Evaluation of symptoms and signs for the management of neuropathic cancer pain (NCP) is challenging. This study aimed to identify clinical predictors of NCP and symptoms and signs most relevant of those in Korean patients.This nationwide, descriptive, cross-sectional, multicenter, observational study included 2,003 cancer patients aged ≥20 years who reported a visual analog scale (VAS) score ≥1 for pain and provided informed consent for participation. The Douleur Neuropathic (DN4) questionnaire (score ≥4) was used to determine symptoms and signs as well as the presence of NCP.The prevalence of NCP was associated with age <65 years , disease duration >6 months , stage IV cancer , history of chemotherapy , and moderate-to-severe cancer pain  after multivariate analysis. The most common descriptive symptoms of NCP were tingling, electric shock, and pins and needles. For NCP patients in the presence or absence of the clinical predictors, pins and needles (p = 0.001) and painful cold (p<0.001) symptoms were significantly frequent in patients with moderate-to-severe pain. Tingling, numbness, and touch hypoesthesia  were more frequent in those with longer cancer duration and hyperesthesia (p = 0.024) was more frequent in young patients.Age <65 years, disease duration >6 months, stage IV cancer, history of chemotherapy, and moderate-to-severe cancer pain, were identified as predictors of NCP. Some symptoms and signs of NCP were associated with these predictors. Further studies are warranted on the pathogenesis and management of NCP with respect to the symptoms and signs, and factors associated with pain severity in Korean patients. One of the most fearful symptoms of cancer is pain. Chronic cancer pain is defined as chronic pain caused by the primary cancer itself, metastasis or its treatment . DespiteThe International Association for the Study of Pain (IASP) classification of chronic pain for International Classification of Diseases ICD-11) identifies specific codes for chronic NCP (neuropathic pain caused by a tumor), as well as neuropathic pain caused by a primary tumor or metastases damaging or injuring the peripheral or central nervous system . Neuropa identifiThis nationwide, cross-sectional, descriptive, non-interventional, multicenter study was conducted from February 2013 to March 2014 in 28 hospitals in Korea, including 21 tertiary referral hospitals, 5 secondary referral hospitals, and 2 municipal general hospitals. Inclusion criteria were as follows: age ≥20 years, diagnosis of cancer, cancer pain with a visual analog scale (VAS) score ≥1, and the ability to understand and sign the informed consent form. Patients with pain not associated with cancer were excluded at the discretion of the attending physician. Patients’ demographic and clinical characteristics  and their treatment history  were collected from medical records. Questionnaires and case report forms were collected, and study data were analyzed. The study (study ID: KCSG PC13-02) was approved by the central institutional review board (IRB) of the Korean Cancer Study Group (KCSG). After central approval, institutional approval was obtained from the institutions of the participating investigators. All procedures were, therefore, performed in accordance with the ethical standards of the institutional and/or national research committee and within the guidelines of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.All patients were evaluated by physicians, who determined the presence of cancer pain using the VAS and the presence of NCP using the Douleur Neuropathic (DN4) questionnaire during patients’ regular visits. We defined a VAS score ≥1 as cancer pain. The DN4 questionnaire includes seven pain descriptors, namely, burning painful cold, electric shocks, tingling, pins and needles, numbness, and itching, along with three additional symptoms, namely, hypoesthesia to touch, hypoesthesia to pinpricks, and allodynia to a paintbrush. The former seven descriptors were assessed via patient interviews, while the latter three were assessed via standardized clinical examinations. We defined a DN4 score ≥4 as NCP.Patients were categorized into NCP (DN4 score ≥4) and non-NCP (DN4 score <4) groups. In the univariable analysis, patients’ demographic and clinical characteristics were compared between the NCP and non-NCP groups using Student’s t-tests for continuous variables and chi-square tests for categorical variables. To identify independent predictors of NCP, multivariable logistic regression analysis was used; the multivariable model included patients’ demographic characteristics (age and gender) and variables with a p-value of <0.1 in the univariable analysis.Differences in symptoms reported by patients through the DN4 questionnaire were analyzed between the NCP and non-NCP groups using logistic regression models. In both univariable and age- and sex-adjusted multivariable analysis, the non-NCP group was the designated reference group. The distribution of clinical predictors in the NCP group was analyzed using chi-square tests.All reported p-values were two-tailed, and a p-value of <0.05 was considered statistically significant. All statistical analyses were performed using IBM SPSS Statistics 20.0 .A total of 2,003 patients participated in this study, and NCP was present in 722 (36.0%) of these patients. According to univariable analysis, using Student’s t-tests for continuous variables and chi-square tests for categorical variables, the proportion of NCP was higher among patients aged <65 years compared to those aged ≥65 years (p<0.001), in patients with cancer duration ≥6 months compared to <6 months (p = 0.001), and in patients with stage I–III cancer compared to those with stage IV cancer (p = 0.021). There were 494 patients with comorbidities  and the proportion of patients with comorbidities was not significantly different between the two groups (p = 0.133). Regarding treatment history, the proportion of patients with NCP was higher among patients with a history of chemotherapy (p<0.001) and among patients with a history of cancer surgery (p = 0.003). Finally, the proportion of patients with NCP was higher among patients with moderate-to-severe pain (VAS score ≥4) compared to those with mild pain , 1.57; 95% confidence interval (CI), 1.27–1.93], cancer duration of >6 months compared to that of <6 months , stage IV cancer compared to stage I–III cancer , a previous or current history of chemotherapy , and moderate-to-severe pain  were significant clinical predictors of NCP .Overall, the most common neuropathic symptom was tingling , followed by electric shocks  and pins and needles . Among the groups categorized on the basis of the DN4 questionnaire score, commonly experienced symptoms were tingling , electric shocks , and pins and needles . An increased OR was noted for all symptoms and signs described in the DN4 questionnaire, indicating the increased incidence of these symptoms in NCP patients in both univariable and multivariable models. Prick hypoesthesia  and touch hypoesthesia  were associated with increased odds of being present in the NCP group by chi-square tests .The prevalence of the clinical predictors  was assessed among the patients in the NCP group for each of the clinical symptoms and signs . Among NIn the present study, we analyzed data from a nationwide cancer pain survey in Korea, focusing on predictors of NCP and the clinical significance of patient-reported symptoms and signs most relevant for these predictors in Korean patients. Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (aged ≥65 years) with gynecologic cancer are at higher risk for NCP . Other sHowever, in our study, surgery had a significant association with NCP in univariate, but not in multivariate, analysis. There were 399 patients with stage I, II, or III cancer and 799 patients underwent surgery. About half of the patients who underwent surgery had palliative surgery rather than curative surgery on the primary tumor, which may explain the difference from the previous report. Additionally, we enrolled various cancer patients in this study. Gastrointestinal cancer was the most common (49% of patients), followed by respiratory cancer (24%), skin, bone, and connective cancer (14%), hematologic malignancy (14%), genitourinary cancer (13%), breast cancer (11%), and head and neck cancer (9%) . Since aEarly neuropathic symptoms and signs of platinum analog-treated patients include loss of ankle jerks and decreased vibratory sensibility in the toes associated with numbness, tingling or paresthesias in finger and toes and prolonged treatment may worsen those symptoms. Pin and temperature sensation, joint position and light touch perception are less severely affected ,20. In oThe evaluation of pain begins with a patient interview regarding the symptoms. Currently, there is no gold standard method for the diagnosis of neuropathic pain. In daily practice, screening questionnaires are suitable for identifying potential patients with neuropathic pain. For cancer patients, these questionnaires are preferred over imaging studies such as electroneuromyography or magnetic resonance imaging. A screening tool for neuropathic pain could alert physicians about the possibility of NCP. Medical oncologists generally use three screening tools for neuropathic pain, namely pain DETECT , the LeeChemotherapy-induced peripheral neuropathy (CIPN) is a frequent, dose-dependent complication of anticancer drugs, including platinum, taxanes, epothilones, vinca alkaloids, and newer agents such as bortezomib . In our This study has some limitations. First, the cross-sectional design limits our knowledge of various pre-referral treatments and their degree of consistency with standard guidelines. Second, the origin of cancer, stage of cancer, and anticancer treatment differed among the enrolled patients. There is controversy over the association of status or site of cancer with NCP ,28, rathIn conclusion, the results of this nationwide cross-sectional study in Korea have shown predictors of NCP and the identification of symptoms and signs associated with NCP. To the best of our knowledge, this is the first study that has analyzed each descriptive symptom and sign based on the predictors of NCP, as obtained by the DN4 questionnaire. More studies to substantiate the characteristics of NCP could help in its early detection, correct diagnosis and efficient management.S1 Table(DOCX)Click here for additional data file. 5 Feb 2021PONE-D-20-33583Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer painPLOS ONEDear Dr. Shin,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.Please submit your revised manuscript by Mar 22 2021 11:59PM. 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Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: YesReviewer #3: NoReviewer #4: Yes**********5. Review Comments to the AuthorPlease use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Reviewer #1: The manuscript by Baek et al. aims to identify new predictors of NCP in Korean population of cancer patients by using the DN4. Although authors identified some signs and symptoms associated with NCP, the main objective and output are not enough empathised leaving in the reader a feeling of non-understanding the relevance of the results.Overall, this is an interesting attempt, but there are some points to address:1) Line 72: authors mentioned that the prevalence of NCP is 20-30% in cancer patients, worldwide? In Korea? Please specify.2) Line 81: according to authors, few studies have reported how patients described the influence of their symptoms, however, no reference is provided. I would appreciate to see the references.3) Patients aged >20 years are included in the present study. However, results only show the comparison between <65 and > 65. Could authors explain the reason for this selection? Have the authors performed any previous analysis to define this age categories?4) In order to facilitate the comprehensive interpretation of the results, I would appreciate the authors to mention which statistical method has been used for each analysis in the results section, including figures and tables, as it is only mentioned in “Statistical analysis”.5) Concerning the Figure 1: please consider that P values less than 0.001 are summarized with three asterisks (***) not two (**).There is not Title nor footnotes in Figure 1.6) Please add a reference in line 203 that confirms that the presence of comorbidities is higher in the elderly.7) Reference 9 in line 206 does not correspond to the sentence as it mentions the results of the current manuscript. Please check.8) In the discussion, authors explain that the longer duration and higher intensity of the treatment received in the younger patients could explain the results. However, there is no information about the treatment dose or the treatment duration in the sample analysed. Therefore, I would recommend showing this information in a table or to elaborate another explanation for the result found.9) If, as mentioned in the discussion, DN4 may have limitations when used in patients with severe pain, why authors have decided to use this questionnaire to evaluate their participants if more than 50% presented moderate to severe pain? Are they sure that this is the appropriate tool for this study? Please justify.10) Has been data provided or deposited to a public repository? If not, more detailed information should be added to the statistics .Reviewer #2: Manuscript Number: PONE-D-20-33583Title: Significance of descriptive symptoms and signs and clinical parameters as predictorsof neuropathic cancer painSummaryI appreciate the opportunity to review this interesting report. This is a nationwide cross-sectional study in Korea that have shown predictors of NCP and the identification of symptoms and signs associated with NCP.Major StrengthsThis is an interesting article that first describe symptoms and signs based on the predictors of NCP, as obtained by the DN4 questionnaire using nationwide data.Major WeaknessPlease describe more specific sources and methods of selection of participants. The authors indicate that the inclusion criteria were cancer pain with VAS ≥ 1. I think the VAS 1 is not suitable. Is there any reason?In my opinion, the diagnosis of NCP is more complex one. Especially in the cancer pain population, in which nociceptive and neuropathic components frequently co-exist. How did the authors differentiate NCP with mixed type pain?In the discussion, page 18, line 266-267, is there any reference? As I know, NCP may occur directly as in tumor-associated neural compression.According to the previous report, surgery is one of predictor of NCP. Please discuss more about the predictor of NCP.Minor CommentsAccording to the STROBE guideline, the title represents “Indicate the study’s design”.Reviewer #3: Authors have presented an analysis of signs and symptoms of cancer pain in a large sample size. The topic is surely interesting and useful for clinicians in order to improve diagnosis of cancer pain. Authors (as they stated in the background) have already published part of the data in a previous paper and some data seem the same. Please control accurately it.The major concern regarding the manuscript is the selection of the patients: it seems that a VAS>1 could lead to wrong results (even though we have no any informations about drugs that patients took).I would suggest to consider only patients with pain more than 3 , eventually stratifying the population in mild (VAS 4-6) and severe (VAS 7-10) pain. This stratification could be more reliable to clinical practice and could be more helpful for a clear analysis of the samples size.I have also some concerns about the statistical analysis and the data presentation. It should be better to evaluate if there are differences in percentages of patients among the same group (NCP and no NCP). As presented, it seems that authors have evaluated differences between NCP and no NCP for the single variable. This analysis could be misunderstanding also considering also the huge heterogeneity of the sample size. Please discuss itCan we have some data about use of analgesic drugs and eventually differences in type of drugs used and pain relief obtained in the two groups?it could be helpful to understand if a better analysis of the signs and symptoms could improve the effectiveness of treatment.Finally it should be necessary to revise English and revise several typos.Reviewer #4: Thanks for opportunity of reviewing this article. This is an interesting study, but there are several limitations with NCP predictor.Method1.In method section, explanation of study design and definition is lacking.2.What are the criteria for determining NCP and Non-NCP? The criteria for diagnosis are unclear.3.P6 L 105 “A VAS score ≥1 was indicative of cancer pain.” Do you have a reference? Is this the standard set by the authors? Are they defined by the authors?ResultTable 11.Comorbidity is also an important factor in determining cancer pain. For example, the case of patient with severe DM, the sensitivity of pain decreases and pain patterns may be different due to DM neuropathy. Could you add details about Comorbidity?2.The type of cancer is also an important factor. If you can, add it.3.The type of cancer is also an important factor. If you can, add it.Cancer patients often use narcotic analgesics, which can also lead to hyperalgesia if prolonged exposure to analgesics. Add the presence or absence of narcotic pain killers.4.P8 L139, Table 1The standard for dividing the VAS score is set to 4, do you have any reference?DiscussionIn the discussion section, the discussion is too long, and the content of the sentence is in conflict. Need to clean up.1. What is the clinical meaning of this investigation result?2. P15 199-206, I cannot understand your explanation3. According to your results, chemotherapy is also a risk factor for NCP. Old age receives less chemotherapy than young age, so why have more NCP in old age? Does cancer pain decrease in young age receiving toxic agent chemotherapy?This section conflicts with your results and needs clarification. In addition, check the reference again.4. P16 L217-239 Combine in one paragraph.Delete "Failure of identifying NCP leads to unsatisfactory pain management in Asian countries where physician–patient communication tends to be reserved or of short duration"(??)**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  13 Apr 202129 March, 2021Dear Editor-in-Chief, PLOS ONEWe deeply appreciate your insightful comments on our manuscript entitled, “Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer pain”. Your comments were really helpful for revising our manuscript. We totally agree with the comments of the reviewers and have revised our manuscript according to reviewers’ comments. All relevant data are within the manuscript, and the changes and responses to specific comments are shown below. We hope that these changes will satisfy the editors and reviewers. Also, we confirm that this study was sponsored by Pfizer Pharmaceuticals Korea Ltd. Ha Yeong Gil, the employee of Pfizer Pharmaceuticals Korea Ltd., contributed in the study design, data analysis, decision to publish, or preparation of the manuscript. We declare that the authors have no other competing interests. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials. Thank you again for providing important comments on our work. We hope you can consider this paper for publication in PLOS ONE.Sincerely,Sang Won Shin, MD, PhD.Medical Oncology, Department of Internal Medicine Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea73, Inchon-ro, Seongbuk-gu, Seoul, 136-705, Republic of Korea Tel:+82-2-920-5350, Fax: +82-2-920-6951shinsw@kumc.or.krE-mail: Response to the Referee29 March, 2021Thank you very much for your comments regarding our manuscript. We answered your comments with point-by-point descriptions and changed the manuscript accordingly.Reviewer #1: The manuscript by Baek et al. aims to identify new predictors of NCP in Korean population of cancer patients by using the DN4. Although authors identified some signs and symptoms associated with NCP, the main objective and output are not enough empathised leaving in the reader a feeling of non-understanding the relevance of the results. Response: We would like to thank you for the careful comments. Based on the reviewer’s suggestion, we revised our paper, again. The revised words and sentences are red colored.Overall, this is an interesting attempt, but there are some points to address:1) Line 72: authors mentioned that the prevalence of NCP is 20-30% in cancer patients, worldwide? In Korea? Please specify.Response: We would like to thank you for the careful comments. As you advised, the references have been reinforced and the sentence was modified as follows. “Neuropathic pain affects up to 40% of cancer patients and is associated with increased pain intensity and decreased quality of life (QOL) [7-9]. Previously, we also reported the incidence rate of NCP in cancer patients in Korea and the relevance that NCP deteriorates patients’ QOL [10].” (line 77-82)Added references: [8] Bennett MI, Rayment C, Hjermstad M, et al. (2012) Prevalence and aetiology of neuropathic pain in cancer patients: a systematic review. Pain 153: 359-365.[9] Rayment C, Hjermstad MJ, Aass N, et al. (2013) Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative-Computerised Symptom Assessment study. Palliat Med 27: 714-721.2) Line 81: according to authors, few studies have reported how patients described the influence of their symptoms, however, no reference is provided. I would appreciate to see the references.Response: We would like to thank you for the careful comments. We have excluded the sentence because it seems to cause confusion.3) Patients aged >20 years are included in the present study. However, results only show the comparison between <65 and > 65. Could authors explain the reason for this selection? Have the authors performed any previous analysis to define this age categories?Response: Thank you for the helpful comments. More than half of new cancer cases are diagnosed in adults over the age of 65 years. Older cancer patients are at high risk for chemotherapy-related toxicities including NCP. Bulls et al evaluated the longitudinal change in patients with NCP in older (>65) and younger (<65) patients. So, we compared patients based on age 65 years. We have added the article of Bulls et al as a reference. “Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (aged ≥65 year) with gynecologic cancer are at higher risk for NCP [13].” (line 217-220)Added reference: [13] Bulls HW, Hoogland AI, Kennedy B, et al. (2019) A longitudinal examination of associations between age and chemotherapy-induced peripheral neuropathy in patients with gynecologic cancer. Gynecol Oncol 152: 310-315.4) In order to facilitate the comprehensive interpretation of the results, I would appreciate the authors to mention which statistical method has been used for each analysis in the results section, including figures and tables, as it is only mentioned in “Statistical analysis”.Response: We would like to thank you for the careful comments. As you advised, we have added a sentence about statistical analysis in the results section, including figures and tables.“According to univariable analysis, using Student’s t-tests for continuous variables and chi-square tests for categorical variables, the proportion of NCP was higher among patients aged <65 years compared to those aged ≥65 years (p<0.001), in patients with cancer duration ≥6 months compared to <6 months (p=0.001), and in patients with stage I–III cancer compared to those with stage IV cancer (p=0.021).” (line 143-147)“Prick hypoesthesia  and touch hypoesthesia  were associated with increased odds of being present in the NCP group by chi-square tests (Table 3).” (line 186-188)Table 1: “χ2 test, Student’s t-tests for continuous variables and chi-square tests for categorical variables” (line 159-160) Table 2: “Logistic regression analysis, variables with p-value<0.1 from the univariable analysis were included.” (line 172-173)Table 3: “Chi-square tests, all statistically significant” (line 190)5) Concerning the Figure 1: please consider that P values less than 0.001 are summarized with three asterisks (***) not two (**). There is not Title nor footnotes in Figure 1.Response: Thank you for your helpful comments. We have converted Figure 1 to Table 2 to explain the Results more easily.Table 2. Clinical predictors of patients with NCP Predictors(Reference) Adjusted OR 95% - CI P-valueFemale  1.036 0.849 - 1.265 0.729Age <65 years (≥65 years) 1.567 1.270 - 1.934 <0.001Cancer duration≥6 months (<6 months) 1.574 1.232 - 2.012 <0.001Cancer stage IV (I-III) 0.752 0.593 - 0.955 0.019Chemotherapy, done (Never done) 1.740 1.225 - 2.472 0.002Surgery, done (Never done) 1.127 0.917 - 1.386 0.256Pain VAS score, Moderate/Severe (Mild) 2.054 1.671 - 2.524 <0.001Logistic regression analysis, variables with p-value<0.1 from the univariable analysis were included. CI: confidence interval; NCP: neuropathic cancer pain; OR: odds ratio; VAS: visual analog scale6) Please add a reference in line 203 that confirms that the presence of comorbidities is higher in the elderly.Response: We would like to thank you for the careful comments. We excluded the sentence while revising the Discussion section. 7) Reference 9 in line 206 does not correspond to the sentence as it mentions the results of the current manuscript. Please check.Response: We would like to thank you for the careful comments. We removed the reference which did not correspond to the sentence.8) In the discussion, authors explain that the longer duration and higher intensity of the treatment received in the younger patients could explain the results. However, there is no information about the treatment dose or the treatment duration in the sample analysed. Therefore, I would recommend showing this information in a table or to elaborate another explanation for the result found.Response: We would like to thank you for the careful comments. We added Supplementary Table1 and revised the sentence.“In the present study, 20% of the older (≥65 years) and 7% of the younger (<65 years) age groups had not received chemotherapy (S1 Table). Older patients are less likely to receive chemotherapy, which can explain the increased association of NCP with the younger age group in our study.” (line 228-232)S1 Table. Comparison of patients receiving/not receiving chemotherapy and age <65 or ≥65 years Chemotherapy Non-chemotherapy Total P-valueAge <65 years 1,123 (92.6) 90 (7.4) 1,213 (60.6) <0.001Age ≥65 years 630 (79.7) 160 (20.3) 790 (39.4) 9) If, as mentioned in the discussion, DN4 may have limitations when used in patients with severe pain, why authors have decided to use this questionnaire to evaluate their participants if more than 50% presented moderate to severe pain? Are they sure that this is the appropriate tool for this study? Please justify.Response: We would like to thank you for the careful comments. Unfortunately, the quote seems to have been wrong. Perez C et al reported the LANSS is considerably more specific than the DN4 if pain is severe and intermittent, not moderate and severe. We removed the sentence.10) Has been data provided or deposited to a public repository? If not, more detailed information should be added to the statistics .Response: We would like to thank you for the careful comments. We have added information about mean and standard deviations in Table 1. All relevant data are within the paper. Table 1. Comparison of the characteristics between the NCP and non-NCP groups N(%) TotalN=2,003 NCPN=722 (%) Non-NCPN=1,281 (%) P-valueGender 0.281Male 1,089 381 (35.0) 708 (65.0) Female 914 341 (37.3) 573 (62.7) Age (years), mean�SD 60.9±11.3 59.5±10.7 61.7±11.5 <0.001<65 1,213 489 (40.3) 724 (59.7) 0.001≥65 790 233 (29.5) 557 (70.5) Cancer duration (months), mean�SD 26.3±37.1 30.1±42.1 24.1±33.7 0.001<6 545 143 (26.2) 402(73.8) 0.001≥6 1,458 579 (39.7) 879(60.3) Cancer stage 0.021Stage I–III 399 163 (40.9) 236 (59.1) Stage IV 1,428 494 (34.6) 951 (66.6) Comorbidities 0.133None 1,509 530 (35.1) 979 (64.9) Present 494 192 (38.9) 302 (61.1) Radiotherapy 0.310Never received 1,401 515 (36.8) 886 (63.2) Received 602 207 (34.4) 395 (65.6) Chemotherapy <0.001Never received 250 54 (21.6) 196 (78.4) Received† 1,751 668 (38.1) 1,083 (61.9) Cancer surgery 0.003Did not undergo 1,204 403 (33.5) 801 (66.5) Underwent 799 319 (39.9) 480 (60.1) Pain VAS score, mean�SD 4.4±2.3 4.9±2.3 4.1±2.0 <0.001<4 (mild pain) 830 225 (27.1) 605(72.9) <0.001≥4 (moderate-to-severe pain) 1,173 497 (42.4) 676 (57.6) χ2 test, Student’s t-tests for continuous variables and chi-square tests for categorical variables NCP: neuropathic cancer pain; SD: standard deviation; VAS: visual analog scale Reviewer #2: Manuscript Number: PONE-D-20-33583Title: Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer painSummaryI appreciate the opportunity to review this interesting report. This is a nationwide cross-sectional study in Korea that have shown predictors of NCP and the identification of symptoms and signs associated with NCP.Major StrengthsThis is an interesting article that first describe symptoms and signs based on the predictors of NCP, as obtained by the DN4 questionnaire using nationwide data.Major WeaknessPlease describe more specific sources and methods of selection of participants. Response: We would like to thank you for the careful comments. We have added the requested information about hospitals.“This nationwide, cross-sectional, descriptive, non-interventional, multicenter study was conducted from February 2013 to March 2014 in 28 hospitals in Korea, including 21 tertiary referral hospitals, 5 secondary referral hospitals, and 2 municipal general hospitals.” (line 96-99)The authors indicate that the inclusion criteria were cancer pain with VAS ≥ 1. I think the VAS 1 is not suitable. Is there any reason? In my opinion, the diagnosis of NCP is more complex one. Especially in the cancer pain population, in which nociceptive and neuropathic components frequently co-exist. How did the authors differentiate NCP with mixed type pain?Response: We totally agree that the diagnosis of NCP is more complex. We thought your opinion was very important. However, we were sorry that we did not differentiate NCP with mixed type pain or explore the cause of NCP. We have added this concern as a limitation.“Third, we did not differentiate dominant or neuropathic components from mixed type with nociceptive and neuropathic pain. As we searched for the frequency and risk factors of NCP in all patients with cancer pain through cross-sectional studies and used DN4 as screening test of NCP, we were not able to study the cause of NCP. This is required through other studies in the future.” (line 310-313)In the discussion, page 18, line 266-267, is there any reference? As I know, NCP may occur directly as in tumor-associated neural compression.Response: We would like to thank you for the careful comments. We agree with your opinion, have revised the sentence, and added the reference.“There is controversy over the association of status or site of cancer with NCP , rather, whether NCP is associated with neurological involvement secondary to the disease or its treatment.” (line 307-309)Added references:[14] Lewis MA, Zhao F, Jones D, et al. Neuropathic Symptoms and Their Risk Factors in Medical Oncology Outpatients With Colorectal vs. Breast, Lung, or Prostate Cancer: Results From a Prospective Multicenter Study. J Pain Symptom Manage. 2015;49(6):1016-24. [28] Oosterling A, te Boveldt N, Verhagen C, et al. (2016) Neuropathic Pain Components in Patients with Cancer: Prevalence, Treatment, and Interference with Daily Activities. Pain Pract 16: 413-421.According to the previous report, surgery is one of predictor of NCP. Please discuss more about the predictor of NCP.Response: We would like to thank you for the careful comments. We have added one paragraph about your comments. “However, in our study, surgery had a significant association with NCP in univariate, but not in multivariate, analysis. There were 399 patients with stage I, II, or III cancer and 799 patients underwent surgery. About half of the patients who underwent surgery had palliative surgery rather than curative surgery on the primary tumor, which may explain the difference from the previous report. Additionally, we enrolled various cancer patients in this study. Gastrointestinal cancer was the most common (49% of patients), followed by respiratory cancer (24%), skin, bone, and connective cancer (14%), hematologic malignancy (14%), genitourinary cancer (13%), breast cancer (11%), and head and neck cancer (9%) [10]. Since approximately half of the patients registered in this study had gastrointestinal cancer, it indicates that there are fewer patients who have undergone chronic pain-related surgeries, such as mastectomy or thoracotomy [17]. Moreover, less invasive surgical techniques might result in less postsurgical pain. Lumpectomy might result in more pain than a modified radical mastectomy [18].” (line 241-254)Minor CommentsAccording to the STROBE guideline, the title represents “Indicate the study’s design”.Reviewer #3: Authors have presented an analysis of signs and symptoms of cancer pain in a large sample size. The topic is surely interesting and useful for clinicians in order to improve diagnosis of cancer pain. Authors (as they stated in the background) have already published part of the data in a previous paper and some data seem the same. Please control accurately it.The major concern regarding the manuscript is the selection of the patients: it seems that a VAS>1 could lead to wrong results (even though we have no any informations about drugs that patients took).I would suggest to consider only patients with pain more than 3 , eventually stratifying the population in mild (VAS 4-6) and severe (VAS 7-10) pain. This stratification could be more reliable to clinical practice and could be more helpful for a clear analysis of the samples size.Response: We totally agree with you. However, our research is a cross-sectional study that shows the frequency and risk factors of NCP in patients with cancer pain, and is limited by enrolling patients with VAS 1 or higher, regardless of treatment. We have included this in the limitations section. “Third, we did not differentiate dominant or neuropathic components from mixed type with nociceptive and neuropathic pain. As we searched for the frequency and risk factors of NCP in all patients with cancer pain through cross-sectional studies, we were not able to study the cause of NCP. This is required through other studies in the future. Fourth, the patients’ narratives, including their interpretation of pain, may be governed by their culture and language [29]. Finally, we defined that patients had cancer pain if they complained of cancer pain (NRS≥1) regardless of treatment. Patients with pain more than VAS 3 were usually considered for treatment in clinical practice. There might be limits to the application of treatment in clinical practice. However, this study is helpful in identifying patients who are expected to have NCP in advance and for monitoring their symptoms and signs by risk factors.” (line 310-325)I have also some concerns about the statistical analysis and the data presentation. It should be better to evaluate if there are differences in percentages of patients among the same group (NCP and no NCP). As presented, it seems that authors have evaluated differences between NCP and no NCP for the single variable. This analysis could be misunderstanding also considering also the huge heterogeneity of the sample size. Please discuss it.Response: We would like to thank you for the careful comments. However, we were sorry that we analyzed a difference between the risk factors of NCP and the descriptive symptoms (with or without NCP) in patients with cancer pain, which makes it difficult to see differences in the same group.Can we have some data about use of analgesic drugs and eventually differences in type of drugs used and pain relief obtained in the two groups? it could be helpful to understand if a better analysis of the signs and symptoms could improve the effectiveness of treatment.Response: We would like to thank you for the careful comments. Previously, we published a study on the association of NCP and QOL in the same patients, and a part relating to treatment was included in that paper . In this study, we presented the results that were not included in the previous study. The contents of treatment were reported in previous study. It is as follows (blue color) for your reference.Previous article:More than half of the patients  had had moderate to severe pain (VAS≥4), implying that cancer pain was not adequately managed. Pharmacologic management for pain was as follows: 1,313 patients received opioids (65.6%), 748 received non-opioid analgesics (37.3%), 464 received anticonvulsants (23.2%), 134 received antidepressants (6.7%), 91 received corticosteroids (4.5%), 68 received benzodiazepines (3.4%), and 16 received phenothiazines (0.8%) (permitted overlap).Finally it should be necessary to revise English and revise several typos.Response: We would like to thank you for the careful comments. We have revised the English throughout the manuscript.Reviewer #4: Thanks for opportunity of reviewing this article. This is an interesting study, but there are several limitations with NCP predictor.Method1. In method section, explanation of study design and definition is lacking.2. What are the criteria for determining NCP and Non-NCP? The criteria for diagnosis are unclear.3. P6 L 105 “A VAS score ≥1 was indicative of cancer pain.” Do you have a reference? Is this the standard set by the authors? Are they defined by the authors?Response: We would like to thank you for the careful comments. We added the definition of cancer pain and NCP.“We defined a VAS score ≥1 as cancer pain.” (line 115)“We defined a DN4 score ≥4 as NCP.” (line 120-121)ResultTable 11.Comorbidity is also an important factor in determining cancer pain. For example, the case of patient with severe DM, the sensitivity of pain decreases and pain patterns may be different due to DM neuropathy. Could you add details about Comorbidity?2. The type of cancer is also an important factor. If you can, add it.3. The type of cancer is also an important factor. If you can, add it.Cancer patients often use narcotic analgesics, which can also lead to hyperalgesia if prolonged exposure to analgesics. Add the presence or absence of narcotic pain killers.Response: We would like to thank you for the careful comments. Previously, we published a study on the association of NCP and QOL in the same patients, and a part relating to treatment was included in that paper . In this study, we presented results that were not included in previous study. Comorbidity and treatment were included in the previous report. We have briefly included comorbidity in the Results section and the type of cancer in the Discussion section. However, we were sorry that we could not include narcotic analgesics. For your reference, the contents of the previous paper on treatment are described below (blue color) Results section:“There were 494 patients with comorbidities  and the proportion of patients with comorbidities was not significantly different between the two group (p=0.133).” (line 147-150)Discussion section:“However, in our study, surgery had a significant association with NCP in univariate, but not in multivariate, analysis. There were 399 patients with stage I, II, or III cancer and 799 patients underwent surgery. About half of the patients who underwent surgery had palliative surgery rather than curative surgery on the primary tumor, which may explain the difference from the previous report. Additionally, we enrolled various cancer patients in this study. Gastrointestinal cancer was the most common (49% of patients), followed by respiratory cancer (24%), skin, bone, and connective cancer (14%), hematologic malignancy (14%), genitourinary cancer (13%), breast cancer (11%), and head and neck cancer (9%) [10]. Since approximately half of the patients registered in this study had gastrointestinal cancer, it indicates that there are fewer patients who have undergone chronic pain-related surgeries, such as mastectomy or thoracotomy [17]. Moreover, less invasive surgical techniques might result in less postsurgical pain. Lumpectomy might result in more pain than a modified radical mastectomy [18].” (line 241-254)Previous article:More than half of the patients  had had moderate to severe pain (VAS≥4), implying that cancer pain was not adequately managed. Pharmacologic management for pain was as follows: 1,313 patients received opioids (65.6%), 748 received non-opioid analgesics (37.3%), 464 received anticonvulsants (23.2%), 134 received antidepressants (6.7%), 91 received corticosteroids (4.5%), 68 received benzodiazepines (3.4%), and 16 received phenothiazines (0.8%) (permitted overlap).4. P8 L139, Table 1The standard for dividing the VAS score is set to 4, do you have any reference?Response: We would like to thank you for the careful comments. We divided patients based on VAS 4 because patients with VAS 4 or more need treatment. There is likely a controversy. We have added that as a limitation. “Finally, we defined that patients had cancer pain if they complained of cancer pain (NRS≥1), regardless of treatment. Patients with pain more than VAS 3 were usually considered for treatment in clinical practice. There might be limits to the application of treatment in clinical practice. However, this study is helpful in identifying patients who are expected to have NCP in advance and for monitoring their symptoms and signs by risk factors.” (line 320-325)DiscussionIn the discussion section, the discussion is too long, and the content of the sentence is in conflict. Need to clean up.1. What is the clinical meaning of this investigation result?2. P15 199-206, I cannot understand your explanation3. According to your results, chemotherapy is also a risk factor for NCP. Old age receives less chemotherapy than young age, so why have more NCP in old age? Does cancer pain decrease in young age receiving toxic agent chemotherapy? This section conflicts with your results and needs clarification. In addition, check the reference again.Response: We would like to thank you for the careful comments. We cleaned up the Discussion section, deleted the sentence, and revised the paragraph. Our study identified age <65 years as risk factors, not old age. We would like to explain the reason that older patients are less likely to receive chemotherapy. “In the present study, we analyzed data from a nationwide cancer pain survey in Korea, focusing on predictors of NCP and the clinical significance of patient-reported symptoms and signs most relevant for these predictors in Korean patients. Our study identified five clinical predictors of NCP: age <65 years, a past or current history of chemotherapy, cancer duration of ≥6 months, moderate-to-severe pain (VAS score ≥4), and early-stage cancer (stage I–III). Bulls et al. reported that older adults (≥65 years) with gynecologic cancer are at higher risk for NCP [13]. Other studies have also reported a higher prevalence of neuropathy in older patients . In the present study, 20% of the older (≥65 years) and 7% of the younger (<65 years) age groups had not received chemotherapy (Supplementary Table 1). Older patients are less likely to receive chemotherapy, which can explain the increased association of NCP with the younger age group in our study. A recent study reported that the predictors of NCP were associated with the location of neural invasion, a longer disease duration, a higher pain intensity, recent surgery or chemotherapy, the use of one or more adjuvant analgesics, and the presence of an episodic incident or breakthrough pain [16]. This was similar to our study, where NCP was found to be associated with chemotherapy moderate-to-severe pain and longer duration of cancer.” (line 213--240)4. P16 L217-239 Combine in one paragraph.Delete "Failure of identifying NCP leads to unsatisfactory pain management in Asian countries where physician–patient communication tends to be reserved or of short duration"(??)Response: We would like to thank you for the careful comments. As you advised, we revised the manuscript as follows. “Early neuropathic symptoms and signs of platinum analog-treated patients include loss of ankle jerks and decreased vibratory sensibility in the toes associated with numbness, tingling or paresthesias in finger and toes and prolonged treatment may worsen those symptoms. Pin and temperature sensation, joint position and light touch perception are less severely affected . In our study, the most frequently reported symptoms were tingling, electric shock, and pins and needles, and these symptoms were most frequently reported by both NCP and non-NCP groups. It is possible for neuropathic pain to begin with common symptoms such as tingling, pins and needles and electric shocks. A Spanish prospective study, conducted over 1 month, that recruited 366 patients with cancer, aged ≥18 years, diagnosed with NCP (DN4 ≥4), and with moderate-to-severe pain (VAS ≥4), reported that the most common symptoms were tingling (79.8%), pins and needles (76.2%) and electric shocks (72.4%) [21]. This showed a similar distribution of descriptive symptoms as the NCP group in the present study. In contrast, an Indian study reported that a pricking type of pain was the most characteristic feature (47.8%), followed by shooting pain (38.3%), in patients with NCP [22]. These differences in descriptive symptoms might be associated with differences in study design, ethnicity, or expressive language used to express patients’ pain. The symptoms and signs of highest relevance to NCP were prick hypoesthesia and touch hypoesthesia. Further studies to clarify symptom definitions and to elucidate the pathogenesis of NCP are needed for its effective management.” (line 255-273)Attachmentauthor response to reviewers_PlosOne_clean_20210408.docxSubmitted filename: Click here for additional data file. 24 May 2021Significance of descriptive symptoms and signs and clinical parameters as predictors of neuropathic cancer painPONE-D-20-33583R1Dear Dr. Shin,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. 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Recent “multimodal” approaches to pain, although understudied, have shown promise in reducing reliance on narcotics in shoulder arthroplasty (SA). Many surgeons report being unsure of how many narcotic pills to prescribe after the surgery. As result, patients are prescribed upwards of 60 oxycodone 5-mg pills for a 6-to-12-week treatment period despite studies showing postoperative pain can be managed without any medication at all.The purpose of this multicenter study was to prospectively determine the number of opiate pills required after SA to develop generalizable, evidence-based prescription guidelines for surgeons. We hypothesized that opioid prescription would be low using a multimodal approach to pain management.The study enrolled 63 patients undergoing SA. Subjects received either an interscalene nerve block with liposomal bupivacaine, standard bupivacaine, or a local infiltration standard bupivacaine field block based on preference. All subjects were provided with postoperative “Pain Journals” to document their daily pain on a Numerical Rating Scale and daily opioid consumption during the 14-day postoperative period.Overall, patients consumed an average of 8.6 oxycodone 5-mg pills  after SA. Seventy-nine percent of patients required 15 or fewer oxycodone 5-mg pills, and 27% successfully managed their postoperative pain with zero opioids. Average pain remained low for patients in all groups.With a multimodal approach, most patients undergoing SA can manage postoperative pain with 15 or fewer oxycodone 5-mg tablets, or 112.5 morphine milligram equivalents. The addition of a liposomal bupivacaine interscalene nerve block may further reduce the consumption of postoperative narcotics compared with a standard interscalene nerve block. This study provides evidence that may be used for surgeon guidelines in the effort to reduce opioid prescriptions after SA. Nearly 15% of opioid-naïve patients treated with opioids after shoulder surgery will continue to consume narcotics beyond 180 days, and more than 50% of patients receiving 90 days of continued opioid therapy are chronic users after 5 years.The purpose of this multicenter study was to prospectively determine the number of opiate pills required after SA to develop generalizable, evidence-based prescription guidelines for surgeons. We hypothesized that opioid prescription would be low using a multimodal approach to pain management.A prospective evaluation was performed of patients who underwent SA between November 2018 and March 2019 at 2 centers: Orthopaedic Neurosurgery and Specialists  or Southern Oregon Orthopaedics . Institutional review board approval was obtained before commencing the study . Eligible subjects were those undergoing primary anatomic TSA or reverse SA, minimum of 18 years of age, willingness to fill out the “pain journal,” ability to understand the informed-consent process and to document informed consent before completion of any study-related procedure, and ability to read, comprehend, and complete subject-reported outcome measures in English.Subjects were excluded for documented history of drug or alcohol abuse, use of narcotic painkillers for greater than 3 months before surgery, neurologic deficit or disability involving the surgical extremity, known allergy to amide anesthetics, known allergy or intolerance to hydrocodone or oxycodone, currently enrolled or planning to enroll in another clinical trial during this study that would affect the outcome of this study, and/or history of a cognitive or mental health status that would interfere with study participation.Ninety-seven SAs were performed during the study period and assessed for study eligibility. These procedures were completed by 3 fellowship-trained surgeons. Indications for surgery included degenerative joint disease, rotator cuff arthropathy, and proximal humeral fracture sequelae. Fourteen patients refused to participate, 8 were excluded for preoperative narcotic usage, and 3 were excluded for revision surgery. Thus, 72 patients were enrolled in the study. Nine patients did not turn in their pain journals, leaving 63 patients (87.5%) with complete follow-up.All patients received the same preoperative and postoperative oral multimodal protocol for pain management . PreoperIntraoperative analgesia was based on surgeon and patient preference after discussion of risk and benefits of an ultrasound-guided interscalene nerve block (ISNB). Subjects were administered either an ISNB with 25 mL of 0.5% bupivacaine with 10 mg of IV Decadron (SB), a solution containing 15 mL of 0.5% bupivacaine and 10 mL liposomal bupivacaine with 10 mg of IV Decadron (LB), or a local field block using a solution of 20 mL liposomal bupivacaine 13.3mg/ml with 20mL normal saline (FB). A total of 29 subjects were allocated to the LB condition, 24 subjects to the SB condition, and 10 to the FB condition based on patient and surgeon preferences.Subjects were provided with a postoperative pain journal to be filled out on the first 5 postoperative days (PODs) and on PODs 7 and 14 as a means to collect data on pain scores and narcotic consumption . At the Immediately after the surgery, NRS pain scores for POD 0 and any administered pain medication were recorded while the subject was fully alert in the postanesthesia care unit. Once discharged, the subject independently recorded his or her numerical pain-rating scale pain score and narcotic pill consumption every 8 hours for the remaining PODs. Subjects were called on PODs 1 and 5 to confirm adequate pain control and were reminded to complete the pain journal. Completed pain journals and the subjects’ remaining opioid medication were presented at the initial postoperative visit. Here, physicians collected the journals and counted the number of remaining narcotic pills, thus completing their involvement in the study.Data from each journal were organized into an Excel spreadsheet analyzed through calculations of means, standard deviations, and time-trend analysis. The NRS scores, recorded 3 times each day, were averaged to obtain a single daily score accounting for daily and nocturnal fluctuations in pain. Narcotic consumption was analyzed as a cumulative daily value in both MMEs and number of oxycodone 5-mg pills.Despite associated biases with observational data, Chi-squared tests were used to address the statistical significance of categorical comparisons between groups. One-way analysis of variance tests were performed to compare mean pain scores and narcotic consumption among the 3 groups . The alpha value was set at 0.05 for significance.P = .13) or pain (P = .052) between reverse SA and TSA.The mean patient age was 69 years; of 63 patients, 30 (48%) were men and 25 (39.7%) underwent reverse SA. There were no observed differences in opioid consumption  after SA. Average narcotic consumption was 1.1 pills (8.22 MMEs) per day . Of 63 pP < .001) (P < .001). Moreover, the LB group consumed significantly fewer narcotics (P < .0000001) and had less pain (P < .0000001) on average throughout the entire study period.Zero narcotics were needed in 55% of LB ISNB subjects vs. 4% and 0% in the SB and FB groups, respectively ( < .001) . In addi < .001)   with a multimodal approach to pain after SA, regardless of intraoperative analgesia. Patients maintained this low narcotic usage while maintaining an average pain rating of less than 2 NRS points. The use of LB may further improve on this recommendation, as only 2 subjects receiving an LB block required opioids before POD 2. However, further study is needed to more accurately compare the efficacy of LB ISNB to current anesthetic techniques.,,,,,Developing evidence-based guidelines to minimize opioid prescription presents an opportunity for orthopedic surgeons to address the continued abuse of opioid medication in the United States.Based on our findings, we recommend that 15 oxycodone 5 mg pills should be used as a guideline after SA. The present study’s recommendation contrasts with multidisciplinary consensus-based panel’s recommendations. The expert panel reported by Wyles et al,,,,The low usage of narcotics in the present study is likely owing to the multimodal approach outlined in The effect of LB usage after TSA has varied results. Patel et alPatient outcomes using SB vs. FB have been investigated in other studies, finding similar use in average narcotic consumption per day, cumulative NRS pain score, and average daily NRS pain score. Over the 14 PODs, 13.6 and 13.2 narcotic pills were taken for SB and FB trials respectively. The average daily NRS pain score for both groups was 2.4, and the cumulative NRS pain score was 19 for the SB block group and 18.9 for the FB block group. These findings align with those of Sicard et al, who demonstrated that the use of LIA is not less effective than interscalene nerve block for pain control after TSA. Sicard et al recorded no significant difference in the average pain score for the 48-hour postoperative period between both LIA and interscalene nerve block groups. However, it was noted that in the recovery room postoperation, the LIA group consumed less opioids and had significantly less severe pain; a finding which was not noted in this study.There are several limitations to the present study. First, patients were not blinded or randomized to the various "block"-type treatments. These conditions were instead allocated based on patient and surgeon preference. Nonrandom distribution is a major source of bias that reduces the present study’s ability to determine whether one group performed better than the others regarding postoperative pain and narcotic consumption. Nonnormal distributions and high variance between groups present further limits these comparisons. However, as a level III cohort study, the generalizable observational data provided in this study can be used toward creating overarching prescription guidelines for physician use. Irrespective of the anesthesia block given or lack thereof, patients can manage postoperative pain with 15 or fewer oxycodone 5-mg tablets after the shoulder surgery. Second, subjects were informed they were taking part in a trial on postoperative pain through the recruitment process. This introduces the potential for response bias  as well as a demand characteristic, whereby keeping an active record of their pain and narcotic consumption for the purposes of this study led subjects to subconsciously change their behavior. Third, we did not collect any data on pain or narcotic consumption between PODs 7 and 14. Minimal change was observed after day 3, yet it is possible that pain spikes were unintentionally omitted from the analysis. Finally, these findings are limited to patients not chronically taking narcotics. Patients were excluded if they took opioids within 3 months before the surgery. Therefore, the findings are not necessarily generalizable to a population with chronic opioid usage.With a multimodal approach, most patients undergoing SA can manage postoperative pain with 15 or fewer oxycodone 5-mg tablets, or 112.5 MMEs. The addition of a LB ISNB may further reduce the consumption of postoperative narcotics compared with a standard ISNB. This study provides evidence that may be used for surgeon guidelines in the effort to reduce opioid prescriptions after SA.Funding: No funding was disclosed by the author(s).Conflicts of interest: Patrick J Denard is consultant for and receives royalties from Arthrex and is a paid speaker for Pacira. Paul M Sethi is a paid consultant for Arthrex and paid speaker for Pacira. The other authors, their immediate family, and any research foundation with which they are affiliated did not receive any financial payments or other benefits from any commercial entity related to the subject of this article.


BackgroundThe increasing burden of musculoskeletal disorders combined with the high utilization of opiates and the relatively limited ability of traditional approaches to satisfactorily address many of these conditions has spurred an increased interest in alternative treatments such as regenerative medicine therapies. Evidence is growing to support the use of regenerative injection treatments, including prolotherapy, platelet-rich plasma (PRP), platelet lysate (PL), and mesenchymal stromal cells. This study aims to offer a proof of concept via a case series of patients with neck pain treated using a functional spinal unit (FSU) model with combination prolotherapy, PRP, and PL injections.MethodologyA chart review identified patients with neck pain treated with a combination of cervical injections using concentrated platelets and prolotherapy.ResultsA total of 14 patients met the inclusion criteria. The average decrease in the Numeric Pain Score was 2.8 (p = 0.002). The mean decrease in the Functional Rating Index was 27.3 (p = 0.004) at 24 months. Two patients had mild adverse reactions.ConclusionsThis case series demonstrates basic safety and clinically significant improvements in patients treated for neck pain with autologous concentrated platelet products and prolotherapy utilizing an FSU treatment protocol. Additional clinical studies are warranted with a larger patient sample size and longer follow-up periods. As people are living longer, musculoskeletal pathology has become the leading cause of disability worldwide, with back pain accountable as the leading driver of years lived with disability . Though Common causes of spine pain, both cervical and lumbar, include spondylosis, discogenic, facet-mediated, and myofascial pain ,8. The tThe increasing burden of musculoskeletal disorders combined with the relatively limited ability of traditional approaches, including treatment with opiates, to satisfactorily address painful conditions of the spine has spurred an increased interest in alternative treatments. One such category is regenerative injection treatment (RIT), defined as injections of proliferative solutions, growth factors, or cells intended to strengthen or repair injured or weak musculoskeletal and nervous structures . EvidencThe emergence of RITs has allowed for the traditional treatment philosophy for interventional pain management to expand beyond the “single pain generator” model to consider the entire osteoligamentous complex, known as the functional spinal unit (FSU) . In suchPatient selectionRegistry data collected at a single center were used to acquire outcomes data. Patients undergoing treatment at a private practice, outpatient-based interventional pain center were encouraged to enroll in a patient registry to track safety and outcomes data. All patients signed a written consent prior to participation, and the registry data protocol was approved by an Institutional Review Board (HHS OHRP #IRB00002637). The registry protocol included prospectively tracking patients’ outcomes using an electronic system, ClinCapture , that automatically generates pre- and post-treatment questionnaires based on the body area treated. After treatment, patients received surveys to self-report complications and outcomes at one, three, six, twelve, eighteen, twenty-four months, and annually through 20 years. Up to five attempts were made to contact patients at each time point before being considered lost to follow-up. Adverse events were documented by asking patients about any complications after receiving the treatment to elicit potentially related issues, which were reviewed, adjudicated by the treating physician, characterized, and indexed.Inclusion criteria for this study were as follows: patients with axial neck pain with or without radiculopathy treated via injections of PRP or PL to cervical facet joints with or without epidural overfill, cervical transforaminal epidural injections with PL, and cervical ligaments injections with combination prolotherapy with or without PL between August 2014 and March 2017. Only patients with available pre- and post-treatment outcome data to 24 months were included. Search criteria to identify patients within the registry included those with axial neck pain with or without radicular symptoms, cervical instability, foraminal or central stenosis, degenerative disc disease, and facet arthropathy, before a more extensive chart review was conducted confirming inclusion criteria.Processing of the Platelet ProductsIn preparation for the treatment, patients were instructed to cease the use of non-steroidal anti-inflammatory drugs and corticosteroids for the preceding two weeks so as not to interfere with platelet activity. Within 24 hours of the treatment procedure, patients underwent a heparinized venous blood draw of approximately 60 mL. The PL and PRP were hand-processed in a sterile ISO-5-class biologic safety cabinet, the details of which have been previously described ,31. In bInjection TechniqueUnder sterile conditions, all patients received percutaneous injections under multiplanar fluoroscopic guidance. Patients received a combination of cervical facet joint injections with or without epidural overfill, cervical ligament injections, and/or transforaminal epidural injections Figure . SpecifiOutcome measuresNeck pain treatment outcomes were measured by several patient-reported questionnaires, including the Numeric Pain Score (NPS), Functional Rating Index (FRI), and a modified Single Assessment Numeric Evaluation (SANE) -34. The Statistical analysisContinuous variables were described using the mean and standard deviation (SD). Individual differences between post-treatment time points and baseline (termed “change scores”) were calculated for NPS and FRI metrics, and the percentages of patients who met or exceeded the MCID for each metric were calculated. Wilcoxon signed-rank tests were used to assess whether post-treatment scores differed significantly from baseline. P-values below 0.05 were considered significant. All analyses were performed using R version 3.5.1 and RStudio version 1.1.456.A total of 14 patients were isolated for the case series who met the inclusion criteria. See Figure Raw outcome scores are shown in Table As has been previously described in the literature, the etiology of neck pain is multifactorial with a constellation of structural, chemical, and neurological factors likely to blame ,19,36-38The case series described here supports the use of autologous platelet-based injections performed under image guidance for the safe and effective treatment of axial neck pain with or without radiculopathy. Because the FSU treatment paradigm was used, the number of and specific levels treated varied based on patient-specific pathology. The injection sites were determined by clinical history, physical examination, and MRI studies. The case series demonstrates clinically significant improvements in pain and functional outcomes in patients undergoing cervical spine injections with concentrated platelets at the 24-month post-injection follow-up. When looking individually at the included patients, 12 patients improved in each category. Though the aggregate data show an overall significant improvement, two patients reported experiencing increased pain and a decrease in function on the FRI at 24 months. There are no clear factors unique to the two patients with poor outcomes and further research is needed to better clarify the predictors of positive responders. Regarding safety, two patients reported minor, self-resolving adverse events.There are several limitations to this study. First, the data were collected via a registry with a relatively small sample size and without a control group for comparison. In addition, only 14 of the many patients treated met the criteria of 24-month follow-up data. Lack of full two-year outcomes data could be due to various reasons, including those lost to follow-up, surgical intervention, steroid injection(s), registry withdrawal request, or a new injury that confounded treatment outcomes, such as an automobile accident. Second, though the principles of treatment remained consistent among patients, there was a lack of standardization of PRP and PL concentrations. Some patients also underwent more than one treatment. Furthermore, at the time of this writing, RITs are not reimbursed by insurance in the United States. Therefore, there is often an out-of-pocket cost and monetary investment by the patient that could in theory lead to biased outcomes and increased motivation to perceive improvement. Demographics are also relatively self-selecting for this same reason. Previous public health analyses in the United States have shown a positive correlation between increasing wealth and better health . The majOur cases series compliments early data demonstrating clinical efficacy with injecting multiple components of the FSU with RITs in the treatment of painful spine disorders. PRP is a safe injectate that shows promise for effective treatment of axial neck pain when utilized in a thoughtful manner targeting ligamentous laxity, intraarticular facet arthritis, and nerve root irritation. Though this early data is encouraging, more comprehensive, randomized controlled trials including a larger number of patients are needed to further validate these findings. Given the significant impact of neck pain on quality of life for an aging population, an overreliance on opioid medications for the management of chronic musculoskeletal pain by providers, and the significant societal costs, both directly and indirectly, a more comprehensive treatment approach from a biomechanical perspective that offers the possibility of disease modification rather than symptom management is needed. This study further underscores the importance of continued research in this area to prove efficacy and help shape medical policy such that more patients have access to care that may prove to be, in the end, safer and more effective than that offered in our current treatment model.


Introduction: Overprescribing by providers is a leading contributor to the opioid crisis. Despite available information regarding the role that physician prescribing plays in the community availability of opioids, guidelines for the management of acute pain remain sparse. This project aims to evaluate opioid prescribing, opioid usage patterns, and postoperative pain control in patients undergoing isolated mid-urethral sling (MUS) placement.Methods: Patients who underwent isolated MUS placement from March 19, 2019 through March 19, 2020 were contacted by telephone in May 2020 and asked a series of questions examining opioid usage, postoperative pain, what they did with unused opioids, and whether they had received education on disposal techniques. A chart review was utilized to determine the amount of opioid prescribed, the presence of any operative complications, and medical and demographic characteristics of subjects.Results: A total of 53 subjects met inclusion criteria, of which 31 participated in a phone interview. Of the 53 subjects, 54.7% received a postoperative opioid prescription, and all but two of these subjects filled their prescription. Of the interviewed subjects, only 66.6% who filled a prescription reported using opioids Fifty percent (n=6) of patients that required oxycodone reported use of four tablets ) or less and used for 1-2 days postoperatively. No patient reported using opioids beyond five days. Only 22.2% reported receiving instruction on opioid disposal, and 16.7% returned unused opioids to a disposal center. 87.1% of subjects rated postoperative pain as “better” or “much better” than expected.Conclusion: Patients undergoing isolated MUS placement require limited amounts of postoperative opioids, if any are needed at all, to achieve satisfactory pain control. Excess prescribed opioids, along with inadequate patient education on proper disposal techniques, may contribute towards opioids that are at risk of diversion for nonmedical use. Opioid misuse continues to be a crisis in the United States. From the years 2007 through 2015, the number of opioid-related deaths tripled . This scPrevious studies have analyzed optimal opioid prescribing following surgery across many specialties -19. WithThe findings of this research were presented at the Society for Gynecologic Surgeons (SGS) 47th Annual Scientific Meeting in Palm Springs, CA June 27-30, 2021.This retrospective cohort study was approved by the Pennsylvania State University College of Medicine Institutional Review Board STUDY 00014899). Enterprise Information Management (EIM) was utilized to identify patients who underwent retropubic MUS placement at two Mid-Atlantic tertiary care hospitals within our academic institution’s Female Pelvic Medicine and Reconstructive Surgery Division, consisting of three Urogynecologists, between March 19, 2019 and March 19, 2020. The year prior to the study’s inception was chosen in an effort to limit time from surgery to telephone survey and therefore limit recall bias. Patient charts were queried for the Current Procedural Terminology (CPT) Code corresponding to a sling operation for stress incontinence (57288) and confirmed to have undergone the surgery of interest. Patients were excluded from the study cohort if they underwent any concomitant surgical procedures other than cystoscopy; sustained a significant intraoperative complication which required additional surgery, or had readmission to the hospital for a surgical complication. Patients were surveyed via a telephone interview between May 5, 2020 and May 28, 2020 regarding pain control, opioid use, and opioid disposal techniques immediately following their procedure , and marital status. Health histories obtained included parity, mental health disorders, chronic pain disorders, history of sexual/physical abuse, diabetes mellitus, prior gynecologic surgeries, and substance history; absence of positive documentation was considered a negative finding. Information pertaining to MUS placement, such as the date of surgery, surgeon, ASA class, estimated blood lost, total operating room (OR) time, resident/fellow involvement, complications, hospital length-of-stay, readmission, voiding trial status, and whether subjects were discharged with a catheter was also obtained. The online Pennsylvania Prescription Drug Monitoring Program (PDMP) was utilized to determine if opioid prescriptions were filled by patients post-procedure. The amount of opioids filled after discharge was converted to oral morphine milligram equivalents (MMEs). Opioids utilized in the hospital prior to discharge were excluded from the analysis.All subjects were contacted by phone by three researchers. A total of three attempted contacts were made for each subject. A telephone message was not left due to lack of universal voicemail box. For those subjects who were consented to participate in the survey, opioid use was quantified by the total number of opioid tablets used and the number of days that opioids were utilized based on patient knowledge or pill count if opioids remained in the home. Subjects were asked to rate the number of opioid tablets prescribed on a scale of one to five; one representing “far too few” and five representing “far more” opioids. Pain was assessed by an 11-point Likert scale, both on average and at its worst postoperatively. Subjects also rated their overall postoperative pain control on a scale of one to five, with one representing “much worse than expected” and five representing “much better than expected.” Pain management strategies were assessed by asking if subjects used additional acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), heat, ice, pressure, or other forms of pain relief. Lastly, subjects were asked what they did with leftover opioid tablets and if they were instructed on appropriate disposal techniques. We utilized the Research Electronic Data Capture  application to store all study data . Descriptive analyses were performed with continuous data summarized as mean ± standard deviation and categorical data as frequency and percent. Fisher’s exact tests were used to examine the association between binary variables. All analyses were performed using SAS software, version 9.4  with p <0.05 deemed statistically significant. EIM records indicated 149 MUS during study dates. A total of 53 subjects met inclusion criteria; subjects that did not meet criteria were due to concomitant procedures. Of these 53 subjects, 31 participated in the telephone survey Figure . DemograAmong the 53 total subjects, chart data revealed that 29 (54.7%) were provided a prescription for postoperative opioids from their primary surgeon based upon shared-decision making with patients and surgeons' professional judgment. All patients received standardized pre-operative counseling on pain control. All but two of these subjects filled their prescription according to the Pennsylvania PDMP search. PDMP reliably tracked opioid prescription filling as our cohort was represented entirely by Pennsylvania residents. Additionally, one subject was a long-term opioid user secondary to chronic pain and filled a prescription obtained from her pain management specialist. Across the 53 subjects, the mean MME filled was 39.4 ± 43.4 MME. For reference, five 5-milligram oxycodone tablets is 37.5 MME. The maximum filled was 150 MME .Among the 31 subjects who completed our telephone interview, 18 (58.1%) filled a prescription according to the PDMP search. Notably, only 12 of the 18 subjects (66.7%) who filled a prescription reported taking opioids following their surgery. Of the 12 subjects who reported using opioids, 11 were prescribed oxycodone and one was prescribed hydrocodone. Six subjects reported using four or less 5-mg oxycodone tablets in total, three subjects reported using five, eight and 10 oxycodone tablets, respectively, and the remaining three subjects were unsure of how many opioids they used. Six subjects reported using opioids for only one or two days after surgery; the maximum number of days reported was five. No subjects who used postoperative opioids felt they were prescribed too few opioids; seven (58.3%) felt they were given an adequate amount, while five (41.7%) rated the amount they were given as “more tablets than needed” or “far more tablets than needed.”On the 11 point Likert pain scale, the mean overall postoperative pain ‘on average’ reported was 3.6 ± 2.4. The mean postoperative pain ‘at its worst’ was 5.5 ± 3.0. Eighteen subjects (58.1%) rated pain much better than expected, nine subjects (29.0%) rated pain better than expected, and four subjects (12.9%) reported pain same/worse/much worse than expected. Use of acetaminophen and/or NSAIDs was reported by 22 subjects (71.0%).Postoperative pain scores dichotomized as high (>four) versus low (≤four) were associated with opioid use. Four was chosen as the cutoff point due to the average postoperative pain score being 3.6. Eight subjects (66.7%) who used opioids reported high (>four) postoperative pain ‘on average’, compared to three subjects (16.7%) who did not use opioids (p=0.01). Similarly, 11 (91.7%) opioid users reported high (>four) postoperative pain ‘at its worst’, compared to five (27.8%) who did not use opioids (p<.001). Neither postoperative opioid use nor high (>four) pain scores were associated with the use of acetaminophen/NSAIDS. Opioid use was not associated with a medical history of depression and/or anxiety.Of the subjects who received opioids, eight (44.4%) reported keeping leftover tablets at home, five (27.8%) reported discarding in the toilet or trash, and three (16.7%) returned their excess opioid to a disposal center. One subject used her entire prescription and one subject was uncertain what she did with her leftover opioids. Only four subjects (22.2%) confirmed receiving instruction on disposal techniques.Our investigation reveals that for most patients undergoing isolated MUS, a limited amount of post-discharge opioid is utilized to achieve satisfactory pain control, and our desire to balance adequate pain control with opioid stewardship more often favors excess opioid dispensation. Among telephone responders, just 12 of 31 subjects reported using opioids following surgery; of these 12, half reported using four 5-milligram oxycodone tablets (30 MME) or less. Postoperative opioids were utilized for five or fewer days after surgery, and half of all users utilized opioids for only two days or less. Despite the low usage of opioids, satisfaction with pain control remained high.Though there is little existing data on opioid use following isolated MUS procedures, our results are consistent with previous literature examining opioid use both within the broader pelvic reconstructive surgery sphere as well as with isolated midurethral sling. We believe our study represents one of the largest retrospective samples of patients who underwent an isolated MUS procedure for which postoperative opioid prescribing, use and satisfaction was analyzed. A recent study examined, among other procedures, postoperative opioid prescribing and usage among 12 patients who underwent MUS placement, with or without anterior and posterior repair . These sSeveral strategies can help to limit the amount of excess opioid prescribed by encouraging safer prescribing practices through the use of technology. PDMPs allow clinicians to determine the amount of controlled substances obtained by a patient prior to prescribing opioids. Additionally, the use of electronic prescribing modalities can allow clinicians to tailor the number of opioids prescribed to the amount needed. In 2019, the state of Pennsylvania enacted a law requiring that all controlled substances are electronically prescribed. This mandate allows providers to remotely prescribe postoperative opioids after discharge, if needed, thus allowing for more limited amounts of opioid to be prescribed at discharge.Beyond careful prescribing practices of opioids, clinicians serve a role in reducing the number of excess or unused opioids among their patients through education. Less than 10% of our patients reported disposing of opioids in a safe manner to opioid disposal centers -28. ReasQuestions remain regarding how best to implement strategies aimed at balancing postoperative pain needs against the risk of excessive opioid prescribing. Among MUS patients, future studies of educational interventions, including proper disposal techniques, non-opioid pain control methods, and responsible prescribing practices for clinicians, will inform strategies to minimize excess opioids associated with MUS procedures. Prospective evaluation of optimal surgeon prescribing practices as well as specific patient and surgical factors impacting opioid use will continue to promote personalized medicine for our female pelvic medicine and reconstructive surgery (FPMRS) patients.Our study has limitations that must be considered. First, although our study represents one of the largest published cohort of subjects evaluated for postoperative opioid prescribing and usage following isolated MUS, our sample size is still limited, at 53 total subjects and 31 interviewed subjects. We therefore may lack the statistical power to detect subtle differences in patient characteristics which could illuminate which patients are more or less likely to need opioids in the postoperative period. Second, because our study was a retrospective review with a telephone interview, recall bias could affect the reported numbers of opioids used, how the opioids were disposed of, and overall pain levels. Patients with surgeries that took place a year before data collection are likely at a higher risk of recall bias than patients that underwent surgery following a smaller time interval. We attempted to mitigate this weakness by limiting the cohort to procedures that occurred within one year prior to study inception and utilizing the Pennsylvania PDMP to verify opioid prescription fill and refill. Third, the study was limited by geographical area: subjects had their MUS procedure at one of two hospitals in the same health system located in central Pennsylvania. Thus, our results may not be generalizable to other patient populations in other regions. Finally, there is a potential for non-responder bias. For those patients we could not contact for telephone interview, their overall pain satisfaction or number of prescribed opioids used could be different than those who responded to our telephone inquiries.In addition to our utilization of the Pennsylvania PDMP to verify opioid prescription and refill rates, additional strengths include the straightforward methodology utilized. By focusing on patients undergoing MUS alone, our study may allow for direct applicability of our findings to practitioners of this patient population.Our data supports that patients undergoing isolated MUS placements require limited amounts of postoperative opioids, if any are required at all, to achieve satisfactory postoperative pain control. Excessive postoperative opioid prescribing and inadequate education regarding proper disposal techniques remain opportunities for improvement in our patient care. We recommend that no opioid be prescribed following an isolated MUS unless the patient's needs or preference dictate otherwise. If needed, no more than five 5 mg oxycodone pills should be prescribed. The use of shared decision-making and personalized risk factors for pain may help surgeons balance adequate pain control with the risks of excess opioid prescribing. Future studies are warranted to examine how to best address these issues following MUS placement.