AimsEnigmatic thigh pain in uncemented femoral components of a total hip replacement can be severe and disabling. Treatment can be conservative or surgical with cortical strut graft or revision of the femoral stem. Cortical strut grafting may offer good results with reduced morbidity. The aim of this study was to report the functional and radiographic outcomes of four patients with enigmatic thigh pain treated with cortical strut allograft.Materials and MethodsBetween 2016 and 2018, four women underwent cortical strut allografting at two centres. All patients had an uncemented, proximally porous S-ROM femoral implant . All other causes of anterolateral thigh pain were excluded. The mean age was 36.7 years (range: 29-51 years). Patients were followed up for a minimum of 14 months (range: 14-38 months). The University of California, Los Angles (UCLA) activity score, pain scores, complications, and radiographs at six weeks, three months, six months, nine months and one year were recorded.ResultsMean UCLA activity scores increased from 3.2 (range: 2-4) to 6.2 (range: 6-7) post-operatively. Radiologically, all four patients had complete osseointegration of their strut grafts. Pain scores decreased at six weeks and at six months. One deep venous thrombosis occurred. One patient experienced recurrence of anterolateral thigh pain 26 months post-strut graft, which resolved with protected weight-bearing and analgesia for three months.ConclusionsIn uncemented femoral prostheses, cortical strut grafting to treat enigmatic thigh pain can reduce symptoms and increase activity without the need to revise a well-fixed femoral stem. We add to the growing body of evidence that this can be a successful surgical technique. Enigmatic thigh pain is a recognised complication following total hip replacement (THR) using uncemented femoral components. The incidence ranges from 0.5% to 40% -5. A smaIt is a diagnosis of exclusion and should only be made after other more common pathology is ruled out. These include factors occurring at the bone prosthesis interface , soft tissue inflammation  and distant sites of referred pain .Pain is thought to arise secondary to a Young’s modulus mismatch between the host femur and the relatively stiff implant, resulting in a stress riser at the stem tip ,4,6. PerSurgical and conservative management options have been described . Non-steThe aim of this study is to report the functional and radiological outcomes of four patients who underwent cortical strut allografting for recalcitrant thigh pain with well-fixed S-ROM femoral components .Four female patients underwent cortical strut allograft procedures between 2016 and January 2018. The diagnosis in all cases was unresolved severe thigh pain following THR using the S-ROM femoral implant. These procedures were performed by experienced surgeons across two institutions. Mean age at surgery was 36.7 years (range: 29-51 years). All patients had S-ROM femoral components and a Pinnacle acetabular component (Depuy Synthes) with ceramic on ceramic bearings. The S-ROM implant was used as a primary THR in three cases and as a revision in one. Indications were hip degeneration secondary to slipped capital femoral epiphysis (two patients), developmental dysplasia and conversion from an excision arthroplasty to THR following treatment for prosthetic joint infection. Clinical and radiological reviews were undertaken at 6 weeks, 3 months, 6 months and 12 months post-operatively and annually thereafter. Data collected at the final follow-up were the University of California, Los Angles (UCLA) activity score, pain scores and complications. All patients consented for their information to be used anonymously in research.Patient selectionAll four patients reported thigh pain at six months following their hip arthroplasty procedure. All patients had experienced an uneventful post-operative recovery and had experienced satisfactory progress in rehabilitation prior to this. Their pain was gradual in onset, severe and affected their activities of daily living. The pain was localised to the tip of the femoral component in all cases. Other causes were excluded through history, examination and investigations. On examination, all patients had full range of movement in their hip, and the hip joint was not irritable. Pre-operative investigations included plain radiographs, inflammatory markers  and single-photon emission computed tomography (SPECT) scan. In all cases the components were well fixed, and WCC, CRP and ESR were normal. All radiographs showed cortical remodelling in zone 3 Figure  8]. The. The8]. Operative techniqueFresh frozen diaphyseal femoral allograft was used in all four cases. All procedures were performed by orthopaedic surgeons experienced in arthroplasty . The skin incision was made using an image intensifier to locate the stem tip. A sub-vastus approach to the femur was used. Four cerclage cables were passed: two above the stem tip and two below. The periosteum was stripped to expose the cortex, and a 15-cm fresh frozen diaphyseal femoral strut graft was contoured to fit the patient’s femur using a high-speed burr. The inner surface and edges of the strut graft were coated with demineralised bone matrix (DBX) and placed on the lateral side of the femur, centred on the stem tip. Morsellised bone graft was placed in the interface between the allograft and the native femur. The position of the strut graft was confirmed on an image intensifier and was then secured with the cables. All patients received three doses of intravenous antibiotic prophylaxis (cefuroxime) and subcutaneous low molecular weight heparin (LMHW) until discharge. All patients were allowed to weight-bear as tolerated with crutches following surgery.Minimum follow-up was 14 months (range: 14-38 months). All patients reported improvement in thigh pain at six weeks and almost complete resolution by six months post-operatively. The mean pre-operative UCLA activity score at the final follow-up increased from 3.2 (range: 2-4) to 6.2 (range: 6-7) post-operatively. Radiologically, all four patients had complete osseointegration of their strut grafts  post-operatively and was treated successfully with rivoraxaban 20 mg once a day for six months. There were no re-operations.One patient experienced recurrence of thigh pain 26 months post-strut grafting. There was no history of trauma, and the pain was located in the mid-thigh. The pain was brought on following long walks or moderate activities and relieved by rest. At this point, she had returned to her normal life and level of activity.On examination, the hip had full range of movement and was not irritable. There was no point tenderness at the stem tip. The operative scar was healthy, inflammatory markers were normal and the radiographs showed a well-integrated strut graft and well-fixed components. The patient was mobilised partially weight-bearing with crutches for four weeks. The patient reported resolution of pain at her three months later. There has been no recurrence of pain.To our knowledge, this is the first report of cortical strut grafting for recalcitrant thigh pain in patients with well-fixed S-ROM femoral stems. All patients had a satisfactory resolution of pain and returned to full function following surgery. Management of unresolved functional thigh pain following total hip arthroplasty can be challenging. Thigh pain after THR often resolves spontaneously. Most patients respond to activity modification, non-steroidal anti-inflammatory drugs and short-term protected weight-bearing. The patients who experience ongoing debilitating thigh pain despite conservative measures might benefit from surgical intervention. The optimal duration for conservative measures is undecided.Young’s modulus of elasticity in the native femur is approximately 10 times less than titanium alloys (Ti-6Al-4V) and 18 times less than cobalt-chromium (Co-Cr). This results in a modulus mismatch or a significant difference in the structural rigidity at the interface between the tip of the stem and the adjacent bone. It has been postulated that stress transfer to the femur at this point results in enigmatic thigh pain .Other hypotheses suggest the pain arises from periosteal and/or endosteal irritation, with basic science studies demonstrating pain mediators substance P and calcitonin gene related peptide in the bone and soft tissues near the stem tip .Implant characteristics such as diameter and material influence stiffness and have been correlated with increased thigh pain. Vresilovic et al. report 0-15% incidence in the smallest sizes rising to 23-40% in the largest, with 12.1% overall incidence of thigh pain at one year . BurkartThe S-ROM prosthesis is a modular, cementless femoral stem consisting of a porous coated proximal titanium sleeve with a conical and spout. The titanium stem is polished distally with integrated splines for rotational stability and a coronal slot to theoretically reduce stem stiffness and the incidence of thigh pain. Thigh pain with this implant is reported between 1.6% and 11.9% -16.Addition of a cortical strut allograft adds rigidity to the femur, which may reduce the difference in structural rigidity between the native femur and the implant and, in turn, reduce the stresses transferred to the femur and the resulting pain caused by this. In addition, denervation of the lateral femoral periosteum when applying the strut graft may also provide pain relief .Femoral strut grafts have been shown to integrate well when used to augment the host femur when revising a THR to an uncemented prosthesis . Their uWe observed pain relief in all cases at the time of the final follow-up. Full incorporation of the graft was also observed in all cases in our cohort. Domb et al. sought to exclude stress fractures at the stem tip using bone scans, which were negative in all patients prior to surgery . SPECT iOne case of DVT occurred post-operatively in our study. The patient was 31 years old, had a body mass index of 35 and took oral contraceptive pills. This was successfully treated with oral anticoagulants. There were no wound healing issues. This illustrates the procedure is not without risk.One patient in our cohort who achieved pain relief experienced recurrence of thigh pain approximately two years post-strut grafting. This differs from the experience of Domb et al. . The femThe results of this study are limited by small patient numbers and 14 months of minimum follow-up. However, we describe a rare technique with positive short-term outcomes and add to the existing body of evidence that cortical strut grafting can be a successful procedure for enigmatic thigh pain.Enigmatic thigh pain in uncemented THRs may be secondary to a Young’s modulus mismatch between the stiff implant and the relatively less stiff femur. Partial weight-bearing with crutches, activity modification and NSAID therapy should be employed for one to two years to allow the femur to remodel to these new stresses. However, should this fail, the results of this study suggest that cortical strut allograft is a viable option for the management of enigmatic thigh pain following uncemented THR. The morbidity associated with this procedure is less than the alternative of revising a well-fixed implant and the associated bone loss.


The superiority of focused shockwave therapy (F-SWT) versus radial shockwave therapy (R-SWT) for treating noncalcific rotator cuff tendinopathies remains controversial. This study is aimed at comparing the effectiveness of F-SWT versus R-SWT for the management of noncalcific rotator cuff tendinopathies. 2 with 5.1 ± 0.5 Hz, while average pressure for R-SW 3000 shots was 4.0 ± 0.35 bar with 3.2 ± 0.0 Hz. Pain level and shoulder function were assessed with the numerical rating scale (NRS) and Constant-Murley Scale (CMS). The primary endpoint was the change in the mean NRS pain score from baseline to 24 weeks after the intervention. Secondary endpoints were changes in the mean NRS pain scores at all other follow-up points, changes in the mean CMS scores, and radiographic findings.  A total of 46 patients affected by noncalcific rotator cuff tendinopathies were randomly divided into 2 groups of 23 individuals. Patients in group A received 4 sessions of F-SWT, while patients in group B were treated by 4 sessions of R-SWT. In each session, mean energy flux density (EFD) for F-SW 3000 shots was 0.09 ± 0.018 mJ/mmp > 0.05). However, F-SWT resulted in significantly lower NRS compared with R-SWT at 24 weeks and 48 weeks after treatment . Similar results were found in CMS changes and radiographic findings.  There were no significant differences between the two groups regarding NRS pain score and CMS score within 24 weeks after intervention . This trial is registered with  Shoulder pain is frequently encountered in medical practice with the prevalence ranging from 7% to 27% in the general population . RotatorOver the past few decades, extracorporeal shockwave therapy (ESWT) has been widely used for the treatment of musculoskeletal disorders such as nonunion of long-bone fractures, lateral epicondylitis of the elbow, plantar fasciitis, chronic heel pain, and calcific rotator cuff tendinopathies . MultiplChiCTR1900022932). Our study was conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each participant.This prospective randomized controlled trial was approved by the Ethics Committee of China-Japan Friendship Hospital (No. 2009-2012), and it was registered at the Chinese Clinical Trial Registry  between 21 and 75 years old; (2) baseline NRS pain score of 5 or higher; (3) pain in the shoulder and/or exacerbation of pain with overhead-throwing activity; (4) decreased range of motion with shoulder flexion, abduction, and internal and external rotation; (5) these symptoms had to be present for at least 3 months; and (6) MRI found only intensity changes in the rotator cuff and absence of full-thickness tears in the tendon. The diagnosis was primarily based on history and MRI; however, X-ray was used to exclude calcific rotator cuff tendinopathies. Patients were excluded if they met any of the following criteria: (1) significant atrophy of any of the shoulder girdle muscles; (2) failed previous focused or radial ESWT in the affected shoulder; (3) previous surgery in the affected shoulder; (4) recent (<6 weeks) corticosteroid injection, needling, or nerve block in the shoulder region; (5) recent (<3 months) platelet-rich plasma or stem cell injection in the affected shoulder; (6) current cancer, or cancer in the past 5 years; (7) coagulation abnormalities, or current prescription strength anticoagulation medication ; and (8) presence of any condition or abnormality that in the opinion of the investigator would compromise the safety of the patient or the quality of the data.Based on previously reported studies , we assuSubjects were randomly allocated to either F-SWT or R-SWT groups based on a computer-generated randomized block design. Block randomization was utilized to balance the group with a block size of 4 and F-SWT: R-SWT ratio of 1 : 1 in each block. The randomization allocation was sealed in opaque envelopes, and the clinical coordinator did not know which group the subject would be assigned to until the envelopes were opened. The assessors and statisticians were blinded until the completion of the study. It is impossible to blind the patients and therapist because the machines can make different sounds.The regions of tendinopathy were identified by MRI, and the corresponding surfaces of the regions were marked. The patients were asked to sit and took some special activities to expose the lesions: with his hands behind his back , to expose the supraspinatus tendon; hands in front with the arm externally rotated to expose the subscapularis tendon; and hands in front with the arm slightly internally rotated to expose infraspinatus tendon and teres minor tendon.2). We started at level 2 within the beginning of 160 shots. Then, we raised one energy level every 160 shots up to a maximum of level 10. All remaining shocks are at the maximum energy level. In general, the maximum energy that people can tolerate is between level 6 and level 10 . As a result, the mean energy flux density for the 3000 focused shots was 0.09 ± 0.018 (mean ± SD) mJ/mm2, and the frequency is 5.11 ± 0.46 Hz (mean ± SD).Each patient will receive ESWT (F-SWT or R-SWT) once a week , for a total of 4 sessions. Every session consists of 3000 shockwaves, targeted to the marked area. F-SWT will be performed using the Dornier Aries device which was an electromagnetic device at level 2-10 . The mean pressure was 4.0 ± 0.35 bar (mean ± SD), and the frequency is 3.2 ± 0.0 Hz (mean ± SD). Ultrasound coupling gel was used to minimize the loss of shockwave energy at the interface between the applicator head and the skin. Start at a low energy  and increase the energy level up to the maximum tolerable within 500 shockwaves. Then, increase the energy level slowly, up to a maximum of level 10 (F-SWT device), 5 bar (R-SWT device). No local anesthesia, analgesics, or nonsteroidal anti-inflammatory drugs were used during the procedure. Because the immediate inflammatory action of ESWT may be important for efficacy in musculoskeletal pain conditions, NSAID use is strongly discouraged during the 4-week treatment period. After the intervention, patients in both groups were required to active their shoulders immediately. They can do daily activities but avoid lifting heavy objects until 12 months later. No other therapies were allowed until they finished the study.All subjects will receive follow-up visits at 4, 12, 24, and 48 weeks after the final treatment session. The primary endpoint was the change of the numerical rating scale (NRS) of pain from baseline to week 24. The 11-point NRS  has been recommended as a primary endpoint for chronic pain studies by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials . The CMSThe MRI examinations were performed based on a standardized protocol for the evaluation of rotator cuff pathology. All patients were placed in the supine position with the arm in external rotation. Proton density, T1-weighted, T2-weighted, and fat-saturated spin-echo images were obtained in oblique, coronal, axial, and sagittal imaging planes. This was achieved by using a 16-channel phased-array sensitivity-encoding (SENSE) body coil on a Philips Ingenia 3.0-T MRI machine . MRI images will be obtained at pretreatment, 24 and 48 weeks after intervention. Images were evaluated by one experienced musculoskeletal radiologist; any ambiguity was resolved through discussion with another radiologist, and two radiologists had to come to a consensus. All the radiologists were blinded to the groups in the process. Rotator cuff tendinopathies were graded according to the criteria established by Sein et al. , 15. In t-test, Mann-Whitney U-test, chi-square test, and Fisher's exact test, as appropriate. Computed p values were two-sided, and p < 0.05 was considered statistically significant.All data analyses were performed using SPSS version 20.0 software . Continuous variables were presented as means ± standard deviations, and categorical variables were presented as counts. Comparisons between groups were performed using the unpaired p > 0.05) between the two randomized groups.From June 2018 to February 2019, 60 patients with noncalcific rotator cuff tendinopathies were assessed for eligibility. Ten patients were excluded according to exclusion criteria; four patients were reluctant to join in the trial, leaving 46 patients for the study. After randomization, there were 23 patients in each group. All patients finished the treatment protocol. After the 48-week follow-up period, each group lost one patient because of changed contact information, so the total of 44 patients entered the result analysis finally . The basp < 0.001; At 24 weeks after intervention, the mean NRS pain score decreased from 5.9 ± 0.9 to 2.7 ± 1.0 in group A, while from 5.5 ± 0.7 to 4.5 ± 1.2 in group B. Moreover, the difference between the two groups is statistically significant (p > 0.05). Another significant difference of NRS pain scores was seen at 48 weeks between the F-SWT group and the R-SWT group  and 48 weeks . The subscales such as pain, ADL, and ROM are generally consistent with the total CMS score. At 24 weeks, significantly higher scores for pain and ADL were observed in the F-SWT group. At 48 weeks, all subscales (except power) showed significantly higher scores in the F-SWT group.p = 0.024). After 48 weeks, 100% (22/22) of patients in group A and 50% (11/22) of patients in group B decreased more than one grade of MRI findings in tendon. As a result, 100% (22/22) of patients in group A are with grade I or II while 82% (18/22) of patients in group B are with grade II or III (p = 0.032).Grades of MRI findings in tendinopathy are presented in An adverse event (AE) is defined as an untoward medical occurrence in a clinical investigation, and it does not necessarily imply a causal relationship with the treatment. Adverse effects were assessed by clinical examination, MRI scan, and patients' feedback. Patients were explicitly asked to report any skin reddening, bruising, ecchymosis, small hematoma, welling, paresthesia, hypoesthesia at the treatment site, myalgia, or rash or itching caused by reaction to ultrasound gel. Patients were also asked to report any other adverse events. In the F-SWT group, 5 patients reported moderate pain, 1 patient reported syncope, and 2 patients occurred skin redness. In the R-SWT group, 3 patients reported moderate pain and 1 reported migraine. No other adverse effects were noted in both groups.Recently, surgery of rotator cuff tendinopathy is gradually being superseded by new options focusing on minimally invasive . SeveralAccording to our study, both types of ESWT can relieve the pain immediately after therapy. The beneficial effect appeared significantly earlier than those in the traditional conservative therapy such as nonsteroidal anti-inflammatory drugs and local corticosteroid injections . There aHowever, there are no statistically significant differences between the two groups until 24 weeks after the intervention. The results are similar to previous studies exploring the effectiveness of the two types of ESWT on other diseases. The trial by van der Worp et al.  compared2] × mm2 × number) (mJ). However, considering the patient's tolerance to ESWT, R-SWT with medium EFD (4.0 ± 0.35 bar) and F-SWT with low EFD (0.09 ± 0.018 mJ/mm2) were used in our study. Using different energy levels may cause unequal total energy delivered to the tissue. According to previous studies [The most important finding of the present study was that focused shockwaves appeared to be significantly superior to radial shockwaves at 24 weeks and 48 weeks. Several studies –29 also  4.0 ± 0. bar and In addition, our results also showed that all subscales (except power) of CMS are generally in line with the total CMS scores. According to Stiller and Uhl , the subWe also found patients treated by F-SWT showed more radiological improvement than R-SWT. The reduction of high signal intensity in T2 paralleled to pain relief and function improvement. This makes the results more reliable. Miniaci and Salonen believed that MRI was the golden standard for the diagnosis of noncalcific shoulder tendinopathies . KjellinAt last, this study provides some suggestions for the use of ESWT in clinical practice. The introduction of R-SWT and F-SWT made ESWT more affordable and easier to administer. However, there is no agreement in the literature as to which ESWT is more effective for tendinopathies. Based on our study, we recommend F-SWT to treat noncalcific rotator cuff tendinopathies. We had better to try this therapy before more radical options like surgery.2) focused ESWT with 5 Hz to medium energetic (4.0 bar approximately correspond to 0.2 mJ/mm2) radial ESWT with 3 Hz. The effect of different energy levels has been considered and discussed in the study; however, different frequencies may also lead to the unequal effect. Further studies are needed to explore the relationship between therapeutic effect and frequency of ESWT. Second, our study is absent of one placebo group receiving sham shockwave therapy. However, it is difficult to create a placebo group, as people generally know that shockwave therapy elicits strong physical sensations and it is an unethical practice to use sham therapy on patients. Third, we lack a control group to test the results of other conservative therapies such as nonsteroidal anti-inflammatory drugs and local corticosteroid injections. Thus, we cannot learn whether the two types of shockwaves will provide more benefits than the other conservative therapies. Last but not the least, we performed the study in a small number of patients, so statistical analyses could be affected by a low sample size.This study is a prospective randomized study with a rigorous design, a clinically feasible intervention, and sufficient follow-up. However, there are still some limitations as follows. First, we roughly compared low energetic (0.09 mJ/mmLow energetic F-SWT appeared to be more effective than medium energetic R-SWT at long-term follow-up (more than 24 weeks). Based on the present clinical results, we recommend F-SWT to treat noncalcific rotator cuff tendinopathies. Our findings need to be confirmed in high-quality randomized controlled trials.


Background: Nefopam is a non-opioid, non-steroidal, central acting drug used effectively for postoperative pain. The efficacy of nefopam for cancer pain remains unclear. We aimed to evaluate the analgesic efficacy of nefopam for cancer pain in a randomized controlled trial.Methods: Patients with moderate to severe cancer pain (n=40) were randomly divided into two groups. The nefopam group (n=20) received three 20 mg doses of nefopam every 8 hours. The placebo group (n=20) received normal saline. Intravenous patient-controlled analgesia with morphine was given for breakthrough pain for 48 hours. The primary outcome was significant pain reduction. Secondary outcomes were morphine consumption over 48 hours and incidence of side effects.Results: The nefopam group showed pain reduction at 12 hours (65% of patients), 24 hours (80%), 36 hours (85%), and 48 hours (65%). The placebo group showed pain reduction at 12 hours (70%), 24 hours (75%), 36 hours (80%), and 48 hours (60%). However, there were no statistically significant differences between the groups (p>0.05). The median dosage of morphine consumption in 48 hours was lower in the nefopam group (25.5 mg) compared with the placebo group (37 mg), but this was not statistically significant (p=0.499). There were no statistically significant differences in blood pressure and heart rate between the groups. Side effects in both groups were comparable.Conclusions: At dosage of 60 mg in 24 hours, nefopam did not provide significant pain reduction in moderate to severe cancer pain patients. However, there was a trend of reduced opioid consumption. Further studies with larger sample sizes, longer duration, or higher doses of nefopam are warranted.Registration: Thai Clinical Trail Registry (TCTR) IDTCTR20181016001; registered on 12 October 2018. The prevalence of pain among patients with cancer remains high worldwide. A systematic review and meta-analysis showed pooled pain prevalence rates of 39.3% after curative treatment, 55% during cancer treatment, 66.4% in advanced or terminal stages, and 50.7% in all cancer stages2.Pain is one of the most common and distressing cancer symptoms. Despite development of new drugs and modalities for treating cancer pain during the past decade, around half of patients with cancer suffer from moderate to severe pain, which impacts their quality of life3. However, these drugs may be contraindicated for some patients. Additionally, these medications may result in various intolerable adverse effects. For example: opioids can cause nausea, vomiting, constipation, drowsiness, and dry mouth4; paracetamol may induce hepatotoxicity5; and NSAIDs should be used with caution in high-risk patients who are aging or with pre-existing renal or gastrointestinal disease, hypovolemia, prior peptic ulcer disease, and renal impairment6.World Health Organization guidelines recommend starting medications such as non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, or opioids in all adults with cancer-related pain when pain management is initiated7. It also inhibits calcium influx and blocks voltage-sensitive sodium channels, which leads to decreased activation of post-synaptic glutamatergic receptors such as N-methyl-D-aspartate (NMDA) receptors8. Nefopam does not bind to the opioid receptors that may suppress respiration and has no anti-inflammatory or antiplatelet effects.Nefopam is a centrally acting non-opioid, non-steroidal analgesic agent that inhibits the reuptake of serotonin, norepinephrine, and dopamine10. However, few studies have evaluated the efficacy of nefopam for cancer pain. It remains unclear whether nefopam has value as an adjuvant or alternative to analgesia in management of cancer pain. This study aimed to evaluate the analgesic efficacy of nefopam for moderate to severe cancer pain. We also evaluated concurrent morphine consumption and adverse effects during nefopam administration.The role of nefopam in treating pain has been investigated in several animal models and clinical human studies. Nefopam was found to be an effective analgesic adjuvant, with studies showing some benefits in reducing postoperative opioid consumption following abdominal and orthopedic surgeriesTCTR20181016001). Written informed consent was obtained from patients to participate in the study. This study was conducted among patients with cancer who were admitted to Ramathibodi Hospital between October 2018 and March 2019.This double-blinded randomized controlled trial was approved by the Ramathibodi Hospital Ethical Committee  and was registered to the Thai Clinical Trials Registry (TCTR) on 12 October 2018 (Inclusion criteria were patients with cancer who: 1) were over 18 years of age, 2) had moderate to severe cancer pain defined by a numeric rating scale (NRS) score of 4/10 or over, and 3) required a strong opioid. Exclusion criteria were patients who were: 1) unable to report on the NRS, 2) unable to use the intravenous patient-controlled analgesia (IV-PCA) machine, 3) currently receiving radiotherapy or chemotherapy (within the past 3 weeks), 4) within 1 week postoperative, 5) receiving a monoamine oxidase inhibitor (within the past 30 days), 6) with a history of convulsive disorder, ischemic heart disease, or allergy to morphine, 7) pregnant, and 8) breastfeeding.After eligible patients signed the informed consent form, they are blindly randomized into two groups (a nefopam group and placebo group) by stratified permuted block randomization in a 1:1 ratio base on two stratification factors: sex  and current opioid use (naïve opioid user vs. non-naive opioid user). The randomization was performed by a research assistance who was not involved in the study. Allocation of the patients to each study group was concealed in an opaque envelope. All participants and outcome assessors were blinded to the group allocation.The nefopam group received 20 mg of nefopam in 100 ml normal saline (NSS) intravenously via an infusion pump over 30 minutes every 8 hours for a 24-hour period. The placebo group received 100 ml NSS intravenous infusion with a similar protocol. The agents, prepared by a nurse who was not involved in the study, were in identical appearance bottles; 100 ml of transparent, colorless solution, containing either nefopam (Acupan® BIOCODEX) or placebo. Other current medications were continued throughout the study period. IV-PCA with morphine was given for 48 hours using a similar protocol for all patients .All patients were educated on rating their pain from 0–10 using the NRS and operating the IV-PCA machine. Morphine consumption, NRS, blood pressure, and heart rate were measured every 4 hours over a 48-hour period and reported side effects were also collected. Significant pain reduction was defined as a decrease on the NRS of at least 30% from the initial score. New onset of tachycardia was defined as a heart rate equal to or higher than 120 beats per minute (bpm) that had increased by 20% from baseline measurements.The patients were withdrawn and labels were opened if they exhibited a heart rate over 150 bpm, arrhythmia, development of extreme unexpected events , or if the patient could not continue to use the PCA machine during the study period.11. Student’s t-tests or Mann-Whitney tests were used to test differences between groups for continuous variables such as body weight and cumulative morphine consumption. Fisher’s exact or chi-square tests were used for categorical variables such as gender and side effects. Repeated measures analysis of variance was used to compare blood pressure and heart rate between the groups over time. SPSS version 20.0  was used for all analyses. Ap-value less than 0.05 was considered to indicate statistical significance.With a desired power of 0.8, alpha level of 0.05, and a 30% dropout rate, the calculated sample size was 20 patients per groupIn total, 40 patients were assessed for eligibility and randomized to a nefopam group or a placebo group (20 patients in each group).The most common cancer type was gastrointestinal cancer (32.5%), and the majority of patients (67.5%) had metastases; consequently, the majority (67.5%) already had prescriptions for opioids for pain management at the time of enrollment. Some patients had also been prescribed analgesic adjuvants, such as tricyclic antidepressants and gabapentinoids. Demographic data for both groups are presented inIn the nefopam group, 65% of patients had significant pain reduction at 12 hours, 80% at 24 hours, 85% at 36 hours, and 65% at 48 hours. In the placebo group, there was significant pain reduction for 70% of patients at 12 hours, 75% at 24 hours, 80% at 36 hours, and 60% at 48 hours. There were no statistically significant differences between the groups at any measurement point p>0.05;.The median cumulative dose of morphine consumption in 48 hours was lower in the nefopam group (25.5 mg) compared with the placebo group (37 mg), but there were no statistically significant differences at any measurement point .p=0.066,p=0.213, andp=0.84, respectively). However, we found new onset of tachycardia in three patients (15%) in the nefopam group and four patients (20%) in the placebo group (p=0.68).Side effects such as nausea, vomiting, sweating, dry mouth, dizziness, and drowsiness were found in both groups . However15. A quantitative systematic review drew three main conclusions for nefopam in postoperative pain prevention: 1) nefopam had a morphine-sparing effect, 2) it decreased pain intensity at 24 hours postoperatively, and 3) it increased the risk for tachycardia and sweating16. Although the effectiveness of nefopam in chronic cancer- and non-cancer-related pain remains unclear, recent studies have investigated the analgesic protocols for nefopam, its effect on hyperalgesia, and its role in neuropathic pain18.In published guidelines, most recommendations concerning nefopam have focused on acute and postoperative pain control19 evaluated the analgesic efficacy of oral diclofenac, nefopam, and aspirin with codeine for chronic cancer pain, and found statistically significant pain relief for all treatments; however, that study had a high dropout rate (73.7%). In our study, the rescue of any breakthrough pain by IV-PCA was thought to prevent dropout because of insufficient pain control. In addition, the intravenous infusion protocol might have been able to prevent dropout because it decreased the risk for side effects.Evidence for the use of nefopam for cancer pain remains limited. Minotti and coworkers23. Central sensitization can also make cancer pain management more complicated. Its “wind up” phenomenon is also activated via NMDA receptors24. Nefopam is a non-opioid analgesia that is considered to act centrally. Its main mechanisms of action involve the inhibition of serotonin, norepinephrine, and dopamine reuptake and modulation of calcium and sodium channels, which leads to decreased activation of postsynaptic glutamatergic receptors  that are involved in development of hyperalgesia8. Consequently, we hypothesized that nefopam could be used as an adjuvant or alternative analgesia for cancer pain based on its various mechanisms of analgesic action. The pathophysiology of cancer-related pain is complex and may include several mechanisms such as local and systemic inflammatory responses, direct tumor-related pain, metastatic cancer-induced bone pain, and neuropathic pain25 or meperidine 50 mg26. Its plasma half-life is 3–5 hours and plasma peak concentration is reached after 30 minutes of continuous intravenous infusion16. Previous studies27 that evaluated higher doses of nefopam (maximum dose of 120 mg per day) in hepatic resection and orthopedic surgery found nefopam had a superior analgesic effect. We investigated the efficacy of nefopam at 60 mg per day, which had been found to be the effective dose 80 for moderate post-operative pain28. However, this dose might have been too low for moderate to severe cancer pain. Second, the treatment period might have been too short to allow discrimination of any differences. Third, the complex mechanisms of chronic cancer pain would be considerably hindrances of effective pain reduction.To the best of our knowledge, this study is the first randomized controlled study to evaluate efficacy of intravenous nefopam in moderate to severe cancer pain. However, nefopam did not show statistically significant pain reduction compared with placebo. This may be explained by various reasons. First, the drug potency might have been too low to control moderate to severe cancer pain. Some studies have suggested that in surgical settings, nefopam 20 mg should be equipotent to morphine 6–12 mg32 on postoperative pain have shown that nefopam reduced morphine consumption at 24–48 hours for 30–50% of patients, our study did not confirm this finding. However, the median cumulative dose of morphine showed a lower trend in the nefopam group at all measurement points, especially in opioid naive patients receiving nefopam. Further studies focusing on nefopam in opioid naive patients with cancer that include a larger sample size, have a longer duration, or use higher doses of nefopam may be beneficial. Although many previous studies16. However, the rate of side effects may be dissimilar in different patients and clinical settings. The low rate of adverse effects in this study might have been due to the mode of drug administration. Continuous intravenous administration avoids the peaks associated with periodic administration, as used in earlier study protocols.We found that side effects such as nausea, vomiting, sweating, dry mouth, dizziness, tachycardia, and drowsiness were comparably low in both groups. In one quantitative review, the results showed an increased risk for tachycardia (21.3%) and sweating (8.8%) in postoperative patients receiving nefopam28. Therefore, the low dose of nefopam and the short study period may explain why our study could not show differences in pain reduction between the two groups. Additionally, the baseline opioid dose in the non-opioid naive subgroup was not controlled, which might have affected the results. In addition, we did not evaluate pain characteristics, psychological parameters, and quality of life, which may have provided helpful information. Moreover, the incidence of analgesic-related side effects might have been underestimated because evaluation of side effects was only performed after 48 hours. Therefore, the incidence of temporary side effects that developed might have been omitted.There were some limitations in this study. We only investigated one dosage of intravenous nefopam (60 mg per day). This may be considered the lowest effective dose and, combined with the short duration of administration, was considered to reduce the risk for unfavorable adverse effectsAt a dosage of 60 mg per day, nefopam did not provide significant pain reduction in patients with moderate to severe cancer pain. However, this study showed a trend towards reduction of opioid consumption in the nefopam group. Further studies with larger sample sizes, longer duration, or higher doses of nefopam are warranted to further investigate the efficacy of nefopam for cancer pain.https://doi.org/10.6084/m9.figshare.1217742333.Figshare: Data of nefopam in cancer pain,https://doi.org/10.6084/m9.figshare.1224956934.Figshare: CONSORT 2010 Checklist for "Analgesic efficacy of nefopam for cancer pain: A randomized controlled study",Creative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the This study is very relevant to our today practice and important for the patients’ well-being and continuous health-care after suffering from cancer pain. Overall coverage and discussion are appropriate. The main limitation for this study is the number of sample and monitoring of the results which may hinder the purpose of the study. Adequate and covering the area of research but some area may need sources of the references. The methodology and flow of the study was clearly organized inclusive the randomization performed. This study was well constructed which included intravenous administration and back up with the patient controlled administration of morphine to hinder potential pain during the study. The table and the analysis of the result are adequate. The coverage of the discussion and suggestion are adequate. I would agree that the result might be different if the samples more that 20 patients for each arm. However, if the monitoring interval be shorter for examples 4 hourly or 6 hourly then we might see the significant different results of the study with the similar sample. Even-though Nefopam have multiple mode of action but how much they covered nociceptive and neuropathic pathway were not covered in this study and discussion. Cancer pain can be prominent either nociceptive or neuropathic pain and sometimes both which  causing dilemma for palliative to manages. It is good if in this study or discussion to highlight more on the aspect of nefopam coverage either on nociceptive or neuropathic or both to certain degree.Is the work clearly and accurately presented and does it cite the current literature?PartlyIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pain and palliativeI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. This is a placebo-controlled double-blind RCT comparing nefopam and placebo in moderate to severe cancer pain. The methodology and analysis is properly done and the results are clear. Unfortunately, the sample size is small with only 20 patients per group.  As the patients in both groups were given an IV-PCA pump to use, I am not surprised that there was no difference in the NRS pain scores for 48 hours. A better indication would be a difference in the morphine consumption - which could have been the primary outcome of this study.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pain ManagementI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


The primary outcomes were pain reduction in numerical rating scale (NRS) and opioid requirement reduction. Secondary outcomes were: successful pain response (NRS decrease ≥50% or ≥3-point reduction from baseline); quality of life; patient satisfaction; adverse events; and survival rate at 3 months postintervention. Both groups reported sustained decreases in pain scores up to 3 months postintervention : −0.8 to 4.2) and 1.7 (95% CI: −0.3 to 2.1); back pain: 1.3 (95% CI: −0.9 to 3.4) and 2.5 (95% CI: −0.2 to 5.2) in EUS-CN, and PCN groups, respectively). The differences in mean pain scores between the two groups at baseline and 3 months were −0.5 (p = 0.46) and −1.4 (p = 0.11) for abdominal pain and 0.1 (p = 0.85) and −0.9 (p = 0.31) for back pain in favor of PCN. No significant differences were noted in opioid requirement reduction and other outcomes. EUS-CN and PCN were similarly effective and safe in managing intractable pain in pancreatic cancer patients. Either methods may be used depending on the resources and expertise of each institution. Although endoscopic ultrasound-guided celiac neurolysis (EUS-CN) and percutaneous celiac neurolysis (PCN) are utilized to manage intractable pain in pancreatic cancer patients, no direct comparison has been made between the two methods. We compared the efficacy and safety of EUS-CN and PCN in managing intractable pain in such patients. Sixty pancreatic cancer patients with intractable pain were randomly assigned to EUS-CN ( Pancreatic cancer has an overall 5-year survival rate of about 6% and is thus one of the leading contributors of cancer-related deaths in the world . WhereasA commonly used method of CN is percutaneous CN (PCN) ,10, whicCN can also be carried out under endoscopic ultrasound (EUS) guidance. Two methods of EUS-guided CN (EUS-CN) are available: EUS-guided celiac plexus neurolysis (EUS-CPN), which injects neurolytic agents at or near the plexus of celiac nerve; and EUS-guided celiac ganglia neurolysis, which directly injects neurolytic agents in the celiac ganglia ,15,16. EAlthough both EUS-CN and PCN are widely used, the selection between the two methods has not been based on robust evidence, let alone a randomized, controlled study comparing EUS-CN and PCN for management of cancer pain. One recent expert panel-based guideline  recommenThis prospective, randomized, assessor blind study was conducted at Asan Medical Center in Seoul, Korea and was registered in Clinical Research Information Service (KCT0002350). The study was approved by the Institutional Review Board of Asan Medical Center . We followed the CONSORT guidelines to report this study. Patients with pancreatic cancer who were deemed as non-surgical candidates and also met the following criteria were considered for randomization: (1) diagnosis of pancreatic cancer based on clinical, radiological, or pathological assessment; (2) referred for abdominal and/or back pain due to pancreatic cancer; (3) between 20 and 80 years of age; (4) no prior CN; (5) cancer pain unresponsive to the WHO 3-step analgesic ladder; and (6) willingness to consent for the participation in the trial. Patients were excluded if they: (1) did not agree to participate in the study; or had (2) surgically resectable pancreatic cancer; (3) documented side effects to local anesthetics or steroids; (4) pain unrelated to pancreatic cancer; (5) hemostatic abnormality; (6) evidence of concurrent infection; (7) yellow flag sign ; or (8) http://www.randomization.com) by a clinical research coordinator who was not involved in patient diagnosis. The patients and the attending physicians  were not blinded to the treatment allocation; the physicians who performed the procedures were not actively involved in the care of the participants. The doses of opioids were adjusted by the attending medical oncologists to provide best supportive care for the patients. Both the assessor (Y.O.) of the patients after the intervention and the statistician (S.Si.C.) who analyzed the data were blinded to the treatment allocation. Patients who met the inclusion criteria were allocated in a 1:1 ratio to EUS-CN or PCN by randomization without risk stratification. Block randomization was employed in order to assign equal numbers of patients in each treatment group; block sizes were randomly permuted to make the allocation process unpredictable. Randomization was conducted by using a web-based program  ranging from 0 (no pain) to 10 (worst pain possible). Changes in concomitant analgesic therapy were evaluated by calculating the changes of daily opioid use converted to total daily oral morphine equivalent dose (MED), which assumes that different opioids with different doses produce a similar analgesic effect . SecondaThe number of participants was determined using the reduction in the severity of pain at 3 months after the intervention as measured with NRS. In previous studies, the difference in average NRS at 3 months after the CN procedure was 4.28 with a standard deviation of 0.68 in patients treated with EUS-CPN , and 3.6p values < 0.05 were considered to indicate statistically significant difference. All data manipulations and statistical analyses except for survival analysis were performed using SPSS version 21  and Stata version 13.1 . Survival analyses were performed using MedCalc for Windows, version 15.0 .All observed data were analyzed on an intention-to-treat (ITT) basis, regardless of loss to follow-up or dropout from the study. Considering possible data loss resulting from dropout and treatment failure, a linear mixed-effect model was used to analyze and compare the continuous variables  between baseline and each follow-up. To compare the repeated data of successful responders (binary outcome) among groups, a generalized estimating equation was used. Patient survival at 3 months was estimated using the Kaplan–Meier method and compared using the log-rank test. Two-tailed n = 3; declined to participate: n = 14). A total of 60 patients who fulfilled the inclusion criteria agreed to participate in this study. Thirty patients were randomized to each group. All participants received the allocated treatment and were included in the ITT population  for EUS-CN group; n = 17 (56.7%) for PCN group). There were no significant differences in the baseline characteristics of the type and amount of the opioids (p = 0.018).The two groups did not show significant differences in the baseline demographic and clinical characteristics . Except  opioids . The meaThe estimated mean changes in pain scores are shown in p = 0.11) in favor of PCN, albeit no significant differences were observed between the two groups at each follow-up time point  at baseline and −1.4 (95% CI: −3.1 to 0.3) at 3 months (me point . Similarp = 0.22), except at 2 months after intervention (p = 0.17).The overall difference in opioid consumption between the two groups was not statistically significant (rvention . Similarp = 0.80), 1 month  for EUS-CN vs. 70.0% (95% CI: 53.6 to 86.4) for PCN, p = 0.29), and 3 months  for EUS-CN and 36.7% (95% CI: 19.4 to 53.9) for PCN, p = 0.26) after treatment, respectively. The overall estimated proportions of successful pain response were not significantly different between the two groups . As shown in p = 0.24).The estimated successful pain response rates were not significantly different between the two groups at 1 week  for EUS-CN vs. 56.7% (95% CI: 38.9 to 74.4) for PCN, Serious AEs were not observed in any study participant, and all AEs that presented during and after interventions were mild and transient . Hypotenp = 0.73; n = 25) had a higher survival rate than those who only underwent EUS-CPN (n = 5), albeit not statistically significant (p = 0.054).Survival rates at 3 months in the EUS-CN group and the PCN group were 56.7% (95% CI: 37.3 to 72.1) and 60.0% (95% CI: 40.5 to 75.0), which did not show significant differences according to Kaplan–Meier analysis  reported in previous studies ,29. HoweIn conclusion, both EUS-CN and PCN may be regarded as viable options in the management of intractable pain in pancreatic cancer patients. Physicians may choose between EUS-CN and PCN depending on the level of technical expertise and availability of resources at each institution.


Background: Pain assessment is a challenge in critically ill patients, in particular those who are unable to express movements in reaction to noxious stimuli. The purpose of the study was to compare the pupillary response and skin conductance to pain stimulation in critically ill unconscious patients. Methods: This observational study included adult patients admitted to the intensive care unit (ICU) with acute brain injury  and/or requirements for deep level of sedation. Automated pupillometry  was used to determine pupillary reflex dilation during tetanic stimulation. The maximum intensity of the stimulation value allowed the determination of a pupillary pain index score ranging from 1 (no nociception) to 9 (high nociception): a pupillary pain index (PPI) score of ≤4 was used to reflect adequate pain control. For skin conductance (SC), the number of SC peaks per second (NSCF) was collected concomitantly to tetanic stimulation. An NSCF of ≤0.07 peak/second was used to reflect adequate pain control. Results: Of the 51 included patients, there were 32 with brain injury and 19 receiving deep sedation. Mean PPI score was 5 (Interquartile Range= 2–7); a total of 28 (55%) patients showed inadequate control of the nociceptive stimulation according to the PPI assessment. Only 15 (29%) patients showed a detectable skin conductance, with NSCF values from 0.07 to 0.47/s. No correlation was found between skin conductance algesimeter (SCA)-derived variables and PPI score or pupillary dilation to pain. Conclusions: Detection of inadequate pain control might vary according to the method used to assess nociception in ICU patients. A poor agreement between quantitative pupillometry and skin conductance was observed. Pain is a frequent event during critical illness; however, its assessment in patients continues to be a challenge for critical care clinicians . In one In this context, efforts have been made to develop non-clinical quantification of nociception. Vital signs, such as changes in heart rate, blood pressure, respiratory rate, and oxygen saturation, were found as poor indicators of nociception . TechnolThe aim of this study was therefore to compare concomitant measurements of pupillometry and skin conductance during noxious stimulation in critically ill unconscious patients. The primary objective of this pilot study was to compare the number of patients with no evidence of nociception using each technique.In this monocentric, prospective, and observational study conducted between 1 April 2019 and 15 August 2019, adult patients admitted to the ICU of Erasme Hospital, Brussels, Belgium were enrolled if they met the following inclusion criteria: an initial Glasgow coma score (GCS) scale <9 with a motor response <5, the requirement of deep level of sedation , and mechanical ventilation. Patients with known pupillary abnormalities, multiple sclerosis, ocular surgery, severe peri-orbital edema limiting pupillary assessment, pregnancy, or burns were not included. Patients were explored during weekdays, using concomitant measurements of quantitative pupillometry and skin conductance within the first 72 h of their admission to the ICU. Clinical assessment of pain was performed using the BPS; in patients receiving NMBAs, BPS was reported with the score of 3. The level of sedation was measured using the RASS score [Quantitative pupillometry was performed by two operators using an automated pupillometer . Two pupillary reflexes were explored: the pupil light reflex (PLR) and the pupil dilation reflex during noxious stimulation. To measure PLR, a burst of light of fixed intensity 320 lux) and duration (one second) was emitted by the device to each eye. A minimum duration of one minute was allowed between appraisals of the two pupils to obtain full recovery of baseline pupil diameter after light stimulation. A total of 4 s is needed to evaluate baseline pupil size (mm), pupillary constriction rate , and constriction velocity (CV) (mm/s). Mean values from both eyes were used for baseline assessment. Anisocoria was defined as a difference of at least 1.0 mm between the two eyes [ lux and After baseline assessment , an elec®; MED-STORM Innovation AS, Oslo, Norway) was used. Three single use Ag/AgCl electrodes were attached to the palmar surface of the patient’s hand , on the opposite site to the pupillometry’s electrodes. The PainMonitorTM, a measurement unit connected with such electrodes, was used to provide a small electrical signal between the electrodes in order to evaluate the skin conductance, which was recorded on a computer with dedicated software to analyze the electrical signal. Skin conductance was measured using an alternating current . The following parameters were collected: (a) the number of skin conductance fluctuations per second (NSCF) or number of peaks/second; (b) average peak ; (c) average rise (μSs) that is the mean of skin conductance related to the basal sympathetic tone; and (d) area under huge peak (μSs) and area under small peak (μSs). These parameters were automatically calculated by the device and analyzed during a window of 15 s, the update being made second by second. The mean value for each of these variables, representing the 15-s window at baseline and after the stimulation, was extracted for analysis. The cut-off that identifies a normal skin conductance is 0.02 μSs, as showed in previous studies [Skin conductance was monitored during five minutes at baseline assessment before the tetanic electrical stimulation. A skin conductance monitor  score on ICU. Reasons for ICU admission as well as the presence of primary brain injury and concomitant therapies ) were also collected. The use of drugs that might interfere with pupillary constriction  and of anti-epileptic drugs was also noted. Typical procedures, such as washing, turning the patient, physiotherapy, or invasive procedures were not allowed during the study period. No adjustment of data to reduce the potential sources of bias was performed.t-test or a Wilcoxon rank test for paired continuous variables, and a t-test or a Mann–Whitney-U test for continuous independent variables. To test the relationship between automated pupillometry and SCA-derived variables, Pearson’s (or Spearman) correlation analyses were performed, accordingly. The agreement between the two techniques was evaluated by comparing the number of patients with adequate pain control (PPI ≤ 4 and NSCF < 0.07) using Cohen’s Kappa coefficient. An additional analysis comparing patients with and without primary brain injury was also performed. Furthermore, characteristics of patients with concordant and non-concordant results from the two techniques were analyzed. A p < 0.05 was considered statistically significant. Statistical analyses were performed using IBM SPSS Statistics 25.0 for Macintosh . Using the upper confidence interval for the population variance approach to the sample size calculation, a pilot sample size between 30 and 50 was chosen, corresponding to standardized effect sizes of 0.4 and 0.7  [Discrete variables were expressed as counts (percentage) and continuous variables as means ± standard deviation (SD) or median (25th–75th percentiles) as appropriate. The Kolmogorov–Smirnov test were used and histograms and normal-quartile plots examined to verify the normality of distribution of continuous variables. Differences between groups were assessed using a χ-square or Fisher’s exact test for categorical variables, as appropriate, a paired ulation) .n = 13), hemorrhagic stroke (n = 13), traumatic brain injury (n = 5), and status epilepticus (n = 1). Other included patients had septic shock (n = 4), cardiogenic shock (n = 4), hemorrhagic shock (n = 2), acute respiratory distress syndrome (n = 7), respiratory failure after heart or lung organ transplantation (n = 2), and acute chronic liver failure (n = 1). The median time from ICU admission to the pain study was 2 (1–4) days. In the study cohort, 39 patients (76%) were receiving opioids (33/39 sufentanil) and 38 (75%) receiving sedatives . Fifteen (29%) patients were treated with a continuous infusion of NMBAs. ICU mortality was 37% (n = 19). A total of 51 patients were included during the study period; 22 other patients were eligible but not included: 11 admitted during the weekend, 9 refusals to participate, and 2 with previous ocular surgery. Characteristics of the study population are shown in At baseline, mean pupil size was 2.7 (2.2–3.2) mm, PLR was 20 (13–25)% and mean constriction velocity was 1.26 (0.98–2.19) mm/s. Only three patients had anisocoria. In two patients, NSCF was 0.27/s and 0.20/s at baseline, while all others had values of 0 for NSCF and other SCA-derived variables . All patp < 0.01), mean arterial pressure significantly increased from 83 (71–99) to 86 (71–101) mmHg (p = 0.01), and heart rate increased from 81 (71–99) to 83 (72–95) bpm (p = 0.04). Among the 36 patients with no NMBA treatment, 7 (19%) showed an increase of BPS from baseline ranged from 4 to 8. Median PPI score after stimulation was 5 (2–7); a total of 28 (55%) patients showed inadequate control of the nociceptive stimulation according to the PPI assessment. Concomitantly, 15 patients had a detectable skin conductance with NSCF ranged from 0.07 to 0.47/s  to 24 (17–30)/min .A disagreement  between the two techniques was found in 25/51 patients: 6 had detectable NSCF with PPI ≤ 4 and 19 had high PPI with undetectable skin conductance . Thus, tOn the day of nociceptive stimulation assessment, patients with brain injury had significantly higher blood pressure and arterial saturation, despite a similar pupil size and a lower constriction rate and constriction velocity at light stimulation compared to others . They alIn this study including a heterogenous population of critically ill patients on mechanical ventilation, 55% of them had inadequate control of the nociceptive stimulation according to the PPI assessment, and 29% of them had a detectable skin conductance. The two techniques showed poor agreement in the assessment of the response to noxious stimulation.Critically ill patients are very likely to experience nociception from many causes; however, as many ICU patients are unable to communicate their nociception because of altered consciousness, sedation, or mechanical ventilation, unrelieved pain is a major challenge for clinicians and requires adequate detection. The gold standard in pain evaluation is patient self-reporting, which is not always possible. Current research has shown that the two tools best validated for patients unable to self-report their pain are the BPS and the critical care pain observation tool . HoweverThe use of pupillary reflex dilation has shown some promising findings. During general anesthesia, pupil reflex dilatation has shown greater sensitivity, when compared with other variables such as heart rate and blood pressure, to assess response to noxious stimulation ,27, and The skin conductance algesimeter is a device that has some potential in ICU patients as its accuracy is minimally biased by confounders, such as shock, medications, or hypothermia, which are frequently observed during critically illness . In one It remains difficult to explain the discrepancy in the number of patients with inadequate analgesia between automated pupillometry and SCA. We can speculate that the two devices have a different sensitivity for pain detection when sedatives and analgesics are used; as this situation is also present in the operative setting, it is possible that the presence of a critical illness, of an inflammatory status, or of brain damage would negatively affect the capacity of skin conductance to adequately assess pain in this setting. Moreover, as critical illness is often associated with microvascular dysfunction, this phenomenon may potentially influence more peripheral release of catecholamines and autonomous nerves than ocular pathways. Moreover, the anatomic pain pathways, which are “tested” by the two monitoring tools, are different and this could also influence our findings. During emotion or pain, skin sympathetic nerves, although under the control of the cerebral cortex, activate palmar and plantar sweat glands that eventually increase skin conductance ; this phenomenon is mediated by the acetylcholine via the muscarine receptors . The conThis study had several limitations. First, the number of included patients was relatively small to make appropriate comparison of patients with and without brain injury. Moreover, the presence of patients with post-anoxic brain injury might provide an additional bias on the alterations of pain pathways and additional data on this specific population are required. Second, treatments for sedation and analgesia were not standardized, which might have introduced bias in the interpretation of data. The small number of patients prevented us from making appropriate adjustments. Third, the electrical stimulation was variable in time and/or intensity, i.e., adjusted according to PDR, and patients received therefore different degree of nociception; whether a tetanic stimulation of fixed and constant intensity would have been more appropriate to test nociception between the two monitoring tools remains unknown. Fourth, the effect of opioids on pupillary light reflex might provide an additional bias on the alterations of pain pathways and further studies are necessary to better define this issue. Finally, age is another important factor that can interfere with pupillary constriction or dilation, because the resting size of the pupil progressively decreases after the fourth decade of life; however, we did not adjust our observations on this variable.In this study, 55% of patients showed inadequate control of noxious stimulation according to the automated pupillometry assessment while changes in skin conductance were more limited. The two techniques showed a poor agreement in assessing pain in critically ill unconscious patients.


ObjectiveWe aimed to study the relationship between psychiatric Disorders (PD), preoperative pain, and opioid medication intake, as well as the quality of life patient-reported outcome measures using the Patient-Reported Outcomes Measurement Information System 29 (PROMIS-29) questionnaire, during the 30-day interval preceding surgery, in a consecutive series of patients who were scheduled to undergo surgical spine procedures. We hypothesized that PD could affect preoperative narcotic use and pain interference in a fashion that was not linearly associated with preoperative pain in spine surgery candidates.MethodsThe records of consecutive adult patients who underwent elective spinal surgery between October 2016 and August 2017 at a single institution were reviewed. We included patients who underwent preoperative pain assessment within 30 days prior to their planned surgery using the PROMIS-29 questionnaire. Patients with PD were compared to controls.ResultsA total of 117 patients matched our criteria. The average rating of pain intensity was notably higher in the PD group as compared to controls (p=0.004). The PD group had more patients complaining of high pain levels (>6) as compared to the control group (p=0.026). Controls with high pain levels had a greater incidence of preoperative narcotic use as compared to the low-pain cohort (p=0.029). However, there was no difference in the actual dose of daily narcotic medication taken between the PD and control groups (P=0.099) or between the low- and high pain score groups in the control (p=0.291) and PD (p=0.441) groups, respectively. Patients with PD and higher pain ratings seemed to have a higher incidence of anxiety (p=0.005) and depression (p<0.001). That was not the case for controls.ConclusionsPDs may impact the degree of preoperative pain interference and the intake of narcotic medication independently from pain intensity ratings. Spine surgery candidates have been shown to have higher exposure to opioid medication than the general population . A depreWe aimed to study the relationship between PD, preoperative pain and opioid medication intake, and quality of life patient-reported outcome measures, during the 30-day interval preceding surgery, in a consecutive series of patients who underwent surgical spine procedures. We hypothesized that PD could influence preoperative narcotic intake, as well as ratings of pain interference with activities of daily living independently from pain scores in surgical spine candidates.ProtocolThe study protocol was approved by our institutional review board (STU# 102017-011). This was a retrospective review of prospectively collected data at a single-center institution that included consecutive patients who underwent elective spine surgery between October 2016 and August 2017. We only included patients who underwent a preoperative pain assessment within 30 days prior to their planned surgery, as we wanted to include the most recent assessment prior to surgical intervention. Patient data were prospectively collected in our Spine Clinical Outcome Registry (SCORe) and retrospectively reviewed using our electronic medical record system for this analysis. Patient consent was not required for retrospective data pooling, as patient data were deidentified once collected as is standard at our institution.Population selection criteriaSpinal procedures included posterior cervical, anterior cervical, thoracic or lumbar short (≤4 segments) and thoracic or lumbar long (≥5 segments) decompression and/or fusion procedures. Inclusion criteria consisted of patients older than 18 years of age who underwent elective spine surgery and had available PROMIS-29 scores within 30 days prior to surgery. The PROMIS-29 questionnaire is a publicly available, validated instrument that has been shown to reliably assess patient well-being, mental and physical health, and overall quality of life -12.The patients were divided into two groups. Patients who had received a psychiatric diagnosis of depression, anxiety, bipolar disorder, and/or post-traumatic stress disorder were labeled as part of the psychiatric disorder group. The remainder of the cohort served as the control group. All patients with psychiatric disorders were diagnosed, followed, and treated by a certified psychiatrist at our institution. All patients in our cohort received a psychiatric assessment prior to surgery.Outcome measuresPerioperative Measures and PrognosisDemographic and clinical variables were collected to ensure uniformity between the psychiatric disorder and control groups. Demographic variables included age, gender, and race. Perioperative outcome measures included preoperative narcotic, alcohol, and tobacco use and prior history of spine surgery. PROMIS-29 criteria included pain, depression, and anxiety ratings collected within 30 days prior to the spinal procedure using the pain intensity, pain interference, depression, and anxiety domains. Pain intensity was assessed on a 10-point numeric scale. High-intensity pain was defined as a score of >6, as it corresponds to “very severe” and “worst pain possible’ on the visual analog scale . The paiStatistical analysisDescriptive statistics included mean and standard deviation (SD). For continuous variables, significance was assessed using a one-tailed t-test. Fisher’s exact test was used to compare dichotomous variables between groups and assess differences in incidence. Statistical significance was set at ɑ = 0.05. The software used for the statistical analysis was the Statistical Package for the Social Sciences (SPSS) version 25 .Patient demographicsA total of 117 patients were identified to be included in the study. The PD group consisted of 61 patients and the control group of 56 patients  with an unspecified mood disorder. Seventy-five percent of patients were on antidepressants, 37.5% on anxiolytics, and 4.17% on a mood stabilizer. All patients were included in our analysis.Pain rating in the PD and control groupsThe average rating of pain intensity was notably higher in the psychiatric disorder group as compared to the control group  Table .Preoperative characteristics and postoperative outcomes in the PD and control groups in the function of pain scoresTable Patient demographicsFor both the PD and control groups, most Black patients were in the high-pain cohort . Amongst controls, Hispanics fell into the low-pain cohort . White patients were similarly distributed between pain groups. The average age of controls in the high-pain cohort was greater than the low-pain cohort , but that was not the case for PD patients.Patient social and past medical variablesThere was no difference in smoking history, ethanol use, and surgical history between patients with psychiatric disorders and controls Table . This rePROMIS-29 ratingsPatients with higher pain ratings appeared to have higher pain interference scores in both the control (p=0.004) and psychiatric disorder (p<0.001) cohorts. Patients with PD who had higher pain ratings seemed to have a higher incidence of anxiety (p=0.005) and depression (p<0.001). That was not the case for controls.Procedural characteristicsIn both the PD and control groups, patients who were scheduled to undergo lumbar short surgeries tended to report higher levels of preoperative pain . Conversely, the majority of patients who had anterior cervical surgery planned reported lower levels of preoperative pain .Perioperative outcomesThe average length of postoperative hospital stay and the incidence of intraoperative and postoperative complications, emergency department visits within six weeks after surgery, and readmission rates 30 days postoperatively were not significantly different between the low-pain and high-pain cohorts Table .The objective of this study was to investigate the impact of PD on preoperative pain ratings, pain interference using the PROMIS-29 questionnaire, and preoperative narcotic use. The population we examined consisted of patients with symptomatic spine disease that underwent surgery at a single institution within 30 days after their preoperative visit and interview. Psychiatric disorders have been shown to negatively impact postoperative pain and outcomes after spine surgery ,15, and The PD and control cohorts had comparable demographic characteristics when examining race, smoking and alcohol consumption history, and the incidence of prior spine surgery. However, there was a preponderance of women in the PD group, which is consistent with previously published data -24. PD pWhen examining the PROMIS-29 questionnaire domains, patients with higher pain scores appeared to have a higher incidence of pain interference in both the control and PD groups. However, it was only in the PD group that higher pain ratings were also associated with a higher incidence of depression and anxiety. It is important to note that the low and high-pain categories in both the PD and control groups were comparable in the incidence of risk factors that have been previously associated with depression and the worsened perception of pain such as smoking  and ethaPrevious publications have shown an increase in preoperative opioid use among spine surgery candidates, especially in patients with depression -2. Our dDespite variable patterns of preoperative pain intensity, pain interference, and opioid consumption, the incidence of intraoperative complications, average length of hospital stay, postoperative complications, emergency department visits within six weeks, and readmission 30 days postoperatively were not significantly different between the low-pain and high-pain cohorts in the PD and control groups but that may be an effect of small sample size. As expected, patients with lumbar disease who were scheduled to undergo lumbar procedures complained of higher pain than patients with anterior cervical disease. Future studies of patient satisfaction at their postoperative follow-up will help us better define the impact of preoperative pain in individuals with PD undergoing spine surgery.Study limitationsOur study has several limitations. First, the retrospective nature of this study imposes limitations on patient selection, which explains the heterogeneous nature of our surgical population. Second, there was a gender disparity between the control and study groups. While the psychiatric disorder group consisted mostly of Caucasian females, our control group was dominated by Caucasian males. This is consistent with current data demonstrating that women are more likely than men to be diagnosed with a psychiatric disorder. The perception of pain may also be influenced by gender, and this may have affected the pain rating comparison between the PD and control groups.Spine surgery candidates with psychiatric disorders are more likely to have a higher preoperative pain rating. The incidence of narcotic medication intake is greater in patients with increased pain scores, although that does not appear to be the case in individuals with psychiatric disorders. It appears that psychiatric disorders may impact the degree of preoperative pain interference and the intake of narcotic medication independently from pain intensity ratings. These findings highlight the importance of detecting and treating depression and anxiety in patients suffering from spine disorders, regardless of surgical intervention planning.


Acute postsurgical pain, probably including acute neuropathic pain (ANeP), starts at the early postoperative period, and chronic postsurgical pain including chronic neuropathic pain (CNeP) persists at least 3 months after surgery. Although it must be important for prevention and treatment of acute and chronic postoperative pain to reveal the time course of postoperative neuropathic characteristics, a neuropathic pain profile after surgery has not been evaluated.Pain status at the surgical site in adult patients who underwent video-assisted thoracic surgery (VATS) for lung cancer was prospectively assessed until 12 months after surgery. Neuropathic characteristics were assessed using the Douleur Neuropathique 4 (DN4) questionnaire until 6 days after surgery and the DN2 questionnaire throughout the study.Twenty-seven patients were enrolled in this study. Pain intensity at surgical sites were significantly higher at 1 and 6 days after surgery during resting state, and were also significantly higher at 3, 6, and 12 months after surgery during movement than those before surgery. The incidence of ANeP was 33.3% at 1 day, and 18.5% at 6 days after surgery. The incidence of CNeP decreased to 12.5% at 3 months, 5.0% at 6 months, and 0.0% at 12 months after surgery. The number of neuropathic characteristics, assessed by DN2 scores, significantly increased at 1 and 6 days after surgery, compared to those before surgery. DN2 scores at 3, 6, and 12 months after surgery, however, showed no significant differences compared to those before surgery.In patients with acute postsurgical pain, 20% to 30% of patients show ANeP characteristics, and the incidence of CNeP gradually decreases after VATS in patients with chronic postsurgical pain. Recently, acute neuropathic pain (ANeP), which may start after trauma at the somatosensory nerve system, likely emerges in the early postoperative period.–5 Since mechanisms of transition from acute to chronic postsurgical pain is thought to include the development of ANeP and CNeP,,4,5 it must be important for prevention and treatment of acute and chronic postsurgical pain to understand the time course of neuropathic characteristics after surgery. A neuropathic pain profile after surgery, however, has not been evaluated. In the present study, to reveal the neuropathic pain profiles after surgery, we prospectively examined the time course of the Douleur Neuropathique 4 (DN4) and DN2 questionnaire scores, which were developed to screen for neuropathic pain,,6 in patients undergoing video-assisted thoracic surgery (VATS).Acute postsurgical pain increases postoperative complications in the early postoperative period, and chronic postsurgical pain, which includes chronic neuropathic pain (CNeP),2This study was approved by the Ethics Committee of the Hyogo College of Medicine (#0239) and was registered in the UMIN Clinical Trials Registry (UMIN000014908).2.1A total of 27 patients with lung cancer who were scheduled for VATS were enrolled in this prospective observational study. Written informed consent was obtained from all participants who met the following criteria: age over 20 years, American Society of Anesthesiologists (ASA) physical status I to III, scheduled to undergo elective VATS. Exclusion criteria included previous thoracic surgery, presence of a psychiatric or neurologic disorder, chronic pain at the other sites of the incision or related areas of the surgery, and liver or renal dysfunction.2.2−1during general anesthesia. Rocuronium bromide was used as needed for muscle relaxation during surgery. The only regional anesthesia method used was intercostal nerve block, obtained by injection of 20 mL of 0.25% levobupivacaine administered by the surgeon at the incision site just before the surgical wound was closed with sutures. After surgery, a continuous intravenous infusion of 25 to 50 μg·h−1 of fentanyl was routinely administered until postoperative day 1. Intravenous flurbiprofen or acetaminophen was used for rescue analgesia.The patients did not receive premedication. Dexamethasone 3.3 mg was intravenously injected for prevention of postoperative nausea and vomiting before induction of anesthesia. General anesthesia was induced with propofol, fentanyl, and rocuronium, with a continuous infusion of remifentanil, followed by insertion of a double-lumen endotracheal tube, and was maintained with a continuous infusion of remifentanil and an intermittent injection of fentanyl and rocuronium, with a target-controlled infusion of propofol. The dose of remifentanil was adjusted to maintain mean blood pressure within the range of ±20% of the pre-anesthesia level. Bispectral index was maintained between 40 and 60 by adjusting the target concentration of propofol administered during surgery. Intravenous fentanyl was administered up to a total dose of 4 to 5 μg·kg2.3,7 The DN4 questionnaire evaluates 10 items: characteristics of pain (burning (1), painful cold (2), electric shocks (3)), symptoms in the region of pain (tingling (4), pins and needles (5), numbness (6), itching (7)), localized pain (hypoesthesia to touch (8), hypoesthesia to pricking (9)) and pain caused or increased by brushing in the painful area (10). Items from #1 to #7 of the DN4 questionnaire are answered by interviewing patients, and items from #8 to #10 require examination of patients. DN4 score is a total count of these 10 items existing in each patient, and the cut-off value for the diagnosis of neuropathic pain is a score of 4/10.,7 Additionally, DN2 score is a total count of 7 items including 3 pain characteristics and 4 pain symptoms, and the cut-off value for the diagnosis of neuropathic pain is a score of 3/7. DN2 questionnaires can also be applied to screen neuropathic pain only by interviewing, instead of DN4 questionnaires.,6 The incidences of ANeP and CNeP were calculated by the ratio between the number of patients whose DN4/DN2 scores were 3/4 or more and the total number of patients having with acute or chronic postsurgical pain. The same investigator interviewed all patients for evaluation of NRS, DN4, and DN2 before surgery (T0), and at 1 (T1) and 6 days (T2) after surgery, sending NRS and DN2 questionnaires and collecting the responses by mail at 3 (T3), 6 (T4), and 12 months (T5) after surgery.Pain intensity was evaluated using a Numerical Rating Scale (NRS). NRS, which comprises assessment using a 0 to 10 points scale, was used to assess pain intensity both at rest and during movement at surgical sites. The lowest value (0) was labeled ‘no pain’ and the highest value (10) was labeled ‘worst imaginable pain’. We used the DN4 and DN2 questionnaires to discriminate neuropathic pain from other pain states at surgical sites.2.4 a standard deviation of DN4 values was 1.6, and a difference in DN4 values before and after surgery was 2. Then, the estimated sample size was 11.The sample size was calculated using software . The calculation was done based on the assumption that a type I error probability of 0.01 (0.05/5 = 0.01) as 5 parameters at T1, T2, T3, T4, and T5 were tested, and power of 0.8. From a previous study,2.5∗P < .0125 and ∗∗P < .0025 vs T0 when 5 parameters at T1, T2, T3, T4, and T5 were tested .All statistical testing was performed using JMS Pro version 13.1.0 . The Kruskal–Wallis test, followed by the Wilcoxon test with Bonferroni correction, was used to compare the time course of changes in pain status. A statistically significant level after a Bonferroni adjustment was considered as 33.1Table 3.2Of the 27 patients, one patient (3.7%) showed neuropathic characteristics at T0, and 33.3% and 29.6% patients at T1 and T2 showed ANeP characteristics, evaluated by the DN2. The incidence of ANeP was 29.6% and 25.9% at T1 and T2, when the DN4 was applied to evaluate neuropathic profile. At T3, T4, and T5, 12.5%, 5.0%, and 0.0% patients showed CNeP characteristics, evaluated by the DN2 , some of which may not cause trauma at the somatosensory nerve system. It is plausible that the incidence of ANeP after VATS in the present study was higher than that in the previous study.This is the first study revealing the time course change of neuropathic pain characteristics, including both ANeP and CNeP, assessed by the DN4 or DN2 questionnaires before and after thoracic surgery for 1 year.There were some differences in the incidences of ANeP, which were 29.6% and 33.3% at T1, and 25.9% and 18.5% at T2 assessed by the DN2 and DN4 questionnaires, respectively in the present study. The DN2 questionnaires do not include three somatosensory examinations for hypoesthesia to touch, hypoesthesia to pricking, and pain caused or increased by brushing, which are the items #8 to #10 in the DN4 questionnaires. Since the degree of somatosensory disturbances caused by surgery changes daily from 1 day to 6 days after surgery, this assessment variance between DN4 and DN2 might affect the results of incidence of ANeP.–14 Although Boloeil et al reported that ANeP increases the risk of CNeP, the incidence of CNeP in the present study was relatively lower than that in the previous reports. Preoperative risk factors for chronic postsurgical pain reportedly include preoperative pain and a history of psychological disorders. Since our exclusion criteria included preoperative chronic pain and presence of a psychiatric disorder, the decreased incidence of CNeP might be explained by preoperative factors rather than ANeP in the present study.Intercostal nerve injury, which is believed to be one of the pathogenic factors of neuropathic pain after thoracic surgery, causes CNeP, of which incidence was reportedly between 23% and 66%.A limitation of this study is the small number of patients enrolled. Further study is needed to evaluate preoperative risk factors for the development of ANeP and CNeP after surgery in a larger number of participants having with a psychiatric or neurologic disorder and preoperative chronic pain in a multi-institutional study.5The incidence of ANeP was 20% to 30% at the early postoperative period, and that of CNeP gradually decreased after VATS.Conceptualization: Munetaka Hirose.Data curation: Shiho Takenaka, Ayano SaekiInvestigation: Shiho Takenaka, Ayano SaekiMethodology: Shiho Takenaka, Ayano Saeki.Project administration: Munetaka Hirose, Shiho Takenaka, Ayano Saeki.Supervision: Norihiko Sukenaga, Ryusuke Ueki, Nobutaka KariyaValidation: Ryusuke Ueki, Nobutaka Kariya, Tsuneo TataraWriting – original draft: Munetaka Hirose, Shiho Takenaka, Ayano Saeki.Writing – review & editing: Munetaka Hirose.Munetaka Hirose: 0000-0003-1291-2827.Munetaka Hirose orcid: 0000-0003-1291-2827.