Pronolis®HD mono 2.5% is a novel, one-shot, high-density sterile viscoelastic solution, recently available in Spain, which contains a high amount of intermediate molecular weight hyaluronic acid (HA), highly concentrated (120 mg in 4.8 mL solution: 2.5%). The objective of the study was to analyze the efficacy and safety of this treatment in symptomatic primary knee osteoarthritis (OA).This observational, prospective, multicenter, single-cohort study involved 166 patients with knee OA treated with a single-shot of Pronolis®HD mono 2.5% and followed up as many as 24 weeks.p < 0.001). The percentage of patients achieving > 50% improvement in the pain subscale increased progressively from 37.9% (at 2 weeks) to 66.0% (at 24 weeks). Similarly, WOMAC scores for pain on walking, stiffness subscale, and functional capacity subscale showed significant reductions at the 12-week visit which were maintained up to the 24-week visit. The EuroQol visual analog scale score increased after 12 weeks (median: 60 versus 70). The need for rescue medication  also decreased in all post-injection visits. Three patients (1.6%) reported local adverse events (joint swelling) of mild intensity.Compared with baseline, the score of the Western Ontario and McMaster Universities Arthritis Osteoarthritis Index (WOMAC) pain subscale reduced at the 12-week visit (primary endpoint, median: 9 interquartile range [IQR]: 7–11 versus median: 4; IQR: 2–6; In conclusion, a single intra-articular injection of the high-density viscoelastic gel of HA was associated with pain reduction and relief of other symptoms in patients with knee OA.NCT04196764ClinicalTrial# The online version contains supplementary material available at 10.1186/s12891-022-05383-w. Knee osteoarthritis (OA) is one of the most frequent causes of disability in elderly individuals . The preRegarding intra-articular injections with HA, they are getting attraction for the treatment of knee OA. Diverse randomized clinical trials have demonstrated the efficacy and safety of HA for the relief of symptoms in knee OA –10. BellPronolis®HD mono 2.5%  is a novel, one-shot, high-density sterile viscoelastic solution, recently marketed in Spain, which contains a high amount of intermediate-MWHA, highly concentrated (120 mg in 4.8 mL solution: 2.5%) –17.The objective of the present study was to analyze the efficacy and safety of a single-shot of this novel high-density viscoelastic gel of HA for the treatment of symptomatic primary knee OA.This observational, prospective, multicenter, single-cohort study involved patients with knee OA who initiated treatment with Pronolis®HD mono 2.5% following manufacturer instructions . A total of 29 healthcare centers from Spain  participated in the study. Main inclusion criteria were: adult men and women (aged over 18); with the diagnosis of primary knee OA, according to American College of Rheumatology criteria .Patients were followed up for as many as 24 weeks. Visits were scheduled after 2, 4, 12, and 24 weeks of the injection. Visits were undergone in-person (face-to-face) at the hospital, except the 2-week visit that consisted of a phone call. The primary endpoint included the change of scores in the pain subscale from the Spanish version of the Western Ontario and McMaster Universities Arthritis Osteoarthritis Index (WOMAC) at the 12-week visit, compared with baseline. The minimal perceptible clinical improvement (MPCI) was analyzed by following the Ehrich et al. methodology . OMERACTThe primary objective included score changes in the WOMAC pain subscale, from baseline. Studies by Zhang et al.  and Pavep < 0.05. All statistical procedures were carried out with SAS 9.4 software.Categorical variables were expressed as absolute and relative frequencies; whereas continuous ones with the mean, SD, median, 95%CI, or interquartile range . Comparisons in variables between baseline and post-injection visits were performed using the paired-samples Student’s t-test or Wilcoxon test, when appropriate. Linear mixed models were used to calculate the estimation (95%CI) of the effect of the studied variables in the primary variable (WOMAC A at 12-week visit). Statistical significance was established when 2), 34.5% were obese (≥ 30 kg/m2), and 16.2% were normal weight (< 25 kg/m2). The mean time from the diagnosis of knee OA to the current HA treatment was 7.2 years (SD: 7.5). Regarding pain, 12.0% of patients considered to control adequately the pain, whereas 79.5% indicated that the treatment, followed to that time (baseline), was not enough for controlling the pain and living a normal life. A total of 150 patients (90.4%) completed the study, however 16 (9.6%) did not so. Information about the early discontinuation was available in seven of them (six due to lost to follow-up and one due to patient decision).A total of 189 patients were initially recruited; however, 23 were not evaluable for the primary objective  in 4.78 points  representing a mean relative reduction of 48.2% (95%CI: 41.4–55.0). No association was observed between this improvement and other variables relevant to WOMAC score (Supplementary Table p < 0.001), self-care , usual activities , pain/discomfort , and anxiety/depression . Similarly, the EQ-VAS score increased after 12 weeks . The need for rescue medication  also decreased in all post-injection visits (p = 0.007 at the 2-week and p < 0.001 at the remaining visits), compared with baseline . None of the AEs was serious, and all of them were mild in severity. A total of 150 patients (90.4%) completed the study; however, 16 did not so. Loss to follow-up was the reason for early withdrawal in 6 out of 7 patients with available information (85.7%).Three patients (1.6%) reported 4 local AEs  than the low one (n = 30). In fact, one patient receiving the high- MWHA experienced a serious AE (pseudo-sepsis in the knee) and required hospitalization [In our study, the use of a novel high-density viscoelastic gel of HA has been associated with a clinical efficacy (in terms of pain relief) for patients with symptomatic knee OA. This benefit was achieved early (two weeks after the injection) and maintained for, at least, 24 weeks. In general, clinical improvement has been established with a minimum difference of 20% in efficacy outcomes , like sclization . Our stulization , 12, 24.Overall, the efficacy of high-MWHA has been demonstrated to be superior to intermediate- and low-MWHA. Altman et al.,  in a metOn the other hand, most HA preparations implicate between 3 and 5 injections, nevertheless, there are cross-linked formulations that require a single-shot, delivering the same HA dose as multi-injection preparations. Petterson et al.,  in a mulIn our opinion, the notable results obtained in our study (presumably associated with the HA), especially the 48% reduction in WOMAC pain subscale, 66.0% of patients achieving more than 50% improvement in pain subscale, the early initiation of the clinical benefit (within 2 weeks), and its maintenance for a long-term period of time , are greater than expected by an intermediate-MWHA preparation. These superior results might be associated with the high concentration and amount of HA, and thus to the high-density of the viscoelastic gel. In HA-based aqueous solutions, higher concentrations of HA are correlated (linear relationship) with higher densities of the viscoelastic solution , 32. Then = 166), not fulfilling the estimated one in the protocol (n = 300). Despite extending considerably the recruitment period, the availability of patients was insufficient. Yet, results found in our study are in concordance with other HA products [The main limitation of our study was the absence of a control or comparator group. Although the treatment of OA has an important placebo effect , and ackproducts , 26, 27.In conclusion, a single intra-articular injection of the high-density viscoelastic gel of HA was associated with pain reduction and relief of other symptoms in patients with knee OA. Further long-term studies, with a larger cohort of patients, and head-to-head non-inferiority analyses should be performed to corroborate the present results.All authors contributed to the study conception and design, material preparation, data collection and analysis. All authors commented on previous versions of the manuscript and read and approved the final manuscript.Additiona file 1:Supplementary Figure 1. Improvement in the painsubscale score of the Western Ontario and McMaster Universities ArthritisOsteoarthritis Index (WOMAC) at different post-injection visits with respect tothe baseline. Supplementary Table1. Inclusion and exclusioncriteria. Supplementary Table2. Linear mixed models fromvisit effect on WOMAC A absolute change, considering patient effect. Supplementary Table 3. Efficacy outcomesduring all post-injection visits. Supplementary Table 4. Relative reductions of WOMAC results at allpost-injection visits compared with baseline. Supplementary Table5. Changein WOMAC results at all post-injection visits compared with baseline. Supplementary Table6. Calculations to analyze theminimal perceptible clinical improvement** with the treatment at the 12-week visit


Despite some advances, treatment of trigeminal neuralgia remains a significant challenge. This study determines the efficacy and safety of autologous conditioned serum (Orthokine) injection into the foramen oval to treat refractory trigeminal neuralgia.p < 0.001), an effect that was retained at week 4 (T4) and month 2 (T5) follow-ups . Carbamazepine consumption was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) , an effect that was retained at week 4 and month 2 follow-ups . There were no serious adverse events in participants.This is a consecutive case series from the Pain and Palliative Care Department of Imam Reza University Hospital, Tabriz, Iran. Eleven Iranian patients, eligible according to the inclusion and exclusion criteria, aged 45.64 ± 11.58 years  with established classical trigeminal neuralgia were injected with Orthokine (2 mL per injection) once a week for three consecutive weeks . Numeric rating scale scores for facial pain intensity and also carbamazepine daily dose were confirmed at pretreatment (T0) and at week 1 (T1), week 2 (T2), week 3 (T3), week 4 (T4), and month 2 (T5) posttreatment. Pain intensity was significantly reduced in the first 3 weeks of follow-up in comparison with baseline (T0 to T3) (8.18 ± 1.99 to 2.82 ± 2.13, Orthokine injection led to consistent pain relief and reduced carbamazepine dosage in patients with trigeminal neuralgia, with acceptable safety. Trigeminal neuralgia (TGN) is described as repeated hemifacial attacks of highly intense, electrical stun-like or electric pains restricted to the area innervated by the first and/or second and/or third distributions of the trigeminal nerve. It lasts from a few moments to a few minutes and is provoked by apparently innocuous sensory stimulants, including airflow over the face, speaking, chewing, or brushing the teeth . As the The underlying cause and mechanisms of TGN are not well understood and are classified into idiopathic TGN, classical TGN, and secondary TGN according to the cause of TGN . UnidentDespite current progress, TGN treatment remains a significant challenge. The only US Food and Drug Administration-approved first-line treatment is carbamazepine, a voltage-gated sodium-channel blocker . MeanwhiVascular compression of the fifth or seventh cranial nerve roots and consequently nerve demyelination in the REZ is the principal hypothesis for classic TGN pathophysiology . Once thAutologous conditioned serum (ACS) is an autologous blood product, where a patient’s peripheral blood is drawn and incubated for hours, throughout which platelets degranulate and mononuclear cells release IL-1 receptor antagonist in addition to a variety of antiinflammatory cytokines and growth factors. The ACS is then retrieved, disinfected, and injected into places of damage or disease . At thisin vivo and in vitro [Over recent decades, the efficacy and safety of ACS for musculoskeletal disorders have been studied in several animal and human investigations, along with in vitro –31. Joinin vitro . Based oin vitro –35. SignIn recent decades, little progress has been made in management of TGN, and there is a lack of high-quality studies in this area. At present, it is irrefutable that less aggressive and remedial rather than palliative therapeutic alternatives  are generally more preferable for both physicians and patients. Considering the close relationship between TGN and inflammation and the evidence of aggregation of a great number of macrophages and mast cells in focal demyelination of the trigeminal root in addition to significant inflammatory infiltrate neighboring the demyelinated areas in TGN animal models , 37, we From July 2019 to March 2020, a total of 23 consecutive patients with medically refractory idiopathic TGN were assessed at the pain and palliative outpatient clinic of Imam Reza University Hospital, Tabriz, Iran, of whom 10 patients did not satisfy the inclusion criteria and 2 rejected participation in the study.Adults aged 18–70 years with confirmed TGN with at least three pain attacks per day, pain intensity of four or more on a pain intensity numerical rating scale (PI-NRS) on at least 7 days before the start of treatment, history of previous intake of carbamazepine 600–900 mg/day, gabapentin 900–1800 mg/day, or pregabalin 300–450 mg/day and tramadol 400 mg/day for more than 3 months with poor clinical response and a desire to participate throughout the study were included. The criteria for TGN were according to the International Classification of Headache Disorders [Exclusion criteria were previous radiofrequency ablation and/or surgical treatment for TGN, existence of a tumor or autonomic symptoms based on brain magnetic resonance imaging (MRI), or other neuropathic pain, cognitive dysfunction, history of drug abuse, or any coagulation conditions or platelet disorders. Imaging was performed to confirm the lack of a secondary cause.Finally, 11 Iranian patients  were included in this study. The right and left side was involved in seven and four patients, respectively. The mean age was 45.64  ±  11.58 years  in accordance with the Helsinki Declaration of the World Medical Association (version 19 October 2013).All patients were visited by a palliative care medicine fellow at the study center, who assessed the eligibility criteria, presented necessary information concerning the study, product, alternatives, and risks, and obtained written informed consent. The participants then completed all the baseline questionnaires.All patients who met the eligibility criteria listed above received diagnostic brain MRI with contrast to rule out any condition or disorder that would deprive them of participation such as compression of Gasser ganglion. Comprehensive demographic information of patients, including age, gender, occupation, and education, was recorded. Medical history concerning consumption of all medications (doses and duration) was obtained.All patients were accurately evaluated concerning the location, duration, nature, and pain intensity. They were asked to rate their pain on a NRS varying from 0 (“none”) to 10 (“unbearable”).®II) [g) for 15 minutes. Before injection, the serum supernatant was filtered and tested for human immunodeficiency virus, syphilis, and hepatitis B and C.Fifty milliliters of whole blood samples were taken from each participant using a special syringe (EOT®II) . MedicalOrthokine serum (2 mL per injection) was injected under fluoroscopy direction. All patients had an appointment for an injection once per week for three consecutive weeks (four injections).We asked the patient to lie in supine position. Then, a sterile 21-gauge needle with a 10-mm naked needle tip was inserted into the skin 1.5–2 cm lateral to the corner of the mouth, below the lower lip, under fluoroscopy direction in aseptic conditions, and advanced into the foramen ovale (FO), then aspirated. The needle was left in place  carefully at 1 week before (T0) and 1 month after treatment end (T5). Additionally, the patients were followed up at 1 week (T1), 2 weeks (T2), 3 weeks (T3), and 1 month (T4) after the start of the study, at the pain outpatient clinic.No drugs were recommended in participants with complete pain relief (NRS < 3). Otherwise, they were counseled to continue carbamazepine up to 400 mg three times a day orally. The same technician executed all follow-up evaluations. The safety profile of ACS was also examined by analysis of AEs at each study visit.Any AEs, comprising bleeding at the injection site, infection, and other possible AEs, were recorded at weeks 1, 2, 3, and 4, and month 2.p-Value < 0.05 was considered significant.Statistical analyses were carried out using SPSS 18.0 software. Continuous variables are presented as mean ± standard deviation, and categorical data as number and percentage. The Shapiro–Wilk test was applied to analyze the distribution. Repeated-measure analysis of variance (ANOVA) testing was applied. Patients most frequently reported multiple pain attacks daily . Two and one patients reported one attack daily and continuous pain, respectively. The mean best and worst pretreatment pain intensity (current 24 hours) was 5.36 ± 2.37 and 10.00 ± 0.00, respectively.Table All patients had used at least one medication for TGN on enrollment in the study. However, they were permitted to continue carbamazepine up to 400 mg three times a day. Carbamazepine consumption was significantly reduced in the first 3 weeks of follow-up compared with baseline (T0 to T3), an effect that was retained at week 4 and month 2 follow-ups  needed for its administration. The total cost of Orthokine and consumables per dose administered was US $35.71 and US $1.54, respectively.n = 1) and postinjection pain for several days (n = 4). There were no serious AEs in participants. No patients were removed from the study because of an AE.Analysis of safety records showed that two transient AEs were reported in five participants: high blood pressure during injection  is the pathophysiological mechanism of TGN , 40. RecVarious strategies have been developed to inhibit the biological activity of IL-1. In particular, IL-1Ra is a naturally occurring IL-1 inhibitor , 42. MacOrthokine is rich in antiinflammatory cytokines and has elevated growth factors such as fibroblast growth, hepatocyte growth, and transforming growth factors . It alsoet al. [et al. [et al. [Extensive phase III clinical trials have confirmed the safety and efficacy of recombinant IL-1Ra in humans . The effet al.  evaluate [et al.  evaluate [et al.  also evaThis study has some limitations that should be considered in future studies. This was a single-center single-arm case series study with a small population. Our study did not involve a control group, and the participants could not be masked to the treatment provided. The participants were only monitored for 1 month after treatment. Future long-term follow-up clinical trials across several clinical sites are necessary. This could be executed by directly comparing Orthokine versus arms with other available treatments and/or their combination. We also suggest evaluating other secondary outcomes such as psychiatric symptoms and quality of life.This study provides significant clinical and therapeutic implications. Though TGN is a rare disorder, it significantly decreases patients’ quality of life because of pain attacks and other related comorbidities, including depression and anxiety. Our study found that patients who underwent Orthokine injection into the FO achieved significantly reduced NRS scores after treatment and significantly lower need for carbamazepine, with no serious AEs, accordingly suggesting the effectiveness of Orthokine treatment. These findings provide solid preliminary evidence that Orthokine is an impressive pain relief technique for refractory TGN.The study findings indicate that injection of autologous conditioned serum (Orthokine) into FO led to consistent pain relief and reduced carbamazepine dosage needed for pain suppression in patients with refractory TGN, with acceptable safety. There is a vital necessity for large RCTs to assess the efficacy of Orthokine in TGN conclusively.


Platelet-rich plasma (PRP) contains high concentrations of growth factors and cytokines and may promote healing and tissue formation and exert anti-inflammatory effects. PRP has been shown to improve intervertebral disc degeneration in vivo and in vitro. This study is aimed at evaluating the effectiveness of autologous PRP on discogenic low back pain (DLBP) at 48 weeks postinjection in patients who received a single intradiscal injection.  All patients received a single intradiscal injection of PRP in a prospective trial. The pain scores, lumbar function, and adverse events were assessed at 1 week, 4 weeks, 8 weeks, 12 weeks, 24 weeks, and 48 weeks postinjection and compared to the preinjection values (0 weeks). P < 0.05) over the 48-week follow-up. Twenty-two (71%) patients were classified as successes after the intradiscal injection of PRP. One patient received surgery at two weeks postinjection due to intervertebral discitis.  Data were analysed from 31 patients with a 94% follow-up rate. Compared to preinjection, pain and lumbar function were significantly improved, and there were significant differences ( Intradiscal injection of PRP can significantly relieve pain sensation and improve lumbar function in patients with DLBP over a 48-week follow-up period. Further randomized controlled clinical trials are needed to assess the effects of this injection therapy. Low back pain (LBP) is now regarded as a primary cause of adult disability, and as many as 84% of people have experienced back pain at least once in a lifetime . In 2017Lumbar disc degeneration is the leading cause of discogenic low back pain (DLBP) . The lumα), are significantly increased, which disrupts the haemostasis of the extracellular matrix (ECM) of IVD tissues by increasing the production of matrix metalloproteinases (MMPs), nitric oxide, and aggrecanases  × 109 cells/L and [0.20 ± 0.3] × 109 cells/L, respectively. The average level of PDGF-BB in the PRP releasate was approximately 2.5 times higher than that in autologous serum (PDGF-BB (ng/μL), autologous serum, 3.1 ± 1.6; PRP, 7.6 ± 3.3).The mean platelet count of PRP was approximately 4.7 times greater than that of whole blood  were also significantly improved . All changes in pain scores were clinically significant, according to predefined MCID criteria . All changes in the clinical significance of the SF-36 physical function scores and FRI scores are shown in Figures Significant improvements in function were observed at 48 weeks postinjection, as assessed by the SF-36 physical function scale (where higher scores indicate better function) and by the FRI (where lower scores indicate better function). SF-36 physical function scale scores improved from 51.8 (13.1) at baseline to 67.7 (14.4) at 48 weeks postinjection. The FRI scores improved from 52.5 (12.1) at 0 weeks to 39.2 (7.0)  indicated that they had taken pain medication following the injection. Nine (29%) patients required additional physical therapy, and there were no patients who received additional PRP injections.P < 0.05).Successes and failures were determined using data from 31 patients. Of these, 22 (71%) patients reported clinically and statistically significant improvements in both pain and function at 48 weeks postinjection and were classified as successes in accordance with the MCID criteria. Nine (29%) patients were classified as experiencing failure because they did not meet the MCID criteria. One patient needed surgery after his intradiscal PRP injections and was classified as experiencing failure; this patient underwent surgery at 2 weeks postinjection due to intervertebral discitis associated with repeated needle puncture in the lumbar 3/4 disc. Sex and age at the time of injection had no effect on the success of the injection ; howeverDegeneration of the IVD is one of the leading causes of chronic DLBP in adults . To asseThe regeneration effect of PRP on IVD cells has been confirmed using in vitro and in vivo studies. An animal study reported that an injured IVD model treated with PRP immediately after injury resulted in the retainment of morphologic features, fewer inflammatory cytokines, and retarded IVD degeneration –43. FurtIn our study, the findings showed significant improvements in pain and function at the 48-week follow-up after a single intradiscal PRP injection, which is consistent with most of the above studies, in accordance with the MCID criteria of the NRS, FRI, and SF-36 , 44. Of Importantly, discography provoking concordant low back pain was used only for the diagnosis of DLBP in this trial, which was similar to many previous studies , 28 and Meanwhile, the safety and adverse events associated with this injection were also assessed throughout the whole follow-up period. In our study, 1 patient experienced severe low back pain after injection for half of a month. Based on the MRI scanning results, intervertebral discitis was observed at the injected disc level. The results may be related to repeated needle puncture, which might irritate the endplate immune infection responses. Fortunately, the patient showed significant improvement in pain and function after receiving surgery for discitis. In this case, repeated puncture was responsible for this adverse event, rather than PRP injection therapy, because PRP was promoting regeneration autologous substance, which is unlikely to have harmful effects on the disc , 46. In Although this study has demonstrated encouraging findings, there were several limitations in this trial. First, the sample size was relatively small, and a control group was not used. Without a control group, nonspecific treatment effects and natural recovery history cannot be ruled out, which may affect the interpretation of the effective results. Second, there is a lack of composition data of PRP on cell count, including platelets, red cells, and white blood cells, as well as biological analysis of various growth factors. Finally, there is no routine radiological assessment of the morphologic changes of the disc treated with PRP during follow-up, preferably with MRI analysis. Further clinical trials will be required to collect these data to confirm the effect of PRP injection on DLBP.In summary, intradiscal injection of PRP is safe and feasible to treat patients with DLBP. Although our results are encouraging, more prospective, double-blinded, randomized, and controlled clinical trials would be required in a large sample size in the future, and the optimal composition and concentration of autologous PRP, whether multiple injections benefit or worsen outcomes, and what radiologic disc changes after injection at longer follow-up are all worth investigating.


Post-injection pain scores were greater for those who experienced treatment failure . Reduced post-injection external rotation in abduction also predicted treatment failure . IA corticosteroid injections are associated with increased rates of failure and progression to surgical management when patients present with increased pain levels as well as with less improvement in pain levels and ROM following injection.Intraarticular (IA) corticosteroid injections have been demonstrated to be an effective management for adhesive capsulitis in both the short- and mid-term. Yet, certain patients fail to improve both subjectively and clinically. This study aims to identify predictive factors for treatment failure of IA injections in management of adhesive capsulitis. A retrospective review found 533 patients undergoing IA corticosteroid or IA NSAID injection for adhesive capsulitis between June 2015 and May 2020 at a single healthcare institution. Patient demographics characteristics, comorbidities, pain scores, and range of motion were compared. Treatment failure was defined as need for subsequent IA injection within 6 months or progression to surgical management within 12 months. 152 patients (28.52%) experienced treatment failure of IA corticosteroid injection. Pre-injection pain scores were greater for those who experienced treatment failure (5.40 vs. 4.21,  Adhesive capsulitis of the glenohumeral joint, also known as “frozen shoulder,” is a common pathology characterized by pain and progressive range of motion restriction ,2,3,4. TConsensus exists amongst clinicians and investigators that initial management for adhesive capsulitis should be non-surgical. Current literature describes a myriad of available treatment modalities including physical rehabilitation, oral NSAIDs, oral glucocorticoids, intraarticular (IA) corticosteroid injection, hyaluronic acid injections, and/or hydrodilation (arthrographic distension). Further, high-level evidence directly comparing treatment modalities is scarce ,13,14,15Intra-articular corticosteroid injections, have been shown by numerous studies to provide significant benefit in function and pain in the short-term ,19,20,21The aim of this study is to identify comorbidities and risk factors associated treatment failure of IA injections for the management of adhesive capsulitis. We hypothesize that increased pre-injection pain level, greater pre-injection ROM restriction, and history of diabetes will result in increased rates of treatment failure of IA corticosteroid injection.After approval from institutional review board was obtained, a retrospective case–control review was performed for all patients treated for adhesive capsulitis at our institution between June 2015 and May 2020. All information was requested utilizing REDCap to search the electronic medical record (EMR), including the EMR data from other participating institutions. Inclusion criteria were patients with a diagnosis of adhesive capsulitis of the shoulder with adequate follow-up data including pain scores and range of motion. Exclusion criteria included absence of follow-up data recorded. Potential candidates for inclusion were identified using ICD-9 code (726.0), ICD-10 codes , CPT codes , and HCPCS codes .A total of 533 patients were included in the study. A diagnosis of adhesive capsulitis was defined as a clinical diagnosis made by a physician based on patient history involving pain and loss of both active and passive range of motion without acute injury and normal radiographs. Each included patient received an intra-articular injection. Intra-articular injections were administered with ultrasound-guidance or landmark-guidance based on physician experience and preference. For a small group of 10 patients for whom corticosteroids were contraindicated based on allergy or brittle diabetes, IA nonsteroidal anti-inflammatory drugs (NSAIDs) were chosen. This subset was too small for separate sub group analysis and were included in the injection group as a whole. Intra-articular injections were standard dosages used at our institution including 10 mg triamcinolone acetonide, 40 mg methylprednisolone acetate, or 15 mg ketorolac tromethamine.Each chart was individually reviewed for data collection . Demographic data recorded included age, sex, race, and BMI. The presence of concurrent medical comorbidities was also documented by review of primary care physician notes, which included diabetes mellitus, hypothyroidism, hyperthyroidism, and smoking history. Descriptors of the disease course of adhesive capsulitis were recorded from orthopedic clinic, primary care, and physical therapy notes including dates of diagnosis, injection, and follow-up visits, laterality of disease, pre-injection VAS pain score and range of motion, and post-injection VAS pain score and range of motion during the initial 3 months after the injection. Range of motion was measured by clinical assessment or by goniometer in external rotation in abduction, external rotation at the side, and forward elevation. External rotation in abduction and external rotation at the side were classified as mild (>45°), moderate (20–45°), or severe restriction (<20°). Forward elevation was classified as mild (>120°), moderate (90–120°), or severe (<90°). Procedure details regarding choice of drug, dosage, and use of ultrasound-guidance or landmark-guidance were collected. Patients underwent concurrent formal standardized physical therapy at our institution or were provided recommendations for home physical therapy exercises if formal physical therapy was declined.Treatment failure was defined as the need for an unplanned, subsequent IA injection within 6 months of previous IA injection or progression to surgical management  within 12 months of previous IA injection. Indications for subsequent injection and progression to surgical management were multivariable in nature after incomplete resolution of symptoms following injection. Considerations in this decision included the physician’s assessment of the patient’s response to the initial IA injection, severity of symptoms, patient satisfaction with function, and patient desire to progress to more invasive levels of care. Indications for progression to surgery included physician assessment and symptoms refractory to IA corticosteroid.p-value of 0.05 was deemed statistically significant.Extracted data was analyzed by statisticians within our institution. Categorical variables are reported in frequencies and percentages. For demographics, comorbidities, and range of motion categorical variables, chi-square tests for association or fisher exact test were used. In addition, statistical analysis was conducted using independent two-tailed t-test or Mann–Whitney to determine significant associations between patient-based variables and treatment failure of IA injections. A 2   . The majA total of 152 patients (28.52%) experienced treatment failure of IA corticosteroid injection, as defined by subsequent IA corticosteroid injection within 6 months or progression to surgery. A total of 115 (21.58%) received a repeat injection within 6 months and 48 (9.01%) progressed to surgery. A total of 11 (2.06%) both received a repeat injection within 6 months and progressed to surgery.p > 0.05).Between those who experienced treatment failure, there were no differences in sex, mean age, mean BMI), or proportion of patients with diabetes or thyroid (p = 0.0068). Other than this, there were no other significant associations between treatment failure and pre-injection or post-injection ROM in external rotation in abduction, external rotation at the side, or forward elevation (p > 0.05).The ROM of each study participant in external rotation in abduction, external rotation at the side, and forward elevation was categorized by severity as mild, moderate, or severe . The relp = 0.0203) and post-injection pain scores  versus those who did not experienced treatment failure.Pre-injection and post-injection (at approximately 3 months) pain levels were measured using VAS pain score. Patients who experienced treatment failure of IA injection had significantly higher pre-injection pain scores  following injection.


The advancement of physiopathological knowledge of tendon structures has shown that, in conditions of overload, there is the onset of both degenerative phenomena, such as the production of metalloproteases, apoptosis of tendon cells and neoangiogenesis, and regenerative and protective phenomena, such as the production of IGF-1 and nitric oxide. Tendinopathy results from the imbalance between these two groups of factors, leading to degeneration, weakening, and fissuring of the tendons, with the presence of local pain. The aim of the study was to evaluate the efficacy and tolerability of cetylated fatty acids (CFA) patch formulation in the control of acute localized shoulder pain and recovery of function in patients with tendinopathies.A prospective, single-center, no-profit observational study conducted in accordance with Good Clinical Practice. Thirty patients with recent onset shoulder pain symptoms (1–3 months) related to bursitis and tenosynovitis, with a diagnosis of shoulder tendon pathology confirmed by ultrasound examination, was evaluated for shoulder pain and function using the Constant Murley Score. Patients used 1 patch containing CFA for 8 h per day for 10 days. At 10 (V1) and 35 (V2) days after the first visit (V0), the Constant Score, treatment compliance and product tolerability were evaluated.p < 0.0001) but did not vary significantly between V1 and V2 (p = 1). The tolerability of the product was excellent.Thirty patients completed the treatment. At V0 the mean Constant Score (CS) was 32.37 ± 11.86, during V1 the mean CS was 50.68 ± 14.30, and at V3 the mean CS was 51.07 ± 15.29. The CS increased significantly between V0 and V1  and conducted in accordance with Good Clinical Practice and the ethical principles outlined in the Declaration of Helsinki. The advancement of knowledge on tendon physiopathology has shown that in conditions of overload, probably associated with oxidative stress mechanisms, happens both degenerative and regenerative and protective phenomena. Degenerative processes include the production of metalloproteases that degrade the extracellular matrix, apoptosis of the tendon cells and neoangiogenesis with vascular infiltration. The regenerative and protective phenomena include the production of IGF-1 (insulin-like growth factor-1) and nitric oxide. Tendinopathy is the result of an imbalance between these two sets of factors, leading to degeneration, weakening, and fissuring of the tendon, associated with local pain [Currently, the treatment of tendinopathy involves the oral administration of NSAIDs, corticosteroid infiltrations, physical therapy  and shock waves . These therapies can have some limitations: 1) the available literature suggests that in absence of an ongoing inflammatory process, NSAIDs are not able to modify the course of chronic tendinopathy –4 ; 2) cIn this context, it is important to emphasize that numerous studies have shown the effectiveness of topically administered cetylated fatty acids (CFA) in improving joints mobility, functionality, strength and endurance, as well as reducing pain symptoms in absence of side effects –14. CFA The aim of this study was to evaluate the efficacy and tolerability of CFA patch formulation in controlling acute localized shoulder pain and recovery of function in patients with tendinopathies.This was a prospective, single-center, no-profit, observational study conducted at the Department of Rehabilitation of the Azienda Usl Toscana Nord Ovest . The study was approved by the local Ethics Committee (protocol code 2018RIAB105) and conducted in accordance with Good Clinical Practice and the ethical principles outlined in the Declaration of Helsinki. All patients signed the informed consent document.Patients referred to the center between 1 October 2019 and 31 July 2020 who had suffered from recent onset (1–3 months) shoulder pain symptoms related to bursitis and tenosynovitis, with a diagnosis of shoulder tendon pathology confirmed by ultrasound examination, were included. The exclusion criteria were the following: previous treatment with NSAIDs or other self-medication products or instrumental techniques for their tendinopathy; known hypersensitivity to CFA or to one of the product excipients, or injured skin in the shoulder area; use of NSAIDs and corticosteroid infiltrations during treatment; cognitive impairment or full-thickness rotator cuff tendon tear.At the first visit (V0) the patients were examined by ultrasound examination, and pain and shoulder function were assessed using the Constant-Murley Score (CS). All patients were prescribed to use at home 1 patch containing CFA  for 8 h a day for 10 consecutive days. The clinician indicated where to apply the patch according to the painful area. The CFA-based patch were used for 8 consecutive hours a day to allow the active ingredient to be fully released though the skin, in accordance with the instructions for use indicated by the manufacturer. Two follow-up visits were carried out: the first (V1) 10 days after the first visit corresponding to the treatment period, the second (V2) 35 days after the first visit  and activities of daily living (ADL) (20 points) and two objective: range of motion (ROM) (40 points) and strength (25 points). The maximum achievable score (100) represents an optimal condition .The sample size was based on the primary endpoint, by assessing the efficacy of CFA patch formulation in controlling acute localized shoulder pain in patients with tendinopathies. A variation of at least 3 points in the Constant Score was estimated, setting a type error α = 0.05 and taking as a starting point a test power (β) of 0.9 (90%), resulting in a sample size of at least 30 subjects in order to ensure adequate statistical robustness of the study.p-value below 0.05 was considered significant. The statistical analysis was carried out using Excel 2020  and GraphPad Prism version 8.3.1 .The normality of the distributions of continuous variables was assessed using the Lilliefors corrected Kolmogorov–Smirnov test. Accordingly, continuous variables were represented as mean ± standard deviation or median and interquartile interval, depending on their distributions. Independently of the distributions, given the small sample size, all comparisons between groups were performed with non-parametric Mann–Whitney test, for unpaired comparisons, and Wilcoxon test, for paired comparisons. The differences among continuous variables on different time points were assessed with Bonferroni corrected Wilcoxon test. In all cases, a A total of 32 patients were recruited. Thirty patients completed the study. One patient failed to complete the treatment due to an irritative reaction not product-related, another was unable to return to the follow-up due to an accident (bone fracture) during the observation period. Table p = 0.3198).The sample was mainly represented by women (19 vs 11 men); most of the participants in the study had dominant shoulder pain. There were no significant differences in the mean age between the two groups (At V0 the mean Constant Score (CS) was 32.37 ± 11.86. At the second visit (V1), performed on average 12 days after the first one, the mean CS value was 50.68 ± 14.30. Ate the tirth follow-up visit (V2), performed on average 35 days after the first visit, the mean CS value was 51.07 ± 15.29. The single indices values constituting the CS for each timepoint are reported in the Table p < 0.0001), whereas it was steady between V1 and V2 (p = 1). Pain, ADL, and ROM followed the same trend as the total score. Strength did not change significantly between V0 and V1 ( p = 0.5208), neither between V1 and V2 (p = 1). The CS values at different time-points are shown in Fig. The CS value increased significantly between V0 and V1  reported a score of 0 to the first question of the section “Pain” (A1) at V1, which on a pain frequency scale represents "permanent" pain without forcing; among these, only 5 (16.7%) still suffered from "permanent" pain at V1 and only 3 (10%) at V2 , which evaluates the patients' limitation for daily activities, it can be observed how 21 patients (70%) reported a severe limitation of their work or daily activities at the first visit, while only 5 (16.7%) reported the same limitation at V1 Fig. .Fig. 4PaThe tolerability of the product was excellent: only 1 case of skin irritation was reported with the use of the patch and, although the irritation was temporary and resolved spontaneously indicating a non-product related effect, the patient preferred not to continue with the study.Constant Score values increased by 10 points or more in 20 patients (66.7%), between 2 and 10 points in 7 patients , not changed in 2 patients , and decreased in 1 patient . Fig. .Fig. 5PeIn percentage there was an average increase in the CS value of 68% between V1 vs V0. Only 3 patients (10%) failed to report an increase in CS value, while 14 patients (46.7%) reported an increase of more than 50% , considering that healthy subjects of the same age and sex should have a CS ranging between 70 and 90 points , 22.After the first treatment period of 10 days, the CS value stabilized for the following 25 days, and approximately the same value was reported at the follow-up visit on day 35. This could be explained by the fact that the 10-day treatment is a time period appropriate for CFA to give rise to an effective pain reduction and to allow physiological changes in tendons, probably due to tissue membrane stabilization. It can be hypothesized that the mechanical changes produced by the CFAs were sufficient to control pain and maintain shoulder function for the follow-up period.The goal of the treatment was that the subjects felt a better shoulder condition after the 10-days treatment, allowing to resume their normal work activities or hobbies, starting again to use and “stress” the shoulder, which was very often the dominant one.The extremely positive finding that makes this observation even more promising is that the results were achieved with the only application of a natural product based on CFAs, without the use of physical therapies or use of corticosteroids. Moreover, the results obtained allows patients to return to their normal activities and the CS value were maintained without the administration of any treatment during the follow-up 35 days later. This observational study included a limited number of patients; integration of the data with a larger number of subjects in the future might be able to consolidate the results obtained. Moreover, the study lack of a control group. According with the experience of the authors, a “non-treatment” or an adhesive patch treatment only was not considered ethical and risked chronicizing tendinopathy. In the future, a study with another treatment as control, e.g. a physical therapy, could be designed to observe differences between two different approaches to shoulder tendinopathy. It would also be desirable to observe the ultrasound evolution of the tendinopathies for objectively assessing the reduction in oedema and the general improvement in tendon tissue.In conclusion, the application of CFA in patch formulation for 10 consecutive days in patients with shoulder tendinopathy was effective in reducing pain and resulted in a good recovery of joint function. The results achieved at day 10 were maintained for 25 days, until the follow-up visit at day. CFA-based patch seems to be a promising solution to improve pain and functionality in subject with shoulder tendinopathy.


Public health issues related to chronic pain management and the risks of opioid misuse and abuse remain a challenge for practitioners. Data on the prevalence of disorders related to the use of prescribed opioids in patients suffering from chronic pain remains rather patchy, in particular because of the absence of a gold standard for their clinical assessment. We estimated the prevalence of prescription opioid misuse (POM), using a specific and validated opioid misuse scale , in adults with chronic non-cancer pain. Nine-hundred-fifty-one (951) patients with opioids prescription and followed-up in pain clinics and addictology centers for chronic non-cancer pain (CNCP) completed the survey interview. The results suggest that 44.4% of participants have POM, accompanied by overuse (42.5%), use of opioids for effects other than analgesia (30.9%), withdrawal syndrome (65.7%), and craving (6.9%). The motivations cited for POM, apart from pain relief, were to calm down, relax and improve mood. POM was shown to be related to male sex (OR 1.52), young age (OR 2.21) and the presence of nociplastic pain (OR 1.62) of severe intensity (OR 2.31), codeine use (OR 1.72) and co-prescription of benzodiazepines (OR 1.59). Finally, despite the presence of three subgroups of misusers, no factor was associated with the intensity of misuse, reinforcing the view that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Almost half of patients with CNCP misuse their prescribed opioid. Practitioners should be attentive of profiles of patients at risk of POM, such as young, male patients suffering from severe nociplastic pain, receiving prescription for codeine and a co-prescription for benzodiazepine. We encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of POM in their patients receiving opioid-based therapy.Clinical Trial Registrationclinicaltrials.gov, identifier NCT03195374 Chronic pain is a common problem, affecting approximately 20%–31% of the general adult population, depending on the country . The manThe pharmacological class of opioid analgesics includes all the natural and synthetic derivatives of the poppy, of which morphine is the foremost. They have in common that they bind to opioid receptors, the source of both their undesirable and desired effects. Their usual indications are moderate-to-severe nociceptive pain . Due to their several adverse effects  and doubts about their efficacy against chronic non-cancer pain (CNCP), their long-term administration should not be recommended . NeverthBased on reports of Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks  and the According to a review by Vowles, among the US patients suffering from chronic pain and taking opioids, about 21%–29% developed a misuse . A FrencComité de Protection des Personnes Sud-Est VI, Clermont-Ferrand, France) on 21 July 2016 (ref: AU1263), the French personal data protection authority  and registered on Clinicaltrials.gov (NCT03195374). The research was conducted in accordance with the World Medical Association Declaration of Helsinki .The study was approved by the Research Ethics Committee (http://project-redcap.org/) possesses the authorization of the French personal data protection authority.Study data were managed using REDCap  electronThis cross-sectional and multicenter study was offered to all adult patients suffering from CNCP for at least 6 months, treated by opioids for at least 3 months, and followed-up in pain clinics and addictology centers. Only patients with sufficient comprehension of French to answer the questionnaires and who volunteered to participate were included in the study.The study was systematically proposed to eligible patients during an addictology or chronic pain consultation as part of their usual care with the investigator. An information form was given to each patient, summarizing the objectives of the study and the strictly confidential aspect of the treatment of their medical data. Patients were free to accept or not to participate in this study, without impact on the quality of care and the relationship with their physician in the case of refusal. In the case of acceptance of participation, the patients had to fill in the paper form  on site and return it to the investigator. At the end of the study, all the patient forms were sent by mail to the University Hospital of Clermont-Ferrand and the data were entered twice and compared by two clinical research assistants in the REDCap database for statistical analysis.The primary objective of the study was to estimate the prevalence of POM in a population of patients with CNCP followed-up in pain clinics and addictology centers. To achieve this objective, the POMI scale, previously translated and validated in French for 154 patients , was useThe secondary objectives were: 1) to investigate the relationship between the presence of POM and type of opioids; 2) to characterize misuser profiles and the modalities of POM; and 3) to identify factors associated with the presence of POM. To address our secondary objectives, a home-made questionnaire  describing all analgesic treatments (including opioids), patient sociodemographic data, clinical data , misuse and associated behavior  was completed.A withdrawal syndrome was confirmed when the patient answered “YES” to at least one of the possible answers to the following question: Have you ever experienced one or more of these symptoms when your opioid medication(s) was/were delayed or in the hours before usual intake or when the dose was decreased or when it was stopped suddenly? .Craving was confirmed when the patient answered “YES” to the following question: Have you ever felt an uncontrollable urge to use your opioid medication(s) in a non-painful setting? Finally, use for other effects  was analyzed with at least one “YES” response to the following question: Have you ever taken this/these pain medication(s) for the following reasons? .This cross-sectional study conducted on a sample should make it possible to generalize the results to the entire target population. A margin of error on the estimate is defined to estimate the number of participants required, in addition to the expected proportion of chronic pain subjects with misuse. Thus, according to the literature, for an expected proportion of misuse subjects of about 40% , the incCategorical parameters were expressed as frequencies and associated percentages, and continuous data as mean ± standard deviation or as median , according to statistical distribution. The assumption of normality (Gaussian) distribution was assessed using the Shapiro-Wilk test.t-test or the Mann-Whitney test if the assumptions of the t-test were not met. The equality of variances was analyzed by the Fisher-Snedecor test. The relationships between POMI-5F score (<2 versus ≥2) and opioid use for non-analgesic effects and type of withdrawal symptoms were also described with the aforementioned statistical tests.The prevalence of a POMI-5F score ≥2 of patients with CNCP was presented with a 95% confidence interval (CI) calculated by an exact binomial distribution. The comparisons according to the POMI-5F score  were conducted using Chi-squared or Fisher’s exact tests for categorical data. For continuous data, the comparisons were performed with Student’s Then, in order to determine factors associated with the POMI-5F score ≥2, a multivariable logistic regression model was run using the stepwise approach (backward and forward) on covariates fixed according to univariate results and to clinical relevance. Particular attention has been paid to the study of multicollinearity and interactions between covariates: 1) studying the relationships between the covariates, and 2) assessing the impact of adding or deleting variables in the multivariable model. Furthermore, variance inflation factor, a measure of the amount of multicollinearity, was also calculated with collin command from Stata. The results were expressed as odds-ratios and 95% CI.Finally, to determine patterns on patients at risk of POM, a multiple correspondence analysis (MCA) followed by a mixed unsupervised classification  were proposed to: 1) study the relations between the modalities of the variables, and 2) determine the profiles of the participants . MCA can be used to perform cross tabulations and can be considered as a useful tool for revealing the relationships among categorical variables. The significance of association as tested by Chi-squared or Fisher’s exact tests provides no information regarding significant individual associations between row-column pairs. On the contrary, factorial analyses such as MCA show how the variables are related, and not just if a relationship exists. This approach enables handling a large amount of data in order to unfold hidden patterns. For these analyses, the variables were chosen according to univariate results, clinical relevance and statistical distribution . Only individuals without missing data were included in this analysis.http://cran.r-project.org/). All the tests were two-sided, with a Type I error set at 0.05. Particular attention was given to the magnitude of differences expressed with effect-sizes, in addition to inferential statistical tests expressed using p-values without Type I error correction.Statistical analyses were performed using Stata software  and R 3.3.3 . Nine hundred and fifty-one patients were analyzable for the primary objective. The first patient was enrolled on 24 August 2018, and the last patient on 09 July 2019.Participating patients were mostly middle-aged women, in a couple and having a professional activity. Among patients in professional activities, 16.3% were in work stoppage and 42.6% were in disability due to their CNCP. Moreover, a majority of patients elicited comorbidities such as sleep and anxiety disorders for about half of them while 29.0% of them had depressive disorders.Regarding the characterization of pain disorders and their opioid treatments, patients suffered mainly from nociplastic pain (64.0%), with a duration longer than 5 years for more than 60.0% of them, and most of them (about 90.0%) had a moderate to severe pain intensity. Finally, opioid treatments used by patients were mainly tramadol (44.2%) followed by oxycodone (20.0%). The median percentage of pain relief by opioids declared by the patient, was 50.0%. In parallel, other concomitant analgesic treatments were prescribed  reported a POMI-5F score ≥2, meaning the presence of POM. The majority reported having withdrawal symptoms when stopping or delaying opioid treatment (81.5%), as well as taking higher doses than prescribed for lack of sufficient pain relief (72.4%). In addition, 45.5% of them reported taking their opioid treatment for something other than pain relief. The different purposes of using their opioids for non-analgesic effects, correlated with the presence of a POM, was to improve mood and to calm-down/to relax (see p = 0.02), with professional activity, suffering from severe nociplastic pain, depressive and sleep disorders (Characterization of the participants was performed according to the POMI-5F score (<2 versus ≥2). Our results from univariate analysis highlighted certain factors that could be associated with POM: younger patient, male sex  shows almost similar populations with a slightly higher proportion of women (p = 0.037) and a slightly lower proportion of neuropathic pain (p = 0.034) in the multivariate analysis population (data not shown). The MCA of the POM population was conducted for 377 patients (377/422 = 89.3%) who had no missing data for the variables included in the analysis, and 45 were removed. These two samples were similar in all assessed criteria (data not shown). The MCA showed the presence of three clusters of patients. The clusters differed mainly in age, type of pain, pain intensity, and type of opioid (weak or strong). Clusters 1 and 3, which were quite similar , differed from each other by the type of pain and their opioid treatment. Cluster 1 included mostly patients with nociplastic pain and weak opioids, whereas cluster 3 included mostly patients with different types of chronic pain and treated with strong opioids. We also noticed that cluster 3 tended to have more depressive disorders and co-prescription of benzodiazepines . Cluster 2 differed from the other clusters in that it corresponded to elderly, retired patients with mild to moderate various chronic pain.From an exploratory perspective, we performed a multivariable analysis to determine associated factors with the presence of POM  and a clCurrently, only the POMI scale  is used et al.  showed a prevalence from 43% to 52% , 26.5% iet al.  also asset al. .et al. study , age (about 50 years old), and marital status (about 35% single) with the studies mentioned previously. It is noteworthy that in the German study, the patients were older (61.8 years old), and we have fewer unemployed patients (32.9%) compared to the studies of l. study . The stuConcerning the characteristics of our patients considered as misusers (POMI-5F score ≥2), we were able to determine POM-related factors and profiles using multivariable analysis. The results obtained show that young male patients, patients suffering from severe nociplastic pain, codeine prescription and a co-prescription of benzodiazepine were associated with a POM. These characteristics are also mainly found as associated factors for misuse, addiction and/or OUD in the literature . InteresLastly, we were able to separate our POM population into three subgroups differentiated mainly by age (cluster 2 = patients aged +60 years) and type of opioid . Interestingly, the clusters did not differ on the POMI-5F score and OUD symptoms . Moreover, there was no difference in the intensity of misuse (POMI score) between the weak versus strong opioid cluster (1 and 3 respectively). This reinforces the fact that the distinction between weak and strong opioids is not appropriate for use disorders, in line with the recent recommendations of the French National Health Authority on opioid drugs  Bon usa. Our thrOur study has certain limitations, such as a measurement bias, which occurs frequently in observational studies . NeverthThe updated prevalence of POM in French patients with CNCP remains high, with almost half of the patients concerned. In view of all our results, certain factors should draw the attention of practitioners to the profile of patients at risk of POM, such as: young age, male, suffering from severe nociplastic pain, having a codeine prescription and a co-prescription of benzodiazepine. Nevertheless, because of the cross-sectional design of this study, further longitudinal studies are required to assess the findings. Our study also highlights that distinguishing between strong and weak opioids is not appropriate in the context of use disorder. Finally, we encourage French-speaking practitioners to use the POMI-5F scale to assess the presence of OUD in their patients receiving opioid-based therapy.Debbah Abdelouahab, Peyre Alexandre, Simon Anna, Defeuillet Catherine, Wiart Catherine, Sureau Christophe, Vulser Cristofini Claire, Bouhassira Didier, Touchard Emmanuelle, Collin Elisabeth, Serra Eric, Perez-Varlan Evelyne, Mohy Frédérique, Peyriere Hélène, Le Borgne Jean-Marie, Poinsignon Jean Paul, Micallef Joëlle, Dy Lénaïg, Amilhaud Marlène, Venard Maria, Dorsner-Binard Marie, Berrier Oui Marie, Martial Maud, Feuillet Maryline, De Rijk Pablo, Ginies Patrick, Kieffert Patrick, Giraud Pierric, Aerts Raluca, Le Boisselier Reynald, Cauchin Sonia, Pouplin Sophie, Corand Virginie, Perier Yannick, Poujol Yves.


Virtual reality (VR) gaming is considered a safe and effective alternative to standard pain alleviation in the hospital. This study addressed the potential effectiveness and feasibility of a VR game that was developed by our research team for repeated at-home burn dressing changes.A randomized clinical trial was conducted among patients recruited from the outpatient burn clinic of a large American Burn Association–verified pediatric burn center between September 2019 and June 2021. We included English-speaking burn patients aged 5–17 years old requiring daily dressing changes for at least 1 week after first outpatient dressing change. One group played an interactive VR game during dressing changes, while the other utilized standard distraction techniques available in the home for up to a week. Both child and caretaker were asked to assess perceived pain on a numerical rating scale (NRS) of 0–10. For the VR group, patients were also asked to rate various aspects of the VR game on a NRS of 0–10 and caregivers were asked questions assessing ease of use.n=19, 54.3%), White , and with second degree burns . Children and caregivers in the VR group reported less pain than the control group at the 4th dressing change. Participants in the VR group showed a clinically meaningful (≥30%) reduction in child-reported overall pain (33.3%) and caregiver-reported worst pain (31.6%) in comparison with subjects in the control group. Children’s satisfaction with the VR remained at a high level across dressing changes over the 1-week period, with reported realism and engagement increasing over time. Over half of the children (54.5%) enjoyed playing the game and did not report any challenges nor any side effects.A total of 35 children were recruited for this study with 24 fully completing study measures. The majority of participants were male (Subjects found the VR to be a useful distraction during home dressing changes and reported no challenges/side effects. VR should be considered as a nonpharmacologic companion for pain management during at-home burn dressing changes.ClinicalTrials.gov Identifier: NCT04548635. Registered September 14, 2020—retrospectively registeredThe online version contains supplementary material available at 10.1186/s40814-022-01150-9. Virtual reality has been shown to be a useful distraction mechanism for inpatient burn injuries, but there is no research indicating if it is still effective and useful at home and whether the device is easy for caregivers to implement.Children and caregivers found the virtual reality to be fun and easy to implement and it was effective at reducing pain.Our study established the study design to be feasible and provided important considerations for a future full-scale randomized clinical trial study.National statistics reported that over 250,000 US children 0–17 years) suffer burn injuries every year 7 years s, 4. AfteThe latest research shows that repeated use of opioid medication for acute pain management is likely to increase the risk of long-term opioid use and risk of opioid addictions , 11. ThePrior research confirmed that VR provides three unique advantages over traditional nonpharmacological interventions for pediatric burn patients , 16. FirRecent meta-analysis and reviews of published studies in the past three decades have provided evidence that VR can effectively distract patients to reduce pain and anxiety across many settings , 22–25. n=40 subjects (n=20 per group) for this study. From September 1, 2019, to May 30, 2021 (the end of the funding period), 35 patients were recruited from the outpatient burn clinic of an American Burn Association (ABA)-verified US pediatric burn center and randomly assigned to either the VR group or the control group which used standard home distraction techniques. Inclusion criteria were (1) pediatric burn patients (5–17 years) who were receiving their first outpatient dressing change at our outpatient burn clinic, (2) have a dressing that requires daily changes at home for at least 1 week, and (3) can communicate orally. Exclusion criteria include (1) any wounds that may interfere with study procedures; (2) vision, hearing, or cognitive/motor impairments preventing valid administration of study measures; (3) history of motion sickness, seizure disorder, dizziness, or migraine headaches precipitated by visual auras; (4) minors in foster care; (5) suspected child abuse; (6) unable to communicate in English; or (7) families who do not have access to a smartphone (due to the VR-PAT game requirement). The institutional review board of the Nationwide Children’s Hospital reviewed and approved this study. Written informed consent (and assent for children aged 9 years and older) was collected. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines—extension to randomized pilot and feasibility trials  used mixed-methods and multiple sources to test whether a smartphone VR-PAT could feasibly and safely reduce pain during repeated pediatric burn dressing changes at home. We also qualitatively assessed the ease of setup and enjoyment of the program. Based on our prior outpatient clinic research and burn patient numbers, we planned to recruit a total of Over the study period, 313 patients were screened, 145 patients were eligible for all factors before knowing the dressing type, and 65 of those patients met our eligibility criteria after learning the dressing type. A trained researcher approached 49 patients for participation and 35 patients consented/assented to this RCT. Of those recruited, 24 participants returned their surveys and completed the study. No other subjects were excluded from the study following recruitment  before being randomly assigned to either the VR-PAT or a standard of care control group using a 1:1 allocation ratio. A simple randomization method was utilized and built using the random number generator function within Excel. The randomization scheme was uploaded to a Research Electronic Data Capture (REDCap) site , 28, andParticipants self-rated overall pain, worst pain, and time spent thinking about pain on a numerical rating scale (NRS) of 0–10 (higher score means more pain). This scale was chosen as it is commonly used to clinically assess pain in the US health care setting and by pain researchers, so we felt subjects would be familiar with and more comfortable answering questions using this scale. It has also been shown to be a quick and appropriate measure for children in this age range , 30. PatGuardians were also asked to report the participants overall pain and worst pain on a NRS of 0–10 (higher score means more pain). Those in the VR group were asked to report time spent using the VR-PAT, whether the participant declined to use the VR, number of voluntary interruptions, whether the device was helpful and easy to use, and any pain medications (including dose) used for the burn.Finally, participants in the VR group were contacted after a week of home dressings to ask post-intervention questions about what they liked about the game, did not like about the game, and whether any part of the game or set-up was too hard.Demographic information was pulled from the electronic medical record. This included date of birth, gender, race, ethnicity, burn date, visit date, percent total body surface area (TBSA), burn severity , and body area burned.Our VR-PAT consisted of a lightweight VR headset with a Virtual River Cruise game that is played on a smartphone. In our pilot study , we founOur standard of care group was able to use any distraction available in the home, including toys, mobile phone, and books. Subjects in the control group were asked not to use the VR device during the first week of dressing changes but encouraged to use it for any dressing following the study week.Our primary outcome was pain associated with burn dressing changes. Pain scores were compared to subsequent surveys over the following week during repeated dressing changes. Secondary outcomes were time spent thinking about pain and caregiver-reported pain, both rated on a NRS of 0–10. We also provided an opportunity for user feedback on VR’s potential effectiveness and areas for improvement.Both children and caretakers were asked to describe the perceived enjoyability and potential adverse effects of the VR. Additionally, patients were asked questions about prior experience with VR and other gaming systems.p values not reported due to feasibility study design and the small sample sizes in each group. Data analyses were conducted in SAS version 9.4 (SAS Institute).Demographic and burn characteristics were described using frequencies and percentages for the categorical variables and means and standard deviation (SD) for continuous variables. Mean, SD, and median were calculated for the primary outcome of reported pain  across dressing changes. Child satisfaction  was calculated as a mean across dressing changes. Qualitative data was collected at follow-up on the child’s utilization experience. Responses naturally fell into some common themes, so data was analyzed using simple counts and reported as frequencies and percentages. Area under the curve (AUC) for child- and caregiver-reported overall and worst pain was calculated by averaging the pain score for each time point, then using the average scores for the control and VR group to calculate the AUC. Since the AUC was calculated based on plots of overall/worst pain score over time using the trapezoid rule, the AUC can exceed 1, depending on the scale of the pain score. AUC can be interpreted as the cumulative exposure to pain over time, and this recent statistical advancement based on AUC methods allows for combining pain intensity score and medication consumption to enhance pain outcomes assessment –35, whicn=29) and male (n=19), making up 88.2% and 64.7% of the VR group and 77.8% and 44.4% of the control group, respectively  after making this change and we attribute it to families forgetting to mail surveys and United States Postal Service slowdowns during the COVID-19. We believe that future studies should request surveys to be returned in person, allow families to e-mail their survey responses or create an online survey for the family to submit their surveys by computer or smartphone. Fifth, there were more patients receiving either a long-term dressing or no dressing than we expected, which reduced the number of eligible patients. Our outpatient clinic did not have data on this prior to conducting this study, so this is something we have learned to take into consideration for future studies. Finally, this was our first feasibility trial, so we did not originally design our study using frameworks , Outcomes for Implementation Research, or the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM)). These are valuable frameworks to guide the process of evaluation during feasibility studies and will be incorporated in our future feasibility research.We encountered several limitations during this randomized controlled trial. First, summers are the time of year where hospitals usually see the highest numbers of burn injuries in our specified age range. We missed the Summer 2019 due to difficulties in setting up the platform that would allow subjects to download the game app, which was not ready until late August 2019. Second, we encountered multiple changes in Apple’s operating platform security surrounding downloading third party apps, which required our RISI team to change how the VR game could be downloaded onto an iPhone. These changes required complicated workarounds that meant we could not recruit iPhone users for periods of time. A consideration for future studies would be to host the game on Apple’s App Store or Android’s Google Play Store which makes downloading apps easier and could circumvent some of these issues. Third, we missed 5 months (March–August) in 2020, which included the summer, due to a pause on in-person recruitment because of COVID-19. Fourth, COVID-19 resulted in institutional changes to in-person research which shifted our study to limit as much patient contact as possible. The best way to do this was to ask participants to mail their surveys back in a pre-paid, self-addressed envelope, and we made three reminder calls to families. Unfortunately, we experienced a higher rate of loss to follow-up  as compared to the control group. Children playing the VR-PAT reported consistent happiness and fun as the week went on and increased realism and engagement, which indicates these results were not just due to the novel experience of VR-PAT. Our recommendation is that VR should be considered as a nonpharmacologic pain management approach for home burn dressing changes. Future virtual reality studies need to consider technology issues (like changes in smartphone operating systems), reducing loss to follow-up, and time required to recruit subjects.Additional file 1.


The purpose of this study was to identify prognostic factors that are associated with improvements in patient-reported outcomes measures (PROMs) related to upper extremity function and pain in those suffering from idiopathic adhesive capsulitis.t-test was used to compare baseline and one-year minimum follow-up PROMs. Odds ratios and their 95% confidence intervals were calculated for each factor; a P value of < .05 was considered statistically significant.All patients treated conservatively for primary idiopathic adhesive capsulitis were identified from our institutional database between 2019 and 2021. Exclusion criteria included any patients treated surgically, follow-up less than one year, or incomplete survey results. PROMs including Patient-Reported Outcomes Measurement Information System (PROMIS) Upper Extremity Computer Adaptive Test Version 2.0 (P-UE), Pain Interference (P-Interference), Pain Intensity (P-Intensity), and visual analog scale (VAS) pain scores. They were obtained at initial consultation and at one year to assess patient-perceived impact of their condition. Multiple linear and multivariable logistic regressions were performed to identify factors associated with improvement in patient-perceived pain and shoulder function using final PROM scores and difference in PROM scores from initial consultation. An independent P < .001) was demonstrated at one-year minimum outcomes for P-UE, P-Interference, P-Intensity, and VAS scores. With respect to comorbid conditions, hypothyroidism [P-UE ] was associated with greater improvements in PROMs, while hyperlipidemia [P-UE  and P-Intensity ] and anxiety [P-UE ] were associated with poorer reported changes in PROMs. Female sex [P-UE  and P-Interference ] and employment in manual labor professions  were associated with significantly better patient-perceived outcomes. Hispanic heritage was associated with higher reported changes of P-Intensity  and VAS .A total of 56 patients  were enrolled in the study with an average age of 54.7 ± 7.7 years. A significant improvement (Patient-perceived improvements in PROMIS score during the natural history of adhesive capsulitis are likely multifactorial, with anxiety, hyperlipidemia, increased body mass index, and Hispanic heritage associated with reduced improvement in PROMIS scores. We hypothesize that patients’ perception of pain and their functional limitations are multifactorial, incorporating both modifiable and nonmodifiable factors.An internal Institutional Review Board Approval was granted for this study with all subjects providing informed consent prior to enrollment (s20-00287).This was a retrospective review conducted on a prospectively enrolled database of consecutive patients treated for IAC using International Classification of Diseases 10  codes between August 16, 2019 and January 1, 2021. Baseline and final follow-up PROMs were assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) scores obtained by telephone, e-mail, or in person during office follow-up visits as per patient preference.Subjects were enrolled in this study if they met the following inclusion criteria: (1) age of 18 years or more at time of initial consultation, (2) underwent nonsurgical treatment for idiopathic adhesive capsulitis, (3) minimum of one-year follow-up from initial to final consultation, (4) completed the required PROMs at initial consultation, and (5) were able to provide informed consent. Subjects were excluded from the study if they were (1) deceased or lost to follow-up, (2) had adhesive capsulitis from a secondary etiology , (3) were unable to communicate in English, (4) underwent any surgery on the affected shoulder, or (5) were unable to provide informed consent or complete the study surveys.All patients underwent plain radiographic imaging  to rule out causes of secondary adhesive capsulitis . The diagnosis of adhesive capsulitis was made by the treating physician based on pertinent clinical history and physical examination. All patients presenting with shoulder pain and global loss of ROM (both active and passive) and radiographs showing no signs of arthritis or calcific tendinitis were diagnosed with adhesive capsulitis.The natural history of adhesive capsulitis was explained to each patient and the benefits and risks for each treatment option were discussed in detail. However, treatment was guided through shared decision-making based on patient preference. Patients were offered nonsurgical treatments in the form of oral anti-inflammatory medications , home exercise program or outpatient-supervised physical therapy, and intra-articular steroid injection. The final determination for intra-articular steroid injection was made by the patient.,,,,,,Subjects’ active ROM was measured individually by 2 trained research fellows using a goniometer. In addition, subjects were required to complete PROMIS Upper Extremity Computer Adaptive Test Version 2.0 (P-UE), PROMIS Pain Interference (P-Interference), and PROMIS Pain Intensity (P-Intensity) and a visual analog pain scale (VAS) at initial consultation and one-year minimum follow-up. Normalized across a scale of 0-100 with a mean value of 50 (SD ± 10) in reference to the general United States population, PROMIS has been established to accurately assess a patient's perceived symptomatology across all facets of orthopedics.PROMIS-based PROMs are derived from 1 of 4 domains , each of which is further divided into a multitude of separate subdomains. In respect to P-UE, P-Interference, and P-Intensity, each of these belong to the physical health domain which is further comprised of subdomains such as physical function, physical activity, pain, fatigue, and sleep disturbances. As patients initially presenting for IAC are typically limited in ROM with concomitant pain in their affected shoulder, these 3 PROMs allow for accurate assessment of the two most common complaints in those afflicted. Specifically, P-UE evaluates one’s ability to use their shoulder, while P-Interference and P-Intensity assess the limitations brought about by their shoulder pain and the severity of pain they are currently experiencing, respectively. While higher scores in P-UE indicate superior upper extremity function, lower scores in PROMIS pain instruments  are indicative of a patient experiencing less pain.,,,,,,,,,,,,,,,,,,,,To determine which factors may influence improvement in PROMs, we evaluated a multitude of factors including previously reported risk factors for primary IAC.3t-test was used to compare baseline and one-year minimum follow-up PROMs. Multiple linear and multivariable logistic regressions were conducted to determine which factors were associated with patients’ improvement in pain and function as determined by the final PROM score and change in PROM scores from initial to final visit. Stepwise selection was applied to each regression model to identify variables that were the strongest predictors of each outcome modeled. Regression coefficients (β) were calculated for each predictor selected for a given model and predictors with P < .05 were considered statistically significant.All statistical analysis was performed in R-studio version 4.0.3  and SAS Studio Version 9.4 . An independent A post hoc analysis was performed using G∗Power version 3.1.9.7  to determine achieved power on multivariable regression analysis. Our analysis was performed using postoperative PROMIS-UE as the outcome and the aforementioned factors as independent variables in a mixed multivariable regression. Using the partial R2 of 0.58, the effect size was determined to be 1.38. Using an F-test family parameter for multivariable regression models, the calculated effect size of 1.38, an alpha error probability of 0.05, and a total sample size of 57 patients, the achieved power for our analysis was determined to be 0.98.A total of 56 patients were included in the study with an average age of 54.7 ± 7.7 (range 43-74 years) years. There were 40 females (71.4%) and 16 males (28.6%). Mean BMI was 27.1 (range 18.97-44.61). Throughout the course of treatment, 39/56 (69.6%) patients received a glenohumeral steroid injection with an average of 1.2 ± 0.4 (range 0-2) and the dominant arm was affected in 46.4% (26/56) of subjects. A complete list of patient demographics is provided in P < .001), P-Interference , P-Intensity , and VAS . Factors associated with changes in final PROM values can be seen in Comparison of baseline PROM scores with one-year minimum follow-up outcomes can be seen in P = .01), P-Interference , VAS score , and a lower P-UE score . Dominant side involvement was also shown to increase patient perception of interference to daily tasks and pain level . Conversely, manual labor professions were found to be a protective factor, demonstrating reduced perception of pain intensity and interference . Similarly, female gender was associated with a reduction in P-Interference  and an increase in P-UE  scores. After accounting for confounding effects, higher P-UE baseline scores  and history of hypothyroidism  were associated with more favorable outcomes, while history of hyperlipidemia  and anxiety  were associated with worse outcomes , P-Interference , P-Intensity , and VAS ]. Hyperlipidemia demonstrated a significant detrimental impact on the change of multiple PROM scores . Similarly, BMI demonstrated a negative impact on the magnitude of change in P-UE  and P-Interference score . As compared to other races, Hispanic patients demonstrated a significantly smaller magnitude of change in P-Intensity  and VAS scores  throughout the course of the study. Female sex demonstrated improvement in initial to final P-UE  and P-Interference scores . Similarly, hypothyroidism demonstrated a likewise association for P-UE    and IV. In our study, we found one-year follow-up PROM scores and the difference from their baseline scores are influenced by a variety of patient-related factors. Notably, increased BMI, hyperlipidemia, and dominant side involvement were associated with a decrease in shoulder functionality and an increase in shoulder pain, while involvement in manual labor professions, lower initial PROM scores, and female sex were associated with an increase in shoulder function and decrease in shoulder pain.P < .001).P = .02), more specifically a 3% increased risk of IAC for every kilogram of lower weight.,P < .001) and an adjusted hazard ratio of 1.50 .P < .001).Knowledge of these modifiable and nonmodifiable factors and their associated effects provide physicians with a better understanding of a patient’s expected outcomes, thereby allowing physicians to better anticipate a patient’s perception and set more realistic treatment expectations. BMI, a modifiable risk factor, was shown in our study to be consistently associated with decreased shoulder function and increased pain. Evidenced by our study, patients with higher BMI experience worse function and increased pain once afflicted by IAC, but this population is also at an increased odds of suffering from IAC, with one study of 2190 patients finding an increased odds ratio of 1.26 (P < .05).P = .0004).In our study, baseline PROM scores, a nonmodifiable factor, proved to be a risk factor for final PROM scores and impactful on the magnitude of change among PROMs. Previous studies have investigated this relationship with the Simple Shoulder Test (SST), showing patients without diabetes with a higher initial SST score were more likely to have scored higher on their final SST (,,Our study does not come without limitations that must be considered. First, patient responses to surveys such as P-UE, P-Interference, P-Intensity, and VAS can vary over time due to recent events and a patient’s health status that are beyond the scope of the condition in question.Patient-perceived improvements in PROMIS score during the natural history of adhesive capsulitis are likely multifactorial, with anxiety, hyperlipidemia, increased BMI, and Hispanic heritage associated with reduced improvement in PROMIS scores.Funding: No outside funding or grants were received in support of the completion of this study.Conflicts of interest: The authors, their immediate families, and any research foundation with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.


We treated a 51-year-old woman with refractory Complex Regional Pain Syndrome type I (CRPS-I) involving her left hand and forearm with subcutaneous injections of BoNT/A. The injections were performed every 3 months, with a total of six treatments. Each treatment was able to effectively improve pain and motor impairment; however, the duration of the effect was limited to only a few months. BoNT/A could improve patients’ quality of life with CRPS; however, extensive clinical studies are needed to determine its role in clinical practice. Complex Regional Pain Syndrome (CRPS) is characterized by chronic regional pain, typically distal and disproportionate to the degree of the noxious insult, associated with abnormal skin tropism, motor, sensory, and vasomotor findings of the affected limb on physical examination . FrequenIn patients with CPRS-I, it is not possible to demonstrate a nerve injury, whereas patients with CRPS-II have a specific nerve injury identified. Although the exact pathophysiology of the syndrome is not known, many findings suggest the involvement of small nerve fibers (A-delta and C fibers). Quantitative sensory testing (QST), laser-evoked potentials (LEP), and skin biopsy are frequently altered in these patients ,3.Botulinum toxin type A (BoNT/A) has been demonstrated to be effective in improving pain in many different neuropathic pain syndromes refractory to conventional treatment  even thoIn the context of CRPS, very few patients have been treated with BoNT/A, with different approaches such as intramuscular injections ,8, intraIn 2016, a 51-year-old woman came to the neurologist with a complaint of severe burning, stabbing, and persistent pain in her left hand, associated with intermittent swelling, tingling, hyperhidrosis, and motor dysfunction; cold temperature triggered or exacerbated the symptoms.Her medical history included chronic migraine and temporal lobe pharmaco-resistant epilepsy. No abnormalities were seen on an MRI of the brain. Her past medication history included gabapentin, carbamazepine, oxcarbazepine, sodium valproate, lacosamide, and levetiracetam. Chronic migraine developed before the onset of CRPS and was treated with flunarizine, amitriptyline, topiramate, and bilateral great occipital nerve anesthetic blocks, with only partial benefit. Three years before the CRPS symptoms, rounds of botulinum toxin therapy permitted optimal control of the migraine. Her epilepsy therapy remained unchanged in the prior three years: levetiracetam 1000 mg BID, lacosamide 200 mg BID, and topiramate 50 mg BID.The patient was diagnosed with CRPS-I according to the Budapest criteria  and starDuring 2016 and 2017, she performed physiotherapy cycles without significant improvement, and, in the last months of 2017, she was treated with two anesthetic brachial plexus blocks with partial control of the pain that lasted until the end of 2019; unfortunately, these blocks triggered a seizure immediately and the patient refused to perform the procedure again. In the first months of 2020, the pain worsened progressively, and we decided to treat the patient with subcutaneous injections of botulinum toxin, considering the evidence of its efficacy in neuropathic pain .Upon a neurological examination, the left hand was cold, cyanotic, and swollen with hypoesthesia and allodynia, predominantly in the territory of the ulnar nerve in the hand and of the medial antebrachial nerve in the forearm. She denied any trauma in the previous months and organic causes were excluded.Thermal quantitative sensory testing (QST) and laser-evoked potentials (LEP) were altered in the affected limb see .Nerve conduction studies were normal but sympathetic skin response was abnormal in her left hand  have receptive fields that innervate structures outside the traditional dermatomes  and theiBoNT/A exerts its functions on modulating neuropathic pain by inhibiting the release of neurotransmitters involved in peripheric and central sensitization, in particular CGRP and substance P ,24,25,26In the first round of injections, we treated only the ulnar territory, while in the following rounds, we decided to apply a more widespread approach with an improvement of the efficacy on the pain and disability as well as a longer duration of the benefit; in fact, low doses of BoNT/A are insufficient for the spreading into the central nervous system ,38. RegaFurther research and extensive clinical studies are needed to determine the most efficient injection technique with BoNT/A in patients with CRPS.The patient gave her informed consent for the treatment with botulinum toxin and for her images and other clinical information to be reported in the journal. The patient did not take any pain medications at the baseline assessment and during the follow-up period; the patient continued her therapy for epilepsy and botulinum toxin for chronic migraine.Injections of BoNT/A and clinical examination were performed every 3 months.Pain and disability assessments were performed at the time of the treatment and 1 month later by the means of VAS; disability of the arm, shoulder, and hand (DASH) ; and neu®) using a 27-gauge × 12.5 mm needle. Local lidocaine 5% pomade was applied for local anesthesia. For subcutaneous injections, we gently grasped the area of the skin surrounding the injection site to separate it from the muscular layer; then, we thrust the needle, with an injection angle of 30°, into the subcutis. This procedure was easy to perform in the forearm and the dorsum of the hand; in the palm, we treated the areas where the skin had better mobility against the underlying layers and better pinching to avoid intramuscular injections. Ultrasound guidance was not used; it could be possible that a minimum amount of BoNT/A IU reached the deep fascia and then the muscular layer beneath; however, the patient did not develop muscular weakness at the visits that were one month after each round of injections.Treatment was performed with subcutaneous injections of botulinum toxin type A  and 25 IU were injected into the ventral aspect of the left forearm, within the territory of the medial antebrachial cutaneous nerve at 5 sites also (5 IU per site).During the following sessions, we decided to modify the dilution with 0.9% sodium chloride to enhance the diffusion in the hand as follows: 2 mL for the forearm and 4 mL for the hand of 0.9% sodium chloride; 40 IU were injected into the ventral aspect of the forearm into the medial and lateral antebrachial nerve territories at 16 sites (2.5 IU per site) and 40 IU were injected into the dorsal and ventral aspects of the hand at 32 sites (1.25 IU per site). The procedures were performed without any side effects and the injection pain was sufficiently tolerated by the patient. The precise sites treated are shown in