To assess the long-term efficacy of arthroscopic subacromial decompression (ASD) by comparing it with diagnostic arthroscopy (primary comparison), a placebo surgical intervention, and with a non-operative alternative, exercise therapy (secondary comparison).We conducted a multicentre, three group, randomised, controlled superiority trial. We included 210 patients aged 35–65 years, who had symptoms consistent with shoulder impingement syndrome for more than 3 months. 175 participants (83%) completed the 5 years follow-up. Patient enrolment began on 1 February 2005 and the 5-year follow-up was completed by 10 October 2018. The two primary outcomes were shoulder pain at rest and on arm activity measured with Visual Analogue Scale (VAS). Minimally important difference (MID) was set at 15. We used a mixed-model repeated measurements analysis of variance with participant as a random factor, the baseline value as a covariate and assuming a covariance structure with compound symmetry.In the primary intention to treat analysis (ASD vs diagnostic arthroscopy), there were no between-group differences that exceeded the MID for the primary outcomes at 5 years: the mean difference between groups (ASD minus diagnostic arthroscopy) in pain VAS were −2.0  at rest and −8.0  on arm activity. There were no between-group differences in the secondary outcomes or adverse events that exceeded the MID. In our secondary comparison (ASD vs exercise therapy), the mean differences between groups (ASD minus exercise therapy) in pain VAS were 1.0  at rest and −3.9  on arm activity. There were no significant between-group differences for the secondary outcomes or adverse events.ASD provided no benefit over diagnostic arthroscopy (or exercise therapy) at 5 years for patients with shoulder impingement syndrome. Up to 70% of patients suffering from shoulder pain without a preceding traumatic event receive a diagnosis of shoulder impingement or subacromial pain syndrome.A recent BMJ Rapid Recommendation, informed by two linked systematic reviews and/or meta-analysesWe conducted a multicentre, randomised, double blind, placebo surgery controlled trial to assess the long-term (5 years) efficacy of ASD in patients with symptoms consistent with shoulder impingement syndrome. Our trial also included an exercise therapy as a non-operative alternative, to allow comparison between ASD and exercise therapy in a more pragmatic setting.We conducted this superiority trial at three orthopaedic clinics in Finland from 1 February 2005 to 10 October 2018. Details of the trial design and conduct, and results at 2-year follow-up have been published.The trial was conducted in accordance with the Declaration of Helsinki. All patients gave written informed consent. On entering the study, they were unequivocally informed that they might undergo diagnostic arthroscopy and that they would be allowed to consider crossing over to ASD if they did not have adequate relief of symptoms, preferably no sooner than 6 months after randomisation.We enrolled patients aged 35–65 years who had subacromial pain for more than 3 months that was unresponsive to conventional conservative treatment, and clinical findings consistent with shoulder impingement syndrome. All patients had MRI with intra-articular contrast to exclude a rotator cuff tear. Detailed eligibility criteria are provided in the Box 1Adult men or women ages 35–65 years.Subacromial pain for greater than 3 months with no relief from non-operative means .Pain provoked by abduction and positive painful arc sign.Positive impingement test .Pain in at least two out of three of isometric tests .Provision of informed consent from the participant.Ability to speak, understand and read in the language of the clinical site.Full thickness tear of the rotator cuff tendons diagnosed on clinical examination (marked weakness in any of the examined muscles) or MRI with intra-articular contrast (MR arthrography).Osteoarthritis of the glenohumeral and/or acromioclavicular joint diagnosed on clinical examination or on X-rays.Substantial calcific deposits in the rotator cuff tendons found in the preoperative imaging.Previous surgical procedure on the affected shoulder.Evidence of shoulder instability (positive apprehension/positive sulcus sign).Symptomatic cervical spine pathology.History of alcoholism, drug abuse, psychological or psychiatric problems that are likely to invalidate informed consent.Patient declined to participate.In an attempt to obtain three balanced study groups of similar group size, we planned a twofold, sequential randomisation: patients were first randomised to surgery or exercise therapy in 2:1 ratio during the baseline appointment. Patients randomised to exercise therapy started standardised physiotherapy within 2 weeks of the baseline appointment, whereas those allocated to surgery were scheduled for surgery with the aim of carrying out the procedure within 12 weeks of this first randomisation. Patients allocated to surgery first had a diagnostic arthroscopy to rule out a rotator cuff tendon tear and other pathology requiring surgical treatment. If a patient had a full-thickness or a partial-thickness rotator cuff tear large enough to require repair (grade III),Randomisation was carried out using sequentially numbered sealed opaque envelopes. Separate randomisation lists for each centre, with blocks varying randomly in size, were prepared by a statistician with no involvement in the clinical care of participants in the trial.A physiotherapist supervised, progressive, individually designed exercise therapy was started within 2 weeks of randomisation. Participants completed 15 visits to physiotherapists and a standardised home exercise protocol , postoperative rehabilitation was identical. It consisted one outpatient visit to a study physiotherapist, blind to the group assignment, for guidance and instructions for home exercises.Given that the pathognomonic clinical sign of shoulder impingement syndrome is subacromial shoulder pain, especially at night and while lifting the arm, our two primary outcome measures were shoulder pain at rest and shoulder pain on arm activity at 5 years. We used a Visual Analogue Scale (VAS) ranging from 0 (no pain) to 100 (extreme pain) to measure the outcomes. We considered 15 points as the minimal important difference (MID).The secondary outcomes were two shoulder function assessment instruments, the Constant-Murley score (CM) and the simple shoulder test (SST), and two health-related quality of life instruments, the SF-36(R) Health SurveyQuestionnaires were administered at baseline and 3, 6, 12, 24 months and 5 years after randomisation. The follow-up questionnaires also included a separate section on adverse events (AEs). AEs were defined as untoward medical occurrences that did not necessarily have a causal relationship with the treatment administered. Serious AEs were events with the potential for substantial disability/incapacity and/or requiring inpatient hospital care or prolonged hospital care, or were life threatening, or resulted in death. In this paper, we report AEs that we deemed to be directly related to the treatments given.To assess whether patients in the placebo surgery group were more likely than patients in the ASD group to guess that they had undergone a placebo procedure, all surgically treated participants were asked at the 3 months follow-up which procedure (ASD or diagnostic arthroscopy) they thought they had had.We powered the study to detect a difference of at least the MID 15 points points15The trial was primarily designed to ascertain whether ASD was superior to diagnostic arthroscopy for pain reduction (two primary outcomes) at 5 years after the procedure (the primary confirmatory comparison). We also included a pragmatic comparison of the relative benefits of ASD vs exercise therapy (the secondary exploratory comparison), at 5 years after the procedure, with the two primary outcomes. All analyses were performed according to the previously published statistical analysis planWe quantified the treatment effect on an intention to treat (ASD vs diagnostic arthroscopy comparison) or full analysis set (ASD vs exercise therapy comparison) basis as the difference between the groups in pain scores (VAS), CM score, simple shoulder test score, 15D score and SF-36 score with the associated 95% CIs and p values at 5 years after the primary randomisation. In intention-to-treat and full analysis set analyses, the participants were included as randomised. We used a mixed-model repeated measurements analysis of variance with participant as a random factor , the baseline value as a covariate, and assuming a covariance structure with compound symmetry. As the mixed-model repeated measurements analysis of variance allows for analysis of unbalanced data sets without imputation, we analysed all available data, the full analysis set. The missingness of the outcome data at different time points is shown in the To safeguard against potential multiplicity effectsNo patients were involved in designing the study, nor were they involved in developing plans for recruitment, design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. When the results of this randomised controlled trial are published, a lay information flyer with final results will be sent to the recruiting centres for dissemination to the trial participants.Of the 281 eligible patients, 71 were excluded . A totalThere was marked improvement from baseline to 5 years for both primary outcomes in the ASD and diagnostic arthroscopy groups  . There wThere was a statistically significant between group difference in CM score in favour of ASD  . The meaSix out of 59 participants in the ASD group and 11 out of 63 participants in the diagnostic arthroscopy group (p=0.25) reported persistent symptoms after surgery, sufficiently severe to lead to unblinding of the study group assignment. Two participants in the ASD group had a reoperation: one had manipulation under anaesthesia, the other had acromioclavicular resection and later manipulation under anaesthesia. In the diagnostic arthroscopy group, 10 participants had a reoperation . Details of unblindings, treatment conversions and reoperations are shown in One participant in the diagnostic arthroscopy group had temporary swelling in the brachial area related to a brachial plexus block. Three participants in the ASD group and one participant in the diagnostic arthroscopy group developed a frozen shoulder . No otheThere was marked improvement from baseline to 5 years for both primary outcomes in the ASD and exercise therapy groups  . We founWe found no significant between group differences in any of the secondary outcomes .Sixteen participants out of 71 who were initially assigned to exercise therapy reported persistent symptoms, sufficiently severe to require unblinding. Fifteen participants subsequently had ASD and one participant had acromioclavicular resection. Three reoperations were performed .Two participants in the exercise therapy group developed a frozen shoulder and one participant reported aggravation of low back pain over the course of exercise therapy regimen . No otheThis multicentre, randomised, placebo controlled trial involving patients with shoulder impingement syndrome showed that ASD was not superior to diagnostic arthroscopy, with regard to any of the outcomes assessed at the end of a 5-year follow-up period. Although both groups had significant improvement in both primary outcomes, the patients assigned to ASD had no clinically relevant improvement over those assigned to diagnostic arthroscopy. In our secondary comparison, ASD was not superior to exercise therapy at 5 years.There is no other randomised, placebo surgery controlled trial of the long-term efficacy of ASD. In the short-term (up to 2 years), ASD did not alleviate shoulder symptoms any more than placebo surgery.Our efficacy trial was designed to detect a treatment benefit of ASD. The surgeons and physiotherapists delivering care were highly experienced. We isolated subacromial decompression, the critical therapeutic element of the ASD procedure, as the only difference between ASD and diagnostic arthroscopy arms, while carefully maintaining all other care identically. We also enrolled only patients most likely to benefit from ASD. The efficacy design increases the generalisability of the findings: When no benefit is detected in an efficacy trial, there is no reason to believe that the tested intervention would be efficacious in a more heterogeneous population or under less than ideal circumstances, such as in a routine healthcare setting with less experienced surgeons.Publication of the short-term results of this trialOur decision to include pain at rest as one of our two primary outcomes can be criticised, as this outcome shows poor performance (responsiveness) and we did not set a threshold level of pain at rest (or activity) for patients to be included at entry. It follows that—theoretically—patients with low scores were eligible for the study and such patients would not have had the opportunity to improve. Although we agree that pain at rest indeed showed poor performance and we should have set a minimum pain threshold for eligibility for both primary outcomes, we respectfully remind the reader that our patients adequately represented the typical candidates for surgery due to ‘shoulder impingement’ as assessed by experienced shoulder surgeons. The patients included in our trial were all highly symptomatic at an average of 19 months after the onset of symptoms despite having undergone various treatments. Most importantly, there were no clinically relevant benefits of ASD in the other primary outcome (pain on activity), or any of the secondary outcomes.Failure of the group differences to reach an MID threshold may hide major differences in the proportion of patients who attain an MID improvement. Thus, it may be argued that we should have reported the number of subjects in each treatment group who attained MID . However, in patients with musculoskeletal conditions, feeling good rather than feeling better matters more),Finally, a higher frequency of crossovers has been used as an argument to assert the superiority of surgery.As thoroughly elaborated previously,Given that recent trials questioning the viability of surgery for patients with subacromial pain syndrome have prompted lively debates, it seems that a wider perspective on this issue can be drawn from our data. All three groups in our trial achieved mean pain scores less than 20 out of 100 in the longer term. Although it may take those allocated to exercise a bit more time to achieve these low levels of pain, the effect does not seem to be explained by a very large number of participants crossing over, one could see this contributes to the argument of the conditions not requiring surgical intervention in the large majority of patients with subacromial pain.The results of this randomised, placebo surgery controlled trial show that ASD provided no clinically relevant medium to long-term benefit over diagnostic arthroscopy in patients with shoulder impingement syndrome. The findings contest the current practice of performing subacromial decompression in patients with shoulder impingement syndrome and lend further support to existing guidelines that make a strong recommendation against surgery as a treatment for patients with subacromial pain. As the current evidence indicates that the impingement theory has become antiquated, we would also recommend to abandon the term shoulder impingement as it refers to this mechanical theory. The more generic term ‘subacromial pain’ should be preferred.Our FIMPACT trial is the only placebo surgery controlled trial to assess the long-term (5 years) outcome of arthroscopic subacromial decompression (ASD) in patients with symptoms consistent with shoulder impingement syndrome.ASD and diagnostic arthroscopy (placebo surgery) (as well as exercise therapy) resulted in significant improvements in pain and functional outcomes with no difference in the incidence of adverse events.Patients assigned to ASD had no superior improvement over those assigned to diagnostic arthroscopy (or exercise therapy) at the 5 years follow-up.The findings contest the current practice of performing subacromial decompression in patients with shoulder impingement syndrome and lend further support to existing guidelines that make a strong recommendation against this surgery as a treatment for patients with subacromial pain.


To examine the long-term outcomes such as recurrence, foreign body feeling and chronic pain of titanium-coated mesh (TCM) versus standard polypropylene mesh (PM) after Lichtenstein repair (LR).In this retrospective cohort study, patients who underwent TCM and PM in LR were evaluated between May 2014 and January 2018 at Ordu University Training and Research Hospital in Turkey. Primary outcomes  and secondary outcomes  were analyzed. Patients were divided into two groups according to the mesh elected (TCM and PM); titanium group (TG) and polypropylene group (PG), respectively.p>0.05). In the analysis of secondary outcomes, surgical site occurence was similar in both groups (p>0.05). Recurrence was observed in 1.39% (n=1) of TG and 2.01% (n=3) of PG. No difference was found between groups in terms of recurrence (p=0.606). Foreign body feeling was observed in 15.3% (n=11) of TG and 27.5% (n=41) of PG. Chronic pain was observed in 4.2% (n=3) of TG and 12.8% (n=9) of PG. Significant differences were found between groups in terms of chronic pain and foreign body feeling .In this study, 221 patients were analyzed; TCM was used in 72 (32.6%) patients and PM was used in 149 (67.4%) patients. No difference was found between groups in terms of primary outcomes (The result of this study shows that in LR, TCM leads to less foreign body feeling and chronic pain than PM. However, there was no difference in terms of recurrence between these meshes. Inguinal hernia repair is a frequent operation in general surgery but recurrence, chronic pain and foreign body feeling after an operation are the issues that should be resolved by surgeons.3Although meshes have some advantages such as high tensile strength and cost-efficiency, they also have complications such as seroma, foreign body feeling and chronic pain. New meshes are produced in order to reduce complications like this.A single-centre cohort study was designed retrospectively and ethical approval for the study was obtained from Clinical Research Ethics Committee of Ordu University Faculty of Medicine . Two hundred and fifty-two patients who underwent LR for inguinal hernia were evaluated between May 2014 and January 2018 at the Ordu University Training and Research Hospital in Turkey. Of those patients who used TCM and PM were included in the study. Patients under 18 and over 75 years of age, with a history of femoral hernia, recurrent inguinal hernia, bilateral inguinal hernia, malignancy, ostomy, chemotherapy or radiotherapy, an ASA score of four or above, patients whose information could not be accessed were excluded. The patients were analyzed in terms of primary outcomes , smoking habits, comorbid diseases, American Society of Anesthesiologists (ASA) score, hernia type, side of hernia, duration of hernia presentation and operative time) and secondary outcomes . Comorbid diseases included cardiovascular conditions , respiratory conditions , diabetes mellitus and chronic renal failure. Surgical site occurrences were defined as surgical site infection (SSI), seroma and hematoma. Operations and postoperative follow-up were performed a single general surgeon. Informed consent about surgery was obtained by the patients before the operation. Patient information was obtained by scanning the medical files or calling the patient on the phone.2, BioCer™, Germany) was produced by coating polypropylene monofilament with titanium dioxide and had a lightweight (47 g/m2) and wide pore size (2.8 mm). Polypropylene mesh (PM)  had a monofilament structure and a highweight (80 g/m2) and low pore size (0.8-1.2 mm). Mesh selection was randomized and was not made according to any patient characteristics. Patients were divided into two groups according to the mesh elected (TCM and PM); titanium group (TG) and polypropylene group (PG), respectively.TCM  and the SPSS  statistics package software was used for calculations.In this study, the identifiers for continuous variables were: mean, average, standard deviation, minimum and maximum values, and the identifiers for categorical variables were: number and percentage. The data distribution was evaluated using the Kolmogorov-Smirnov test. The Fisher’s exact and chi-square test were used to identify the relationship between categorical variables. The Mann-Whitney U test was used to compare group averages in terms of continuous variables. In calculations, the statistically significant level was determined as 5% . Primary outcomes are shown in p=0.331).The groups were similar in terms of patient and hernia characteristics (p>0.05). Recurrence was observed in 1.39% (n=1) of TG and 2.01% (n=3) of PG. Foreign body feeling was observed in 15.3% (n=11) of TG and 27.5% (n=41) of PG. Chronic pain was observed in 4.2% (n=3) of TG and 12.8% (n=9) of PG. No significant difference was found in terms of recurrence between groups (p>0.05), and foreign body feeling and chronic pain were significantly lower in TG than PG (p<0.05). Secondary outcomes were showed in Surgical site occurence was similar in both groups .The ideal mesh is identified as a mesh that is cheap, cost-effective, low-complication, most comfortable and easy to apply, but this has still not been discovered. These are classified according to the composition or type of material as: (1) first-generation , (2) second-generation (mixed or composite prosthesis-TCM), and (3) third-generation .Firstly, the numbers of patients were relatively small and retrospective design. Secondly, we could not perform strong and valid tools like the Carolinas Comfort Scale or McGill Pain Scale for postoperative pain and functionality. Despite these limitations, the advantages of this study are that all operations were performed by a single surgeon, that it was a single-centre study, and that only a limited number of studies that investigate recurrence, foreign body feeling and chronic pain in LR are available at all.In conclusion, in LR, TCM lead to less foreign body feeling and chronic pain than PM, and there is no difference in terms of recurrence between the two meshes. LR is still one of the commonly used inguinal hernia repairs used today with reduction of complications related to the mesh to a minimum among the aims of surgeons. We believe our manuscript will contribute to science on this topic.


BackgroundWeightlifting is a common type of sports training that develops the strength and size of skeletal muscles. Low back pain (LBP) is one of its most common complaints. This sport has become prevalent among adolescents and young adults as they work to enhance their physique and body image. The aim of our study is to explore the nature and cause of LBP in weightlifting adolescents and young adults in an aim of extrapolating proper preventive measures.MethodsParticipants were patients who engaged in weightlifting sports and had presented to our clinic with nonspecific LBP. They were examined and asked to rate and localize their pain. Back positioning during weightlifting techniques along with other exercise habits was explored. Patients with congenital or systemic diseases and fractures were excluded from our study.ResultsA total of 93 patients presented with LBP (age range: 16-26 years), all of whom partook in weightlifting (N=93). Localized pain was found in 43 patients (46%). Pain radiating to the left side was found in 31 patients (33%), while pain radiating to the right was found in 19 patients (21%). LBP localized at the level of L4-L5 was found in 44 cases (47%), while that localized at L5-S1 was found in 43 cases (46%). Only six cases localized pain at the level of L3-L4 (7%). A total of 23 cases required surgery (25%), while others were managed conservatively. All the participants (100%) reported their pain to be initiated during or after weightlifting maneuvers. Psychological symptoms were found in 13 cases (19%). Factors that helped relieve the pain included surgery, swimming, and wearing a back brace.ConclusionWeightlifting is a sport that utilizes heavy weights to engage the muscles in the body, and consequently, predisposes athletes to LBP. Using excessive weights and performing improper techniques puts the back in a compromising position that may lead to injury. Medical and sports personnel should raise awareness on the biomechanical properties of the lumbar spine and the correct spine-protective posture during training to help prevent these injuries in the future. Weightlifting is a sport that revolves around a regimen of exercises designed to improve the muscular development of the human body and endorse a healthy fit lifestyle . It is aWeightlifting and other forms of strength training are becoming more popular due to an increased awareness of the need to maintain individual physical fitness . When coInjuries to the lower back often arise in weightlifting due to improper execution of exercises and using excessive weights, and as a result, low back pain (LBP) is considered one of the most common complaints in the sport . AdolescObtaining a deeper knowledge with regards to the nature and cause of an injury is pivotal for establishing novel therapeutic modalities and proper prevention guidelines. Accordingly, this study aims to examine the characteristics of LBP in weightlifting sports in an attempt to extrapolate protective measures in the future.This study explored cases of admitted to our clinic with nonspecific LBP. Demographic information, such as age, sex, weight, height, level of activity, and exercise habits and techniques, was collected from individuals and their parents.Ages of interviewed individuals ranged between 16 and 26 years. All individuals partook in the sport of weightlifting and bodybuilding. Patients were asked to localize the pain on themselves and on a model provided to them. Neurological assessment was conducted to test for motor and sensory deficits. Patients were also asked about their pertinent exercise habits, weightlifting moves, and whether any exercises exacerbate the pain or relieve it. Further investigation explored whether the techniques used were implemented properly; participants were asked to show their usual back position when engaged in several weightlifting and fitness exercises. All interviewees underwent radiographic imaging to rule out scoliosis or any other pathology at the lumbar spine level. In addition, psychological and social symptoms were investigated by interviewing the patients and/or their parents. All patients were diagnosed and managed by the same spine surgeon.For the purposes of this study, we did not include patients reporting pain associated with congenital or systemic diseases, such as scoliosis. We also excluded patients reporting pain resulting from frank injuries, such as fractures, and pain following surgical interventions.A total of 93 patients, 87 men and six women, presented to our clinic with nonspecific LBP, all of which partook in weightlifting and fitness exercises. Ages of the patients ranged from 16 to 26 years with a mean age of 21 years. The 93 patients did not suffer from any systemic or congenital condition that caused their LBP, and were thus, the focus of our study (N=93) , 31 reported LBP radiating to the left leg (33%), and 19 reported LBP radiating to the right leg (21%). Of the total number of cases, 23 required surgery (25%). LBP was mostly localized at the level of L4-L5 with 44 cases (47%) and L5-S1 with 43 cases (46%). Only six cases (7%) reported pain at the level of L3-L4  and physical therapy for several years, with recurrent back pain. Recurrent pain caused psychological consequences on 13 of the nonsurgical cases (19%), mainly due to their inability to partake in sports activities. These patients reported feeling “hopeless” and “disabled”.In all patients, reported LBP was caused by improper or flawed techniques adopted during weightlifting or fitness activities, especially during squats and deadlifts. Factors that helped relieve the pain included surgery, swimming, and wearing a back brace. Factors that exacerbated the pain included noncompliance with treatment regimen and a premature return to weightlifting exercises and sports.LBP is a very common condition that impacts many sports and can affect any sex or age group; nevertheless, LBP is especially common in adolescents and young adults . StudiesIn the sport of weightlifting, LBP is considered one of the most common complaints with incidence rates reaching 40.8% ,9. This It has often been reported that body tilt and back flexion seen in many weightlifting techniques cause greater loads on the lumbar spine, damage the musculoskeletal system, and lead to pain . DeadlifThe variation in severity and presentation of LBP in weightlifting entails a subsequent variation in the modalities of treatment. While the majority of the patients in our study underwent conservative therapy, many cases necessitated surgical requirement. The primary method of intervention often included reassurance, analgesic medications, and physical therapy; in the cases where the pain persisted, surgical interventions were suggested . Lumbar The absence of validated instruments to measure LBP is a limitation to similar studies . This leLBP is a very common condition that affects many people worldwide. Weightlifting is a popular sport that uses heavy weights to extensively engage the muscles in the body, and as a result, predispose athletes to LBP. Using excessive weights during weightlifting techniques can compromise body posture and lead to body tilt and back flexion. This increases the stress on the spine of the weightlifter and renders the lumbar area highly prone to injury. Proper knowledge on weightlifting techniques and close monitoring by physical specialists can help reduce lower back injuries in the weightlifting setting. Moreover, spine surgeons, physical therapists, and physical trainers should raise awareness on the biomechanical properties of the lumbar spine to help prevent these injuries in the future.


The undertreatment of cancer pain is a global issue although many international guidelines and various studies bloom to explore the approaches in pain management. However, there is no standard care for cancer pain in routine practices. To set up a standardized procedure for improving cancer pain management in Taiwan, the Good Pain Management (GPM) program is explored to provide treatments following the US National Cancer Care Network (NCCN) Adult Cancer Pain Guideline.Patients diagnosed with moderate-to-severe cancer pain were eligible and randomized into the GPM or control arm and observed the first 48 h to evaluate the effects of pain management between 2 arms. Pain control, adequacy of treatments, patient satisfaction, and quality of life (QoL) of eligible patients were analyzed. Ad hoc analyses based on the pain medication category were also conducted.p < 0.05). Ad hoc analyses revealed that the patient subgroups using strong opioids showed better patient satisfaction in GPM arm when compared with the same subgroup in the control arm.Fifty-one patients were enrolled, with 26 and 25 assigned to the GPM and control arms, respectively. Significant differences among the GPM and control arms were found including a greater decrease in the mean numerical rating scale (NRS) score in the GPM arm (− 4.6 vs. − 2.8), a lower proportion of moderate-to-severe pain in the GPM arm (23.2% vs. 39.8%), and a higher pain management index (PMI) score in the GPM arm (0.64 points vs. 0.33 points)  showed significant improvements on pain relief, decreased the portion of moderate-to-severe cancer pain, and increased patient satisfaction in the 1st 48 h after admission. The implementation of the GPM approach in the cancer ward may provide sooner and better improvement of cancer pain management for patients who suffered moderate-to-severe cancer pain.ClinicalTrials.gov (Identifier: NCT03155516) Pain is one of the most common symptoms occurring in 53% of cancer patients in all stages of the disease, and over 70% of patients in advanced stages experience uncontrolled pain of moderate-to-severe intensity worldwide –3. Also,Results from several investigations advocate the implementation of a standardized pain management plan. In America, various randomized studies were conducted for the assessment of effects on the education for pain in cancer patients and results showed a decrease in pain intensity following the education –16. AddiNevertheless, a Taiwanese population–based study revealed that 23.6% of cancer patients had inadequate pain medication and 47.4% were not satisfied with the pain relief during admission . ComparaThis study aimed to investigate the benefits and effects of optimal pain control within the first 48 h after cancer patients with moderate-to-severe cancer pain were hospitalized and planned to demonstrate the viability of the GPM ward in daily practices in Taiwan.ClinicalTrials.gov (Identifier: NCT03155516) before enrolling study participants. Adult patients with moderate-to-severe cancer pain and hospitalized over 24 h were eligible and randomized into either GPM or control arm in a 1:1 ratio. Patients were excluded if they had non-cancer pain or unexplained pain based on the evaluation of their medical history, moderate-to-severe mental disorder, or received surgery within 24 h before admission. Data was collected in approximately 48 h after the entry of this study to evaluate the pain management status of the enrolled patients with moderate-to-severe cancer pain. In the control arm, the pain management for patients was performed under the routine practice with less regular assessments (once every 8 h) and reassessments after rescue medication provision. In the GPM arm, patients were evaluated by brief pain inventory (BPI) within 1 h after admission and treated with analgesics based on a numerical rating scale (NRS) [This randomized, current practice-controlled study was approved by the Institutional Review Board of our Hospital (KMUHIRB-F(II)-20160086) and registered on le (NRS) , 22. TheThe pain control, adequacy of pain treatments, patients’ satisfaction, and QoL were compared between the GPM and control arms. The pain intensity was evaluated using NRS and classified into none (0 points), mild (1–3), moderate (4–6), and severe (7–10). The association between pain intensity and adequacy of analgesics was estimated by PMI . MoreoveAd hoc subgroup analyses based on the pain medication category were also conducted. Two subgroups (strong opioids and non-strong opioids) in both GPM and control arms were divided and parameters such as pain control, patient satisfaction, and QoL were analyzed and compared.After the randomization, patients in the control arm received treatments following routine practice for pain management, while patients in the GPM arm received analgesics according to pain levels classified by NRS. Non-opioids  were given to manage mild pain, and weak/low-dose strong opioids or strong opioids  were given to manage moderate or severe pain. All analgesics were introduced at a tolerable frequency and dosage per physicians’ judgments.t test or Wilcoxon signed rank test based on the normality assumption, and the difference between groups was compared by two-sample t test for normal distribution or the Wilcoxon rank sum test for non-normal distribution. Categorical variables were tabulated as frequency and percentage and compared by the chi-square test or Fisher’s exact test as appropriate between groups. The pain reporting outcome was presented as a proportion of different pain intensity among all events. The significant difference was defined by two-sided p value < 0.05. Data analysis was performed using SAS® statistical software  9.4.Continuous variables were described using the number of observations, mean, median, standard deviation (SD), and 95% confidence intervals (95% CI). Changes from baseline were analyzed by paired n = 26) or the control arm (n = 25) . The frequency of pain reporting stratified by pain levels is shown in Fig. p < 0.0001).The mean change from baseline in the NRS score is presented in Fig. p = 0.0343), suggesting that patients in the GPM ward were more likely to receive adequate pain relief.The summary of analgesic administration following different pain management is tabulated in Table p > 0.05) and had no significant difference.Figure p < 0.0001, data not shown). There was no significant difference in the moderate-to-severe reporting rate between the GPM and control arms within the non-opioid patient subgroup .To have a deeper understanding of the results from the study, an ad hoc analysis was conducted. Based on the pain medication that the patients were prescribed, the data of the 2 patient groups (strong opioid group and non-strong opioid group) were divided for further analysis. Thirty-seven patients were identified as a strong opioid group and 14 patients as non-strong opioid group. The ad hoc analysis of the pain control rate showed no statistical difference between the strong opioid subgroup and non-opioid subgroup in the GPM arm, while there was a significant difference in the higher moderate-to-severe pain reporting rate in the strong opioid subgroup compared with the non-opioid subgroup in the control arm Fig. . This map = 0.0329, Fig. p = 0.8697, Fig. Since there was no significant difference in patient satisfaction between the GPM and control arms, another ad hoc subgroup analysis was also conducted. Significant patient satisfaction was observed in the GPM arm compared with that in the control arm when the patients were in the strong opioid subgroup , somehow indicating more adequate cancer pain care management in our hospital system using GPM approaches.The assessment of the patients is always the very first step for cancer pain management . CompareHowever, studies in other countries following the WHO guidelines , 26 to mWith respect to the influence on patients’ quality of life, no significant difference in satisfaction/QoL between the two arms was noted. The ad hoc subgroup analysis of patient satisfaction showed significant patient satisfaction observed in the strong opioid patient subgroup of the GPM arm compared with the subgroup in the control arm but no difference in the non-opioid patient group. This may be because the GPM approach can provide more pain assessments on patients who need strong opioids so that healthcare professionals can identify more patients’ needs and provide more help to relieve their cancer pain. The ad hoc analysis results were similar to the results from the GPM program in China and showed an improved satisfaction/QoL in the GPM group , 31.In addition, another study conducted by Wang et al.  showed cOur study had some shortcomings. First, the patient number enrolled was relatively small. Second, we only followed up patients for 48 h for the study purposes and we were not able to see a long-term effect even after discharge from the hospital. Third, previous researches , 33 poinBased on this preliminary study, we may consider different parameters that can demonstrate more details in future studies in Taiwan. Large-scale studies focusing on 48 h and a longer follow-up period may be necessarily performed to confirm our findings in more detail. Quality-/quantity-related indicators may be identified through those studies so that they will help the HCPs to manage cancer pain in a cost-effective manner.This pilot study revealed that the implementation of the GPM ward program is viable in daily practices and effective for the improvement of cancer pain management in Taiwan, especially in the first 48 h after admission, especially for those patients with moderate-to-severe cancer pain who need strong opioids. The GPM ward program may help to optimize cancer pain management in cancer wards with clear key monitoring indicators in Taiwan.


Ketamine administration in sub-dissociative doses in the emergency department (ED) results in effective pain relief in patients with acute traumatic and non-traumatic pain, chronic pain, and opioid-tolerant pain. This case series describes five adult ED patients who received nebulized ketamine for predominantly acute traumatic pain. Three patients received nebulized ketamine at 1.5 milligrams per kilogram (mg/kg) dose, one patient at 0.75 mg/kg, and one patient at 1 mg/kg. All five patients experienced a decrease in pain from the baseline up to 120 minutes. The inhalation route of ketamine delivery via breath-actuated nebulizer may have utility for managing pain in the ED. Ketamine is a non-competitive N-methyl-D-aspartate/glutamate receptor complex antagonist that decreases pain by diminishing central sensitization, hyperalgesia, and “wind-up” phenomenon at the level of the spinal cord  and central nervous system.6Nebulized administration of ketamine has been studied in the areas of palliative care, therapy for asthma, and acute postoperative management of sore throat.We describe five patients, ages 30–54, who presented to the ED with acute painful conditions: four patients with traumatic musculoskeletal pain, and one with abdominal pain .A 44-year-old man without prior medical history presented to the ED with one-day history of traumatic injury to his right wrist and hand with severe 8/10 pain and moderate swelling along the dorsal aspect of the right hand and wrist. Radiographs were negative for acute fracture or dislocation. The patient received only two doses of nebulized ketamine at 0.75 mg/kg with change in pain score from eight at the baseline to one at 120 minutes (min) . The patA 43-year-old woman without prior medical history presented to the ED with a chief complaint of 8/10 severe bilateral knee pain over the prior six months with pain radiating to both of her calf muscles and associated with stiffness. On physical examination the patient had moderate right patellar tenderness, no appreciable joint effusion, and no evidence of infectious/inflammatory processes. She received a single dose of nebulized ketamine at 1 mg/kg with a change in pain score from eight at baseline to zero at 120 min . The patA 30-year-old man without prior medical history presented to the ED with severe, 8/10 pain to his left hand after slamming it with a car door. On examination, the patient was noted to have swelling and tenderness to palpation at the dorsal aspect of the left hand/metacarpal region with decreased range of motion at the second through fifth metacarpal joints and intact neurovascular status. He received nebulized ketamine at 1.5 mg/kg with change in pain score from eight at the baseline to two at 120 min . The patWhat do we already know about this clinical entity?Ketamine is used in the emergency department (ED) via intravenous, subcutaneous, and intranasal routes for managing acute painful conditions.What makes this presentation of disease reportable?This is the first description of the use of ketamine analgesia via breath-actuated nebulizer for adult ED patients presenting with acute painful conditions.What is the major learning point?Nebulized ketamine at doses of 0.75 milligrams per kilogram (mg/kg), 1 mg/kg, and 1.5 mg/kg alleviates acute pain in adult ED patients.How might this improve emergency medicine practice?Ketamine administration via breath-actuated nebulizer may serve as an additional non-invasive route for delivering analgesia in the ED.A 54-year-old man without prior medical history presented to the ED with severe, 9/10 acute lower back pain after a fall at home that resulted in the patient landing on his back and subsequently sliding down 10 steps. On examination, he had prominent paraspinal tenderness at the lumbar region without swelling, ecchymosis, or laceration. He received nebulized ketamine at 1.5 mg/kg with change in pain score from nine at the baseline to zero at 120 min . The patA 38-year-old woman without prior medical history presented to the ED with chief complaint of severe 9/10 crampy abdominal pain and nausea and single episode of loose stool. On examination, the patient had prominent epigastric and periumbilical tenderness without rebound and guarding. She received IV famotidine and ketorolac without appreciable pain relief and subsequently received two doses of nebulized ketamine at 1.5 mg/kg with change in pain score from nine at the baseline to zero at 120 min . The patThree patients were male and two were female. None of the patients had absolute contraindications to ketamine such as allergy to ketamine, pregnancy, or history of schizophrenia. We used a standard verbal numeric pain-rating scale to evaluate patients’ pain scores at the baseline and at 15, 30, 60, 90, and 120 min.11Three patients received nebulized ketamine via breath-actuated nebulizer at 1.5 mg/kg dose, one patient at 0.75 mg/kg, and one patient at 1 mg/kg. Two patients requested and received a second dose of nebulized ketamine. The dosages of nebulized ketamine (ordered and received) as well as baseline vital signs are presented in One patient experienced dizziness of modest intensity that was self-limited after 60 min and felt fatigued at 90 min. Another patient experienced a mood change, self-described as feeling “relaxed and happy,” at 15 min . No patiIn situations when intravenous access and/or mucosal atomization devices are not readily available, inhalation (nebulization) route might be considered for provision of timely and effective analgesia in the ED. However, safety and efficacy of ketamine in a nebulized form as an analgesic in the ED setting has yet to be shown.Nebulized administration of ketamine has been studied in the areas of palliative care, asthma therapy, and acute postoperative management of sore throat.15Pharmacokinetic properties of inhaled ketamine have not been studied broadly, but a single observational study evaluated pharmacokinetics of S-ketamine administered via nebulization to 12 healthy volunteers at doses of 0.35, 0.5, and 0.7mg/kg and inhalation duration of 20–40 min. The study demonstrated a time to maximum concentration of 15–22 min and a maximum concentration of 128ng/ml.15In addition, based on the bioavailability of intranasal ketamine (25–50%) and oral ketamine 16–24%), the bioavailability to nebulized ketamine ranges between 20–40% of IV route.–24%, theAll five patients had a decrease in pain from the baseline to 120 min with average change in pain score of 3.6 at 15 min, 4.6 at 30 min, 6.4 at 60 min, 7.6 at 90 min, and 7.8 at 120 min. Furthermore, only one patient experienced dizziness of modest intensity. While the descriptive nature of this report cannot be used to make any conclusion of safety and efficacy of nebulized ketamine in managing pain in the ED, the non-invasive route, titratability, and self-administration (by the patient) make this analgesic modality an attractive choice, especially when IV access is not readily available or unobtainable. There is a need for larger, dose-finding studies in a prospective, randomized fashion to fully evaluate the safety and efficacy of nebulized ketamine for analgesia in the ED.The inhalation route of ketamine delivery via breath-actuated nebulizer for managing pain in the ED may add an additional modality to the analgesic armamentarium of ED clinicians in providing rapid, effective, and non-invasive pain relief.


Escalation or switching of immunotherapies in patients with non-inflammatory pain, may be ineffective and unnecessarily risk loss of control of inflammation, as well as exposing patients to treatment-related adverse events. Furthermore, better understanding of non-inflammatory pain mechanisms may enable the development of targeted treatment strategies for specific subgroups of patients. The pain experience in RA is multifactorial, resulting from a complex interaction between genetics, psychology, comorbidities, joint pathology and alterations in both peripheral and central pain processing.5 Diagnosing, measuring and appropriately managing pain in RA is very challenging. There is accumulating evidence to suggest that targeting the Janus kinase/signal transducer and activator of the transcription (JAK-STAT) pathway may improve pain outcomes in RA. Here, we describe the impact, mechanisms and difficulties associated with measuring pain in RA and emerging role of JAK inhibition.Rheumatoid arthritis (RA) is an archetypal chronic, autoimmune inflammatory polyarthritis, which is characterized by peripheral joint pain, stiffness, and swelling. There have been considerable advances in management of RA, which has been revolutionized by the early and intensive use of immunotherapies. Despite these advances, pain is one of the largest unmet needs. Pain is multidimensional, defined by the International Association for the Study of Pain as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”.6 Patients with RA commonly highlight pain as their most important problem, as demonstrated by a study of 96 patients who ranked pain as the most important out of 17 patient-related outcomes (PROs).7 68% of RA patients rate pain as their highest priority for improvement, and 90% of RA patients rate pain as one of their top three priorities.8 In an international observational study of PROs, the majority of the cohorts with established RA in Europe (60%) and the US (65%) reported discontent with pain management9. Contemporary unmet needs in RA are changing; health domains of pain, fatigue and mood disturbance are closely linked and associated with restrictions in social participation.11 In distinction to past generations of RA patients, where joint deformity and consequent disability were very evident to the treating physician, these contemporary unmet needs are of a subjective nature, and known only to the patient themselves.11 However, key treatment goals of physicians are achieving remission, reduction in inflammation, prevention of structural damage and disability.13 It is therefore important that the treating physician recognises this dichotomy and having identified the issues that concern an individual patient, address them where possible with both pharmacological and non-pharmacological interventions as appropriate.Despite therapeutic advances and improved clinical outcomes, pain remains a considerable unmet need, which affects both quality of life and work capacity.14 and can be reduced by early effective treatment of inflammatory disease.15 Female sex16 may be related to worse pain over time, and psychological factors influence pain reporting in RA17 and radiographic changes may be linked to future pain.14 Pain scores of patients with early severe rheumatoid arthritis are correlated with higher levels with patients’ global assessment of disease, morning stiffness and to a lesser degree disability  rather than with radiographic changes.18Pain is associated with high disease activity19. The development of generalized and widespread pain in RA may be in large part related to the inflammatory impact on the peripheral nerves.20 Thus, inflammatory actions on nerve endings, including nociceptive fibres, may result in long-term sensitization, which contributes to chronic pain conditions. Proinflammatory cytokines like tumour necrosis factor (TNF) and interleukin 6 (IL-6) are both of specific importance in RA pathogenesis, and cytokine blockade is therapeutically beneficial. Both TNF and IL-6 also affect pain thresholds in experimental arthritis,22 as well as long-term sensitisation of joint nociceptors.19 It is postulated that arthritic joints expand their total receptive field to the surrounding area of normal noninflamed tissue. The enhanced response to stimulation of joints that are inflamed could be mediated by peripheral sensitization.23 Additional increased pain responses to noninflamed tissue could be generated in the spinal cord, leading to central sensitisation. Central sensitisation occurs when normal inputs begin to produce aberrant feedback due to the excitation of the neurons in the central nervous system. Studies have shown that anxiety, low mood, and depression have an impact on clinical pain reporting in RA and can influence brain activation in frontal regions, measured by brain functional neuroimaging studies.24 Interestingly, patients with RA treated with biologic therapies were found to have early improvements in brain pain sensitization, observed by brain functional imaging using blood oxygen level-dependent signals, within days of treatment with biologic agents, predating an observed clinical response in peripheral joint synovitis.25Clinically, RA is identified by synovitis, which classically corresponds with inflammation-driven pain. Studies have shown that inflammation of the synovium is accompanied by prostaglandin and bradykinin production, which leads to the activation of thin unmyelinated sensory nerves (C fibers) in the synovium26, and decreased pain thresholds over nonpainful areas have been shown in both early27 and established28 RA. It is unclear when central sensitisation patterns are established in the disease course of RA, or if they are reversible or amenable to specific targeted therapy. It is important to remember that central sensitisation may result from sustained nociceptive input from joint inflammation or from comorbid conditions such as fibromyalgia, secondary osteoarthritis, chronic lower back pain, obesity, smoking and diabetes.It is thought that central sensitization to nociceptive stimuli results in a decrease in the threshold  and an increase in the responsiveness  to noxious stimuli. In RA, general hyperalgesia to mechanical and thermal stimuli have been reported,Pain is considered to be one of the cardinal features of inflammation and therefore physicians have historically considered pain a marker of disease activity. Current management recommendations emphasise a treat-to-target approach to achieve remission, in which treatment is titrated according to composite measures of disease activity. The DAS28 is comprised of tender (TJC28) and swollen joint count (SJC28) out of a defined set of 28 joints, a patient self-reported global health evaluation assessed on a visual analogue scale (VAS-VAS-GH), and an acute phase marker (CRP or ESR [Erythrocyte Sedimentation Rate]). A DAS28-ESR >5.1 is the threshold used to determine high-disease activity and biologic eligibility in the UK; a DAS28-ESR ≥3.2–5.1 indicates moderately active disease, and <2.6 disease remission. Of these components, SJC28 and acute-phase marker are observed by the assessor, and VAS-GH and TJC28 are reported by the patient.Non-inflammatory pain (and its effects on the TJC and VAS-GH) can confound interpretation of the DAS28-ESR ≥3.2 as a measure of active inflammation. Non-inflammatory pain can result in misclassification of patients in remission as having active inflammation leading to inappropriate escalation of treatment and can compromise clinical trial inclusion criteria and outcomes. These scores also serve as regulatory efficacy endpoints for drug-licensing and are commonly criticised for not fully capturing the patient-experience or being sensitive enough to personalise treatments.29 Patients with fibromyalgia (without RA) generate high DAS28 scores comparable to patients with active RA, mainly due to high reporting of TJC, despite low SJC and acute phase markers.30 Central sensitisation and joint inflammation may coincide in patients with confirmed RA; patients with RA and comorbid fibromyalgia report increased pain31 and have higher DAS28 scores32 than those with RA alone, suggesting that central sensitisation influences the score. It is unclear if fibromyalgia is a true co-morbidity of RA, or whether this represents a mechanism of pain processing as part of RA. Other symptoms such as anxiety, depression and fatigue are strongly associated with chronic pain, may influence the DAS28, and might also reflect overlapping mechanisms within the central nervous system in people with RA.5Self-reported disease activity and joint tenderness on palpation may increase with inflammation from active RA, but may also be increased by changes in pain processing  or comorbidities. TJCs and the VAS-GH were high in patients with established RA fulfilling fibromyalgia (FM) classification.Pain is a difficult symptom to measure because it fluctuates and may be experienced or described differently by people at different times (inter- and intra- patient variability).33 Data from a Swedish national registry suggested that the ratio of tender to swollen joint might predict a reduced treatment response of RA to biologic therapy.34 The DAS28-P is the proportion of DAS28-ESR attributable to patient-reported components (TJC and VAS-GH) and is only calculated for active RA cases due to loss of normality at low values of DAS28.35 The DAS28-P index is a derived index, calculated using the following equation: (0.56 × √TJC)+(0.014 × VAS-GH) / (0.28 × √SJC) × (0.56 × √TJC) + (0.7 × ln(ESR)) + (0.014 × VAS-GH).35. Higher baseline DAS28-P in early RA (in the Early Rheumatoid Arthritis Network (ERAN) inception cohort) predicted less improvement in pain at 12 months.35 DAS28-P was associated with pain severity and predicted future pain in early35 and established36 RA and in patients commencing or changing biologic or non-biologic disease-modifying antirheumatic drugs (DMARDs).36 The DAS28-P has been associated with increased pain sensitivity and concurrent FM in people with RA.37 However, the DAS28-P may have limited utility when the DAS28 is <3.2, as small denominators used in its calculation would likely lead to high measurement error.There have been several attempts to measure non-inflammatory pain contributions using the components of the DAS28-ESR. The absolute difference in tender and swollen joint has been shown to be associated with FM status  in a population of RA patients.27 Derived indices were the proportion of DAS28 attributable to patient-reported components (DAS28-P), tender-swollen difference and tender:swollen ratio. CRP was used as a co-variate marker for inflammatory disease activity. Pressure pain detection threshold (PPT) at a distance from affected joints was used as an index of central sensitisation. DAS28, TJC, VAS, DAS28-P, tender-swollen difference and tender:swollen ratio were more strongly associated with pain, PPT and fibromyalgia status than were SJC or ESR. DAS28-P, tender-swollen difference and tender:swollen ratio better predicted pain over 1 year than did DAS28 or its individual components. With respect to other PROs, DAS28-ESR and its components and each of the derived indices (including DAS28-P) were significantly associated with SF-36 Bodily Pain scores in each participant group. There were no significant associations between SJC or ESR and PPTs or FM classification, suggesting that ongoing inflammation might not be necessary to sustain central sensitisation in RA, but may have contributed to the development of sensitisation earlier in the disease course. Self-reported fatigue and poor mental health scores are associated with worse pain and greater central sensitisation in people with RA. Fatigue and/or poor mental health might, therefore, be additional centrally mediated non-inflammatory mechanisms that confound inflammatory disease assessment using DAS28-ESR. Limitations of this study include using the CRP as a sole measure of inflammation, as some patients with RA have ongoing inflammation, despite a normal CRP and the absence of imaging (MRI or ultra-sound) to evaluate subclinical synovitis.A recent study demonstrated the utility of derived indices as measures of non-inflammatory mechanisms of pain in patients with active RA. The authors obtained data from multiple observational epidemiology studies of people with active RA (DAS28>3.2), using baseline and follow-up data from the BSRBR participants (1) commencing anti-TNF therapy , or (2) changing between non-biologic DMARDs (n=2992), (3) Early Rheumatoid Arthritis Network participants (n=813), and (4) participants in a cross-sectional study exploring fibromyalgia and pain thresholds (n=45).38 Multiple randomized controlled trials have reported significant pain reduction associated with treatment with DMARDs, but many patients still experience clinically meaningful levels of remaining pain despite treatment.39 A minority of patients attain and sustain remission.40 However, even in patients achieving remission, residual pain may be present in 28%, suggesting that not all experiential pain is inflammatory in origin.39 A study from the British Society for Rheumatology Biologics Register (BSRBR) reported that bodily pain scores improved in both RA patients started on biologic DMARDs and non-biologic DMARDs.36 However, after 1 year of treatment, pain scores in both groups continued to be greater than 1 standard deviation, worse than the general population average. These patterns were noted even among individuals with moderate to good responses to DMARD treatment, assessed by the European League of Rheumatism (EULAR) response criteria, EULAR remission criteria, and absolute values of SJC and ESR. In a study of DAS28 remission in the Arthritis and Rheumatology Clinic of Kansas and the RA Evaluation Study databases, mean and median pain scores were 2.43 and 1.50 on a 0-to-10 visual analogue pain scale.41 Although these values were relatively low, they were higher than the cut point of 1.25, which separated patients who were satisfied with their health from those who were not. This observation indicated that, even among patients in DAS28 remission, many still have enough pain to negatively affect health satisfaction.In early arthritis, it is thought that active joint inflammation causes a significant burden of pain. However, several studies show that pain may persist in inflammatory remission.4 Among 157 patients  in sustained DAS28-CRP remission for longer than 1 year, the prevalence of clinically significant pain (MDHAQ pain ≥4) was 11.9% at baseline and 12.5% at 1 year. No markers of inflammatory activity were associated with increased pain severity at baseline or 1 year. Patient global assessment, disability (MDHAQ function), fatigue (MDHAQ fatigue), sleep problems (MDHAQ sleep), and self-efficacy were strongly associated with pain at both baseline and 1 year. Inflammatory disease activity and joint damage (assessed using sharp scores) were not significantly associated with MDHAQ pain at baseline or at 1 year. Fatigue, sleep problems, and poor self-efficacy are part of a noninflammatory symptom cluster associated with “symptom intensification” syndromes, which may result from deficits in central sensitisation, resulting in allodynia and hyperalgesia. Disease duration was also significantly associated with pain severity at 1 year, which may reflect accrual of joint damage with time or progression towards a hyperalgesic state. Disease duration, however, was not associated with pain severity at baseline, suggesting that the observation may have been due to chance or a fibromyalgic state that was present at one year, but not at baseline. Clinically significant pain was not seen in patients with ACR/EULAR remission, likely due to the ACR/EULAR criterion limiting the patient global assessment score to ≤1. As the patient global assessment is heavily influenced by pain, this criterion essentially excludes patients with high pain scores. This study was limited by the lack of assessments involving the feet, subclinical synovitis and racial heterogeneity (which may influence pain perception). The authors discussed the difficulty in evaluating change in pain levels. They used a median improvement in pain of 20% in logistic regression models as a threshold for determining improvement; however, a clinically meaningful improvement threshold is unclear.One study demonstrated that clinically significant pain continues among a substantial proportion of patients in DAS28 remission, but not among those in ACR/EULAR remission.39 Remaining pain, in spite of good EULAR response, was associated with higher baseline disability, using the HAQ  and less baseline inflammation, using ESR (adjusted OR 0.81 [95% CI 0.70–0.93] per 10-mm increase). In addition, higher baseline VAS-GH associated with remaining pain, but markers of ‘inflammation’  and TJC28, current smoking, RF and anti-CCP antibody positivity were not associated with remaining pain. Similar associations were detected for remaining pain at follow-up, despite low inflammatory activity defined as a CRP <10 . In this group, remaining pain was significantly associated with baseline HAQ (OR 1.45 [95% CI1.17–1.79]), VAS-GH (adjusted OR 1.1 [95% CI 1.05–1.16]), and TJC28 (adjusted OR 1.04 [95% CI 1.01–1.06]), but not with baseline ESR (OR 0.86 [95% CI 0.81–0.91]), adjusted for age and sex, or CRP level (adjusted OR 0.83 [95% CI 0.79–0.88]). This suggests that patients with low inflammation at baseline may have a reduced ability to respond to DMARD treatment with respect to pain. Furthermore, baseline pain and VAS-GH and lower baseline ESR and CRP were predictive for remaining pain, suggesting that a substantial proportion of patients may already have a widespread pain syndrome at diagnosis, which is unlikely to respond to anti-inflammatory, immunosuppressive therapy. Patients with remaining pain, also displayed significant reductions of ESR, SJC28 and TJC28 at three months, indicating the presence of a reversible joint inflammation at diagnosis. CCP and RF status in patients with remaining pain and good EULAR response was similar, suggesting that a misclassification of fibromyalgia and RA was unlikely. Although subclinical synovitis was not directly assessed in this study, baseline pain was low in the subgroup with remaining pain; the converse would have been expected if there was subclinical inflammation. This study suggested that patients who develop remaining pain, may have been sensitised by initial low-grade inflammation on nociceptive fibres. Almost 20% patients had an increase in pain over the three month follow-up period, predicted by low baseline VAS-VAS-GH and low TJC28, suggesting the development of fibromyalgia or central sensitisation throughout the disease course (rather than at diagnosis) or poor pain coping strategies. The study was limited by the lack of assessment for subclinical synovitis, depression/anxiety and short treatment duration, as 12 weeks may be too short a duration to observe the full treatment effect of an immunosuppressive therapy.A study of 1241 unselected, early RA patients from the Swedish registry demonstrated that 58% patients had remaining pain (pain >20mm using a 100mm VAS) in spite of a good EULAR response at 3 months of treatment with methotrexate (MTX) monotherapy.42Most disease-modifying therapies may exert benefit by suppressing inflammation, but may not improve or reverse dysregulated pain thresholds, hyperalgesia or allodynia. Of note, similar patterns have been shown in models of transient experimental arthritis, where initial joint inflammation was followed by a long-lasting pain behaviour, persisting after resolution of inflammation and non-responsive to anti-inflammatory medication.43 There was a positive correlation between VAS and painDETETCT (r2=0.757). Obese patients were more likely to report pain than subjects with a normal BMI. Mood disorders (likely to influence pain) were not evaluated in this study. In the DANBIO Danish registry of 3,826 RA patients, 20% of patients had neuropathic pain using painDETECT scoring, which was associated with DAS28-CRP and VAS, but not with indicators of peripheral inflammation (CRP and SJC).44 In the prospective FRAME-cohort 102 RA patients were studied using clinical assessments, MRI hand imaging and PROs, including painDETECT, in order to evaluate the prognostic value of pain classification by the painDETECT score in relation to change in DAS28-CRP, VAS pain, and RAMRIS (MRI) score in RA patients initiating or escalating anti-inflammatory treatment.45 No prognostic value of painDETECT pain classification was found in relation to change of DAS28-CRP, RAMRIS score, or VAS pain. Intriguingly a high painDETECT score (non-nociceptive pain) at baseline was not associated with worse outcomes, in fact these patients had numerically greater improvement in DAS28-CRP, ie, reversible inflammatory driven pain hypersensitivity. Pain classification by painDETECT was not independently associated with change in DAS28-CRP, RAMRIS score, or VAS pain in the prognostic models. Patients with unclear pain mechanisms had reduced numerically treatment response, suggesting that their pain experience had been uncoupled from inflammation.The painDETECT questionnaire was originally designed using chronic lower back pain patients and is used as a surrogate marker for the presence of neuropathic pain and central sensitisation. It has not been validated in RA, but studies have demonstrated its utility. In a study of 100 RA patients with well-controlled disease (mean DAS28 2.07+/−0.9), 28% had possible neuropathic pain and 5% had features of likely neuropathic pain by painDETECT scoring.46 which may in turn lead to mechanical reasons for pain. Assessment for subclinical synovitis with ultrasound or MRI is important in spite of DAS28 remission, and may help to titrate treatment to achieve remission, especially where non-inflammatory mechanisms might conceal contributions of persistent synovitis to DAS28-ESR.Articular or peri-articular inflammation may cause pain. The presence of non-inflammatory pain mechanisms does not exclude concurrent inflammation, and even moderate disease activity is longitudinally associated with both poor function and joint damage,Non-inflammatory mechanisms underlying important symptoms such as pain, fatigue, depression or anxiety are important when patients have persistent pain, despite the DAS28-ESR suggesting that inflammation is well-controlled. Derived measures (such as the DAS28-P) are unlikely to be appropriate for patients in DAS remission, where more experimental measures such as PPT or other forms of quantitative sensory testing might reveal non-inflammatory pain mechanisms.47 In RA-BEAM, a Phase 3 clinical trial of baricitinib, an oral, selective inhibitor of JAK1 and JAK2, baricitinib plus methotrexate (MTX) was associated with significant clinical improvements compared to patients treated with adalimumab plus MTX or placebo plus MTX. Baricitinib- and adalimumab-treated patients demonstrated similar improvement in SJC, with both groups demonstrating statistically significantly greater improvement relative to the placebo group beginning at Week 1 that was maintained through the placebo-controlled period (Week 24). For patient-reported pain, however, baricitinib-treated patients reported statistically significantly greater improvements as early as Week 1 compared to placebo-treated patients, and as early as Week 2 when compared with adalimumab-treated patients.There are no clear accepted definitions of thresholds for pain and remaining pain. Traditionally studies have evaluated pain improvement using ‘change from baseline’ measures. A recent post-hoc analysis of the RA-BEAM trial focussed specifically on pain outcomes.48 A 30% improvement threshold is described as “much improved, meaningful differences” and 50% represents “very much improved, substantial improvement” in chronic pain conditions. A 70% improvement threshold, although not defined in IMMPACT, was also evaluated, because it is analogous to ACR response endpoints. To evaluate absolute pain, the authors studied thresholds of remaining pain  of ≤10 mm, ≤20 mm, or ≤40 mm, at Week 24. The ≤20 mm threshold indicates when satisfaction with health is not negatively affected by pain, and was the cut-off selected for ‘remaining pain’. The ≤40 mm threshold was derived from observed cut-off points between the pain VAS and 122 the Patient Acceptable Symptom State (PASS). A mediation analysis with multiple mediators was conducted to evaluate the relationship between levels of inflammation and pain relief. The total treatment effect on pain relief over placebo, that could be accounted for by changes in CRP, ESR and SJC in the mediation analysis, was the ‘indirect’ or mediation effect, whilst the total treatment effect remaining was termed the ‘direct’ effect.In the absence of standard pain thresholds in RA, the authors took two approaches. First, they applied percent change from baseline threshold recommendations from the chronic pain literature from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), an organisation which aims to improve clinical trials of treatments for pain.47Baricitinib demonstrated greater and more rapid achievement of clinically significant levels of pain relief than adalimumab or placebo through Week 24. Furthermore, this differential effect became more marked as the pain relief thresholds increased, with approximately 40% of the patients receiving baricitinib achieving ≥70% pain relief from baseline by Week 24.47 For those patients achieving ≥50% or ≥70% pain relief, baricitinib had a shorter median time to achieving these pain relief thresholds than placebo or adalimumab. Specifically, for ≥50% pain relief, the 4 weeks needed for baricitinib was approximately half that of adalimumab treated patients (8 weeks). For patients achieving ≥30% pain relief, baricitinib and adalimumab had similar median time to onset (approximately 2 weeks). Interestingly, the differences in pain relief between baricitinib and adalimumab could not be accounted for by effects of inflammation, as measured by CRP.47Intriguingly there was a very rapid onset of effective mean pain relief at a cohort level with baricitinib and MTX.49 Tofacitinib, administered 5 mg bd, was associated with a 45%–54% improvement in the patients’ assessment of pain and a 44%–60% improvement in Physician Global Assessment (PGA) score, while placebo resulted in less improvement .These findings are also demonstrated by tofacitinib, which blocks JAK 1 and 3, and is the most extensively studied JAK inhibitor. There is significant reduction in RA patients’ assessment of pain with tofacitinib compared to placebo. Some patients reported pain relief within the first 24 hours of JAK inhibitor administration, well before a demonstrable effect on inflammation.50 Pro-inflammatory cytokines that may contribute to hyperalgesia include TNF-α, IL-6, IL-4, IL-1β, IL-12, IL-18 and granulocyte macrophage colony stimulating factor (GM-CSF).50 Of these, all but TNF-α, IL-1β and IL-18 signal via the JAK-STAT pathway. IL-6 induces JAK (JAK1 and JAK2) mediated phosphorylation of STAT1 and STAT3 proteins. IL-6 and STAT3 are key mediators of both chronic inflammation and joint destruction in RA. In the CNS, STAT3 plays an essential role in IL-6 signalling. The blockade of the JAK-STAT3 activity prevented the strong expression of IL-6 and of other factors induced in the spinal cord after nerve lesion in rats and attenuated mechanical allodynia.51 GM-CSF signals through JAK2 homodimers. In a rodent collagenase-induced instability model of osteoarthritis, pain was shown to be GM-CSF dependent and neutralising GM-CSF rapidly and completely abolished arthritis pain.52The JAK-STAT intracellular pathway, is involved in a complex cytokine cascade, generating both pro-nociceptive as well as pro- and anti-inflammatory cytokines.Pain represents a significant unmet need in managing many rheumatic conditions and results from a complex interaction of structural damage, inflammation, peripheral sensitisation and central amplification. The observation of JAK inhibitors ameliorating not only inflammation but also pain in patients with RA is very promising. Although the exact mechanisms of pain modulation associated with the JAK-STAT pathway is unknown, multiple, simultaneous cytokine blockade with JAK inhibitors, is likely to play a key role. Further investigation into the mechanistic basis for pain relief and the impact on suffering associated with JAK inhibition is warranted. In time, clinicians will have better tools to personalise therapies according to the individual pain profiles/signatures to improve the outcome for patients.


To compare physical therapy strategies involving abdominal muscle stabilization, with and without upper limb movement, in patients with sternal instability after heart surgery and during in-hospital care.This prospective, longitudinal, randomized, and comparative clinical study included 20 patients, which were divided into two groups: ARM, the arm group (n=10), and LEG, the leg group (n=10). The study involved the evaluation of scores of visual analog scales for sternal instability, pain, discomfort, functional impairment, lung function, and maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) before and after the interventions. Two protocols consisting of abdominal exercises in both groups with upper limb movements (ARM) and just abdominal activation with leg movements (LEG) were used for three weeks.P≤0.01) improvements in pain, discomfort, and functional impairment scores, and in MIP (P=0.04) and MEP (P≤0.01) after intervention in both groups and just LEG showed improvement in forced vital capacity (P=0.043) and forced expiratory volume in one second (P=0.011).There were statistically significant (Both strategies promoted improvement in pain, discomfort, and functional impairment scores and in the values of inspiratory and expiratory pressures. Perhaps they were influenced by the time and resolution of the infection process, although exercises with upper limb movements seem to be safe in this population. The activation of the infra-abdominal muscles through leg movements seems to bring more benefits to lung function. However, some complications have been described, including mediastinitis, with or without sternal instability. Even with low incidence (0.4 to 5%), it presents high mortality (14% to 47%),3. That is one of the most feared complications by the cardiovascular surgery team, for generating large commitments and functional damages to the patient,4. The early recognition and diagnosis of sternal complications is imperative to ensure timely management,5. Nowadays, the treatment of mediastinitis consists in drainage, debridement, or complete sternectomy. The use of the vacuum-assisted closure (VAC) system and continuous closed mediastinal irrigation with antibiotics has improved the prognosis of these patients,8. Sometimes the fibrous union is an end point acceptable process, but patients may experience instability and severe symptoms of pain that affect the quality of life.Cardiovascular surgery is a common procedure, and the mediastinum is accessed via median sternotomy,11. These limitations affect lung function, leading to atelectasis and pneumonia secondary to decreased inspiratory capacity and added to inability of the respiratory muscles to generate expiratory flows rates. The sternotomy incision is oriented in the sagittal plane in the same direction of the sacroiliac joint. Contraction of the abdominal muscles, especially the transverse abdominal muscle, exerts “corset-like” forces that decrease sacroiliac joint laxity. This effect is also observed in the intercostal muscles that are involved in forced expiration and that pull the sternum downward and inward. Therefore, in cases of sternal instability, the contraction and activation of abdominal muscles associated with active expiration could minimize the excessive movement of the sternum and contribute to its stabilization during trunk and upper limb movements.Movements such as trunk rotation, arm swinging, switching from the sitting to the standing position, and holding objects above shoulder height are limited in these patients, causing pain and discomfort. On the basis of the principle that the activation of the abdominal and thoracic cage muscles is the key point to sternal stabilization, we would like to ensure the use of upper limb exercises without causing functional impairment and to investigate if it brings more benefits to an exercise program during in-hospital care.In clinical practice, it is common to instruct patients to avoid movements involving the upper limbs. The prescription of arm exercises after sternotomy varies among physical therapists even after six weeks of surgery. An Australian study indicated that 95% of the professionals impose movement restrictions, mainly resistive/resistance exercises involving bilateral arm elevationThe objective of this study is to compare physical therapy strategies involving abdominal muscle stabilization, with and without upper limb movement, in patients with sternal instability after heart surgery and during in-hospital care.www.clinicaltrials.com under NCT02513576.This prospective, longitudinal, randomized, and comparative clinical study was conducted at the Physiotherapy Department of the Instituto do Coração do Hospital das Clínicas da Faculdade de Medicina da Universidade of São Paulo (InCor/HC-FMUSP). The study was approved by the Research Ethics Committee – CAPPesq of the HC-FMUSP on July 4, 2012, under Protocol No. 51770, and it was registered at . All patients who participated in the study used VAC and finalized the intra-hospital protocol. The protocol was started as soon as the instability/wound infection was diagnosed. The study’s flow chart is shown in The study included individuals aged > 18 years, who had been subjected to cardiovascular surgery by median sternotomy. These patients presented sternal instability with or without mediastinitis confirmed by physical examination and chest computed tomography (CT). Patients who were unable to perform the exercise program, had active infection with fever ≥ 38ºC for > 24 hours, and had previous chronic pulmonary disease were excluded. All of the participants signed the informed consent. Patients with wound infection/mediastinitis after sternotomy present a long time of hospitalization in our service, in most cases, more than 15 days with antibiotics and extensive surgical debridement of surgical wound, treatment with negative pressure therapy, and closure of the wound with myocutaneous or fasciocutaneous flaps according to the protocol developed by the InCor/HC-FMUSP,16,17, even before and during protocol inclusion, and that routine includes walking for all patients as soon as possible. The exercise session was performed once a day, five times a week, for at least 20 minutes, during three weeks, by the physiotherapist team researchers. The physiotherapist team was trained previously to apply the protocol and collect data and evaluation by the same therapist, who was not blinded. The program of exercises is explained in Simple random sampling was used to define the groups: ARM, the arm group, which performed abdominal exercises and movement of upper limbs, and LEG, the leg group, which performed abdominal exercises and movements of lower limbs. All exercises involving lower limbs are only for activation of the infra-abdominal muscles and not for strengthening the leg muscles alone. Considering that movement of lower limbs is related only to the activation of lower abdominal muscles, we suggest that this group can be considered as only abdominal exercises. All the patients followed the institutional exercises program according to benefits related to mobilizationPatients could receive analgesia according to the presence of pain, and the drugs of choice were dipyrone (metamizole) and tramadol..Each exercise was made with maximum voluntary contraction of the abdominal muscles and maintenance of trunk stabilization during expiration, seated on a pattern chair without arm support, and their feet flat on the floor with knees below the hip level, so as to ensure the adequate curvature of the lumbar spineDemographic, clinical, and surgical data were collected from the medical records. Data on surgical wound infection, microorganisms, treatment, and use of the VAC system were collected at the start of the study. Chest X-ray and CT images were analyzed to confirm the diagnosis of separation of the sternal edges, mediastinitis, and pleural effusion.,14, previously the VAC intervention.Sternal instability was quantified using the Sternal Instability Scale: 0 (stable sternum), 1 , 2 , 3 , and 4 Pain scale was assessed using the visual analog scale, in which score 0 means absence of pain and 10 corresponds to extreme pain.Discomfort scale was assessed using the visual analog scale, in which score 0 means absence of discomfort and 10 corresponds to extreme discomfort.Functional impairment was based on a numerical scale from 0 to 10, as follows: 0–3, did not interfere with activities; 4–6, interfered but did not prevent activities; 7–9, prevented activities; and 10, prevented activities and/or caused lack of control.The identified daily activities that caused pain and discomfort included coughing, trunk rotation, lying on the side, arm swinging while walk, simulate driving a car, switching from sitting to standing or from lying to sitting, holding an object above shoulder level, and sudden loss of strength during walking.®) according to the recommendations of the Sociedade Brasileira de Pneumologia e Tisiologia/American Thoracic Society (2002) and adapted to the Brazilian population, according to Pereira et al. (2007). The forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow (PEF) were recorded and the obtained values were compared with the expected values,19.Lung function was evaluated by spirometry (EasyOne.Maximum inspiratory pressure (MIP) and maximum expiratory pressure (MEP) were measured using a vacuum manometer (Record®), the measurements were repeated for tree times, and the highest values, excluding the last one, were usedt-test and Mann-Whitney U test were used. The paired Student’s t-test was used to analyze the variables before and after the intervention and the Wilcoxon test was applied when the hypothesis of normality was rejected. The chi-square (x2) test was performed for comparing categorical data. To the intragroup variables, it was used the two-way analysis of variance (ANOVA) for repeated measurements. P-value < 0.05 was considered statistically significant. The statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 21.0 (SPSS Inc).Data were expressed in terms of percentages and frequencies for categorical variables and in means and standard deviation for continuous variables. To test the normality in the distribution of continuous variables, the Kolmogorov-Smirnov test was used. For comparison between groups, Student's Of the 24 eligible patients, 20 were included in the protocol: 10 patients in ARM and 10 in LEG. The characteristics of the study sample are shown in P<0.01 for all measures . There was a significant reduction in the pain, task performance, and discomfort scores in both groups after three weeks of the exercises program with measures .The activities that caused the largest number of complaints of pain and discomfort before the intervention were trunk rotation, lying on the side, coughing, switching from lying to sitting, and holding an object above shoulder height. After the intervention, there was a reduction in the complaints of pain and discomfort related to activities such as lying on the side and coughing. In addition, pain/discomfort related to coughing and to trunk rotation persisted in LEG. Before the exercises, no patient received analgesia.In the evaluation of the lung function and maximal respiratory pressures, it was used the two-way ANOVA to treat the intragroup and intergroup factors and they are described below :P=0.009) and there is an interaction between time and group. Analyzing the groups separately, LEG presents significant increase of FVC from the initial to the final moment (P=0.043) and ARM does not show significant changes (P=0.104); the groups do not show differences at the initial time (P=0.250).FVC: The groups showed a significant difference in behavior (P=0.027), but LEG (P=0.063) and ARM (P=0.258) do not show differences between the initial and the final moment. However, LEG has more delta variation than ARM (P=0.023), which proves the tendency of differences between the initial and the final moment in LEG.FVC (%): The groups showed a significant difference in behavior (1: The groups showed a significant difference in behavior (P=0.003). LEG presents significant increase of FEV1 from the initial to the final moment (P=0.011) and ARM does not show significant changes (P=0.213).FEV1 (%): The groups did not show any difference in behavior (P=0.125) and they did not present significant differences in means at the initial and final moments (P=0.766). Both groups present a significant increase in FEV1% from the initial to the final moment (P=0.024).FEVP=0.819) and they did not present significant differences in means at the initial and final moments (P=0.888). Both groups present a significant increase in MIP from the initial to the final moment (P=0.046).MIP: The groups did not show any difference in behavior (P=0.957) and they did not present significant differences in means at the initial and final moments (P=0.626). Both groups present a significant increase in MEP from the initial to the final moment (P=0.010).MEP: The groups did not show any difference in behavior (P=0.073) and they did not present significant differences in means at the initial and final moments (P=0.740). Both groups did not present changes of PEF from the initial to the final moment (P=0.703).PEF: The groups did not show any difference in behavior (P=0.065) and they did not present significant differences in means at the initial and final moments (P=0.655). Both groups did not present changes of PEF% from the initial to the final moment (P=0.782).PEF (%): The groups did not show any difference in behavior (Staphylococcus aureus (40% of patients in ARM and 60% of patients in LEG), followed by S. epidermidis (20% in ARM and 10% in LEG). Other microorganisms, including Klebisiella, Candida albicans, and Streptococcus, were found in 40% of patients in ARM, and K. pneumoniae carbapenemase and Proteus mirabilis were found in 20% of patients in LEG. Only one individual in LEG did not have a mediastinal exudate culture, corresponding to 10% of the sample.Regarding the microorganisms found in surgical wound exudates, there was a predominance of -13.An exercises program based in the stabilization of trunk and maximum abdominal muscles contraction seems to be beneficial to patients with sternal instability, independently of using arm movements. More important than that, upper limb exercises appear to have no functional impairment over time. Pain, discomfort, and lung function scores improved significantly in both groups, obviously greatly influenced by the time and resolution of the infection process, but the activation of infra-abdominal muscles, the main objective of lower limb exercises, seems to bring benefits to pulmonary function. Contraction and activation of the abdominal and chest muscles are the main points to trunk stabilization and to reduce the pain and discomfort caused by sacroiliac joint laxity, as described by other studies. Adipose tissue is susceptible to the microbial colonization and proliferation. Several studies reported that patients who smoke, in particular those with chronic obstructive pulmonary disease, are vulnerable to surgical wound infections due lower lung capacity, which impairs tissue oxygenation,5. Even though our study exclude chronic pulmonary disease, the effect of active smoking on sternal healing should not be dismissed.Myocardial revascularization surgery procedures could involve an internal thoracic artery graft and may decrease the blood supply, leading to hypoxia of sternal bone tissue and regional tissues, which favors the development of infectious microorganisms and mediastinitis. Our finding is that 90% of ARM patients and 80% of LEG patients underwent myocardial revascularization with the use of a thoracic artery graft. Moreover, the previous clinical manifestations, including those related to diabetes mellitus, that changes in the microvasculature, can lead to changes in tissue repair and healing and may predispose to and increase the likelihood of infections. All study patients underwent treatment of surgical wound infections using the VAC system. This treatment tends to be more painful than only antibiotic therapy because of increased invasiveness and the need for debridement of the surgical incision,8. However, the treatment used in our sample decreased significantly the overall mortality and the rates of recurrence and readmission.Pain, functional impairment, and discomfort may be explained by the excessive motion of the sternal edge, which induces an inflammatory response, and which, in turn, promotes bacterial colonization and infection. Some studies suggest that pain may be related to hypersensitivity reaction to wire, scar entrapped neuralgia, and sternal irritations,13. In addition, pain/discomfort related to coughing and to trunk rotation persisted in LEG, despite the improvement in other activities. Avoiding movement in order to avoid pain deconditions muscle, whereas exercise improves muscle function, and this perhaps justify the permanence of pain in activities that demand greater strength for thoracic stability in the group without training of upper limb muscles.The pain and discomfort reported by the participants in the surgical wound area may also be associated with the magnitude of sternal separation1, and PEF) were lower than expected in both groups,19. This finding may be explained by the surgical procedure, the surgical access via median sternotomy, the number of required repeat surgeries, and wound infection. All these factors lead to a decrease in the compliance of the thoracic cage, resulting in a reduction in lung volumes and capacities.Prolonged surgical time, hemorrhage, high risk score, and ineffective antibiotic therapy increase the prevalence of mediastinitis. Therefore, a reduction in lung volume and capacity, a decrease in lung compliance, and changes in gas exchange favor alveolar collapse caused by hypoventilation, such as atelectasis. These changes were observed in the present study, wherein the values of the lung function  and MEP (P<0.01) in both groups, considering the absolute value that represents the pressure developed by the respiratory muscles. A previous study indicated that respiratory muscle performance was decreased significantly in the postoperative period and that this reduction was related to the presence of pain, and that analgesics and heart surgery affected muscle function. The reduction in MEP may be associated with the changes in respiratory muscle function combined with sternal instability caused by sternum bone section, which affects the adequate activation of the abdominal muscles during physical activities and leads to thoracic/abdominal imbalance and a decrease in inspiratory and expiratory muscle strength.The values of MIP/MEP were altered in both groups, which indicated respiratory muscle weaknessP=0.043), ARM does not show significant changes (P=0.104), and LEG have more delta variation than ARM (P=0.023), which proves the tendency of difference between the initial and final moments in LEG and this group presents significant increase of FEV1 from the initial to the final moment (P=0.011). Therefore, the abdominal exercises performed by LEG may have provided a greater abdominal stabilization, with the best activation of infra-abdominal muscles and improvement of body awareness and increased recruitment of respiratory muscles, than those performed by ARM.About FVC, LEG presents significant increase from the initial to the final moment  on the outcomes of the groups. Moreover, although the European System for Cardiac Operative Risk Evaluation (EuroSCORE) did not showed statistical difference, there is a clinically significant difference in both groups, with score 3 in LEG meaning a moderate risk, LEG could possibly have a faster recovery after the protocol than ARM. Several studies have shown that patients with left ventricular dysfunction have greater improvements with postoperative rehabilitation compared to normal left ventricular function subjects.The cardiac function related to EF (%) presented a statistical difference between the groups. However, the risk scores showed no difference and the lowest mean EF value of this is study is 48% in LEG. The literature considered EF ≤ 40% to estimate risk of mediastinitis. Regarding the microorganisms identified in cultures of the surgical wounds, the incidence of S. aureus both in ARM (40%) and LEG (60%) was higher than that of other microbial agents, which confirms the results reported in the literature,7. However, the cultures of surgical wound exudates may be negative for microorganisms in some cases because of the prophylactic use of antibiotics.Surgical wound infection is a severe postoperative complication and leads to prolonged in-hospital stay, increased hospital costs, and high rates of patient morbidity and mortalityThe limitations of this study were: 1) the low incidence of sternal instability/mediastinitis that makes this a small sample; 2) the use of the VAC system that did not allow the adequate palpation of the bone structure during the pre-intervention evaluation; 3) the study was not conducted in a blind manner.Although statistical analysis had demonstrated a reduction in the pain and discomfort scores in both groups, it did not only attribute those to abdominal exercises. Since inflammation and pain usually decrease over time, this improvement could be a natural response to postoperative recovery.Both strategies promoted improvement in pain, discomfort, and functional impairment scores, perhaps influenced by the time and resolution of the infection process, however, the use of protocols with upper limb movements seems to be safe and, more than that, the activation of the infra-abdominal muscles through leg movements seems to bring more benefits to lung function. We emphasize the need for larger studies on the rehabilitation of patients with sternal instability during in-hospital care.