)
37/33 17 (24)
0.431 0.862
3/99/98 89 (45)
1/60/69 27 (21)
2/39/29 62 (89)
0.181 <0.001
CPSP ¼ chronic postsurgical pain; VATS ¼ video-assisted thoracic surgery; ASA ¼ American Society of Anesthesiologists. Results are expressed as mean SD or number of patients and percentage. All percentages in parentheses refer to column group. Bold values are statistically significant (P < 0.05).
P 0.026
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during 3 decades, based on 1439 patients from 17 studies at three months and 1354 patients from 15 studies at six months, showed a CPSP incidence of 57% and 47%, respectively.4 The incidence of CPSP from the present study appears to be lower compared with several data reported in the literature.4,5,9,17e20 Possible reasons could be different time definitions cutoff for CPSP after thoracic surgery (three months of duration in this study vs. 6e18 months in other studies9,17), different postoperative pain management (intercostal nerve block vs. epidural analgesia9,19), and different surgical approaches included (minithoracotomy and VATS in this study and only thoracotomy in some reported studies9,17e19). Few studies investigated the epidemiology of NP after thoracic surgery. CPSP associated to NP occurrence identified in this study (31.5%) is in accordance to previous findings in the literature.10,11,21 Several screening tools for NP have been developed, including the DN4, Identification Pain questionnaire, Neuropathic Pain Scale, the Leeds Assessment of Neuropathic Symptoms and Signs, the Neuropathic Pain Questionnaire, and others. Among these patient-reported scales, DN4 showed high sensitivity and specificity and is a widely accepted test in the diagnosis of NP.12 No patient underwent surgery through VATS developed NP, therefore, no further conclusions may be drawn about role of surgical access on NP development. According to the literature, acute postoperative pain proved to be the most important risk factor in developing CPSP.6,8,9,17,18 These findings, in particular, may reflect the prominent role of nerve damage in the development of CPSP. Acute post-thoracotomy pain arises from multiple mechanisms, including the surgical incision, injury of ribs and intercostal nerves, inflammation of chest wall structures adjacent to the
Table 2 Relationship Between Severity of Acute Postoperative Pain and the Presence of CPSP Acute Postoperative Pain
No CPSP; n ¼ 130 (%)
No pain Mild Moderate Severe
64 39 12 15
(49) (30) (9) (12)
CPSP; n ¼ 70 (%) 0 8 39 23
(0) (11) (56) (33)
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P <0.001 <0.001 <0.001 <0.001
CPSP ¼ chronic postsurgical pain. Results are expressed as number of patients and percentage. No pain (Numeric Rating Scale [NRS] score 0); mild pain (NRS score 1e3); moderate pain (NRS score 4e6); and severe pain (NRS score 7e10).
chronic pain. Furthermore, our study showed that patients with CPSP had a higher occurrence of acute postoperative pain. It was also reported that patients with more extensive surgical access (minithoracotomy vs. VATS) and female gender experienced CPSP more frequently. Moderate-to-severe acute postoperative pain occurrence and open surgery were found to be significant independent risk factors for chronic pain development after lung resection. NP incidence was 31.5% with a statistically significant higher occurrence in the female population. Patients with CPSP also showed worse quality of life, especially those with NP. To our knowledge, the present study first investigates the prevalence of CPSP, its neuropathic component, and impact on quality of life, respectively, using the DN4 pain questionnaire and an Italian version of SF36 Health Survey. Previous data in the literature showed an extremely variable incidence of CPSP because of the lack of standardized criteria to classify subjects suffering from postsurgical pain, to the differences in the follow-up period, and to diagnostic tools to assess postoperative pain.1,4 A meta-analysis including studies published
Table 3 Risk Factors for CPSP According to the Univariate Analysis and Multivariate Regression Model Multivariate Regression Model Factors Related to CPSP Gender Male Female VATS Thoracotomy Age 65 yrs and older Age 65 yrs and younger Length of postoperative stay, four and/or less days Length of postoperative stay, days, four and/or more days Discharge without chest tube drainage Discharge with chest tube drainage Chest tube drainage, number, less than one Chest tube drainage, number, greater than one Absence to mild acute postoperative pain Moderate-to-severe acute postoperative pain
OR (95% CI) 1 1.82 1 4.69 1 0.96 1 0.97 1 1.03 1 1.49 1 31.19
P
OR (95% CI)
P
(1.01e3.29)
0.044
1.58 (0.68e3.65)
0.279
(1.87e11.74)
0.001
6.78 (2.18e21.03)
0.001
(0.53e1.71)
0.898
(0.52e1.80)
0.929
(0.52e2.05)
0.913
(0.85e2.62)
0.159
(13.30e73.14)
CPSP ¼ chronic postsurgical pain; OR ¼ odds ratio; VATS ¼ video-assisted thoracic surgery. Bold values are statistically significant (P < 0.05).
<0.001
32.61 (13.37e79.54)
<0.001
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Table 4 Risk Factors for NP According to the Univariate Analysis and Multivariate Regression Model Multivariate Regression Model Factors Related to NP Gender Male Female Age 65 yrs and older Age 65 yrs and younger VATS Thoracotomy Length of postoperative stay, four and/or less days Length of postoperative stay, four and/or more days Discharge without chest tube drainage Discharge with chest tube drainage Chest tube drainage, number, less than one Chest tube drainage, number, greater than one Absence to mild acute postoperative pain Moderate-to-severe acute postoperative pain
OR (95% CI) 1 2.91 (1.09e7.79) 1 1.41 (0.57e3.47) NA 1 0.99 (0.38e2.56) 1 1.61 (0.61e4.22) 1 1.06 (0.45e2.48) 33.97 (4.46e258.33)
P
0.033
OR (95% CI)
1.98 (0.69e5.63)
P
0.199
0.452
0.985 0.333 0.893 <0.001
30.37 (43.97e232.42)
0.001
NP ¼ neuropathic pain; OR ¼ odds ratio; VATS ¼ video-assisted thoracic surgery; NA ¼ not applicable. Bold values are statistically significant (P < 0.05).
incision, damage of pulmonary parenchyma or pleura, and thoracostomy drainage tubes. Perioperative intercostal nerve damage, such as nerve crush during rib retraction or nerve constriction when suturing, can be responsible for the raised postoperative pain and the long-term NP.17 Several data demonstrated that women are at increased risk for chronic pain.6,17,22e24 According to
the literature, a higher incidence of CPSP and NP in women was reported. However, female gender did not result as an independent risk factor for CPSP or NP development according to logistic regression analysis in this study. The relation between pain and gender is a complex process that has not yet fully understood and results from the interaction of multiple physiological and psychological factors.25 Some of these
Fig. 2. SF-36 domain scores of patients with no pain, acute pain, CPSP, and NP. SF-36 ¼ Short Form-36; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health; CPSP ¼ chronic postsurgical pain; NP ¼ neuropathic pain.
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Fig. 3. SF-36 domain scores of patients with CPSP and without CPSP (no CPSP). SF-36 ¼ Short Form-36; CPSP ¼ chronic postsurgical pain; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health (*P < 0.001).
mechanisms may involve sex-related different processing of pain-related stimuli,26 sex hormones’ receptors role in pain sensitivity,24 and major susceptibility of female sex to painful syndromes after nerve damage.27
A small number of studies reported chronic pain after VATS. CPSP reports are mostly from open thoracotomy procedures,4 and the incidence and severity of chronic pain after VATS is still not well defined.
Fig. 4. Short Form-36 domain scores of patients with NP and without NP (no NP). NP ¼ neuropathic pain; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health (*P < 0.001).
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Chronic Postsurgical Pain: A Retrospective Study
In a recent prospective study of 107 patients undergoing thoracotomy and thoracoscopy approach, the reported incidence and severity of pain six months after thoracic surgery were similar.8 Landreneau et al.28 showed that VATS reduces the occurrence (30% vs. 44%) and severity of chronic pain and shoulder dysfunction during the first year after thoracic operations compared with thoracotomy; however, the VATS approach was not likely to affect the prevalence of long-term chronic pain after pulmonary resection. Wildgaard et al.29 also reported in a prospective observational study of 47 patients submitted to VATS a low incidence (11%) of chronic pain at three months. In this study, a lower incidence of CPSP in patients who underwent surgery through VATS than through minithoracotomy was reported. Moreover, open surgery was identified as an independent rick factor for CPSP development. It is important to underline that patients who underwent VATS approach were only 45 of 200; thus, further prospective studies are needed to confirm these results. However, it is possible to speculate that patients with more invasive surgical access are at high risk to develop CPSP.9 An extended nociceptive stimulation can indeed result in intense and continuous postoperative pain and predispose to CPSP.9 VATS seems to reduce the incidence of CPSP, probably because the minimally invasive access produces less nerve injury than open thoracotomy.30 In this study, all patients received, as part of a standardized protocol, a low dose of ketamine during anesthesia induction (0.3 mg/kg). Among the complex nociceptive pathway, N-methyl-D-aspartate (NMDA) receptors have a potential therapeutic application in chronic and NP prevention. Glutamatergic excitation caused by tissue injury results in calcium influx, triggering intracellular signaling pathways that lead to phosphorylation of NMDA receptors and prolonged nociceptive transmission. With excessive and persistent postoperative pain, these changes in the central nervous system become progressively harder to reverse and can cause nerves hyperexcitability and finally result in pain chronicization.9 NMDA receptor blockade has been shown to attenuate central sensitization. Ketamine, a noncompetitive NMDA receptor antagonist, is an effective adjunct for postoperative analgesia, independent of the type, timing of administration or dose, especially in painful procedures such as thoracic surgery.31 Although ketamine role on acute postoperative pain is well established, its role on preventing CPSP is not yet determined.32e34 However, it can be suggested that helping to reduce acute postoperative pain, which is the most important risk factor for the development of chronic pain, can certainly contribute to reduce the phenomena involved in chronicization and ultimately the occurrence of CPSP. All patients also received an intrapleural intercostal nerve block, one of the most used analgesic
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techniques besides thoracic epidural analgesia and thoracic paravertebral block. Intercostal nerve block before thoracotomy closure can provide better pain relief than narcotics alone, possibly lasting for three to five days, although the intercostal block was not repeated.35,36 Although no exhaustive data about the role of locoregional techniques to reduce CPSP are actually available,37 blocking the afferent nociceptive stimuli induced by surgical incision can effectively reduce postoperative pain intensity.17 However, a multimodal pre-emptive analgesia strategy for thoracic surgery, as the one reported in this study, has been emerging as the standard of care, because of an aggressive modulation of pain at multiple different receptors along the pain pathways.38 Despite the fact that most patients reported only mild pain, in this study, SF-36 scores showed that CPSP is associated with a significant decrease in all domains. Schulte et al.39 prospectively evaluated 159 patients showing that the lowest PF score was at three months post-thoracotomy, and pain scores peaked at that time. They also suggest that patients who undergo lung resection do not completely recover, even by 24 months after surgery, in contrast to patients submitted to major visceral operations. Kinney et al.19 in a prospective study including 110 patients who underwent lung resection reported lower SF-36 scores in PF (P ¼ 0.049), BP (P ¼ 0.0002), and vitality (P ¼ 0.044). A retrospective study of Peng et al.11 also confirmed that CPSP after thoracic surgery and its neuropathic component negatively impacts quality of life, with significant decrease in PF score and BP score for patients with CPSP (P < 0.05); in addition, compared with patients with CPSP without neuropathic component, the authors found a significant decrease in PF for patients with CPSP with neuropathic component (P < 0.05). There is therefore no doubt that CPSP affects and worsen patient’s quality of life in several aspects. Important limits of this study are as follows: the telephone interview, so the reliability of this study is strictly dependent on the memory of the patients; CPSP incidence could be overestimated because patients who experience chronic pain are actually dealing with this situation and are more likely to respond to the interview than people without pain; a clinical assessment of NP, considered the gold standard for this diagnosis, was not performed, but only a questionnaire detection method was used; eventual analgesic therapy after hospital discharge was not investigated because of the high heterogeneity that could have been found; and the retrospective nature of the study and significant numeric difference between patients who underwent surgery through VATS approach or through minithoracotomy.
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In summary, this study showed that just more than one of three patients who underwent minithoracotomy and VATS developed CPSP, with about one-third of them with neuropathic component. Acute postoperative pain, open surgery, and female gender could be associated to CPSP. Higher occurrence of NP in female patients was also reported. Chronic pain resulted to have a negative impact on quality of life, decreasing the SF-36 scores of all domains, especially in patients with NP. Preventing moderate-to-severe acute postoperative pain occurrence and avoiding invasive surgical approach when possible, resulting both independent risk factors for chronic pain development after thoracic surgery, could help to reduce CPSP incidence. In the early recovery after surgery era, the use of less invasive surgical techniques and a multifaceted approach to shorten the chest tube drainage to minimize surgical nociceptive inputs (nociception reduction), regional nerve blocks, and multimodal and aggressive pharmacological approaches (pre-emptive analgesia), and coadjuvants such as ketamine (nociception suppression and modulation) can synergically help to reduce pain sensitization and chronicization and improve postoperative quality of life of patients who underwent thoracic surgery, decreasing CPSP occurrence.
Disclosures and Acknowledgments
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7. Mauck M, Van De Ven T, Shaw AD. Epigenetics of chronic pain after thoracic surgery. Curr Opin Anaesthesiol 2014;27:1e5. 8. Bayman EO, Parekh KR, Keech J, Selte A, Brennan TJ. A prospective study of chronic pain after thoracic surgery. Anesthesiology 2017;126:938e951. 9. Pluijms WA, Steegers MA, Verhagen AF, et al. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiol Scand 2006;50:804e808. 10. Searle RD, Simpson MP, Simpson KH, Milton R, Bennett MI. Can chronic neuropathic pain following thoracic surgery be predicted during the postoperative period? Interact Cardiovasc Thorac Surg 2009;9:999e1002. 11. Peng Z, Li H, Zhang C, et al. A retrospective study of chronic post-surgical pain following thoracic surgery: prevalence, risk factors, incidence of neuropathic component, and impact on qualify of life. PLoS One 2014;9:1e8. 12. Padua L, Briani C, Truini A, et al. Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain. Neurol Sci 2013;34:373e377. 13. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29e36. 14. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain 2013;154:95e102. 15. Ware JE, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998;51:903e912. 16. Haefeli M, Elfering A. Pain assessment. Eur Spine J 2006;15:S17eS24.
This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.
17. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain 1996;12:50e55.
References
19. Kinney MA, Hooten WM, Cassivi SD, et al. Chronic postthoracotomy pain and health-related quality of life. Ann Thorac Surg 2012;93:1242e1247.
1. Hazelrigg SR, Cetindag IB, Fullerton J. Acute and chronic pain syndromes after thoracic surgery. Surg Clin North Am 2002;82:849e865. 2. Kehlet H, Jensen TS, Woolf CJ, Centre M. Persistent postsurgical pain: risk factors and prevention. Lancet 2006; 367:1618e1625. 3. Classification of chronic pain. In: Merskey H, Bogduk N, eds. IASP Task Force on taxonomy, 2nd ed. Seattle, WA: IASP Press, 1994. 4. Bayman EO, Brennan TJ. Incidence and severity of chronic pain at 3 and 6 months after thoracotomy: metaanalysis. J Pain 2014;15:887e897.
18. Wang HT, Liu W, Luo AL, Ma C, Huang YG. Prevalence and risk factors of chronic post-thoracotomy pain in Chinese patients from Peking Union Medical College Hospital. Chin Med J (Engl) 2012;125:3033e3038.
20. Maguire MF, Ravenscroft A, Beggs D, Duffy JP. A questionnaire study investigating the prevalence of the neuropathic component of chronic pain after thoracic surgery. Eur J Cardiothorac Surg 2006;29:800e805. 21. Steegers MA, Snik DM, Verhagen AF, van der Drift MA, Wilder-Smith OH. Only half of the chronic pain after thoracic surgery shows a neuropathic component. J Pain 2008;9:955e961. 22. Gotoda Y, Kambara N, Sakai T, et al. The morbidity, time course and predictive factors for persistent post-thoracotomy pain. Eur J Pain 2001;5:89e96.
5. Perttunen K, Tasmuth T, Kalso E. Chronic pain after thoracic surgery: a follow-up study. Acta Anaesthesiol Scand 1999;43:563e567.
23. Ochroch EA, Gottschalk A, Augostides J, et al. Longterm pain and activity during recovery from major thoracotomy using thoracic epidural analgesia. Anesthesiology 2002; 97:1234e1244.
6. Wildgaard K, Ringsted TK, Aasvang EK, et al. Post thoracotomy pain management: a review of current available modalities. Eur J Cardiothorac Surg 2009;9:1e8.
24. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth 2013;111:52e58.
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25. Fillingim RB, King CD, Ribeiro-Dasilva MC, RahimWilliams B, Riley JL 3rd. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain 2009;10: 447e485. 26. Paulson PE, Minoshima S, Morrow TJ, Casey KL. Gender differences in pain perception and patterns of cerebral activation during noxious heat stimulation in humans. Pain 1998;76:223e229. 27. Coyle DE, Sehlhorst CS, Behbehani MM. Intact female rats are more susceptible to the development of tactile allodynia than ovariectomized female rats following Partial Sciatic Nerve Ligation (PSNL). Neurosci Lett 1996;203: 37e40. 28. Landreneau RJ, Mack MJ, Hazelrigg SR, et al. Prevalence of chronic pain after pulmonary resection by thoracotomy or video-assisted thoracic surgery. J Thorac Cardiovasc Surg 1994;107:1079e1086. 29. Wildgaard K, Ringsted TK, Hansen HJ, Petersen RH, Kehlet H. Persistent postsurgical pain after video-assisted thoracic surgerydan observational study. Acta Anaesthesiol Scand 2016;60:650e658. 30. Della Corte F, Mendola C, Messina A, Cammarota G. Post thoracotomy pain syndrome. In: Nazari S, ed. Front Lines of Thoracic Surgery. IntechOpen, 2012. ISBN: 978953-51-6761-7. 31. Laskowski K, Stirling A, McKay WP, Lim HJ. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anesth 2011;58:911e923.
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32. Hu J, Liao Q, Zhang F, Tong J, Ouyang W. Chronic postthoracotomy pain and perioperative ketamine infusion. J Pain Palliat Care Pharmacother 2014;28:117e121. 33. Humble SR, Dalton AJ, Li L. A systematic review of therapeutic interventions to reduce acute and chronic postsurgical pain after amputation, thoracotomy or mastectomy. Eur J Pain 2015;19:451e465. 34. Mendola C, Cammarota G, Netto R, et al. S(þ)-ketamine for control of perioperative pain and prevention of post thoracotomy pain syndrome: a randomized, double-blind study. Minerva Anestesiol 2012;78:757e766. 35. Detterbeck FC. Efficacy of methods of intercostal nerve blockade for pain relief after thoracotomy. Ann Thorac Surg 2005;80:1550e1559. 36. D’Andrilli A, Ibrahim M, Ciccone AM, et al. Intrapleural intercostal nerve block associated with mini-thoracotomy improves pain control after major lung resection. Eur J Cardiothorac Surg 2006;29:790e794. 37. Wildgaard K, Ravn J, Kehlet H. Chronic postthoracotomy pain: a critical review of pathogenic mechanisms and strategies for prevention. Eur J Cardiothorac Surg 2009;36:170e180. 38. Moyse DW, Kaye AD, Diaz JH, et al. Perioperative ketamine administration for thoracotomy pain. Pain Physician 2017;20:173e184. 39. Schulte T, Schniewind B, Dohramn P, K€ uchler T, Kurdow R. The extent of lung parenchyma resection significantly impacts long-term quality of life in patients with nonsmall cell lung cancer. Chest 2009;135:322e329.
Journal of Pain and Symptom Management
Vol. 60 No. 2 August 2020
Original Article
Chronic Pain After Lung Resection: Risk Factors, Neuropathic Pain, and Quality of Life Silvia Fiorelli, MD, Luigi Cioffi, MD, Cecilia Menna, MD, Mohsen Ibrahim, MD, PhD, Roberto A. De Blasi, MD, Erino A. Rendina, MD, Monica Rocco, MD, and Domenico Massullo, MD Department of Clinical and Surgical Translational Medicine (S.F., L.C., R.A.D.B., M.R., D.M.), Anesthesia and Intensive Care Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Rome; and Department of Clinical and Surgical Translational Medicine (C.M., M.I., E.A.R.), Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy
Abstract Context. Chronic postsurgical pain (CPSP) can occur frequently after thoracic surgery. Objectives. This retrospective study aimed to determine CPSP prevalence, risk factors, neuropathic pain (NP) occurrence, and its impact on quality of life. Methods. About 200 patients who underwent lung resection via minithoracotomy or thoracoscopy between January 2017 and December 2017 were assessed 4e12 months postoperatively via phone interview for chronic pain by a 0e10 Numeric Rating Scale, for NP using the Douleur Neuropathique 4 test, and for quality of life using a Short Form-36 (SF-36) Health Survey (Italian version). Results. CPSP incidence was 35% (n ¼ 70 of 200; 95% CI 41e28) of which 31.5% (n ¼ 22 of 70; 95% CI 41e21) was with NP. Only 10% of patients with CPSP reported severe chronic pain. According to univariate analysis, CPSP was associated to moderate and severe acute postoperative pain (P < 0.001), open surgery (P ¼ 0.001), and female gender (P ¼ 0.044). According to multivariable analysis, independent risk factors for CPSP development included moderate-to-severe acute postoperative pain occurrence (odds ratio 32.61; 95% CI 13.37e79.54; P < 0.001) and open surgery (odds ratio 6.78; 95% CI, 2.18e21.03; P ¼ 0.001). NP incidence was higher in female patients (16% in women and 6% in men, respectively; P ¼ 0.040). A significant decrease in all SF-36 Health Survey domain scores was recorded for patients with CPSP and NP (P < 0.001). Conclusion. More than one of three patients who underwent lung resection could develop CPSP, frequently showing neuropathic component. Female gender reported a higher CPSP and NP incidence. Moderate-to-severe acute postoperative pain occurrence and open surgery seem to be independent risk factors for CPSP. Chronic pain and NP have a negative impact on quality of life, decreasing the SF-36 scores of all domains. J Pain Symptom Manage 2020;60:326e335. Ó 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Pain, chronic postsurgical pain, thoracic surgery, neuropathic pain, quality of life
Key Message
Introduction
This retrospective study describes chronic postsurgical pain (CPSP) prevalence after lung resection. The results indicate that more than one of three patients could develop CPSP, frequently showing neuropathic component, and affecting postoperative quality of life. Acute postoperative pain occurrence and open surgery resulted to be risk factors for CPSP.
Thoracotomy is considered one of the most painful surgical access1 not infrequently causing chronic postoperative pain and disability.2 Chronic postsurgical pain (CPSP) is defined as persistent pain for at least three months after thoracic surgery, pain is different from preoperative pain, and pain caused by other conditions, such as continuing malignancy or chronic infection
Address correspondence to: Silvia Fiorelli, MD, Department of Clinical and Surgical Translational Medicine, Anesthesia and Intensive Care Medicine, Sapienza University of Rome,
Sant’Andrea Hospital, Via di Grottarossa 1035, 00189 Rome, Italy. E-mail: [email protected] Accepted for publication: March 15, 2020.
Ó 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
0885-3924/$ - see front matter https://doi.org/10.1016/j.jpainsymman.2020.03.012
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should be excluded.3 Previous studies have reported an extremely variable incidence of CPSP ranging from 25% to 75%.1,4e14 The wide variability of the reported incidence is due to differences in definitions and time of postoperative follow-up.4 Among patients affected by CPSP, only 3%e16% experience moderate-to-severe pain.5,6 The pain is typically pleuritic or aching and might be described by the patients as a continuous dysesthetic burning at the dermatomic level of thoracic incision. Moreover, symptoms can be aggravated by touch, changes in temperature, or shoulder girdle movements.1 Chronic pain is equally common after surgery for a benign disease or a malignant disease.5 Several known risk factors could be associated to the development of CPSP with variable results:6,7 severe acute post-thoracotomy pain, high consumption of analgesics, female sex, age, radiation/chemotherapy, tumor recurrence, psychosocial factor, and extensive surgery. It is not clear whether the surgical access (thoracotomy or thoracoscopy) could influence the incidence and severity of CPSP.7,8 Pathogenesis and specific changings occurring in neural circuits responsible for nociception are not fully known.7 The etiology of CPSP seems to be the result of several mechanisms involving both nociceptive and neuropathic pain (NP), central sensitization, and tumor recurrence.9 The direct damage of the intercostal nerves is a significative risk factor. Rib injury from the spreading of the intercostal space by the thoracic retractor, posterior rib fractures at the costovertebral junction, and costochondral separations anteriorly may also have a determining role.1 CPSP, especially when associated with a neuropathic component, can result in a significant negative impact on patients’ quality of life10 with higher morbidity.11 Although several studies investigated various treatments to attempt to reduce CPSP incidence, chronic pain after thoracic surgery is still the most common complication after thoracotomy7 and represent a major public health concern. Improvements in perioperative care have decreased the severity but not the incidence of CPSP.4 A better knowledge of the mechanisms underlying CPSP development can help to improve perioperative pain management and postoperative patients’ quality of life. Chronic pain with neuropathic component can be diagnosed by history and clinical examination. Among screening tools for NP, the Douleur Neuropathique 4 (DN4), it is a widely accepted and accurate test to identify the presence of a neuropathic component.12,13 Although NP-specific questionnaires may underestimate patients with clinician-diagnosed NP, reporting chronic pain co-occurrence with the sensory disturbance items of these questionnaire could allow identification of NP cases.14 The Medical Outcomes Study Short Form-36 (SF36) Health Survey, established by the International
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Quality of Life Assessment Project, is a well-validated and used tool15 to assess health-related quality of life for patients who suffer from chronic postoperative pain or NP. Although CPSP has been widely studied, few reports investigated pain occurrence with neuropathic component after thoracic surgery and the related impact on the quality of life. The first aim of this study was to investigate the CPSP prevalence after lung resection. Second aims were to assess neuropathic component of pain, identify potential protective or risk factors for chronic pain, and determine its effects on quality of life. A better knowledge of CPSP risk factors may help to reduce its incidence, ameliorate postoperative pain management, and ultimately improve patients’ qualify of life.
Methods This retrospective study, approved by the Bioethics Committee of Sapienza University of Rome (no. 5105_2018), conducted from January to April 2018 included 690 patients who underwent thoracic surgery in the period between January 2017 and December 2017 at our institution (Department of Thoracic Surgery, Sant’Andrea Hospital, Sapienza University of Rome, Rome, Italy). Patients who underwent lung resection via minithoracotomy or video-assisted thoracic surgery (VATS) were included in the study. Exclusion criteria were extended surgery, emergency surgery, pregnancy, aged 18 years and younger, American Society of Anesthesiologists classification $IV, history of previous thoracic surgery or reinterventions, any pre-existent chronic pain, radiant therapies, neurological disease, and surgical site infection. All patients received a letter by electronic mail at the beginning of the study stating the purpose and methods of the study and asking them to participate. Patients were contacted at least four up to 12 months after surgery. Before proceeding to interview, informed consent was obtained. Patients were asked whether they were in pain because of the surgical procedure at the moment of interview. The degree of pain was assessed by a 0e10 Numeric Rating Scale (NRS) and classified in the absence of pain (NRS score 0), mild pain (NRS score 1e3), moderate pain (NRS score 4e6), and severe pain (NRS score 7e10). Zero usually represents no pain at all, whereas the upper limit represents the worst pain ever possible.16 Neuropathic component was also assessed using DN4 test. This questionnaire consists of 10 items, seven concerning the quality of pain and three items analyzing the presence or the absence of tactile hypesthesia and allodynia. A score of 1 is given to each positive item, and a score of 0 is given to each negative
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item. Scores $4 of 10 are considered indicative of NP. During the interview, patients were also submitted to an SF-36 Health Survey (Italian version). The SF-36 survey consists of eight scaled scores. The eight sections assessed by this survey are as follows: vitality, physical functioning (PF), bodily pain (BP), general health, role limitations because of physical problems (role physical), role limitations because of emotional problems (role emotional), social functioning, and mental health.15 Each subscale score was converted to a range from 0 to 100, with higher scores indicating better levels of functioning. Demographic data, medical history, comorbidities, surgical procedure, operative time, surgical approach (VATS or minithoracotomy), postoperative 24 hours NRS value, perioperative pain management, number of draining chest tubes, and duration of chest tube placement were collected from the electronic medical records system. Acute postoperative pain was classified in: absence of pain (NRS score 0), mild pain (NRS score 1e3), moderate pain (NRS score 4e6), and severe pain (NRS score 7e10).
Perioperative Management Before surgery, patients received premedication with ondansetron 8 mg, ketorolac tromethamine 30 mg, dexamethasone 4 mg, and pantoprazole 40 mg intravenously. Anesthesia was induced using propofol 1.5e2 mg/kg, fentanyl 2 mg/kg, ketamine 0.3 mg/kg, and rocuronium bromide 0.6 mg/kg. Maintenance of general anesthesia was achieved with desflurane (minimum alveolar concentration at 1 atmosphere) and continuous infusion of remifentanil, using a target-controlled infusion system in effect-site target mode with AlarisÒ PK Syringe Pump (Cardinal Health, Rolle, Switzerland). The target effect-site concentration of remifentanil was calculated by a Minto pharmacokinetic set. The surgical approach was based on minithoracotomy or VATS. Muscle-sparing minithoracotomy was performed through the fifth intercostal space, usually extended from the posterior to the anterior axillary line for a length ranging between 10 and 13 cm and applying limited rib retraction. At the moment of thoracotomy, an intrapleural intercostal nerve block from the fourth to the eighth space was performed by the surgeon using 20 mL of ropivacaine 0.75% (4 mL for each space). Injection of the local anesthetic in each intercostal space was performed approximately 2e3 cm from the spine. Video thoracoscopy was performed using an anterior approach and three surgical incisions. The first surgical access (1 cm) was performed at the seventh or the eighth intercostal space at the anterior axillary line and was used to insert an optic (10 mm) in the pleural
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cavity. A second incision (1 cm) was placed anteriorly from the first to the fifth intercostal space based on the tumor localization. The last incision (1 cm) was performed at the sixth intercostal space at the posterior axillary line. No rib or soft tissue retractors were used. All surgical access points were infiltrated with 10 mL of ropivacaine (7.5 mg/mL). The chest tube insertion point was also infiltrated with 10 mL of ropivacaine (7.5 mg/mL). Postoperative analgesia was delivered using a 24-hour continuous intravenous infusion of tramadol 0.1 mg/kg/hour and ketorolac 90 mg with an elastomeric pump. Paracetamol 1 g was administered four times a day.
Statistical Analysis Statistical analysis was performed using SPSS, Version 25.0 software (SPSS, Inc., Chicago, IL). The Shapiro-Wilk test was used to assess the normality of distributions. For the comparison of the parametric data, Student’s t-test and analysis of variance test were applied. Continuous nonparametric data were analyzed using Kruskal-Wallis test. Bonferroni correction was applied for multiple comparisons. Fisher’s exact test was applied for qualitative variables. Univariate analyses and multiple forward stepwise logistic regression analyses were performed to identify protective or risk factors for CPSP and its neuropathic component, considering age, gender, surgical access, number of drainages, duration of drainages, length of stay, and acute pain as potential covariates in the model. After univariate analyses, variables with P-value less than 0.05 were included in a multivariable logistic regression model to identify potential independent protective or risk factors for CPSP and NP. P-values less than 0.05 were considered statistically significant.
Results A total of 690 patients were contacted and evaluated for enrollment as shown in Fig. 1. After phone contact, 80 patients were excluded because they were either deceased (n ¼ 80), not answering phone calls (n ¼ 309), or not giving consent to participate (n ¼ 101). We were able to collect and analyze the data from the rest 200 patients, whose characteristics were summarized in Table 1. At the time of the telephone interview, the incidence of chronic post-thoracotomy pain was 35% (n ¼ 70 of 200; 95% CI 41e28). Only 7 of 70 (10%) patients experienced severe chronic pain (NRS score 7e10). Twenty-eight patients (40%) and 35 patients (50%), respectively, reported mild (NRS score 1e3) and moderate (NRS score 4e6) chronic pain. A statistically significant higher CPSP incidence in female
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TELEPHONE CONTACT, N=690
PATIENTS INTERVIEWED, N=200
CPSP, N=70
NP, N=22
Chronic Postsurgical Pain: A Retrospective Study
PATIENTS EXCLUDED, • N=80, deceased • N=309, not answering phone calls • N=101, refused to participate
NO-CPSP, N=130
NO NP, N=48
Fig. 1. Flow diagram of the study. CPSP ¼ chronic postsurgical pain; NP ¼ neuropathic pain.
gender and patients submitted to minithoracotomy approach was reported. About 31.5% of patients with CPSP (n ¼ 22 of 70; 95% CI 41e21) developed NP with a DN4 score greater than 4. Among all enrolled patients, NP incidence was statistically significantly higher in the female patients than male patients (16 patients [16%] and six patients [6%], respectively; P ¼ 0.040). All patients with NP underwent surgery through thoracotomy. Moderate and severe acute postoperative pain occurrences were significantly higher in patients who
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developed CPSP than in patients who did not develop CPSP; conversely, mild acute postoperative pain or the absence of pain occurrence was significantly higher in patients without CPSP than in patients with CPSP, as shown in Table 2. In the univariate analysis, thoracothomic access, female gender, and moderate to severe acute postoperative pain were associated with chronic pain (P ¼ 0.001, P ¼ 0.044, and P < 0.001, respectively). According to logistic regression analysis, risk factors for developing CPSP included moderate-to-severe acute postoperative pain occurrence and thoracotomy access (Table 3). Univariate analysis and logistic regression were also used to determine potential risk factors for NP occurrence in patients who developed CPSP after lung resection. Only moderate-to-severe acute postoperative pain occurrence was identified to positively correlate with NP according to logistic regression (Table 4). SF-36 domain scores of patients with no pain, acute pain, CPSP, and NP are shown in Fig. 2. Compared with patients with no CPSP, there was a significant decrease in the scores of all domains for CPSP patients (P < 0.001), as shown in Fig. 3. Compared with patients without neuropathic component pain, there was a more significant decrease in the scores of all domains for patients with NP (P < 0.001), as shown in Fig. 4.
Discussion This study showed an overall incidence of CPSP at the interview time (4e12 months postoperatively) of 35%. Only 10% of patients experienced severe
Table 1 Main Characteristics of All Patients, Patients With, or Patients Without CPSP After Thoracic Surgery Participants Gender, n (%) Male Female Age (yrs) Surgery, n (%) Minithoracotomy VATS Surgery duration (minutes) Malignancy, n (%) Smoking history, n (%) Length of postoperative stay four and/or more days, n (%) Chest tube drainage, number 1/2 Discharge with chest tube drainage, n (%) ASA I/II/III Moderate-to-severe acute postoperative pain
All Patients (n ¼ 200)
No CPSP (n ¼ 130)
CPSP (n ¼ 70)
100 (50) 100 (50) 63.43 10.48
73 (56) 57 (44) 63.45 10.85
27 (39) 43 (61) 63.39 9.82
0.965
155 (78) 70 (22) 62.5 28.3 188 (94) 125 (63) 64 (32)
91 (70) 39 (30) 60.58 27.65 119 (92) 84 (65) 42 (32)
64 (91) 6 (9) 64.71 30.41 69 (99) 41 (59) 22 (31)
0.001 0.104 0.060 0.445 1
118/82 47 (24)
81/49 30 (23)
37/33 17 (24)
0.431 0.862
3/99/98 89 (45)
1/60/69 27 (21)
2/39/29 62 (89)
0.181 <0.001
CPSP ¼ chronic postsurgical pain; VATS ¼ video-assisted thoracic surgery; ASA ¼ American Society of Anesthesiologists. Results are expressed as mean SD or number of patients and percentage. All percentages in parentheses refer to column group. Bold values are statistically significant (P < 0.05).
P 0.026
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Fiorelli et al.
during 3 decades, based on 1439 patients from 17 studies at three months and 1354 patients from 15 studies at six months, showed a CPSP incidence of 57% and 47%, respectively.4 The incidence of CPSP from the present study appears to be lower compared with several data reported in the literature.4,5,9,17e20 Possible reasons could be different time definitions cutoff for CPSP after thoracic surgery (three months of duration in this study vs. 6e18 months in other studies9,17), different postoperative pain management (intercostal nerve block vs. epidural analgesia9,19), and different surgical approaches included (minithoracotomy and VATS in this study and only thoracotomy in some reported studies9,17e19). Few studies investigated the epidemiology of NP after thoracic surgery. CPSP associated to NP occurrence identified in this study (31.5%) is in accordance to previous findings in the literature.10,11,21 Several screening tools for NP have been developed, including the DN4, Identification Pain questionnaire, Neuropathic Pain Scale, the Leeds Assessment of Neuropathic Symptoms and Signs, the Neuropathic Pain Questionnaire, and others. Among these patient-reported scales, DN4 showed high sensitivity and specificity and is a widely accepted test in the diagnosis of NP.12 No patient underwent surgery through VATS developed NP, therefore, no further conclusions may be drawn about role of surgical access on NP development. According to the literature, acute postoperative pain proved to be the most important risk factor in developing CPSP.6,8,9,17,18 These findings, in particular, may reflect the prominent role of nerve damage in the development of CPSP. Acute post-thoracotomy pain arises from multiple mechanisms, including the surgical incision, injury of ribs and intercostal nerves, inflammation of chest wall structures adjacent to the
Table 2 Relationship Between Severity of Acute Postoperative Pain and the Presence of CPSP Acute Postoperative Pain
No CPSP; n ¼ 130 (%)
No pain Mild Moderate Severe
64 39 12 15
(49) (30) (9) (12)
CPSP; n ¼ 70 (%) 0 8 39 23
(0) (11) (56) (33)
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P <0.001 <0.001 <0.001 <0.001
CPSP ¼ chronic postsurgical pain. Results are expressed as number of patients and percentage. No pain (Numeric Rating Scale [NRS] score 0); mild pain (NRS score 1e3); moderate pain (NRS score 4e6); and severe pain (NRS score 7e10).
chronic pain. Furthermore, our study showed that patients with CPSP had a higher occurrence of acute postoperative pain. It was also reported that patients with more extensive surgical access (minithoracotomy vs. VATS) and female gender experienced CPSP more frequently. Moderate-to-severe acute postoperative pain occurrence and open surgery were found to be significant independent risk factors for chronic pain development after lung resection. NP incidence was 31.5% with a statistically significant higher occurrence in the female population. Patients with CPSP also showed worse quality of life, especially those with NP. To our knowledge, the present study first investigates the prevalence of CPSP, its neuropathic component, and impact on quality of life, respectively, using the DN4 pain questionnaire and an Italian version of SF36 Health Survey. Previous data in the literature showed an extremely variable incidence of CPSP because of the lack of standardized criteria to classify subjects suffering from postsurgical pain, to the differences in the follow-up period, and to diagnostic tools to assess postoperative pain.1,4 A meta-analysis including studies published
Table 3 Risk Factors for CPSP According to the Univariate Analysis and Multivariate Regression Model Multivariate Regression Model Factors Related to CPSP Gender Male Female VATS Thoracotomy Age 65 yrs and older Age 65 yrs and younger Length of postoperative stay, four and/or less days Length of postoperative stay, days, four and/or more days Discharge without chest tube drainage Discharge with chest tube drainage Chest tube drainage, number, less than one Chest tube drainage, number, greater than one Absence to mild acute postoperative pain Moderate-to-severe acute postoperative pain
OR (95% CI) 1 1.82 1 4.69 1 0.96 1 0.97 1 1.03 1 1.49 1 31.19
P
OR (95% CI)
P
(1.01e3.29)
0.044
1.58 (0.68e3.65)
0.279
(1.87e11.74)
0.001
6.78 (2.18e21.03)
0.001
(0.53e1.71)
0.898
(0.52e1.80)
0.929
(0.52e2.05)
0.913
(0.85e2.62)
0.159
(13.30e73.14)
CPSP ¼ chronic postsurgical pain; OR ¼ odds ratio; VATS ¼ video-assisted thoracic surgery. Bold values are statistically significant (P < 0.05).
<0.001
32.61 (13.37e79.54)
<0.001
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Table 4 Risk Factors for NP According to the Univariate Analysis and Multivariate Regression Model Multivariate Regression Model Factors Related to NP Gender Male Female Age 65 yrs and older Age 65 yrs and younger VATS Thoracotomy Length of postoperative stay, four and/or less days Length of postoperative stay, four and/or more days Discharge without chest tube drainage Discharge with chest tube drainage Chest tube drainage, number, less than one Chest tube drainage, number, greater than one Absence to mild acute postoperative pain Moderate-to-severe acute postoperative pain
OR (95% CI) 1 2.91 (1.09e7.79) 1 1.41 (0.57e3.47) NA 1 0.99 (0.38e2.56) 1 1.61 (0.61e4.22) 1 1.06 (0.45e2.48) 33.97 (4.46e258.33)
P
0.033
OR (95% CI)
1.98 (0.69e5.63)
P
0.199
0.452
0.985 0.333 0.893 <0.001
30.37 (43.97e232.42)
0.001
NP ¼ neuropathic pain; OR ¼ odds ratio; VATS ¼ video-assisted thoracic surgery; NA ¼ not applicable. Bold values are statistically significant (P < 0.05).
incision, damage of pulmonary parenchyma or pleura, and thoracostomy drainage tubes. Perioperative intercostal nerve damage, such as nerve crush during rib retraction or nerve constriction when suturing, can be responsible for the raised postoperative pain and the long-term NP.17 Several data demonstrated that women are at increased risk for chronic pain.6,17,22e24 According to
the literature, a higher incidence of CPSP and NP in women was reported. However, female gender did not result as an independent risk factor for CPSP or NP development according to logistic regression analysis in this study. The relation between pain and gender is a complex process that has not yet fully understood and results from the interaction of multiple physiological and psychological factors.25 Some of these
Fig. 2. SF-36 domain scores of patients with no pain, acute pain, CPSP, and NP. SF-36 ¼ Short Form-36; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health; CPSP ¼ chronic postsurgical pain; NP ¼ neuropathic pain.
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Fig. 3. SF-36 domain scores of patients with CPSP and without CPSP (no CPSP). SF-36 ¼ Short Form-36; CPSP ¼ chronic postsurgical pain; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health (*P < 0.001).
mechanisms may involve sex-related different processing of pain-related stimuli,26 sex hormones’ receptors role in pain sensitivity,24 and major susceptibility of female sex to painful syndromes after nerve damage.27
A small number of studies reported chronic pain after VATS. CPSP reports are mostly from open thoracotomy procedures,4 and the incidence and severity of chronic pain after VATS is still not well defined.
Fig. 4. Short Form-36 domain scores of patients with NP and without NP (no NP). NP ¼ neuropathic pain; PF ¼ physical functioning; RP ¼ role limitations because of physical problems; BP ¼ bodily pain; GH ¼ general health; VT ¼ vitality; SF ¼ social functioning; RE ¼ role limitations because of emotional problems; MH ¼ mental health (*P < 0.001).
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In a recent prospective study of 107 patients undergoing thoracotomy and thoracoscopy approach, the reported incidence and severity of pain six months after thoracic surgery were similar.8 Landreneau et al.28 showed that VATS reduces the occurrence (30% vs. 44%) and severity of chronic pain and shoulder dysfunction during the first year after thoracic operations compared with thoracotomy; however, the VATS approach was not likely to affect the prevalence of long-term chronic pain after pulmonary resection. Wildgaard et al.29 also reported in a prospective observational study of 47 patients submitted to VATS a low incidence (11%) of chronic pain at three months. In this study, a lower incidence of CPSP in patients who underwent surgery through VATS than through minithoracotomy was reported. Moreover, open surgery was identified as an independent rick factor for CPSP development. It is important to underline that patients who underwent VATS approach were only 45 of 200; thus, further prospective studies are needed to confirm these results. However, it is possible to speculate that patients with more invasive surgical access are at high risk to develop CPSP.9 An extended nociceptive stimulation can indeed result in intense and continuous postoperative pain and predispose to CPSP.9 VATS seems to reduce the incidence of CPSP, probably because the minimally invasive access produces less nerve injury than open thoracotomy.30 In this study, all patients received, as part of a standardized protocol, a low dose of ketamine during anesthesia induction (0.3 mg/kg). Among the complex nociceptive pathway, N-methyl-D-aspartate (NMDA) receptors have a potential therapeutic application in chronic and NP prevention. Glutamatergic excitation caused by tissue injury results in calcium influx, triggering intracellular signaling pathways that lead to phosphorylation of NMDA receptors and prolonged nociceptive transmission. With excessive and persistent postoperative pain, these changes in the central nervous system become progressively harder to reverse and can cause nerves hyperexcitability and finally result in pain chronicization.9 NMDA receptor blockade has been shown to attenuate central sensitization. Ketamine, a noncompetitive NMDA receptor antagonist, is an effective adjunct for postoperative analgesia, independent of the type, timing of administration or dose, especially in painful procedures such as thoracic surgery.31 Although ketamine role on acute postoperative pain is well established, its role on preventing CPSP is not yet determined.32e34 However, it can be suggested that helping to reduce acute postoperative pain, which is the most important risk factor for the development of chronic pain, can certainly contribute to reduce the phenomena involved in chronicization and ultimately the occurrence of CPSP. All patients also received an intrapleural intercostal nerve block, one of the most used analgesic
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techniques besides thoracic epidural analgesia and thoracic paravertebral block. Intercostal nerve block before thoracotomy closure can provide better pain relief than narcotics alone, possibly lasting for three to five days, although the intercostal block was not repeated.35,36 Although no exhaustive data about the role of locoregional techniques to reduce CPSP are actually available,37 blocking the afferent nociceptive stimuli induced by surgical incision can effectively reduce postoperative pain intensity.17 However, a multimodal pre-emptive analgesia strategy for thoracic surgery, as the one reported in this study, has been emerging as the standard of care, because of an aggressive modulation of pain at multiple different receptors along the pain pathways.38 Despite the fact that most patients reported only mild pain, in this study, SF-36 scores showed that CPSP is associated with a significant decrease in all domains. Schulte et al.39 prospectively evaluated 159 patients showing that the lowest PF score was at three months post-thoracotomy, and pain scores peaked at that time. They also suggest that patients who undergo lung resection do not completely recover, even by 24 months after surgery, in contrast to patients submitted to major visceral operations. Kinney et al.19 in a prospective study including 110 patients who underwent lung resection reported lower SF-36 scores in PF (P ¼ 0.049), BP (P ¼ 0.0002), and vitality (P ¼ 0.044). A retrospective study of Peng et al.11 also confirmed that CPSP after thoracic surgery and its neuropathic component negatively impacts quality of life, with significant decrease in PF score and BP score for patients with CPSP (P < 0.05); in addition, compared with patients with CPSP without neuropathic component, the authors found a significant decrease in PF for patients with CPSP with neuropathic component (P < 0.05). There is therefore no doubt that CPSP affects and worsen patient’s quality of life in several aspects. Important limits of this study are as follows: the telephone interview, so the reliability of this study is strictly dependent on the memory of the patients; CPSP incidence could be overestimated because patients who experience chronic pain are actually dealing with this situation and are more likely to respond to the interview than people without pain; a clinical assessment of NP, considered the gold standard for this diagnosis, was not performed, but only a questionnaire detection method was used; eventual analgesic therapy after hospital discharge was not investigated because of the high heterogeneity that could have been found; and the retrospective nature of the study and significant numeric difference between patients who underwent surgery through VATS approach or through minithoracotomy.
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In summary, this study showed that just more than one of three patients who underwent minithoracotomy and VATS developed CPSP, with about one-third of them with neuropathic component. Acute postoperative pain, open surgery, and female gender could be associated to CPSP. Higher occurrence of NP in female patients was also reported. Chronic pain resulted to have a negative impact on quality of life, decreasing the SF-36 scores of all domains, especially in patients with NP. Preventing moderate-to-severe acute postoperative pain occurrence and avoiding invasive surgical approach when possible, resulting both independent risk factors for chronic pain development after thoracic surgery, could help to reduce CPSP incidence. In the early recovery after surgery era, the use of less invasive surgical techniques and a multifaceted approach to shorten the chest tube drainage to minimize surgical nociceptive inputs (nociception reduction), regional nerve blocks, and multimodal and aggressive pharmacological approaches (pre-emptive analgesia), and coadjuvants such as ketamine (nociception suppression and modulation) can synergically help to reduce pain sensitization and chronicization and improve postoperative quality of life of patients who underwent thoracic surgery, decreasing CPSP occurrence.
Disclosures and Acknowledgments
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7. Mauck M, Van De Ven T, Shaw AD. Epigenetics of chronic pain after thoracic surgery. Curr Opin Anaesthesiol 2014;27:1e5. 8. Bayman EO, Parekh KR, Keech J, Selte A, Brennan TJ. A prospective study of chronic pain after thoracic surgery. Anesthesiology 2017;126:938e951. 9. Pluijms WA, Steegers MA, Verhagen AF, et al. Chronic post-thoracotomy pain: a retrospective study. Acta Anaesthesiol Scand 2006;50:804e808. 10. Searle RD, Simpson MP, Simpson KH, Milton R, Bennett MI. Can chronic neuropathic pain following thoracic surgery be predicted during the postoperative period? Interact Cardiovasc Thorac Surg 2009;9:999e1002. 11. Peng Z, Li H, Zhang C, et al. A retrospective study of chronic post-surgical pain following thoracic surgery: prevalence, risk factors, incidence of neuropathic component, and impact on qualify of life. PLoS One 2014;9:1e8. 12. Padua L, Briani C, Truini A, et al. Consistence and discrepancy of neuropathic pain screening tools DN4 and ID-Pain. Neurol Sci 2013;34:373e377. 13. Bouhassira D, Attal N, Alchaar H, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 2005;114:29e36. 14. Haroutiunian S, Nikolajsen L, Finnerup NB, Jensen TS. The neuropathic component in persistent postsurgical pain: a systematic literature review. Pain 2013;154:95e102. 15. Ware JE, Gandek B. Overview of the SF-36 Health Survey and the International Quality of Life Assessment (IQOLA) Project. J Clin Epidemiol 1998;51:903e912. 16. Haefeli M, Elfering A. Pain assessment. Eur Spine J 2006;15:S17eS24.
This research received no specific funding/grant from any funding agency in the public, commercial, or not-for-profit sectors. The authors declare no conflicts of interest.
17. Katz J, Jackson M, Kavanagh BP, Sandler AN. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain 1996;12:50e55.
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