This randomized clinical trial compares the effectiveness of a strong opioid (oxycodone hydrochloride) vs a mild opioid (acetaminophen codeine combination) when taken postdischarge for subacute pain among patients who underwent orthopedic surgical treatment for fracture. Does a strong opioid (oxycodone hydrochloride 5 mg or 10 mg 4 times daily) provide better analgesia than a mild opioid (acetaminophen codeine combination 500 mg and 8 mg or 1000 mg and 16 mg 4 times daily) when taken postdischarge among patients who underwent orthopedic surgical treatment?In this randomized clinical trial of 120 patients with 1 or more acute orthopedic fractures requiring surgical fixation, the mean of daily mean pain scores from day 1 to 7 postdischarge was 4.04 in the strong opioid group and 4.54 in the mild opioid group. The between-group difference was neither statistically nor clinically significant despite a 6-fold higher dose of opioid being delivered in the strong opioid group.This study found that oxycodone did not provide superior pain relief compared with combination acetaminophen and codeine during the first 7 days of treatment despite a 6-fold higher dose of opioid being delivered in the strong opioid group. Patients with a surgically managed fracture are commonly discharged from the hospital with a strong opioid prescription, but limited evidence exists to support this practice.To test the hypothesis that strong opioids provide greater analgesia than mild opioids over the first week postdischarge from hospital after fracture surgical treatment.This double-blind, superiority, randomized clinical trial was conducted at a single-center, major trauma hospital in Sydney, Australia. Participants were inpatients who had sustained an acute nonpathological facture of a long bone or the pelvis, patella, calcaneus, or talus who were treated with surgical fixation and enrolled from July 27, 2016, to August 22, 2017. Data were analyzed from June through October 2018.Initiation at discharge of oxycodone hydrochloride 5 mg of 10 mg  or combination acetaminophen and codeine 500 mg and 8 mg or 1000 mg and 16 mg  4 times daily for a maximum duration of 3 weeks.The primary outcome was the mean of daily pain scores collected during week 1 of treatment measured using the Numerical Pain Rating Scale (NRS). Participants were asked to rate their mean pain over the previous 24 hours daily using an NRS score from 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable. The key secondary outcomes were EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) responses, worst pain, medication adverse events, global perceived effect, and return to work.P = .11) despite a 6-fold increased dose of opioids being delivered in the strong opioid group.A total of 120 patients with 1 or more acute orthopedic fractures requiring surgical fixation were randomized, including 59 patients in the strong-opioid group  and 61 patients in the mild opioid group . From days 1 to 7 postdischarge, the mean daily NRS mean pain score was 4.04  in the strong opioid group and 4.54  in the mild opioid group. The between-group difference of the primary outcome was not statistically significant (−0.50 ; This study found that treatment with strong opioid medication subacutely was not superior to treatment with milder medication for treatment of pain among patients with surgically managed orthopedic fractures. These findings suggest that ongoing first-line strong opioid use after discharge from the hospital should not be supported.ACTRN12616000941460Australia New Zealand Clinical Trial Registry No.:  However, the evidence does not support using opioid therapy for chronic noncancer pain.4 The prescribing of opioids for chronic pain has increased despite evidence of the association of their long-term use with adverse outcomes.7While there is little debate over the short-term use of opioids, their use longer term is controversial, with increasing reluctance among some physicians to prescribe these medications.8 The most powerful opioid analgesics are also the most liable to be associated with abuse and addiction.9 With global attention on increased opioid prescription and the opioid abuse epidemic, reconsideration and reexamination of opioid pain management are being undertaken.Opioids have been used for centuries and are the most potent analgesic agents.10 Severe postoperative pain is common after orthopedic surgical treatment, and safe and effective management of this pain can be challenging for everyone on the health care team.11 Adequate relief of pain is a measure of patient satisfaction and may be associated with decreased chronic postsurgical pain; however, taking opioids for acute pain is associated with increased likelihood of long-term opioid use.12 Furthermore, increased initial opioid exposure  is associated with increased risks of long-term use, misuse, and overdose,14 suggesting that strong opioid prescription following discharge from the hospital should be considered carefully. Many choices are available for postoperative pain, but evidence to inform clinical choice after discharge in the subacute setting is sparse. However, patients with surgically managed fractures are commonly  discharged home from the hospital with a strong opioid prescription.15Orthopedic surgeons are among the top prescribers of opioid analgesics.16 With this in mind, we undertook a superiority trial to determine if a strong opioid (as per current practice) provided better analgesia than a mild opioid (a combination acetaminophen and low dose codeine) when taken postdischarge among patients who received orthopedic surgical treatment.In the interest of minimizing the potential problems associated with long-term opioid use, we propose that discharge from the hospital signifies the most suitable time to transition people down the World Health Organization (WHO) analgesic ladder from step 3 (strong opioid) to step 2 (mild opioid) analgesics if strong opioids are not shown to be superior.CONSORT) reporting guideline recommendations for randomized clinical trials.This study is a double-blind, randomized clinical trial comparing oxycodone hydrochloride (strong opioid) vs combination acetaminophen and codeine (mild opioid) for the treatment of postdischarge pain after orthopedic fracture surgical treatment. This study and protocol  was apprParticipants were patients admitted to 1 major trauma hospital in Sydney, Australia, with at least 1 acute fracture requiring surgical treatment from July 2016 to August 2017. The research team obtained relevant medical history to assess the patient against the eligibility criteria. Eligible participants were required to have sustained a nonpathological fracture of a long bone  or the pelvis, patella, calcaneus, or talus treated with surgical fixation; be age 18 years or older; and be able to comprehend the study protocol, written in English. Patients were excluded if they had known or suspected multisystem trauma injuries ; known or suspected major infection after surgical treatment; known or suspected opioid dependency; or contraindications to study treatment or were pregnant or breastfeeding.A researcher not involved in participant recruitment or data collection generated a randomization schedule a priori using a computer-derived random number sequence. Study medication in the groups was identically overencapsulated and prepared according to the randomization schedule  and sealed in medication-blinded blister packages. Upon the participant’s discharge from the hospital, the pharmacy dispensed a sealed medication package  to the participant. Once the package was opened, the participant was randomized to 1 of 2 groups (at a 1:1 ratio). The identical overencapsulated study packages ensured concealed allocation. Researchers, participants, and outcome assessors (DEJ and IAH) were blinded. To assess blinding integrity, the participants were asked to guess treatment allocation at the end of the study treatment period. Statistical analysis and preparation of the manuscript results and discussion  were performed prior to unblinding.Before study enrollment, participants were administered oral oxycodone during their hospital admission and any other standardized hospital care. Members of the strong opioid group were prescribed oxycodone hydrochloride immediate release at 5 mg or 10 mg  4 times per day. Members of the mild opioid group were prescribed acetaminophen and codeine at 500 mg and 8 mg or 1000 mg and 16 mg  4 times per day. The maximum allowed daily dose  was supplied for 2 weeks (14 days). Study medication was titrated down to cessation during the third and final treatment week (days 15-21). Oxycodone monotherapy was selected to reflect standard therapy, while combination oxycodone and acetaminophen is not locally available. Combination codeine and acetaminophen was chosen as the comparator given that it was the lowest opioid dose available. If the participant considered pain well controlled during days 1 to 14, decreased dosing or cessation was allowed. Participants experiencing uncontrolled pain were discontinued from the study.Data collection was conducted by researchers in person at baseline and via telephone at days 3, 7, 14, and 21 postdischarge. Participants recorded mean pain, worst pain, and adverse effects daily for 3 weeks or until study completion, with a minimum of days 1 through 7 collected, using a diary , which ranges from 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable. The primary outcome was collected daily, with participants asked to rate their mean pain over the previous 24 hours. The mean of the daily mean pain scores collected from day 1 to 7 postdischarge was calculated. The primary outcome was compared as between-group difference in daily pain during week 1 of treatment .17 Worst pain was measured daily using the NRS. Participants were asked to rate their worst pain over the previous 24 hours on a scale of 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable. Medication adverse events were measured daily and recorded in the diary using a list of common adverse effects experienced, with participants asked to answer yes or no for each outcome (eAppendix in EuroQol 5-Dimension 5-Level Questionnaire (EQ-5D-5L) answers were collected at day 3 postdischarge and weeks 1, 2, and 3 postdischarge to assess health-related quality of life (HRQL). The EQ-5D-5L descriptive system is a preference-based HRQL measure with 1 question for 5 dimensions, including mobility, self-care, usual activities, pain and discomfort, and anxiety and depression.Descriptive data were collected on study entry during hospital admission. These data included age, sex, employment status, diagnoses, type of surgical treatment, mechanism of injury, insurance status, pain, and quality of life.The primary comparison was the difference between the means of the daily mean pain scores over the first 7 days, measured on an 11-point NRS. Because group was a patient-level factor, sample size was estimated on this level. A sample of 46 participants per group  will provide more than 90% power to show at least a 1.0-unit  advantage of oxycodone over acetaminophen and codeine assuming an SD of 1.5 between patients and a 1-sided type 1 error rate of 5%. A sample of 120 participants was randomized to allow for a loss to follow-up of 20%.t test, and Fisher exact test were used, as appropriate. A generalized estimating equation with cumulative logit link was used to analyze EQ-5D-5L outcomes at days 3 and 7, clustered by patient with days , treatment group, and interaction days and treatment group as independent variables. The sample size was 1-sided, although there is no mechanism to allow for 1-sided P values in a multilevel model. For all analyses, a P value < .05 was considered statistically significant. The data analysis for this paper was generated using SAS Enterprise Guide statistical software version 7.15 (SAS Institute). Data were analyzed from June through October 2018.The distributions of characteristics of patients included in the study were described for the treatment groups. Significance testing to compare baseline covariates was not used. Data were analyzed by a statistician (JD) who was blinded. All analyses were intention-to-treat analyses (including outcomes for participants who discontinued the study drug). We conducted 3 additional per-protocol analyses of the primary outcome to compare participants who discontinued the study drug during day 1 to 7 for various reasons. Analysis 1 excluded participants who never commenced the allocated medication. Analysis 2 excluded participants who never commenced the allocated medication and those who discontinued the medication owing to adverse effects. Analysis 3 excluded participants who discontinued for any reason. Missing data did not meet the predetermined threshold for imputation. We had no missing data from baseline to primary end point (up to day 7). The primary analysis was a multilevel model using a random slope model with maximum likelihood estimation comparing the mean of daily mean pain scores between treatment groups while accounting for repeated measures over time by patients. The model included days and treatment groups as independent variables. The secondary outcomes were analyzed using similar multilevel models; student During a 13-month period , 899 patients were screened for participation. Of these, 161 individuals were eligible and 134 individuals provided written consent. A total of 120 patients were randomized at a 1:1 ratio, including 59 patients in the strong-opioid group  and 61 patients in the mild opioid group  . PatientP = .11). The per-protocol analyses supported the intention-to-treat primary analysis  of daily NRS mean pain scores was 0.69. The mean of daily NRS mean pain scores was 4.04  in the strong opioid group and 4.54  in the mild opioid group. The difference between groups in the mean daily mean pain during days 1 to 7 after discharge from the hospital  was not statistically significant  or days 1 to 21 . The morphine equivalent of the mean opioid use during day 1 to day 7 in the strong opioid group was 32.9 mg of oral morphine daily , while the morphine equivalent of the mean opioid use in the mild opioid group was 5.5 mg of oral morphine daily .18 No secondary outcome measures, including patient-reported outcomes  correctly thought that they were taking oxycodone, 18 patients (30.5%) incorrectly thought that they were taking acetaminophen and codeine, and 33 patients (56.0%) would not guess an assignment. For participants assigned to combination acetaminophen and codeine, 21 patients (34.5%) correctly thought that they were taking combination acetaminophen and codeine, 16 patients (26.2%) incorrectly thought that they were taking oxycodone, and 24 patients (39.3%) could not guess an assignment.20 The 95% CIs of the primary intention-to-treat analysis included the prespecified conservative MCID selected, so the possibility of a clinically important difference (at 1.0 unit) cannot be excluded. However, the findings support the inference that there is no clinically important benefit to strong opioids vs mild opioids. The results further suggest that a mild opioid combination of acetaminophen and codeine may represent a viable alternative to the standard practice of prescribing a strong opioid analgesic for the treatment of surgically managed orthopedic fractures upon discharge.Among patients discharged home following orthopedic surgical fixation for 1 or more acute traumatic bone fractures in this randomized clinical trial, oxycodone did not provide superior pain relief compared with combination acetaminophen and codeine during the first 7 days of treatment, despite a 6-fold higher dose of opioids being delivered in the strong opioid group. This study additionally found that oxycodone did not provide superior pain relief compared with combination acetaminophen and codeine over 3 weeks of treatment. The largest difference in mean NRS pain score between treatments (0.5) was not statistically significant and was less than 0.9 to 1.9, which is a commonly reported range to define the minimal clinically important difference (MCID) in pain.21 There is evidence that strong opioids do not provide superior pain relief to nonopioid or mild opioid alternatives within similar acute settings, but most studies providing this evidence are single-dose trials or of short duration.30 There is substantial evidence and acceptance that strong opioid use is not justified longer term in the treatment of chronic noncancer pain.32 Furthermore, a greater amount of initial opioid exposure  is associated with increased risks of long-term use, misuse, and overdose.14 Considering the concern pertaining to opioid harms, dose reduction after acute hospitalization and after surgical treatment is a priority.Strong opioids are commonly prescribed at discharge after orthopedic fracture management.16 Depending on the intensity of pain, nonopioids  are prescribed first and then mild opioids  as necessary, followed by strong opioids . For individuals sustaining orthopedic fractures, initiation of strong opioids on admission is common. The findings of our study coupled with the existing literature suggest that a reduction down the WHO pain ladder from strong opioids to mild opioids upon discharge, rather than continuing strong opioids, should be supported. This change in prescribing habit could potentially help mitigate the harms from ongoing opioid use by decreasing the number of individuals initially exposed to opioids in the community and the subsequent risk of future addiction. In addition, this study challenges the concept of categorizing pain analgesics in general, at least in terms of their analgesic effects, given that single-dose trials of nonopioids, mild opioids, and strong opioids can provide similar analgesic effects in a variety of clinical settings.33 These findings suggest that current community perceptions and attitudes according to which strong opioids are considered the most effective and most appropriate approach in the management of subacute pain should be rethought.The concept of nonopioid and opioid dichotomy  providing varying levels of effectiveness is evident in the WHO pain ladder that has guided clinicians in the treatment of cancer since 1986 and noncancer pain at a later date.18) over the first week of treatment, group allocation was random, the loss to follow-up was minimal, analgesic consumption was closely monitored, and blinding was considered successful, given that most participants were unable to guess allocation. The study followed a pragmatic design, reflecting current prescribing habits, and limited the primary end point to the first week postdischarge assuming that many patients would recover and not require ongoing treatment after this point. This assumption was correct, with almost 31% of patients not requiring study treatment beyond day 7.This study’s findings should be considered in light of its strengths and weaknesses. The study was adequately powered to detect a conservatively selected MCID  after day 7, adding potential bias for findings from days 8 to 21. Additionally, we acknowledge that while we determined that strong opioids were not superior to mild opioids for pain relief, we could not determine if mild opioids were inferior. However, a larger sample size may have clarified whether adverse effects were increased in the strong opioid group, and if they were increased, establishing noninferiority may not be important.This study found that treatment with strong opioids was not superior to treatment with a milder opioid medication for postdischarge treatment of subacute pain among patients with surgically managed orthopedic fractures. These findings suggest that ongoing strong opioid use after discharge from the hospital should not be supported.


Spine is a frequent site of bone metastases, with a 8.5 months median survival time after diagnosis. In most cases treatment is only palliative. Several advanced techniques can ensure a better Quality of Life (QoL) and increase life expectancy. Radiofrequency ablation (RFA) uses alternating current to produce local heating and necrosis of the spinal lesion, preserving the healthy bone. RFA is supported by vertebral reinforcement through kyphoplasty and vertebroplasty in order to stabilize the fracture with polymethylmethacrylate (PMMA) injection, restoring vertebral body height and reducing the weakness of healthy bone. The aim of this study is to demonstrate the efficacy and advantages of RFA plus vertebral reinforcement through PMMA vertebroplasty and fixation in patients affected by bone spinal metastases. We retrospectively analyzed 54 patients with thoraco-lumbar metastatic vertebral fractures admitted to our Unit between January 2014 and June 2020. Each patient underwent RFA followed by PMMA vertebroplasty and transpedicle fixation. We evaluated pain relief through the Visual Analogue Scale (VAS) Score and PMMA vertebral filling based on the mean Saliou filling score. Analysis of variance (ANOVA) was used to test pain relief with statistical significance for p<0.05. A total of 54 patients , with a total of 63 infiltrated vertebrae, were treated with RFA, PMMA vertebroplasty and transpedicular screw fixation; average operative time was 60.4 min (range 51–72). The preoperative average VAS score decreased significantly from 7.81 to 2.50 (p < 0.05) after 12 months. Based on Saliou filling score, filling was satisfactory (12–18) in 20 vertebrae , mediocre (6–11) in 33 vertebrae , inadequate (0–5) in 10 vertebrae . A consistent PMMA filling of vertebral bodies was successfully achieved with significant pain relief. Concomitant RFA, PMMA vertebroplasty and pedicle screw fixation represent a safe and effective technique for the management of spinal metastases, improving clinical outcome and pain control. Spine is a frequent site of bone metastases. The high vascularity related to the Batson’s venous plexus and arterial spreads may contribute to metastatic localization , 2. In URadiofrequency ablation (RFA) uses alternating current to produce local heating and necrosis of the spinal lesion, while preserving the healthy bone. In 1931, RFA was used for the first time by Krischner to treat trigeminal neuralgia through thermocoagulation of gasserian ganglion. In late 1950s, Cosman and Aronow fine-tuned the first radiofrequency machine. Finally, RFA has been used by Rosenthal since 1992 as palliative treatment of bone metastases –11.In several cases of metastatic lesion, pain can be caused by a combination of fractures and related vertebral instability, periosteal involvement, and pro-inflammatory cytokines, and pain relief is probably achieved by reduction of osteoclast activity and destruction of periosteal nerve endings , 12–15.Percutaneous techniques, such as vertebroplasty, kyphoplasty and RFA achieve a key role in management of vertebral metastatic lesions –20.This technique has been already performed to treat colon cancer, liver, and kidney tumors. However, vertebral RFA alone may increase the risk of fracture since it can weaken healthy bone. For this reason, this technique is usually supported by vertebral reinforcement through kyphoplasty and vertebroplasty, in order to stabilize the fracture with injection of bone cement , thus restoring vertebral height , 21–23. From January 2014 to June 2020, a total of 54 patients  affected by thoraco-lumbar vertebral body metastases were admitted to the Department of Neurosurgery, BIND, University of Palermo  and they were retrospectively analyzed. All the patients underwent RFA plus vertebral body reinforcement for the treatment of vertebral metastases. In addition, pedicle screw fixation of the adjacent vertebrae was performed to restore stability.Inclusion criteria were: Karnofsky score >= 60, unremitting thoraco-lumbar pain (VAS score >=5), osteolytic lesion on neuroimaging, unresecable tumors (according to Tokuhashi score), intractable pain with chemotherapy, radiation therapy and refractory to analgesic drugs. Exclusion criteria were: Karnofsky score <60, mild thoraco-lumbar pain (VAS <5), osteoblastic tumors on neuroimaging, general contraindications for surgery , intradural and intramedullary tumors and neurological impairments caused by spinal metastasis itself. Patients’ demographics and relative comorbidities are summarized in via a transpedicular approach, in order to avoid vascular injuries. The ablation zone has 3: 2 length-to-width aspect ratio, with a maximum ablated zone of 3 cm × 2 cm when the proximal thermocouple reaches 50 degrees Celsius. This system has been used to treat pedicles and anterior/posterior vertebral bodies metastasis especially thanks to the STAR probe that can be curved to reach different vertebral portions through the same entry point. The MetaSTAR generator continuously displays the temperature from the two thermocouples, in order to allow real-time monitoring of the peripheral edge of the ablation zone. After RFA, cement reinforcement  was performed in all cases through the same working cannula. The entire procedure was performed under fluoroscopic guidance to evaluate cement distribution and screw trajectories.Before the procedure, written informed consent was obtained from all patients. Each patient underwent radiofrequency ablation followed by PMMA vertebroplasty and subsequent open or percutaneous transpedicle screw fixation with or without posterior decompression during the same surgical procedure. RFA was performed with the STAR Tumor Ablation System . The SpineSTAR is an articulated navigational bipolar radiofrequency electrode containing a pair of thermocouples positioned along the length of the electrode, 10 and 15 mm from the center of the ablation zone. This area is reached In the first post-operative day, each patient performed a thin-slice CT scan. PMMA vertebral filling was evaluated using the mean Saliou filling score. Each vertebral body was divided into 18 3D equal portions . Each portion was considered filled if cement was visible inside. Filling score ranged from one to eighteen. According to Saliou et al., we considered the filling satisfactory if the score was more than twelve, mediocre when the score ranged from six to twelve, inadequate if the score was less than six .We evaluated use of analgesic drugs  and pain relief through Visual Analogic Scale score (0 to 10 ranged). The questionnaire was administered before surgery, one week, one, three, six months after surgical procedure.. Levels of metastatic vertebrae were showed in During the abovementioned time frame, 54 patients for a total of 63 vertebrae were treated. Median age was 63,44 years (range 34-86 years). The primary neoplasms sites associated to vertebral metastasis in order by frequency were lung, breast, kidney, melanoma, liver, bladder, prostate, multiple myeloma, sarcoma, chordoma . Levels The most common patients’ comorbidities are hypertension (14%), diabetes , smoking , asthma, pneumonia , glaucoma , Crohn’s disease , abdominal unruptured aneurysm, Chronic obstructive pulmonary disease (COPD) , gastric ulcer , dyslipidemia , cardiovascular disorders , bowel disease , amyloid angiopathy , stroke , migraine . Table 1 These results, compared to preoperative data, suggest that our combined treatment had a significant impact on pain relief (p < 0.05), and in QoL as consequence. Intraoperative neuromonitoring (IONM) was performed during the entire procedure in order to avoid neurological complications. PMMA injection within the ablated cavity was monitored by continuous fluoroscopic guidance. After surgery, a thin-slice CT scan was performed, in order to evaluate cement distribution. According to the previously described radiological evaluation, Saliou filling score was satisfactory (12–18) in 20 vertebrae , mediocre (6–11) in 33 vertebrae , inadequate (0–5) in 10 vertebrae . Surgical treatment had a significant impact on pain relief. Mean preoperative VAS score was 7.81/10 (range 6-10). A significant reduction of overall subjective pain perception was registered, with a persistent reduction in VAS score 1 week , 1 month , 3 months  and 6 months  respective after surgery.  These reA small amount of cement leakage into perivertebral tissues was found in 7 vertebrae . However, no neurovascular structure was affected and no vascular or neurological injuries were recorded. Peri-operative mortality related to the surgical procedure was 0%., which worsened two weeks before admission. A lumbar CT scan showed an osteolytic L1 vertebral body lesion. 6 TherefRFA is currently used as one of the most safe and effective technique for bone metastases. This technique, based on the use of alternating current with a bipolar or monopolar device, provokes a coagulative necrosis of the tumoral lesion. Nevertheless, as a main consequence, this technique can weaken surrounding healthy bone. For this reason, the concomitant use of Polymethylmethacrylate (PMMA) guarantees a good result in terms of pain and stability. PMMA is placed with a needle in the affected vertebra and it acts as a “glue”: it fills the vertebra and then it is fixed through an exothermic reaction –27.Pain relief is obtained through the techniques previously mentioned, with a lesser use of painkillers during follow up. Nerve fibers transmission, tumor cells and their microenvironment enriched by proinflammatory cytokines, osteoclast activity may together participate to the pathophysiology of metastatic pain. Since RFA interferes with these mechanisms, it has a positive effect on pain. In our cohort we obtained a harmless ablation through the use of an articulated electrode with two thermocouples and a continuous monitoring of local temperature and tissue impedance. In particular, mean VAS scores were at baseline , at 1 week , and at months 1, 3 , and 6 months  respectively; with an optimum decrease in post-operative course. As regards recent literature, our series was compared to the largest case series in order to evaluate the positive impact of RFA in relieving pain. Table 2.Indeed, Sandri et al. in their systematic review reported that 11 patients treated with RFA and vertebroplasty presented a significant pain relief . FurtherMoreover, PMMA neurotoxicity could contribute to RFA painkiller effect since it could destroy nerves terminations and it gives a better stability to the spinal column at the same time , 44–46. To our knowledge this is the first reported experience on combined RFA and vertebral reinforcement followed by transpedicular screw fixation. Cianfoni et al. reported a percutaneous technique called SAIF  following RFA and vertebral reinforcement that, through a minimal invasive procedure, ensures stability and height restoration in pathological and osteoporotic vertebral bodies. This is the unique study provided by the literature review that looks up to our same goal. Nevertheless, although this is an interesting and innovative procedure, transpedicular screw fixation represents a faster and more accessible technique to reach the same results –49.In our single center experience, we noticed that, according to literature data about RFA plus vertebral reinforcement Table 2,This study has certainly some limitations. This is a retrospective analysis of a single medical center, without control group. Nevertheless, it shows an heterogenous group of patients with different vertebral locations and different clinic features. Further prospective studies with larger patient’s cohorts are mandatory to better evaluate the specific role of RFA procedure combined with vertebroplasty and followed by spinal fixation in the management of vertebral metastatic disease.The combination of RFA, PMMA vertebroplasty and transpedicle screw fixation represents a safe and effective technique for the management of spinal metastases guarantying a good and long-lasting clinical outcome in terms of pain relief.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.Conceptualization, GG, RC, and RM. Methodology, GG. Investigation, RC. Resources, UB, MP, and FP. Data curation, LBr, LBa, and CG. Writing—original draft preparation, RC and MAP. Writing—review and editing, GG, PP, and GS. Visualization, GU, DM, FG, and RG. Supervision, DI, MM, and RM. Project administration, DI. All authors have read and agreed to the published version of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The effectiveness of Tai Chi Chuan in treating various ailments has been well reported; however, its effect on back pain and lumbar spondylosis remains unclear.  We performed this meta-analysis under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the research-associated search was performed over the provided databases: Embase, Cochrane Library, Web of Science, PubMed, Scopus, and CINAHL in the period of 2008 to 2016, to recognize the related studies. We used the Physiotherapy Evidence Database (PEDro) scale to measure the standard of the involved randomized control trials (RCTs). The accumulated outcomes with parameters of weighted mean difference (WMD) and confidence level (CI) of 95% were evaluated to discover the influence of Tai Chi over pain as well as dysfunction among the patients suffering from pain depending on the outcome model. I2 = 0% for the overall effect Z = 9.42 (P < 0.00001); pain intensity of Tai Chi was compared with the control group, where 95% CI for -1.62  was observed for Z = 6.69 (P < 0.00001). The forest plot subgroup analysis of Tai Chi was compared with the control group for an unchanged lifestyle, where 95% CI for -2.26  was observed for Z = 12.76 (P < 0.00001).  Seven eligible studies with a total of 296 participants were identified that met inclusion criteria for the systematic review; in the forest plot analysis, it was noted that for 95% CI, the standardized mean difference found to be -1.58  with the heterogeneity of 87%, thereby favoring Tai Chi over the control group; a comparison was drawn for Tai Chi with routine therapy against the routine therapy alone, where 95% CI for -1.22  is observed for  Our results indicate that Tai Chi individually or with additional treatment along with routine physical exercises might reduce the pain and functional disorders for the patients suffering from back pain. Health is an important topic because of the increase in the elderly population and the expansion of medical expenses . The lumThe noninvasive treatment procedures, like antibiotics, behavioral therapy, tricyclic antidepressant, and spinal operation, were frequently practiced to alleviate the pain during the premature as well as the middle phase of the patients suffering from back pain. For those patients who were not benefitting from the expected treatment procedure, harmful treatments like trigger point-based injection therapy, lumbar disc replacement operation, acupuncture, or the flexible fixation of the lumbar functional unit were advocated –5.Exercise-based therapy has been extensively implemented as a supplementary technique to process chronic back pain and lumbar spondylosis . The claThe conventional Chinese aerobic exercise form, i.e., Tai Chi, has been determined for multiple age-associated disorders, especially cardiovascular disorders along with the metabolic syndrome, as it can reduce blood pressure and regulate the signs of metabolic syndrome . The praIt has a low influence along with a modest rate of intensity in aerobic exercise, which is identified by the moderate circular mobility, concentration, or mindfulness as well as controlled breathing. Tai Chi Chuan was proven to lay a positive influence over the immunity, strength, mood, and stability along with its significance over some researches. Not long ago, this form of martial art was established as a form of exercise which is implemented by millions of people in China .The rising interest towards Tai Chi has extended beyond the borders of China. In the past 20 years, Tai Chi and its capacity for health advantages have started to receive substantial awareness by the western medical as well as scientific boards and committees . These pThe Tai Chi Chuan technique is primarily used to unwind both body and mind. It thus enabled the professional to upgrade his or her mental as well as physical status. Multiple new studies are still being conducted as well as published; there is no review performed to measure the existing researches critical about how Tai Chi is utilized in curing back pain and lumbar spondylosis. In this study, we present a meta-analysis to evaluate the efficacy of Tai Chi Chuan individually among patients suffering from back pain or lumbar spondylosis.We performed this meta-analysis under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), and the research-associated search was performed over the provided databases: Embase, Cochrane Library, Web of Science, PubMed, Scopus, and CINAHL in the period of 2008 to 2016, to retrieve the related studies.The keywords associated with these researches were as follows: “Tai Chi Chuan,” “lumbar spondylosis,” “back pain,” “lower back pain,” “randomized control trial,” “disability,” “chronic back pain,” “spinal manipulation,” “lumbar vertebrae,” and “magnetic resonance imaging.” The source lists of the primary, as well as review, articles were manually searched for and eventually after the completion of the electronic searches. There were narrow inclusion and exclusion criteria formed based on which the studies were shortlisted for the meta-analysis.The researches comprised the following inclusion criteria of the study selection: the randomized clinical control trials (RCTs), which comprise patients with primary signs of back pain. Tai Chi was the only involvement or the combination with the other treating procedures, with research outcome measures which shall comprise a minimum of one to two crucial evaluations be it pain and disability.To analyze the consequences of Tai Chi for the back pain and lumbar spondylosis, the randomized control trial differentiations were found eligible: Tai Chi in comparison with control (the unchanged lifestyle); Tai Chi with other treating procedures in comparison to the other treatment. Pain intensity and disability were evaluated according to the visual analogue scale (VAS), Oswestry disability index (ODI), numerical pain rating scale (NPRS), Roland-Morris Disability Questionnaire, or the Japanese Orthopaedic Association (JOA).The above The above In the forest plot analysis, it was noted that for 95% CI, the standardized mean difference was found to be -1.58  with the heterogeneity of 87%, thereby favoring Tai Chi over the control group; similar results were noted in the funnel plot for pain treatment analysis  Figures.In the above I2 = 0% for overall effect Z = 9.42, P < 0.00001.In the above The above scattered plot analysis uses a funnel plot to show the comparative analysis of Tai Chi with routine therapy against routine therapy (as shown in The above Z = 12.76 (P < 0.00001).The above The above scattered plot analysis uses a funnel plot to show the subgroup analysis of Tai Chi in comparison to the control group for an unchanged lifestyle (as shown in The above Z = 6.69 (P < 0.00001).The above The above scattered plot analysis uses a funnel plot to show the comparative activity of Tai Chi for disability against the control group concerning the level of intensity of pain among the patients  is observed as with the least change of symptoms that were clinically found meaningful for the patients. MCID can regulate the clinical relevance of the results, thus showcasing the efficacy of the involvement as well as the patient reaction to the intervention. The overall outcome of pain in this study was observed as -1.58  where 95% CI, which surpassed the MCID value, proposing the accumulated result was found clinically significant.There were multiple sessions, frequency, time-span, as well as the style of Tai Chi intervention, along with varied results and assessment tools, with well-constructed heterogeneity of the accumulated outcomes of this research. We performed an attentive inference where we comprehended that Tai Chi individually or with other involved therapy with routine treatment may lead to a reduction in the intensity of pain and functional disorder for the patients suffering from back pain. Therefore, as an appropriate, inexpensive as well as favorable exercise activity, the Tai Chi technique can be advised for the patients suffering from back pain, either individually or integrated with other regular treatments.


Recent clinical studies have demonstrated the effectiveness of specific, multidisciplinary, bio-psychosocial, rehabilitation programmes for chronic neck pain. However, prognostic factors for the improvement of pain and disability are mostly unknown. Therefore, the aim of this study was to explore prognostic factors associated with improvements in chronic neck pain following participation in a three-week, multidisciplinary, bio-psychosocial, rehabilitation programme.In this observational, prospective cohort study, a total of 112 patients were assessed at the beginning, end, and 6 months following the completion of a multidisciplinary, bio-psychosocial, rehabilitation programme. Inclusion for participation in the rehabilitation programme depended upon an interdisciplinary pain assessment. The primary outcome was neck pain and disability, which was measured using the Northern American Spine Society questionnaire for pain+disability and was quantified with effect sizes (ES). Multivariable linear regression analyses were used to explore potential prognostic factors associated with improvements in pain and disability scores at discharge and at the 6-month follow-up period.p < 0.001), which was sustained at the 6-month follow-up . Prognostic factors associated with improvement in pain+disability scores at discharge included poor pain+disability baseline scores , older age , a good baseline cervical active range-of-motion (ROM) , and improvements in the Short-form 36 mental health scale  and cervical ROMs  from baseline values. Prognostic factors associated with improvements in pain+disability at the 6-month follow-up were similar and included poor pain+disability baseline scores , improvements in the Short-form 36 mental health scale , cervical ROMs , and better cervical ROM baseline scores. However, older age was not a factor .The mean age of the patients was 59.7 years (standard deviation = 10.8), and 70.5% were female. Patients showed improvement in pain+disability at discharge (ES = 0.56; Future prognostic models for treatment outcomes in chronic neck pain patients should consider cervical ROM and mental health status. Knowledge of prognostic factors may help in the adoption of individualized treatment for patients who are less likely to respond to multidisciplinary rehabilitation.The online version contains supplementary material available at 10.1186/s12891-021-04194-9. Neck pain is a musculoskeletal health condition with a high burden of disease. Previous epidemiological studies have reported a lifetime prevalence of the condition ranging from 14 to 71% . A signiClinical guidelines and reviews recommend several treatment options for chronic neck pain (CNP); however, due to the small number of neck-pain-specific clinical trials, the evidence for beneficial interventions is weak to moderate –8. CurreRisk factors for developing neck pain include socio-demographic variables such as being female , 4, physPre-treatment factors associated with poor outcomes include catastrophizing –16 and dOne recent systematic review included many studies that have been investigated prognostic factors for the course of disease in patients with neck pain . HoweverMore knowledge regarding prognostic factors associated with outcomes following an MBR programme in CNP patients is essential for adapting programme content to patients who show minimal improvement. Moreover, identifying associations between changes in physical and psychological health co-variates and outcomes would help to validate the existing content of MBR programmes.Therefore, the objective of this study was to explore prognostic factors associated with improvements in pain and disability in CNP patients following their participation in an intensive, three-week, out-patient MBR programme. The primary aim was to investigate associations between changes in physical and psychological factors with pain and disability outcomes independently from baseline factors. The secondary aim was to advance the understanding of pre-treatment factors associated with outcomes.Due to the bio-psychosocial treatment concept, we hypothesised that improvements in physical functioning and psychological health would be associated with less pain and disability.A database from an observational prospective cohort study for the evaluation of outcomes from a CNP-specific MBR programme was analysed. Data were collected at an assessment before treatment (T0), at the beginning of treatment (T1), at the end of treatment (T2), at 6-months post-treatment (T3), and at 12-months post-treatment (T4). Due to the explorative nature of this study, we used all available data from time points T1, T2 and T3 and did not perform a sample size calculation. Moreover, we did not use the T4 data due to the high number of missing values for the relevant co-variates. Furthermore, the post-MBR programme effects at T4 were individually compared to patient health statuses from T0 and T1 in a previously published study .The study was conducted at the day clinic in the Department of Physical Medicine and Rehabilitation at University Hospital, Ludwig Maximilian University, Munich, Germany. It was carried out in compliance with the protocols of the Helsinki Declaration of 2004. All participants provided signed, informed consent prior to study participation. The Ethics Committee at the medical faculty of the Ludwig Maximilian University Munich did not have any objections against the publication.Patients were referred to an interdisciplinary assessment at our clinic by a family physician or specialist. Depending on the primary diagnosis, patients were allocated to one of four condition-specific assessments for neck pain, lower back pain, osteoporosis, or osteoarthritis of the knee and hip. Assessments were conducted by a specialist in physical and rehabilitation medicine (PRM), a physiotherapist, and an occupational therapist. A psychologist from the treatment team also assessed patients who were suspected of suffering from a mental health disorder.At the end of each assessment, the treatment team either recommended participation in a three-week MBR programme or another treatment option. The MBR programme was recommended according to predefined inclusion criteria, an appraisal of the results of standardised clinical tests and patient questionnaires, and the general impression of the day clinic treatment team. The predefined inclusion criteria for the neck-pain-specific MBR programme were: CNP lasting at least three months (with or without pain radiation in the upper limbs), previous out-patient physical therapy that did not result in improvement according to the patient, limitations in activities, and sufficient German language skills to follow the instructions of the MBR programme. Previous out-patient treatment was defined as conventional care for at least three months and typically included 3 × 6 sessions of physiotherapy for 20–30 min per session.major depression), acute neck trauma in the previous three months, former whiplash injury with proven structural damage, neurological deficits occurring within the previous three months, chronic neurological deficits that would have prevented participation in exercise interventions, dizziness or vertigo with unclear aetiology, diffuse idiopathic skeletal hyperostosis (DISH), shoulder abduction or flexion less than 90°, or patients undergoing a pension application.The MBR programme was not recommended if patients had severe somatic or mental illnesses that limited their ability to participate  pain+disability scales , 25 at bAt the beginning (T1) and the end (T2) of the MBR programme, patients completed a set of questionnaires and underwent standardised clinical tests. Each patient was assessed by the same trained physiotherapist or occupational therapist both times. Data was collected using the NASS questionnaire , 25, theThe clinic provides condition-specific, 3-week MBR programmes for patients with CNP, chronic lower back pain, osteoporosis and osteoarthritis of the knee and hip. Each programme alternates one after the other.Patients completed a three-week, neck-pain-specific MBR programme that included a total of nine treatment days and 44 treatment hours. The programme fulfilled the German procedure classification (Operationen- und Prozedurenschlüssel (OPS)) 8–563.1 criteria of the German health care system, which requires at least 15 treatment units (a minimum of 30 min) of physical therapy or psychological therapy per week [The treatment team consisted of a specialist in PRM, physiotherapists, occupational therapists, psychologists, medical massage therapists, and a swimming trainer. Most treatments were provided to groups; although, all participants had two individual physiotherapy lessons that occurred at the beginning and end of the programme. During the initial, individual physiotherapy lesson, patients were trained in deep neck muscle strengthening exercises using biofeedback . During The NASS is a condition-specific instrument with specific modules for lower back and neck pain , 25. ItsThe German language version of the cervical spine NASS has demonstrated good criterion and discriminant validity, and sensitivity to change in validation studies , 33. It Subsequent validation studies of the cervical spine NASS have shown a better fit in factor analyses and good responsiveness for separated scales for pain (two items) and disability (eight items) , 35. In The SF-36 is the most widely used generic instrument for measuring health-related quality of life , 27. UsiA CROM instrument  was used to measure the cervical spine ROM in degrees. The instrument consists of a mounting device for the head, two gravity-dependent goniometers, and a compass that measures rotation in 2° increments. A validation study showed good intra- and inter-tester reliability , and relInformation concerning co-morbidities was collected using the standardized Self-Administered Comorbidity Questionnaire (SCQ) , and socDescriptive statistics were calculated for the baseline characteristics. Effect sizes (ESs) for the primary outcome (NASS pain+disability) and the secondary outcomes  were determined by dividing the mean change between baseline and discharge (T1 and T2), and between baseline and the 6-month follow-up (T1 and T3), by the standard deviation of the baseline score . An ES aIn the primary exploratory linear regression models, the dependent variables were ∆ discharge – baseline, and ∆ 6-month follow-up – baseline of the NASS pain+disability scale. For additional linear regression modelling, the dependent variables were the ∆ discharge – baseline of the separated NASS pain and disability scales.Independent variables were selected from candidate variables in the database and based on previous research concerning risk factors and prognostic factors in neck pain patients , 42, 43,The analyses were adjusted for the baseline variables of the change scores and important socio-demographic characteristics. The total number of co-variates was limited to 10, as 10 cases per co-variate were needed for the finite models and sufficiently valid estimates of the regression coefficient .The independent variables were sex, age, living with a partner, education level, number of co-morbidities, SF-36 mental health baseline value and mean change, the total active cervical ROM, and the change in the total active cervical ROM. All models were adjusted for the baseline score of the corresponding NASS scale, of which the change in score was the dependent variable. To adjust for any confounding, all listed co-variates were kept in the models, irrespective of whether their correlation was statistically significant. Multivariable partial correlations were determined and adjusted for all other potentially confounding co-variates . The oveFor missing values of single co-variates, the mean imputation method was used . This method was provided by the linear regression module of the statistical software program SPSS 25.0. Imputation by linear regression would have been inappropriate as it was the same strategy as the evaluation of prognostic factors and, therefore, would have increased the number of valid cases, but not the outcome of the prognostic parameter estimates. We assumed missing values were due to random processes, as the main reasons for missing data were incomplete distributions of the questionnaire regarding socio-demographic characteristics (12 patients = 10.7%) and incomplete clinical tests at T1 or T2 (10 patients = 8.9%) and not due to refusals by the patients to fill-in questionnaires or undergo clinical tests. This assumption was further supported by 97% completeness of the SF-36 mental health scale at baseline and 98% at follow-up, despite patients typically viewing questions about mental health as more sensitive compared to those concerning physical health.All statistical analyses were calculated using SPSS 25.0 for Windows . ESs were calculated using Microsoft Excel 2010.Table p < 0.001), NASS pain , NASS disability , SF-36 mental health , and total active cervical ROM  (Table At discharge T2), patients showed better scores in comparison to baseline in all outcomes: NASS pain+disability , improvements in the NASS scores were sustained with ES levels similar to those at discharge (T2) , the total active ROM , age , and for poor NASS pain+disability baseline scores .In the multivariable regression model, the change in the NASS pain+disability scale between baseline (T1) and discharge (T2) was modelled with 10 co-variates that explained 27.3% of the variance Table . Positivp < 0.001), older age , and a high total active ROM at baseline  were all correlated with improved NASS disability at programme discharge (T2). However, only a high baseline NASS pain score was significantly correlated with pain relief on the NASS pain scale at T2 .Additional regressions were used to model changes in NASS disability and pain as dependent variables and are presented in additional files Univariable associations between the co-variates and changes in the NASS pain+disability score between baseline (T1) and the 6-month follow-up (T3) are presented in Table The regression model explained 21.3% of the variance Table . Due to p = 0.204) and in the SF-36 mental health score between T1 and the T3  were significantly correlated to improvements in NASS pain+disability between T1 to T3. Furthermore, poor baseline NASS pain+disability scores  and total active ROM  were associated with a better outcome at the 6-month follow-up.Improvements in the active cervical ROMs between T1 and T2  [p < 0.1) [Mental health at baseline was associated with a change in pain and disability, and consistently showed relatively weak correlations (r ≤ 0.180) at both follow-ups . In one study that investigated whiplash injury patients receiving a multi-modal intervention, the association at the 6-month follow-up period was stronger  . Howeverp < 0.1) .Baseline co-morbidities did not correlate with treatment outcomes. To our knowledge, this potential prognostic factor had not been previously evaluated in CNP patients. However, for musculoskeletal health conditions including lower back pain and osteoarthritis of the knee and hip, a low number of co-morbidities has been associated with better outcomes , 22. DisOne strength of this study was the generalizability of the results to similar MBR programmes. In contrast to most RCTs, this research applied no artificial restrictions to participation or made adaptations to the intervention, which is routinely reimbursed by German statutory health insurance. Another strength concerns the application of a primary outcome measure that was both reliable and valid and included the International Classification of Functioning, Disability and Health (ICF) components of body function, activity and participation , 50, 51.One limitation of this study was the relatively low levels of explained variance. This indicates that some important prognostic factors for pain and functioning were not assessed. In particular, potential prognostic occupational context factors , 43 or cAnother limitation concerns the loss to follow-up. There were 145 patients who began the MBR programme, yet 23 and 43% were not included at discharge and the 6-month follow-up, respectively. Although loss to follow-up is less problematic in a prognostic factors study compared to an efficacy study, it may have influenced the associations found in this study.A further limitation was the absence of a control group. The Hawthorne effect refers to individuals modifying their behaviour in response to an awareness of being observed . In thisFuture prognostic models for treatment outcome in CNP patients should consider cervical ROM and mental health factors. Given large samples sizes, subsequent studies should include additional psychological variables such as catastrophizing, occupational factors, and cognitive-behavioural co-variables including coping styles and self-efficacy, in multivariable analyses. Knowledge of prognostic factors may help in the adoption of individualized treatment for patients who are less likely to respond to MBR programmes.Additional file 1: Table. Multivariable regression of the changes in NASS disability between baseline and programme discharge (n = 112)Additional file 2: Table. Multivariable regression of the changes in NASS pain between baseline and programme discharge (n = 112)


In order to make a complete diagnosis of all the factors influencing whiplash associated disorders (WAD), the evidence suggests that the condition evaluation should follow an integrated biopsychosocial model. This perspective would offer a fuller view of it, recognizing the interplay between the medical, biomechanical, social, and psychological factors. Despite the progress made in the subject, evidence of which psychosocial factors influence the experience of pain in litigant WAD patients is limited. A cross-sectional design and a cluster analysis was used to study the experience of pain and the psychosocial factors included therein in 249 patients with WAD assessed after suffering a motor vehicle accident. Three clusters were obtained: C1, with low scores of pain and a slight-moderate alteration of the Health-Related Quality of Life (HRQoL); C2, with medium scores of pain, alteration of HRQoL and a perception of moderate disability; and C3, with medium-high scores of pain, alteration of the HQoL, perception of moderate disability, presence of anxious-depressive symptomatology, poorer comprehension of the condition suffered, and the belief that it will extend over a long period of time. The results show a heterogeneous experience of pain in WAD, compatible with the biopsychosocial model of disease and the multidimensional approach to pain. The role of the psychologist in the evaluation of the condition could be useful to obtain a complete view of the condition, thus ensuring that the treatment is adapted to the needs of the patient. The term whiplash refers to an injury caused by a sudden acceleration/deceleration movement that generates hyperextension in the cervical region. This type of injury causes physical damage, and triggers a wide spectrum of symptoms, collected under the term of Whiplash Associated Disorders WAD; . As TurkIt is estimated that the high incidence of this condition is because the main etiology of WAD is the cervical hyperextension related to MVA. These cases are frequently associated with a compensation procedure, which promotes the demand for compensation and makes the risk of malingering a potential problem in the forensic and insurance medicine context . Also, WIn fact, MVA victims involved in what is known as “compensation-related factors” are believed to overreport symptoms, and a worse illness situation . This haHowever, the relation of pain and other variables like the above-mentioned is not unidirectional. Psychological and social factors like anxiety, depression, illness perception, disability perception, health-related quality of life (HRQoL), or poorer self-efficacy are especially relevant in the clinical experience and presentation of pain . For exaIn order to make a complete diagnosis of all the factors influencing WAD, the evidence suggests that its medico-legal evaluation should follow an integrated biopsychosocial model . This peDespite the progress made on the subject, the evidence of which psychosocial factors influence the perception of pain in litigant WAD patients is limited. Knowing these factors would help to understand the different perception profiles in which the condition may manifest and to provide treatment and medico-legal assessment tailored to the particular needs of each case.The main objective of the present study is to analyze the perception of pain in a forensic population of victims of MVA reporting WAD. The specific objectives are: (a) to derive psychosocial subgroups of MVA victims using an exploratory cluster analysis; (b) to investigate the differences of the obtained subgroups in several outcomes  of sociodemographic and medico-legal variables; and (c) to observe possible differences in the profiles of pain found in this medico-legal sample (litigant patients) and the clinical samples described in the literature.A cross-sectional  design was used with participants recruited from a multidisciplinary medical center specializing in bodily injury assessment of the Region of Murcia (Spain), during the years 2017–2019. Patients went to the clinic to be assessed after suffering an MVA.During the study period, participants underwent a full clinical evaluation by one of three physicians who were experts in bodily injury assessment and who participated in the research. At the end of this evaluation, the experts invited the patients who met the selection criteria (specified in the following section) of the study to participate, providing them with a detailed explanation of its purpose and procedure, and emphasizing its anonymous and voluntary nature. Those individuals who agreed to participate signed the informed consent and were assessed by a forensic psychologist who applied the prepared scale battery.To perform this study, we followed the ethical considerations proposed by the We used as case selection criteria: (a) victims of MVA (car crash); (b) adults (≥18 years); (c) submitting to a medico-legal assessment by one of the three medical experts who participate in this study, to ensure their experience in injury assessment  and data reliability; (d) diagnosed with WAD ; (e) estFor this study, the variables of interest were divided into two groups: (a) Clustering variables, used in the cluster analysis to form the subgroups, considering health-related quality of life, presence and severity of depression, presence and severity of anxiety, and cognitive and emotional representations of illness and (b) profiling variables, with which the subgroups resulting from the prior analysis were compared, which include pain perception, perception of disability, sociodemographic variables, and variables of medico-legal interest.Health-related quality of life (HRQoL), measured by the 36-Item Short Form Survey , Role Physical , Bodily Pain, General Health, Vitality (energy/fatigue), Social Function , Role Emotional , and Mental Health. Each one of the subscales yields a score from 0 to 100, with higher scores indicating the patient’s better quality of life. The Spanish version was used, with a general Cronbach’s alpha of 0.85 and 0.75 for all dimensions except for Social functioning  to 10 (extreme pain) on a visual analog scale (VAS) that was developed to allow the patients to measure the severity of the clinical pain suffered, as well as the degree of social disturbance  and medico-legal interest . The inclusion of the variable “speed of the car at the moment of impact” was initially considered, but it was discarded due to the impossibility of determining it objectively. To determine the causal link, we used the four criteria set out in Section 135 of Spanish Law 35/2015 of the scale of traffic accidents: (a) exclusion, which means that there is no other cause that fully justifies the injury/symptomatology; (b) chronological, which consists of the symptomatology appearing within a medically explainable time; (c) topographic, which means that there is a relationship between the body area affected by the accident and the injury/symptomatology referred unless a pathogenic explanation justifies otherwise; and (d) intensity, consisting of the adequacy between the injury/symptomatology referred and the mechanism of the trauma, taking into account the intensity of the accident and the other variables affecting the likelihood of the symptom’s existence. To consider the existence of a causal nexus, all the above criteria must be met.An Statistical analyses were performed using SPSS software version 25. Descriptive and frequency statistics were obtained from the total sample, and significant differences in the clustering and sex profiling variables were studied using one-way analysis of variance (ANOVA).post hoc tests for the continuous variables and the chi-squared test for the categorical variables. Discriminant analysis was then performed with a stepwise method on the variables used to form the clusters, thus evaluating the ability of that group of variables to predict group membership.Three steps were performed for the cluster analysis: (1) determination of the optimal number of clusters. For this purpose, the procedure of Due to differences in the format of the scale results, the clustering variables were standardized as Z-scores. After performing these analyses, the Z-scores were converted to the original values of each scale to facilitate the presentation and comprehension of the results.n = 126). All claimed to suffer from cervical pain, with an average severity of 6.17 (SD = 0.92) in BPI, 96.1% (n = 237) excessive sensitivity of the cervical region, 20.6% (n = 51) dizziness, and only 3.3% (n = 8) of the sample expressed another symptom in addition to those mentioned, with 11 cases (4.4%) reporting pain in the lumbar area. None of them referred suffering from pain in any other part of the body, tinnitus, ocular pain, neurological symptoms, or gastrointestinal disorders. MVA-related data are described in The assessment was carried out after an average of 38.24 days (SD = 9.25) since the accident, with a range of 26–60 days. Participants had a mean age of 36.36 years , and 51% were men  because the 2- and 4-cluster solutions obtained a higher BIC and a lower RDM . The Silhouette measure of cohesion and separation considered the cluster quality as “fair” (0.87).A K-means cluster analysis was performed for the variables shown in M = 2.74, SD = 3.88; BDI, M = 1.92, SD = 2.35) and low alteration of HRQoL , except for a medium alteration of Physical and Social Functioning .Cluster 1 (C1) includes patients who obtained overall low scores in all the analyzed variables and present no anxious-depressive symptomatology , significantly higher than the C1 group except for Role Physical , and presenting no anxious-depressive symptomatology .Cluster 2 (C2) is characterized by overall scores of low-medium severity, with medium-low alteration of HRQoL , medium-high alteration of the HRQoL variables, measured by the SF-36 , worse knowledge about the condition  and worse prognosis of improvement .Cluster 3 (C3) is characterized by higher scores than the other two clusters in the studied variables, with the exception of the variables in which no differences were found. The results showed that this group presents anxious-depressive symptomatology , the three groups have a similar profile in the illness perception variables of the BIPQ, with a medium-high control capacity, both for treatment and personal control, low concern about the disease, and good identity of symptoms.F = 103.43, p = 0.00; maximum pain, F = 65.75, p = 0.00; minimum pain, F = 16.38, p < 0.001; perception of disability, F = 35.73, p < 0.001; and time elapsed since the accident, F = 16.24, p = 0.00. No significant differences were found as a function of age, F = 0.29, p = 0.74.the analysis of the subgroups produced by cluster analysis based on the variables of medico-legal and sociodemographic interest is presented in 2 = 6.25, p = 0.39, Wilks λ = 0.20; Seat occupied: χ2 = 8.27, p = 0.08, Wilks λ = 0.23; Location of the impact: χ2 = 0.77, p = 0.92, Wilks λ = 0.07; Road type: χ2 = 4.39, p = 0.17, Wilks λ = 0.35; Seat belt fastened: χ2 = 0.32, p = 0.84, Wilks λ = 0.04; Head position: χ2 = 5.52, p = 0.23, Wilks λ = 0.19; Car Status: χ2 = 4.40, p = 0.62, Wilks λ = 0.17; Sex: χ2 = 2.65, p = 0.26, Wilks λ = 0.13).The subgroups were also analyzed as a function of the variables related to the accident and sex, finding no significant differences in any of them (Time of day of the collision: χp < 0.001), Anxiety , Role Emotional , Vitality , Mental Health , Social Function , General Health , Physical Function , Role Physical , Timeline , and Coherence .To validate the cluster solution obtained with the methodology presented in the previous section, discriminant analysis was performed with the variables that the cluster analysis had used to form the subgroups: Depression  and in the Function of test 2 .The analysis showed two functions with significant results for variables in Functions 1 to 2  and 3.2% . Stronger relationships for Function 1 were observed in Role Emotional, Mental Health, and BDI and for Function 2, in Role Physical and Social Function. Finally, cross-validation of the classification showed that the model could correctly classify 96.1% of the 3 subgroups .The main objective of the present study was to analyze the perception of pain in victims of MVA suffering from WAD. We evaluated the factors that have been cited most frequently as contributing to WAD symptoms, as well as WAD-related impairment and disability . The stuConcerning the specific objectives of this work, through the results of the cluster analysis, three different groups  of WAD patients were found using psychosocial variables as the clustering input. Group C3 is composed of patients who show a general moderate-high overall severity profile, consistent with the acute phase profile presented by Group C2 is composed of patients who have moderate general severity, with no anxious depressive symptomatology and a moderate-low alteration of HQoL/cognitive representation of the disease. Alterations in physical and social function, vitality, and Role Emotional are observed, but these patients are more capable of performing the activities that make up their Role Physical than the C3 group. Similarly, they show a more adaptive cognitive representation of the disease than the other two groups.Pain severity and perception of intermediate disability, less than group C3 but significantly higher than the third and final group (C1) were observed. The C1 group is composed of patients with low scores in the presented variables, but who still have some alteration in HQoL, especially in Vitality and the Social and Physical Functions, and suffer mild pain and alteration in the perception of disability.Significant differences were also observed depending on the time elapsed since the accident. In Group C1, which shows mild symptoms, the average time was significantly higher than in the other two. This suggests that the severity of symptoms decreases two or three months after their origin, but some symptoms, such as pain, persist. These results coincide with the synthesis of On the other hand, we consider of interest the absence of significant differences between groups C2 and C3 in this variable. These two groups show a similar time since the accident just over 1 month—but they have a different severity profile. As no differences were observed in the collision variables, a possible explanation for this difference in profiles is the interaction between the psychological variables and pain. The presence of the psychological symptoms may provoke a higher perception of pain in the patient because of the attentional bias that they can cause . DepressGroup differences in the perception of disability can also be explained from the influence of psychological variables. The presence of anxious-depressive symptomatology is associated with the avoidance of activity and a perception of high disability . PatientConcerning the other variables studied in the comparison of the subgroups, no significant differences were found in the factors related to the accident , indicating that these variables do not influence the severity of symptoms. These findings are consistent with the results obtained by other authors, where these variables have not been observed to be associated with the prognosis of the condition .On the other hand, no significant differences were found depending on age or sex in any of the variables studied. These results coincide with the recent study of Generally speaking, our results show a WAD pain profile consistent with what was previously presented in the bibliography . It is aWe consider that the three groups obtained may be of interest to the medico-legal context, as they provide evidence of the different litigant WAD patient profiles that the professional may encounter. As can be seen, the classification performed by the cluster analysis indicates that some patients have a pattern of symptoms that could be considered atypical, which is not explained by the time elapsed since the accident or the influence of factors related to the collision. As noted above, this magnification of symptoms is often interpreted as a sign of malingering and can create a false alarm effect in which the litigant patient is considered to be exaggerating the symptoms to obtain greater financial compensation, with the psychological and social consequences that this entails . As MercSimilarly, legislation for the management of road accidents in the country to which the person being assessed belongs is also an issue that needs to be analyzed. We believe that the evaluation of the litigant WAD patient should be conducted from a multidisciplinary and biopsychosocial approach e.g., . This peThe results obtained in this study should be interpreted according to several limitations. Due to the conditions and design used, it was not possible to use probabilistic sampling. Another limitation of the study is that we could not follow up the patients evaluated to check the interaction between pain severity and the selected variables. We consider that studying this interaction could be useful to identify possible modulating variables. Also, the cut-off points used belongs to a spanish sample and this should be taken into account when considering the implications of the results. Finally, due to limitations imposed by the medical center, we had a short lapse of time to apply the evaluation protocol, so it was not possible to include other variables of interest like pain catastrophizing.The cluster analysis shows three different profiles and a symptomatic heterogeneity, which supports the evaluation of WAD from the biopsychosocial model of disease and the evaluation of pain from the multidimensional model. The comparison of the groups showed that the patients of the group of high-perceived pain presented a profile of greater severity in the psychosocial variables studied. Given these results, we consider that the biopsychosocial evaluation of WAD, with a multidisciplinary approach, could be useful to obtain a complete view of it, avoiding diagnostic errors between genuine patients and malingerers, and ensuring that the treatment follows an approach adapted to the real needs of the patient.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Consejo de coordinación del Programa de Doctorado de Ciencias Forenses de la Universidad de Murcia. The patients/participants provided their written informed consent to participate in this study.DP, EP-L, and JR-H contributed to conception and design of the study. EP-L organized the database, performed the statistical analysis, and wrote the first draft of the manuscript. DP, AR-C, TM, and LA wrote sections of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The experience and causes of pain in patients with nontuberculous mycobacterial pulmonary disease (NTM-PD) have not been clarified.This study aimed to determine the prevalence and severity of bodily pain (BP) in patients with NTM-PD. We also investigated the clinical indicators that contribute to pain.We used a retrospective cross-sectional study design. The participants were 114 NTM-PD patients (109 women) with a mean age of 65 years. The prevalence and severity of pain were measured using 2 items from the 36-Item Short Form Survey version 2 (SF-36), and the BP score was calculated. Functional limitation due to dyspnea was quantified using the Modified Medical Research Council Dyspnea Scale (mMRC), depression was assessed using the Center for Epidemiological Studies Depression Scale (CES-D), sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI); health-related quality of life was assessed using the Leicester Cough Questionnaire (LCQ), and exercise tolerance was measured using the Incremental Shuttle Walk Test (ISWT).Pain was reported by 70.2% of the patients (n = 80), and of these, 35.7% (n = 25) reported moderate to very severe pain. NTM-PD patients with high levels of pain had significantly higher scores on the mMRC, CES-D, and PSQI scores, and significantly lower performance on the ISWT and LCQ. Multiple regression analysis identified ISWT, CES-D, and PSQI as independent factors that affected BP scores.Our findings suggest that pain significantly impacts daily life associated with reduced exercise tolerance, the presence of depressive symptoms, and poor sleep quality in patients with NTM-PD. Furthermore, as the disease progresses, additional symptoms, such as fever and weight loss, arise.–8 Munro et al reported that the presence of phlegm has a significant impact on the development of chest pain. Moreover, chronic cough is associated with pain and is thought to result in chest and skeletal muscle pain.–12 The assessment of pain is an important element of clinical assessment because the sensation of physical pain leads to inactivity and is thus associated with depression, poor sleep quality, and impaired health-related quality of life (HRQOL).,14 Therefore, patients with NTM-PD who typically have chronic cough and phlegm symptoms are at risk of developing pain and may be affected by depression, poor sleep quality, and reduced HRQOL.In recent years, the prevalence of nontuberculous mycobacterial pulmonary disease (NTM-PD) has increased worldwide. In patients with NTM-PD, Mehta et al showed that bodily pain (BP) measured using the 36-Item Short Form Survey version 2 (SF-36) was worse than norm-based scores in a Canadian population.Pain associated with respiratory disease has been extensively studied in patients with chronic obstructive pulmonary disease (COPD). In these studies, the prevalence of pain has been reported to be 66% in patients with moderate to severe COPD, and pain intensity was significantly associated with the severity of dyspnea.However, there are no previous studies pertaining to the prevalence of pain in patients with NTM-PD, and the experience of pain and its causes in this population are not well understood. The purpose of this study was to determine the prevalence of pain in patients with NTM-PD and to examine the clinical indicators that contribute to pain.22.1We used a retrospective cross-sectional study design. The study was conducted at Fukujuji Hospital of the Japan Anti-Tuberculosis Association , which is a 340-bed facility that specializes in pulmonary diseases and mycobacteriosis in particular. The study was approved by the Institutional Review Board on Human Research of Fukujuji Hospital . The exclusion criteria were patients whose condition was not stable during the 3 months before assessment as a result of pneumonia or pneumothorax, any recent fractures, those who did not give consent to the study, and patients with missing laboratory data.From April 2016 to March 2020, 180 patients (160 inpatients) with NTM-PD received pulmonary rehabilitation at Fukujuji Hospital. Pain and exercise tolerance were assessed immediately before the program of pulmonary rehabilitation. In addition, the patients completed several questionnaires. The diagnosis of NTM-PD was made in accordance with the American Thoracic Society/European Respiratory Society/European Society of Clinical Microbiology and Infectious Diseases Society of America criteria by a respiratory physician specializing in infectious diseases.2.2 Spirometry data comprised forced vital capacity expressed as percent predicted (FVC % pred), forced expiratory volume in one second percent predicted (FEV1% pred), and FEV1/FVC. Imaging findings obtained from high-resolution computed tomography were classified into the following 4 patterns: noncavitary nodular bronchiectasis type, cavitary nodular bronchiectasis type, fibrous cavity type, and unclassified type. Respiratory symptoms  were assessed using the COPD Assessment Test (CAT). The CAT is an eight-item self-administered questionnaire that includes three items related to respiratory symptoms , with a score of 0 being asymptomatic and 1 to 5 being considered as having respiratory symptoms. Dyspnea was assessed using the Modified Medical Research Council dyspnea scale (mMRC). This scale ranges from 0 to 4, where a higher score indicates greater functional limitations due to dyspnea.Sex, age, body composition , smoking history, duration of disease, presence of any underlying pulmonary disease, and the presence of pain and pain-related medications were recorded from patients’ medical charts. Pulmonary function testing was performed when the patient was in a stable condition, using an electronic spirometer  in accordance with published guidelines.2.3 The questionnaire comprises eight subscales: physical functioning, role-physical, BP, general health, vitality, social functioning, role-emotional, and mental health. All scores were transformed to fit a norm-based score for the general Japanese population, with a mean score of 50 and a standard deviation of 10. Lower scores indicated poorer HRQOL. Two items from the SF-36 were used to measure pain, consistent with a previous study. The first pain question asks, “How much bodily pain have you had during the past 4 weeks?” The response options are “none,” “very mild,” “mild,” “moderate,” “severe,” or “very severe.” The second question asked, “During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the home and housework)?” The choices are “not at all,” “a little bit,” “moderately,” “quite a bit,” or “extremely”. Responses to the first item were used to determine pain prevalence and severity. Responses to the second item were used to determine the impact of pain. We classified patients with BP score <50.0 into the “Pain group” and patients with BP score ≥50.0 into the “No pain group.”The SF-36 assesses 36 self-reported health aspects.2.4 The CES-D is a 20-item self-administered rating scale developed for the purpose of investigating the prevalence of depressive symptoms in the general population. The highest possible score was 60. A score of 16 or higher indicated the presence of clinical depressive symptoms. As in a previous study, the patients were divided into 2 groups: those who scored <16 were classified as having no depressive symptoms, whereas those who scored ≥16 were classified as having depressive symptoms.The Japanese version of the Center for Epidemiological Studies Depression Scale (CES-D) was used to screen for depressive symptoms.2.5 The PSQI generates a 7-component score (range 0–21); the higher the total score, the poorer the subjective sleep quality, and a score >5 is classified as having poor sleep quality.Sleep quality was assessed using the Japanese version of the Pittsburgh Sleep Quality Index (PSQI).2.6 The 19-item questionnaire consists of three domains . Each item is rated on a 7-point Likert scale for symptoms or the impact of symptoms over the past 2 weeks. The mean score for each of the 3 domains was calculated . The total score was calculated by summing the domain scores (range 3–21). A higher score indicates a better quality of life. The questionnaire has demonstrated validity and reliability, and is easy to administer and score. Permission to use the Japanese version of the LCQ in this study was granted by Akio Niimi and Haruhiko Ogawa.The Leicester Cough Questionnaire (LCQ) is a symptom-specific quality of life measure for patients with chronic persistent cough.2.7 The ISWT is a threshold symptomatic field test that uses a 10-meter course with walking speed dictated by an audio signal. The test is continuous and incremental, with the walking speed increasing every minute. The test was terminated by the patient if they experienced excessive breathlessness or by the operator when the patient failed to maintain the required speed. One practice ISWT was performed to counteract any learning effect. The ISWT distance (ISWD) was recorded and expressed as a percentage of the predicted values obtained from a Japanese sample (ISWD % pred).Exercise tolerance was assessed using the incremental shuttle walk test (ISWT) and conducted in accordance with a standardized protocol.2.8t tests. The Mann–Whitney test was performed to compare nonparametric data. Categorical variables were analyzed using theχ2 test.Data are presented as percentages for categorical variables and median (interquartile range) for continuous variables. Data distribution was examined using the Shapiro-Wilk test. For the sensitivity analysis, patients were divided into a “No pain” (BP score ≥50.0) group or “Pain” (BP score <50.0) group. To test for between-group differences in data that conformed to a normal distribution, we used 2-sample P value <.2 in the correlation and single linear regression analysis, and forward selection was used to derive the final model. All analyses were performed using SPSS Statistics for Windows version 25.0 . A probability value of P < .05 was used to determine statistical significance.Associations between BP scores and clinical indicators  were assessed using Pearson or Spearman correlation analyses. In the multiple linear regression analysis, the variables were selected on the basis of 33.1During the study period, 1 patient with a history of forearm fractures was excluded. In addition, we excluded 18 patients who did not complete the questionnaires and 47 patients who had missing data. The final sample comprised 114 patients , CES-D (P < .001), and PSQI (P = .007) were significantly higher, and FVC % pred (P = .032), ISWD % pred (p = .005), and LCQ total (P = .001) were significantly lower in the pain group than in the no pain group. Between-group differences were found for pain and pain-related medications (anxiolytics/sedatives/hypnotics [P = .014]), and at least 1 pain or pain-related medication (p = .009). There were no significant differences in age, sex, duration of disease, smoking history, radiographic features, bacterial species, or respiratory symptoms between the 2 groups.Table 3.3Table 3.4Multiple regression analysis was performed to determine the independent factors affecting the BP score Table . Stepwis4This study is the first to evaluate the prevalence and severity of pain in patients with NTM-PD using a validated pain measure. It is noteworthy that 70% of patients with NTM-PD reported some level of pain, and of these patients, just over one-third reported pain of moderate to very severe range intensity. Moreover, pain interfered with normal work in almost half of our patients.,33 Conversely, a study of Japanese patients with Mycobacterium avium complex pulmonary disease reported that the BP score did not differ from a norm-based score. In our study, most of the participants were female, and about half reported that pain did not affect their lives, suggesting that the type of work may have affected the BP score.The BP scores of the subjects in our study were 49.0, which was not different from the norm-based score for the general Japanese population. In previous studies, scores for BP were lower in Canadians with NTM-PD and in a Spanish study of patients with bronchiectasis. We predicted that cough symptoms would also be associated with pain in patients with NTM-PD, whose main symptoms are cough and phlegm. In our sample, many NTM-PD patients had cough symptoms, and although a higher proportion of patients with pain had cough symptoms, this finding was not significant. The lack of studies on pain in NTM-PD makes it difficult to draw definitive conclusions about the cause of pain. Therefore, additional studies using pain-specific measures  are needed to clarify the specific etiology of pain reported by NTM-PD patients.Previous studies have reported that cough symptoms are associated with pain in the general adult population.,38 In addition, in patients with COPD, a condition characterized by symptoms of dyspnea and cough, pain is associated with exercise tolerance and physical activity, and pain intensity is associated with dyspnea severity.,39 To date, there have been no reports investigating the association between dyspnea, exercise tolerance, and pain in patients with NTM-PD. In our study, NTM-PD patients in the pain group had significantly more chest tightness symptoms, which suggests that dyspnea may have an influence on pain. However, it did not explain the cause or mechanism underlying the pain.This study showed that pain in patients with NTM-PD was associated with dyspnea, low exercise tolerance, symptoms of depression, poor sleep quality, and impaired HRQOL. The perception of pain and dyspnea is correlated in healthy individuals, and an inverse correlation between pain severity and physical performance has been reported in patients with chronic pain.–42 Furthermore, in contrast to the findings in patients with depression or pain alone, patients with pain and depression have been reported to experience a greater decrease in physical, mental, and social functioning. In our study, compared with NTM-PD patients without pain, those with pain were significantly more likely to be prescribed anxiolytics/sedatives/ hypnotics, or at least 1 pain or pain-related medication. NTM-PD is a chronic disease that requires prolonged multidrug treatment. During treatment, patients are known to experience negative emotions. In a previous study, patients with NTM-PD showed high levels of depressive symptoms, and cough was found to be an important predictor of the clinical symptoms of depression. Chest physiotherapy, a nonpharmacological intervention, has been reported to reduce the symptoms of cough and phlegm, improve pulmonary function in patients with NTM-PD, and may also help to improve depressive symptoms. However, whether chest physiotherapy improves pain in patients with NTM-PD is unclear and requires further investigation.Symptoms of depression, poor sleep quality, and impaired exercise tolerance may be independent predictors of pain in patients with NTM-PD. Pain can result in depression and sleep disturbances, which have been reported to interact with each other.This study has several important limitations. First, the sample was almost entirely female, and thus it is not possible to make inferences about males with NTM-PD. Second, because pain assessment was administered as part of the questionnaire, a detailed pain assessment  was not undertaken. Therefore, little is known about the causes and characteristics of pain in this sample. Prospective studies are required to enable more detailed assessments. Because of these limitations, our findings cannot be generalized to all patients with NTM-PD.5This is the first study to investigate the prevalence and severity of pain in patients with NTM-PD using the BP score and the pain domain of the SF-36 to analyze predictors of pain. Approximately 70% of our sample of patients with NTM-PD reported experiencing pain, and of these patients, over one-third reported moderate to very severe pain. Factors predicting pain in patients with NTM-PD included the presence of depressive symptoms, poor sleep quality, and reduced exercise tolerance. Our findings suggest that pain significantly affects the daily life of patients with NTM-PD. All relevant data are within the paper and its Supporting Information files. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.https://en-author-services.edanz.com/ac) for editing the draft of this manuscript.The authors thank all the subjects, technical staff, management support teams, and colleagues for their cooperation in this study. Dr. Akihiro Ohkado for his statistical advice. We thank Sarina Iwabuchi, PhD, from Edanz Group (Hideaki Senjyu was the principal investigator and contributed to the design of the study, administered the funding, supervised the team's work, and made critical revisions to the paper for intellectual content. Kosuke Mori designed the study, drafted, revised, collected, analyzed, and interpreted the data and prepared the paper. Mitsuru Tabusadani contributed to data analysis and made critical revisions to the paper for important intellectual content. Kazumasa Yamane, Satoshi Takao, Yuki Kuroyama, Yusuke Matsumura, Kazuki Ono, Kazuma Kawahara, Shunya Omatsu, Keiji Fujiwara, Koji Furuuchi, Kozo Morimoto, and Hiroshi Kimura collected and interpreted the data, drafted the manuscript, and made critical revisions to the paper for important intellectual content. All authors read and approved the final paper and agreed to be accountable for all aspects of the work.Conceptualization: Kosuke Mori, Hideaki Senjyu.Data curation: Kosuke Mori, Mitsuru Tabusadani, Kazumasa Yamane, Yuki Kuroyama, Yusuke Matsumura, Keiji Fujiwara, Hideaki Senjyu.Formal analysis: Kosuke Mori, Mitsuru Tabusadani, Hideaki Senjyu.Funding acquisition: Hideaki Senjyu.Investigation: Kosuke Mori, Kazumasa Yamane, Satoshi Takao, Yuki Kuroyama, Yusuke Matsumura, Kazuma Kawahara, Kazuki Ono, Shunya Omatsu, Koji Furuuchi, Hideaki Senjyu.Methodology: Kosuke Mori, Mitsuru Tabusadani, Satoshi Takao, Hiroshi Kimura, Hideaki Senjyu.Project administration: Hideaki Senjyu.Resources: Hideaki Senjyu.Software: Hideaki Senjyu.Supervision: Kozo Morimoto, Hideaki Senjyu.Validation: Kosuke Mori, Hideaki Senjyu.Visualization: Kosuke Mori, Hideaki Senjyu.Writing – original draft: Kosuke Mori, Hideaki Senjyu.Writing – review & editing: Hiroshi Kimura.