This study aimed to determine the long-term level of pain after surgical treatment of one or more symptomatic rib fracture nonunions. Secondary aims were to evaluate the occurrence of adverse events, satisfaction, and activity resumption. The final aim was to assess the association between pain and the presence of bridging callus at the nonunified fracture. Hypothesized was that thoracic pain would diminish after surgery.This retrospective case series included adults who underwent surgery for a symptomatic rib fracture nonunion from three hospitals. Symptomatic nonunion was defined as persistent pain associated with nonbridging callus of ≥1 rib fractures on a chest CT scan at ≥3 months after the initial injury. Patients completed questionnaires about pain, satisfaction, and activity resumption ≥3 months postoperatively.25–P75 49–62) years and 169 acute rib fractures were included. Nonunion occurred in 98 (58%) fractures of which 70 (71%) were treated surgically. After a median of 11 months (P25–P75 7–21), 13 (36%) patients reported severe pain, in contrast to 26 (72%) preoperatively. Patients who underwent intercostal neurectomy or neurolysis in addition to surgical stabilization less often reported pain reduction. Twenty-six (72%) had postoperative complications, for which 12 (33%) underwent additional surgery, mostly for persistent pain. The majority  was satisfied with their functional recovery. Of patients who had paid work pre-trauma, 65% had resumed working.Thirty-six patients , with a median age of 55 (PMost patients reported less pain and better daily functioning after surgical stabilization of symptomatic rib fracture nonunions, although causality cannot be proven with this retrospective case series. Additional intercostal nerve treatment was not associated with pain relief. Despite surgery-related complications being common, patient satisfaction was high.Level of evidence: Level V.Study type: Therapeutic.The online version contains supplementary material available at 10.1007/s00068-021-01867-x. Approximately 10% of blunt trauma patients and almost 50% of polytrauma patients sustain rib fractures . BesidesUntil recently, it was common practice to surgically resect the symptomatic rib nonunion, creating a defect pseudoarthrosis , 9 withoTo date, literature addressing the outcomes after surgical treatment of rib fracture nonunion has remained scarce, with the largest study describing 24 patients , 6. ThesThis multicenter retrospective case series enrolled adult patients from three hospitals, two level I and one level II trauma center. All three hospitals each have at least 40 admissions of patients who sustained acute rib fractures per year. The surgeons from these three centers  have a referral role for complicated rib fracture patients.All patients aged 18 years or older, with symptomatic nonunion after one or more rib fractures, who underwent surgical treatment between January 1, 2015 and October 31, 2020 were considered eligible. Patients were identified via the hospital records. Symptomatic rib fracture nonunion was defined as pain or discomfort at the site of a rib fracture where the bone failed to unite, without formation of bridging callus, confirmed on a chest Computed Tomography (CT) scan at least 3 months after the initial injury , 17. PatPreoperative chest CT scans were used to localize the nonunion as an adjunct to physical examination. During the surgical procedure, the nonunion was exposed with attention to the subcostal neurovascular bundle. After debridement of the nonunion, the fracture was fixated. Depending on the hospital, either the MatirixRIB , the RibFix Blu™  or NiTiRib-plate   was used for osteosynthesis. Additional techniques were used in case of interposition of tissue, suspected intercostal nerve entrapment, or an abnormal configuration of the ribs. Bone graft was not used. A chest tube was placed in presence of an intra-operative air leak.Demographics, comorbidities, preoperative analgesic use, and injury details  ranging from 0 (no pain) to 10 (worst possible pain). The pain level at follow-up was evaluated for various situations and activities; at night, at rest, during deep inspiration, during high-pressure moments such as coughing or sneezing, and during housekeeping, work, and sports. Preoperative pain at the side with the rib fracture nonunion(s) and the unaffected contralateral side were also scored as a reference.Secondary outcome measures were the presence of bridging callus in the nonunion, and adverse events including severity, graded according to the Clavien–Dindo classification , and theData were analyzed using the Statistical Package for the Social Sciences (SPSS) version 25 . Normality of continuous data was tested with the Shapiro–Wilk test. All continuous variables were nonparametric and are presented as median with percentiles. Categorical variables are presented as frequencies and percentages. Missing values were not replaced. To evaluate the association of pain at follow-up with the presence of bridging callus and intercostal nerve treatment in addition to SSRF, group comparisons were conducted using a Chi-squared test. Statistical significance of changes in pain score before and after surgery was assessed using the Wilcoxon signed-rank test.n = 26) or coughing/sneezing (n = 6). For one patient, the details of the injury, including mechanism and concomitant injuries, were not recorded in the medical files. Of the trauma patients, 15 (58%) sustained also extrathoracic injuries, including 5 with head injuries. Injury Severity Scores were only available in the minority of the patients and therefore not collected. Other baseline characteristics and injury details are shown in Table During the study period, surgical treatment for rib fracture nonunion was performed in 41 patients, of whom 36 were included; 2 declined to participate, 2 sustained the nonunions after radiation therapy for malignancy and 1 could not be reached (Online Resource 1). The three hospitals enrolled 10, 11, and 15 patients. The median age was 55 years and 26 (72%) were men (Table 25–P75 6–12) after trauma. Most of the rib fractures and nonunions occurred laterally and posteriorly in ribs five to ten . The maximum number of rib fracture nonunions was six.The 36 included patients sustained a total of 169 rib fractures. For 82 of the 169 acute fractures, the initial fracture type and displacement were unknown, because no direct post-injury chest CT was available. For the 87 CT-visualized acute rib fractures, 23 fractures (26%) were diagnosed as displaced with no contact between cortices. The preoperative chest CT scan showed 98 rib fracture nonunions, at a median of 8 months , release of the intercostal nerve (n = 6), infiltration with a mix of local anesthetics and corticosteroids (n = 4), or a combination of these. In two out of three patients with intercostal bridging of heterotopic ossification, the heterotopic ossification was resected. In five patients, a partial rib resection was performed; in two patients to recontour the chest wall and create alignment at the ends of the rib, in three patients to remove infected or necrotic bone. Intraoperative adverse events occurred in four (11%) patients. Three patients developed a pneumothorax and in one patient, it was impossible to remove the hardware applied in an earlier attempt to treat the rib nonunion. The median hospital length of stay was 3 days .In 14 patients, the intercostal nerve was treated in addition to stabilization of the rib fracture nonunion by either a neurectomy (25–P75 7–21) after the nonunion surgery, 26 (72%) participants reported severe pain before the nonunion surgery, and 13 (36%) reported persistent severe pain at follow-up , except for sports (p = 0.062). Twenty-one (58%) patients reported less pain at follow-up than before the nonunion surgery. The overall pain remained similar for 12 (33%) and worsened in three (8%) patients. In two patients, this worsening was due to neuralgic pain. In the third in whom the nonunions developed after multiple thoracotomies for pleural empyema, the reason for worse pain was unclear. Two of these three patients were referred to a pain specialist.After a median of 11 months (Pp < 0.001).Especially painful were the moments of high pressure on the thorax, such as coughing or sneezing, during which 23 (64%) patients reported severe pain on the affected side before the surgery. At follow-up, this diminished but remained painful with seven (19%) patients reporting severe pain after surgery when coughing or sneezing,  than patients without evidence of bridging callus  than by patients who did undergo intercostal nerve treatment . For the other differences in surgical technique, no additional analyses were performed because of the limited number of patients.Patients in whom there was bridging callus in all rib fracture nonunions at follow-up more often reported pain reduction n = 19; 7% than paIn the postoperative course, 26 (72%) patients experienced an adverse event, in which the highest Clavien–Dindo classification was class I in seven patients (19%), II in seven (19%) patients, and IIIb  in 12 (33%) patients. A detailed list of these adverse events and their clinical management is provided in Table At the final follow-up, analgesics were used by 11 31%) patients, of whom four (11%) still used opioids. Of the 26 patients who had paid work before surgery, 17 65%) had fully resumed working, 14 already before the nonunion surgery, and 3 more after the surgery. Before the injury, 16 patients were doing sports. After the nonunion surgery, 13 (81%) resumed their sports activities and 1 started doing sports  was performed. At follow-up over half of the patients still reported pain and one-third of the patients needed additional surgery, mostly to treat persisting symptoms. Most patients were satisfied with the results and could resume their work and sports.These findings are consistent with previously published results. In a case series of 18 patients, 56% still experienced moderate or severe pain (NRS ≥ 4) at follow-up, and 32% needed additional surgery . In a seSince most ribs heal after surgical nonunion treatment, sufficient stability seems to be the main goal for the treatment of these nonunions, also because treatment of the intercostal nerve does not seem to improve the outcome. For two (5%) patients in this study, the reason for reoperation was hardware failure. This has been described before in SSRF for nonunion, although there is insufficient literature to evaluate the rate of hardware failure in nonunion SSRF. However, it is larger than the 2% that was previously described in 1224 patients who underwent SSRF for acute rib fractures . A plausThe operative technique varied across the three participating hospitals. Two hospitals used plate and screw osteosynthesis, whereas the third mostly used nitinol plates that lock themselves around the rib when on body temperature. The sample size was insufficient to evaluate differences in biomechanics and outcomes for the different rib fixation systems. Furthermore, various treatments of the intercostal nerves were described. These differences are not surprising, since literature on intercostal nerve treatment during SSRF is scarce . The curWhether the reason for the relatively high patient satisfaction in combination with the large proportion of remaining complaints could be explained by patient selection is unclear. Many patients experienced severe pain for a long period. Patients are counseled preoperatively about the risk of remaining symptoms, and the decision to treat the rib fracture nonunions is reached by shared decision making. This could possibly lead patients to more acceptance of their persistent symptoms after surgery. Also, the fact that even invasive techniques do not solve their problems might result in resignation.This study has several limitations. First, the retrospective design could have introduced a risk of recall bias, because patients were asked about their preoperative situation after their nonunion surgery, which was at least several months earlier. This risk of recall bias is especially high in patients who sustained their rib fractures during a thoracotomy performed for other reasons. Second, because of the absence of a control group, it is not completely certain that the improvement of pain should be attributed to the surgery, instead of the passing of time alone. Third, there was a wide range in months between surgery and the final follow-up. This variation in passing of time could have led to differences in reported pain at follow-up. In addition, in a substantial number of patients, no chest CT scan was available in the acute setting. This might have led to missed rib fractures or concomitant injuries, resulting in an overestimation of the percentage of rib fractures that became nonunions, which probably is already higher than average due to the patient selection. Furthermore, postoperative imaging was not routinely conducted. Assuming that without postoperative symptoms bridging callus was present might have affected the comparison of pain in patients with and without bridging callus. Bridging callus formation might also have been influenced by variations in the width of the fracture gap that was traversed with the plating system, since the largest fracture gap described was 6 mm after debridement. Moreover, a defect pseudoarthrosis after partial resection of the rib on the nonunion site could also have led to pain relief. Another consideration is that the more rib fracture nonunions per patient, the smaller the chance that all nonunions are healed at follow-up. Finally, biological factors influencing fracture healing including smoking status, vitamin D and parathyroid hormone (PTH) levels were not measured. Despite the limitations, this is the largest cohort study describing outcomes for patients who underwent surgical treatment for one or more symptomatic rib fracture nonunions.The finding that 87% of the initially displaced fractures were ultimately nonunions, suggests that displacement could be a risk factor for the development of a symptomatic nonunion, whereas the location of the acute rib fractures seemed not to be related to the development of symptomatic nonunions. Future prospective studies with routine imaging could help to identify risk factors for symptomatic nonunion, potentially providing a window of opportunity for prevention by early SSRF . RandomiAfter surgical stabilization of symptomatic rib fracture nonunions, most patients reported pain reduction and improved daily functioning. Causality cannot be proven with this retrospective case series. Although persistent pain and additional surgical interventions are common, surgery is associated with high patient satisfaction. Surgical treatment of the intercostal nerve in addition to SSRF does not lead to relief of symptoms. Future studies on the prevention of nonunion development and optimal treatment strategies of rib fracture nonunions are needed to improve the outcome in these patients.Supplementary file1 (PDF 144 KB)Below is the link to the electronic supplementary material.


Self-fixed mesh is an alternative to suture mesh fixation in inguinal hernia repair. The aim of this study was to evaluate postoperative pain after open inguinal hernia surgery using self-fixed meshes.A randomized clinical trial comparing self-adhesive mesh (Adhesix™) and self-gripping mesh (Progrip™) was conducted from November 2018 through March 2021. Patients included were male, 18–85 years old, and suitable for day case surgery. The primary endpoint was the number of patients needing follow-up visits due to postoperative pain during the first 3 postoperative months. Secondary endpoints included the intensity of pain, the time of return to work and normal daily activities, quality of life measures and postoperative complications.p = 0.001). The P group had higher numeric rating scale of pain while coughing  and during exercise  at 3 months postoperatively. The time of return to normal activity was 16.6 days in the A group and 22.9 days in the P group, (p = 0.004). The postoperative day being fit for work was sooner for the A group .270 patients were enrolled, 132 received Adhesix™ mesh (A group) and 138 Progrip™ mesh (P group), 231 (85.6%) completed 1- or 3-month follow-up. The number of patients needing follow-up for postoperative pain was significantly higher in the P group (19 vs. 4, This study demonstrated an advantage of self-adhesive mesh over self-gripping mesh with respect to acute postoperative pain and thus faster recovery after surgery. Inguinal hernia repair is one of the most performed surgical operations . For decThe self-gripping mesh (Progrip™) consists of resorbable microgrips fixing the mesh , whereasToday, the most frequent problem after hernia repair is chronic inguinal pain , 8, 9. TAnother important aspect is acute pain affecting the return to work and daily activities as well as affecting the requirement for the use of pain medication after the operation. Previous studies indicate less early postoperative pain when using glue fixation for the mesh , 12, 13.Several published trials and meta-analyses comparing self-gripping mesh, glue fixation and sutured mesh, have indicated that glue fixation seems to cause less pain in the early phase after the operation , 12–14. The aim of this trial was to evaluate postoperative pain after open inguinal hernia surgery using two different self-fixed meshes. The hypothesis for the study was that the use of a non-traumatic sutureless self-adhesive mesh might reduce early postoperative pain compared to a self-gripping mesh.A randomized clinical trial comparing two different self-adhering meshes in open hernia repair was conducted from November 2018 through March 2021. The study was approved by the national ethics committee of Helsinki University hospital (HUS/459/2018) and registered in ClinicalTrails.com (NCT03734224). Participants were recruited from two surgical units in Finland, Helsinki University Hospital and Päijät-Häme Central Hospital.The enrolled subjects were male, aged between 18 and 85 years and suitable for day case surgery. All subjects had a symptomatic primary unilateral inguinal hernia confirmed by clinical examination..The study excluded subjects with a bilateral, recurrent, or incarcerated hernia, an American Society of Anaesthesiologists physical status (ASA) of IV or more and a body mass index higher than 35 or lower than 18. The patients were also excluded if the surgeon was not experienced with both meshes or due to teaching surgery . An experience of both meshes at least five times was required. The patients were also excluded if they did not agree to participate or had inadequate language skills. The excluded patients were recorded, Fig. 1The eligible subjects received oral and written information about the study. Each participant signed an informed consent.n = 8) were experienced in open hernia surgery.The operating surgeons  or self-gripping mesh  in an otherwise similar open surgical procedure. Randomization was stratified in groups for each center, with block randomization of 10. Numbered and sealed opaque envelopes were opened by the operating surgeon just before the procedure.The operation was performed using local or general anaesthesia, with preference of local anaesthesia. The local anaesthetics (Ropivacaine) was administered by the operating surgeon. General anaesthesia was used only if the local anaesthesia was insufficient or at patient request. An inguinal skin incision was made, the external oblique aponeurosis was divided, the inguinal canal was exposed through an open anterior approach and the spermatic cord was dissected free. Direct hernia was inverted, and indirect hernia sacs were dissected and resected. The regional nerves were preserved when possible. The mesh was placed on the inguinal ligament, the pubic bone and the internal oblique aponeurosis. No additional fixation was used. The external oblique aponeurosis, Scarpa fascia and skin were closed.The primary endpoint was the number of patients needing unplanned visits to a physician in the health-care center  due to postoperative pain during the first 3 months after the operation. Secondary endpoints included use of pain medication, the intensity of pain , the time of return to work and normal daily activities, quality of life measures  and posAge, weight, height, body mass index, ASA classification and use of anticoagulants were recorded. The patients reported intensity of pain in various situations and the use of pain medication before the operation. The physical requirements of work were inquired of the patient. Operation time, the type of mesh, the type of anaesthesia, hernia type and possible nerve resection were recorded.Clinical examination was conducted before the operation. Inquiries were collected by the surgeons at 1 and 3 months after the operation and the patient´s medical records were reviewed postoperatively. The NRS pain scale from 0 to 10 were assessed at rest, when coughing and during physical activity before surgery and at one and 3 months after the operation. The NRS scale is a simple and commonly used pain measurement tool, from 0 to 10, where 0 being “no pain” and 10 “the worst pain imaginable”. To assess quality of life outcomes the RAND-36 item health survey was used preoperatively and at follow-up 1 and 3 months after surgery. The patients continuously followed-up and reported use of regular and intermittent pain medication, the postoperative day of return to normal physical activity and the day of being fit for work during the postoperative inquiries. Complications and number of follow-up visits due to pain or other problems were recorded. Additional evaluations at the outpatient clinic were performed only in patients with pain or complications needing treatment.α 0,05, β 0,80). We aimed for 480 patients in total, to allow a 10% dropout rate. An interim analysis was conducted halfway as planned, and the recruitment of the patients was terminated at this point due to significant difference between the groups in primary outcome.Prior to this study, sample size estimation based on our earlier published retrospective study (14), indicated that approximately 216 patients should be included in each group to detect clinically relevant difference between the outcomes  for numeric data and as frequency for categorical variables. A value of All statistical analyses were performed using IBM SPSS statistics version 27.In June 2021, a formal interim analysis for the primary endpoints was performed. Data of 270 patients were reviewed, 231 (85.6%) of whom had completed a 1- or 3-month follow-up. The response rate for the 1-month follow-up was 73.3% and 74.5% for the 3-month follow-up. The recruitment of patients was discontinued at this stage due to the findings and the results obtained were analyzed. Here, we publish the data of the 270 patients who were included in the interim analysis.A total of 270 patients were randomly assigned into two groups between November 2018 and March 2021, 132 of whom received Adhesix™ mesh (A group) and 138 Progrip™ mesh (P group). Table p = 0.007). No intra-operative complications were observed. The mean operation time was 42 min in both groups. Nerve resection was performed in 18 (6.7%) surgeries, with comparable results for both groups.The two groups had similar operating details, as seen in Table n = 19 vs. n = 4, p = 0.001). During the first month of follow-up 14 (14.3%) patients in the P group had a follow-up visit at a doctor´s appointment due to pain, while during the following 2 months up to 3 months after surgery an additional of five patients in the P group needed an evaluation for their pain. The equivalent result for patients in the A group was 2 (2.1%) and 2 (2.0%), respectively. The difference between the groups was significant during the first month (p = 0.002), but not after that (p = 0.149) Table 3.The primary outcome was the number of patients needing follow-up visits in the health-care center due to postoperative pain in the inguinal area during the first 3 months after the operation, which was significantly higher in the P group (p = 0.803) and there was no difference in the number of patients with more severe pain in both groups.When comparing patients using pain medication preoperatively for inguinal pain with those who did not need pain medication, the number of pain-related follow-up visits were equal  and during exercise . Within the groups, NRS assessed at rest was not yet significantly improved at 1 month compared to the preoperative situation, however, at 3 months, most patients had significantly lower NRS. NRS when coughing or during physical activity showed distinct improvement at 1 month compared to the preoperative situation, continuing at 3 months with even lower numbers in both groups, as shown in Table The degree of pain was estimated preoperatively and at 1- and 3-month surveys with numeric pain scores (NRS) assessed at rest, when coughing and during physical activity. The preoperative NRS score was higher 4.81) in the P group during exercise, compared to the A group (4.09), .81 in thn = 6/6.1%, Pn = 12/11.9%).The use of regular and intermittent pain medication postoperatively was comparable between the groups. The patients were routinely prescribed paracetamol and ibuprofen. Only a minority of the patients used pain medications more than 1 month postoperatively (A p = 0.025). According to patients´ own estimate, the mean time of return to normal activity was 16.6 days in the A group and 22.9 days in the P group, (p = 0.004). Additionally, the postoperative day being fit for work was sooner for the A group , Table 20.2% of the patients in the P group versus 9.0% in the A group had not returned to normal activity at 1 month postoperatively, the number was significantly higher in the P group (27 (13.7%) patients had complications that needed a doctor’s evaluation or treatment at the outpatient clinic. 3.6% had a postoperative infection treated with antibiotics, one patient suffered from a large postoperative haematoma, which was evacuated on the first postoperative day. Other reasons were superficial wound problems, i.e. haematomas and swelling in the operated area. In the inquiries, patients were asked to report clinical findings after the operation. Beyond complications mentioned above, superficial skin bruising was common among the patients, 36.4% reported bruising in the inguinal region and 49.5% in the scrotum. None of the patients had a recurrence during the first 3 months. Table .The RAND 36-Item Health Survey  contains2p = 0.026). The same decrease was not seen in the A group. Neither group had any change in pain at 1 month, yet at 3 months patients in both groups experienced less pain (p < 0.001).Physical functioning was improved in both groups at 1 and 3 months compared to the preoperative situation. However, role limitations due to physical health problems in the P group was significantly inferior at one month compared to the preoperative state, 46.4 and 58.8, respectively (p = 0.001), particularly during the first postoperative month. This finding is in line with our retrospective study showing that the use of self-adhesive mesh was associated with less postoperative pain compared to self-gripping mesh [To our knowledge, this is the first study comparing self-adhesive and self-gripping meshes in a randomized setting. This trial showed that in a short follow-up time of 3 months, a self-adhesive mesh caused less early postoperative pain compared to a self-gripping mesh, with otherwise comparable results. Here, we focused on a clinically relevant endpoint, that is the number of patients needing additional follow-up due to postoperative pain which was significantly higher in the P group  indicated some better results for the self-adhesive mesh. These patients also recovered more rapidly when considering return to work and other daily activities. On the other hand, no difference in the amount of pain medication after surgery was observed between the groups.In earlier analyses , 14, 17,Additionally, we are aware of the fact that glue fixation and self-adhesive mesh consisting of a glue surface are not totally equal, even though glue is the fastener in both. But, as there are currently no clinical trials comparing self-adhesive mesh to self-gripping mesh or any other kind of fixation, we suggest that glue fixation is the closest comparable type. As to the evaluation of self-adhesive mesh (Adhesix™) applied in this study, earlier studies report low pain and complication rates , 15 for Severe early postoperative pain is a predictive factor for developing chronic pain, as shown in a randomized clinical trial  with 625p = 0.475), the actual number of indirect hernias was higher in self-gripping mesh group (58.0%) compared to the self-adhesive mesh group (47.7%) which may have effect on our results.One explanation for more severe pain in the early postoperative time in the self-gripping group might be the microgrips on the surface of the self-gripping mesh, which had not resorbed by the time of follow-up. The resorption time of microgrips are 12 months . FurtherPrevious papers –8, 12 haApart from pain-related problems, this study demonstrated a low complication rate during or after surgery in the short follow-up time of 3 months. This confirms the findings of earlier studies , 13, 18 This study has some limitations. First, it is well known that acute pain is subjective and difficult to measure reliably. Many factors influence the sensation of pain. Second, the patients were not routinely checked up after surgery, except for the symptomatic patients needing an evaluation. Third, response rate of the postoperative questionnaires could have been higher but, however, the response rate was similar for both groups.The strength of this study is the randomized clinical design and the follow-up of the outcomes of patients suitable for day-case surgery during the first 3 postoperative months. This provides reliable results on pain and its impact on daily life during the early postoperative phase.In summary, the present study demonstrated an advantage of self-adhesive mesh over self-gripping mesh with respect to acute postoperative pain and thus faster recovery after surgery. Both meshes had low and comparable complication rates.


Biomechanical reduction techniques for shoulder dislocations have demonstrated high reduction success rates with a limited pain experience for the patient. We postulated that the combination of biomechanical reduction techniques with the shortest length of stay would also have the lowest pain experience and the highest first reduction success rate.A randomized multicenter clinical trial was performed to compare different biomechanical reduction techniques in treating anterior shoulder dislocations without the use of invasive pain relief. Patients who were able to perform adduction of the arm were randomly assigned to Cunningham, the modified Milch, and the scapular manipulation technique. Those who were not able to do so were randomly assigned to modified Milch and the scapular manipulation technique. Primary outcomes were emergency department length of stay and pain experienced during the reduction process, measured by the numeric pain rating scale. Secondary outcomes were reduction time, reduction success, use of analgesics or sedatives, and complications.p = 0.016), within protocol 61% (p = 0.94), and with sedation in the ED 100% ( −). In the no-adduction group, the modified Milch was also the most successful primary reduction technique with 51% success (p = 0.040), within protocol 66% (p = 0.90), and with sedation in the ED 98% (p = 0.93). No complications were recorded in any of the techniques.Three hundred eight patients were included, of whom 134 were in the adduction group. In both groups, no differences in emergency department length of stay and experienced pain were observed between the treatment arms. In the adduction group, the modified Milch technique had the highest first reduction success rates 52% (A combination of biomechanical techniques resulted in a similar length of stay in the emergency department and showed similar pain scores with an overall high success rate of reduction. In both groups, the modified Milch had the highest first-reduction success rate.Netherlands Trial Register NTR5839—1 April 2016. Ethical committee Noord-Holland with the CCMO-number NL54173.094.15The online version contains supplementary material available at 10.1186/s12245-023-00480-6. An anterior shoulder dislocation has a major impact on the patient and places high demands on emergency department (ED) facilities.The dislocation is often very painful, and the primary treatment is a timely closed reduction. Pain is caused by muscle spasms in the rotator cuff, which also causes the biceps to contract, thus maintaining the dislocation. More than 50 reduction techniques have been described that can be grouped into traction-counter-traction techniques (TCT), leverage techniques, and biomechanical techniques , 2.For the patient, as well as for the likelihood of reduction success, an important element is pain relief. Procedural sedation and analgesia (PSA) or intra-articular lidocaine (IAL) techniques require additional personnel and take time to set up, and PSA in particular extends emergency department stay considerably. These techniques also carry a risk of complications , 4. AnotPrevious randomized trials concerning shoulder reduction techniques, without the use of PSA or IAL, showed mixed results in success rate and pain relief , 6. In tIn previous studies on shoulder dislocation, the primary outcome parameter was reduction success. Although initial success rates vary across studies, eventually almost all techniques appear to have a success rate of 80–90% , 9, 10. The Cunningham technique (CH), modified Milch (MM), and scapular manipulation technique (SMT) are among the most frequently used biomechanical reduction techniques . In contTherefore, the aim of this study was to compare these different biomechanical reduction techniques without the use of invasive pain relief regarding emergency department length of stay (LOS) and experienced pain. We hypothesized that the combination technique with reduced LOS would also have the lowest pain experience and the highest first reduction success rate.For a detailed description of the design of this study, we refer to the study protocol . During From August 1, 2016, to December 31, 2018, all patients who presented with an anterior shoulder dislocation at the emergency departments of four regional hospitals across the Netherlands were screened for enrolment. All involved hospitals are level 2 trauma centers with an annual ED volume of approximately 30,000 patients.Eligible patients, with an anterior shoulder dislocation confirmed by radiograph, were included by the treating clinicians when aged ≥ 18 years old. In patients who suffered recurrent shoulder dislocations, minimal trauma , and a strong clinical suspicion of dislocation, the radiograph could be omitted. Patients were excluded if they suffered from multi-trauma, if the dislocation coincided with a fracture of the proximal humerus, or if the presence of the dislocation was more than 24 h. The latter is due to the possible increased risk of treatment failure as previously described and for comparison purposes with existing literature , 6, 14. The participants were classified by the treating physician based on the ability to perform adduction (active or passive) of the injured arm by touching the torso with the elbow. Adduction is an important part of the Cunningham technique, without adduction, this technique cannot be performed.Within each of the groups (“adduction” versus “no adduction”), patients were then randomized with equal probability to the different treatment arms using a computer-generated block randomization, stratified by center, with a block size of 10. When a patient with a possible anterior shoulder dislocation entered the emergency department, the treating physician was given two blinded envelopes containing the randomized techniques. A green envelope was opened if adduction could be performed and a red envelope was opened if adduction could not be performed. The unused envelope was returned. The envelopes were numbered for each individual hospital in order to maintain randomization order. Patients and doctors could not be blinded to the individual techniques as this was technically impossible.In the “adduction” group, patients were randomized to one of three techniques: the Cunningham (CH), the modified Milch (MM), and the scapular manipulation technique (SMT). See Fig. To compare the techniques as reliably as possible, the study protocol explicitly advised against the use of pain medication during the process of shoulder reduction. Any medication given before arrival in the emergency department or during triage was recorded. If the study protocol was not successful and a third technique was used, the treating physician could use medication to his or her discretion, this was also recorded. After shoulder reduction, all patients received a radiograph to confirm reduction and the shoulder was immobilized in internal rotation with a sling. Regular follow-up in the outpatient clinic was scheduled in accordance with regular care.All involved medical staff underwent training from the two lead investigators of the reduction techniques prior to the study, theoretical as well as a hands-on training. Additional information was also provided in the form of a pocket card and the URL of our YouTube channel (see link under videos). In all four participating centers, one of the investigators was available for questions if requested about the techniques and the study protocol.In our work in the ED, we asked patients during their ED visit about their key points of attention in both the reduction as the process of the ED visit. We have based our research questions on those stories.. Because most patients have had a shoulder dislocation only once or a limited number of times, we found it difficult to engage them in research. And we did not involve patients or the public in the development of the protocol or analysis of the results.The primary outcomes were the length of stay at the emergency department, defined as the time between the moment of arrival at the emergency department until the patient was discharged, and the maximum levels of pain experienced by the patient during the reduction. The pain was measured using the numeric rating scale (NRS), which ranges from 0 to 10.The secondary outcomes were the time needed for the reduction in minutes from the start until the end of reduction, the reduction success, effect of habitual dislocation on reduction success, the number of techniques used for reduction, use of analgesia or sedatives administered in the ED, and possible complications of the reduction (bony or neurovascular).The physician responsible for study inclusion prospectively recorded pain scores, reduction time, reduction success, age, sex, dislocation side, dislocation time, previous dislocations, history, injury mechanism, any complications, reduction time, and neurovascular examination before and after reduction. In addition, the time required for actual reduction was recorded using a clock present in the treatment room, different timepoints of the ED stay  and NRS were also noted during the reduction by the treating medical staff present at the reduction  and binary outcomes using the chi-squared test. Only observed outcomes were included for analysis. A p value < 0.05 was considered statistically significant. All analyses were conducted using SPSS version 21 [The sample size was calculated based on a clinically relevant difference in length of stay at the emergency department of 15 min between different techniques. The probability of a type 1 error  was set at 0.05 and with a power of 0.80; this led to a required total sample size of at least 62 in the no-adduction group and 123 in the “adduction” group, based on an assumed standard deviation of 20 min in both groups. Analyses were conducted according to the intention-to-treat principle. Continuous outcomes were compared using ANOVA (no-adduction group) or rsion 21 .Out of 472 eligible patients, 308 patients were included in the study. Of the 164 patients not included, 54 did not provide consent and 110 were excluded as the treating physician did not ask for consent. All randomized patients were included in the analyses  (see Table The baseline characteristics of the 134 patients included in the adduction group are presented in Table p = 0.45.The mean LOS at the emergency department for the adduction group was 120 min (SD 68 min). The mean total LOS at the ED was similar across treatment arms: in the MM/CH arm 110 min (SD 61 min), the CH/MM arm 125 min (SD 75 min), and the SMT/MM arm, it was 126 min (SD 69 min); p = 0.21 for comparison between treatment arms).There was no difference between the treatment arms regarding the maximum level of pain experienced by patients during reduction with the first technique Table . The meaOverall, the mean time from the start of the reduction until the end of the reduction was 23 min (SD 35), without differences between the treatment arms (Table p = 0.016). Ultimately, with the use of PSA, all patients could be treated in the emergency department and no patient required neuromuscular blocking agents or general anesthesia for the reduction. No complications were documented for any of the reduction techniques.The overall success of reduction within the protocol (the two techniques combined) was 63%, with no relevant difference in the treatment arms. There is a relevant difference between treatment arms in first technique success: MM was successful in the first attempt in 52% of patients, while for CH and SMT, this was 23% and 33%, respectively  , in the MM/SMT arm 114 min (SD 60 min), and in the SMT/MM arm 104 min (SD 64 min); p = 0.91 for comparison between treatment arms).There was no difference between the treatment arms in this group regarding the maximum level of pain experienced by patients during reduction with the first technique Table . The meap = 0.93).The overall success of reduction within the protocol (both techniques combined) was 66%, with no relevant difference in the treatment arms. Relevant differences were observed between treatment arms regarding the success rate of the first reduction technique: MM was successful in 51% of patients and SMT in 36% of patients (p = 0.040).Overall, the mean time from the start of the reduction until the end of the reduction was 20 min (SD 15 min). The difference between the treatment arms was not significant: in the MM/SMT arm 25 min  medication use, which we think is a confounder in reduction studies. In a recently performed survey, we showed that ED providers use traction techniques and biomechanical techniques almost as often as their first technique, this study could warrant the use of biomechanical techniques even further .This study also has limitations. First, patients may have wrongfully entered the no-adduction group, for example, due to the inexperience of medical staff who had to classify participants. Proper judgment of the ability to adduct the arm in a painful situation of a shoulder dislocation requires experience. Second, despite the training of the medical staff, it is possible that there has been variation in the implementation of the techniques. Third, due to a large number of treating clinicians, including residents, and the relatively small number of reductions per physician, there could have been knowledge decay of the techniques. Fourth, traction-counter traction or leverage techniques were not included in our study for comparison as, in our experience, patients require sedation for proper reduction with these techniques. Fifth, the power calculation of our primary outcome LOS was based on the assumption that the standard deviation (SD) of LOS would be approximately 20 min, while this turned out to be 75 min. The larger SD makes our study (in hindsight) underpowered to detect a difference in LOS of 15 min between the techniques. Finally, after a review of the sealed envelopes at the end of the study, there were six envelopes missing in total, four in the adduction and two in the no-adduction group. This is less than 2% of the total inclusions, and therefore, we do not think this has substantially influenced the outcome of the study.Ultimately, one might conclude that LOS is not the ideal primary outcome measure to analyze the reduction success. The influence of the other factors turned out to be much greater than the actual reduction time. In future research, reduction success is the better choice as the primary endpoint.Future research should focus on several areas: (1) the influence of muscle tension and muscle group relaxation on successful reduction, (2) the effect of the learning curve of the biomechanical techniques on reduction time and success, and (3) it would be interesting to see if there are techniques that have a faster turnaround time and higher success rate in older patients.This is the first randomized study to compare multiple biomechanical shoulder reduction techniques with regard to the patient length of stay in the emergency department and pain experience, minimizing and recording the impact of confounders, especially medication use. The different techniques did not appear to influence the total length of stay in the emergency department or the reduction time. There was also no difference in perceived pain. This study demonstrates that a near 100% reduction success in the ED is possible when using a combination of biomechanical shoulder reduction techniques, encouraging every ED physician to acquire these techniques. We recommend starting a reduction with the modified Milch technique.Additional file 1. Consort checklist BRASD.Additional file 2. Recorded data.Additional file 3: Table S1. Supplement group characteristics and results: ‘Adduction group’.Additional file 4: Table S2. Supplement group characteristics and results: ‘No-Adduction group’.


Pain associated with cancer diagnoses is a serious concern and one of the most common symptoms reported by cancer patients. The insufficient relief of cancer pain can have a major impact on patients’ quality of life. Recent developments in oncology such as new pain management guidelines, drugs and treatment strategies may have had a positive effect on the prevalence and severity of pain. Therefore, the aim of this systematic literature review was to assess the prevalence of pain and pain severity in cancer patients throughout all phases of treatment in the 2014–2021 literature period. Our results show a decline in both the prevalence and severity of cancer pain, compared to previous research. Nevertheless, with 44.5% of cancer patients still experiencing pain, the prevalence remains high, emphasizing the need for ongoing attention regarding the management of cancer pain.Experiencing pain and insufficient relief can be devastating and negatively affect a patient’s quality of life. Developments in oncology such as new treatments and adjusted pain management guidelines may have influenced the prevalence of cancer pain and severity in patients. This review aims to provide an overview of the prevalence and severity of pain in cancer patients in the 2014–2021 literature period. A systematic literature search was performed using the databases PubMed, Embase, CINAHL, and Cochrane. Titles and abstracts were screened, and full texts were evaluated and assessed on methodological quality. A meta-analysis was performed on the pooled prevalence and severity rates. A meta-regression analysis was used to explore differences between treatment groups. We identified 10,637 studies, of which 444 studies were included. The overall prevalence of pain was 44.5%. Moderate to severe pain was experienced by 30.6% of the patients, a lower proportion compared to previous research. Pain experienced by cancer survivors was significantly lower compared to most treatment groups. Our results imply that both the prevalence of pain and pain severity declined in the past decade. Increased attention to the assessment and management of pain might have fostered the decline in the prevalence and severity of pain. Each year, more than ten million people worldwide are diagnosed with cancer . Pain asDespite increased attention to the assessment and management of pain in cancer patients, previous research concluded that no major advances have been made in the management of cancer pain in 50 years ,8. A recLiterature indicates several reasons for the lack of improvement in the prevalence of cancer pain. Common professional barriers include a lack of knowledge and skills, clinicians’ reluctance to prescribe opioids, and poor pain assessment . PatientGlobal trends may have influenced the prevalence of cancer pain. People worldwide are living longer, and ageing populations are associated with increased multimorbidity ,15,16. DMany new studies have been published on the prevalence of cancer pain since the 2016 systematic literature review of van den Beuken-van Everdingen et al. The review of Evenepoel et al. (2022) was limited to cancer patients receiving curative treatment, excluding other phases of the disease. Therefore, the aim of this systematic literature review was to assess the prevalence of cancer pain and pain severity in cancer patients throughout all phases of the disease.A systematic literature review was performed in accordance with the recommendations of the “Preferred Reporting Items for Systematic Reviews and Meta-analyses” (PRISMA) guidelines .A systematic electronic search of the literature published from January 2014 until December 2021 was performed on the 19th of January 2022 using the databases PubMed, Embase, CINAHL, and Cochrane. The search string was inspired by the search strings of van den Beuken-van Everdingen et al. (2016), Evenepoel et al. (2022) and Rietjens et al. (2019) ,9,29. ImAfter identification and exclusion of duplicates, one author (R.A.H.S.) screened the titles and abstracts. Full texts of selected studies were examined by all four authors  regarding the eligibility criteria. Studies that reported on the prevalence of cancer pain were eligible for inclusion. Inclusion of studies was based on the design, including original studies and secondary analyses of studies in which the patient group had not been included yet, population , setting ), while studies performed in pain clinics/including only patients with pain were excluded . In caseCorresponding authors of studies that met the inclusion criteria were contacted by e-mail to obtain missing information on the prevalence of pain. If this information remained unclear after a term of two weeks, the respective percentages of pain were estimated based on study figures.A standard extraction form was developed for consistent data extraction across the authors. General characteristics were listed for each study and included the author(s), year of publication, continent of origin, study design, method of data collection, aim of the study, and the sample size. Study population characteristics included: ethnicity, gender, age, setting , Eastern Cooperative Oncology Group performance status (ECOG), and the type of cancer . Studies that included >3 types of cancer were registered as such.Phases of the disease trajectory were registered and used to categorise studies. Nine groups were defined. Group 1—treatment-naïve cancer patients; Group 2—including cancer patients receiving curative treatment; Group 3—including cancer patients receiving palliative treatment; Group 4—including patients with either curative or palliative treatment, or treatment intent not specified; Group 5—including patients after curative cancer treatment; Group 6—including patients for whom anti-cancer treatment is no longer feasible or wanted; Group 7—including patients in different phases of treatment; Group 8—including patients on anti-cancer treatment ; Group 9—including patients with advanced, metastatic or terminal disease (Group 3 and Group 6).With regard to the experience of pain, the main percentage of pain (%) in a study was extracted. In cases where a study reported on different types of pain  and did not report an overall percentage of pain, the highest percentage was registered. In addition, pain severity was extracted and registered as prevalence (%) of mild, moderate, moderate–severe, and severe pain. In case the severity of pain was not specified in the study and presented with Visual Analogue Scale (VAS) or Numeric Rating Scale (NRS), the rating of Serlin et al. (1995) was applied: none (0), mild (1–4), moderate (5–6), and severe (≥7) . FinallyThe quality of the included studies was assessed by all four authors  using the scoring criteria presented in Descriptive statistics are presented for both studies with <15 points, and studies with ≥15 points on the methodological quality assessment. Details of the studies scoring <15 points on the methodological quality assessment can be found in 2). If the heterogeneity test was significant (p < 0.05), extra variation was incorporated into the analysis by use of the random-effects model. If the prevalence of pain was 100%, the percentage was set as 99.9% in the analysis to avert statistical issues.A meta-analysis was performed on the included studies using STATA . The meta-analysis included studies with ≥15 points, a defined sample size, and pain prevalence or proportion of moderate to severe pain reported. Prevalence rates were pooled for each defined patient group with reference to pain, and pain severity (moderate–severe pain). The reciprocal of variance was chosen as a weighting factor to reflect the amount of information that each study contained as it is closely related to the study’s sample size . The 95%A meta-regression analysis was performed to explore if the pooled pain prevalence rates differed significantly between the patient groups. In addition, meta-regression analyses were also used to explore the association between the prevalence of pain and the type of cancer, ECOG score, age of the population, ethnicity, continent of origin, recall period, setting and method of data collection. The coefficient in the meta-regression analysis indicates how each subgroup differs from the nominated reference group; a negative coefficient in each subgroup suggests a lower prevalence of pain compared to the reference. A number of cancer types were regrouped for the analyses; pancreatic and other gastro-intestinal were regrouped as gastro-intestinal; ovary, uterus and other gynaecological were regrouped as gynaecological cancers.n = 6) were e-mailed to obtain missing prevalence data, of which pain prevalence was estimated in five studies because they did not respond.The electronic literature search identified 13,483 studies; PubMed yielded 3227 studies, Embase 8340 studies, CINAHL 1200 studies, and Cochrane 716 studies. After the exclusion of duplicates, titles and abstracts of 10,637 studies were screened, of which 1147 were selected for a full text evaluation. The full text assessment resulted in the inclusion of 444 studies. An overview of the reasons for exclusion is presented in n = 46), and the least in Australia/New Zealand (n = 6). In 24 studies, the primary objective was to evaluate the prevalence of pain in cancer patients. Most studies included solely gastro-intestinal cancer patients (n = 20) and 54 studies included patients of more than three types of cancer , and the least in Africa (n = 7). In 99 studies, the primary objective was to evaluate the prevalence of pain in cancer patients; 185 studies focused on another primary study objective . Most studies included solely breast cancer patients (n = 72), and 91 studies included patients of more than three types of cancer. Two hundred seventy-seven studies of the 284 with a quality score of ≥15 points were included in the meta-analysis.This systematic literature review included 284 studies with a quality score of ≥15 points . Of the The meta-analysis of the pooled pain prevalence rates including all groups (Group 1–Group 7) resulted in an overall pain prevalence of 44.5% (95% CI 41.1–47.9). The pooled pain prevalence rates from the group analyses are presented in p = 0.000, and p = 0.031; and Group 6, p = 0.001, and p = 0.038. Furthermore, the prevalence of pain was significantly lower in the group after curative treatment (Group 5) compared with the group receiving curative treatment , the group receiving all kinds of treatment , and the group including patients in different phases of treatment .Patients in both the group after curative treatment (Group 5) and the treatment-naïve group (Group 1) experienced less pain compared with patients in the palliative treatment group and the group without feasible anti-cancer treatment, respectively Group 3, The meta-analysis of the pooled pain severity including all treatment groups (Group 1–Group 7) resulted in a prevalence of moderate to severe pain of 30.6% (95% CI 26.9–34.4). The results of the group analyses on the pooled moderate to severe pain prevalence rates are presented in p = 0.035 and, p = 0.023; and Group 5, p = 0.006, and p = 0.005. In addition, the prevalence of moderate to severe pain was significantly higher in the group including patients in different phases of treatment (Group 7) compared with the group including patients after curative treatment .Patients in both the palliative treatment group (Group 3) and the group without feasible anti-cancer treatment (Group 6) experienced more moderate to severe pain compared with patients included in the all-treatments group and the group after curative treatment, respectively; Group 4, p = 0.034, p = 0.039, and p = 0.036 respectively). Age, ethnicity, and performance status (ECOG) were not associated with the overall prevalence of pain (p > 0.05). Recall periods of a week(s) (p = 0.013) or a month(s) (p = 0.001) did result in lower pain rates compared with using point prevalence. Studies that used medical records for data collection showed significantly higher pain rates than studies that used a patient questionnaire (p = 0.007). The prevalence of pain in patients who stayed in a palliative care setting was significantly higher compared to the prevalence of pain in outpatients (p = 0.040). Studies from South America, Asia and Africa showed significantly higher pain rates compared to studies from Europe . Moreover, studies from Africa showed a significantly higher prevalence of pain compared to studies from all other continents, North America (p = 0.000), Asia (p = 0.000), South America (p = 0.014) and Australia/New Zealand (p = 0.000).The results of the meta-regression analyses that included all treatment groups (Group 1–Group 7) are presented in The current literature on the prevalence of pain and pain severity in patients with cancer shows that both the prevalence of pain and pain severity have declined over the past decade. Pooled pain prevalence rates resulted in an overall prevalence of 44.5%. The treatment group with the lowest prevalence of pain was the group after curative treatment (35.8%). Despite the decline found, the results of this systematic literature review show that the prevalence of pain remains high, especially in advanced, metastatic and terminal cancer patients (54.6%).The meta-analysis of moderate to severe pain resulted in an overall prevalence of 30.6%. The treatment group with the lowest proportion of moderate to severe pain was the group after curative treatment (22.8%). Moderate to severe pain was most frequently reported in the group including patients without feasible anti-cancer treatment (43.3%).Some findings deserve attention. First, a slight decrease in the prevalence of pain was found compared with the 2016 systematic literature review by van den Beuken-van Everdingen et al. for the group after curative treatment 35.8% < 39.3%), and for the group during anti-cancer treatment (50.3% < 55.0%) . A more .3%, and Second, the prevalence of moderate to severe pain decreased (30.6% < 38.0%) compared with the rate presented in the study by van den Beuken-van Everdingen and colleagues (2016) . In contSeveral factors may have played a role in the decrease in the prevalence of pain and pain severity in cancer patients. In the literature review of Kwon (2014), the suggestion is made that a multidirectional interdisciplinary approach might be the best way to improve cancer pain management . TherefoThe observed decrease in cancer pain prevalence and pain severity may also be positively impacted by raised awareness and knowledge of healthcare professionals about cancer pain treatment and the publication of new pain therapy guidelines ,27. HoweFurthermore, in line with our results, previous research on the prevalence of undertreatment of pain in cancer patients indicate that undertreatment of pain decreased over time ,321,322.Developments in oncology, including new drugs and treatment strategies, may also have had a positive impact on the prevalence of cancer pain and pain severity. Targeted therapy and immunotherapy changed the paradigm of cancer treatment. Compared to conventional chemotherapy, these treatment strategies more subtly reduce and control tumour growth, achieving better survival outcomes and improving patients’ quality of life ,324. TheA strength of this systematic literature review is its scope, including cancer patients at all stages of the disease. This allowed us to examine differences in the prevalence of pain and pain severity between treatment groups.However, this systematic literature review has some limitations that should be taken into account when interpreting the results. First, not every study used the criteria of Serlin et al. (1995) for defining mild, moderate or severe pain . This haAlthough our analyses did not allow us to draw conclusions about detailed subgroups, this review provides a valuable overview of cancer pain prevalence and pain severity over the past decade.In conclusion, this systematic literature review shows that both the prevalence of pain and pain severity have declined in the past decade. The development of new treatment strategies and increased attention on assessment and management of pain may have facilitated the decreases in the prevalence and severity of pain. However, with more than half of the patients experiencing pain, the prevalence in advanced, metastatic and terminal patients remains high. To further decrease the prevalence of pain and pain severity, ongoing attention and improved educational programs on cancer pain management are needed.


Chronic pain disorders are often associated with cognitive-emotional dysregulation. However, the relations between such dysregulation, underlying brain processes, and clinical symptom constellations, remain unclear. Here, we aimed to characterize the abnormalities in cognitive-emotional processing involved in fibromyalgia syndrome (FMS) and their relation to disease severity.Fifty-eight participants, 39 FMS patients (35F), and 19 healthy control subjects (16F) performed an EEG-based paradigm assessing attention allocation by extracting steady-state visually evoked potentials (ssVEP) in response to affective distractors presented during a cognitive task. Patients were also evaluated for pain severity, sleep quality, depression, and anxiety.EEG ssVEP measurement indicated that, compared to healthy controls, FMS patients displayed impaired affective discrimination, and sustained attention to negative distractors. Moreover, patients displayed decreased task-related fronto-occipital EEG connectivity. Lack of adaptive attentional discrimination, measured via EEG, was predictive of pain severity, while impairments in fronto-occipital connectivity were predictive of impaired sleep.FMS patients display maladaptive affective attention modulation, which predicts disease symptoms. These findings support the centrality of cognitive-emotional dysregulation in the pathophysiology of chronic pain. Pain is a complex perceptual phenomenon that involves sensory as well as affective and attentional aspects . AttentiIn this study, we examined the contribution of affect-biased attention, i.e., the predisposition to attend to affective stimuli , to the To assess affect-biased attention, we continuously recorded EEG signals while participants were required to detect minor changes in the movements of task stimuli (flickering dots) that were superimposed on distracting background pictures of either aversive or neutral content . We usedOur first aim was to characterize patterns of affect-biased attention in the presence of chronic pain. According to previous findings, FMS patients display reduced ability to discriminate between threatening and non-threatening sensory signals , 2018 asClinicalTrials.gov Identifier: NCT02146495): 39 FMS patients  and 19 healthy controls . Patients were recruited from the fibromyalgia clinic of the Institute of Rheumatology and the Institute of Pain Medicine at the Tel Aviv Sourasky Medical Center in Israel. All patients had a diagnosis of fibromyalgia according to the ACR, 2010 criteria  were evaluated using self-report questionnaires: the McGill pain questionnaire , the PitssVEPs were evoked using randomly moving dots flickering at a rate of 7.5 Hz, while superimposed on emotional or neutral background pictures  and the BrainCap™ electrode cap with sintered Ag/AgCI ring electrodes providing 16 EEG channels  and two ECG channels. . Electrodes were positioned according to the standard 10/20 system. The reference electrode was between Fz and Cz. The raw EEG signal was sampled at 250 Hz and recorded using the Brain Vision Recorder™ software (Brain Products) with scalp impedance for each electrode kept below 20 kΩ.p < 0.05 and 90% CI was calculated for the effect size η2. P values in post hoc analyses were corrected using the conservative Scheffé’s procedure, correcting for all possible contrasts (Time-varying amplitudes at the stimulation frequency (7.5 Hz) were extracted employing a Hilbert transformation of the time-domain averaged data using in-house MATLAB scripts: data were filtered with a 10th-order Butterworth bandpass filter having a width of 0.5 Hz around the center frequency of 7.5. The time-varying amplitude was extracted as the complex conjugate of the bandpass-filtered signal and the Hilbert-transformed analytic signal for each time point. The temporal smearing introduced by this procedure was 440 ms as measured by the full width at half maximum of the impulse response function. Subsequently, mean amplitudes were extracted across occipital electrodes , at a time window corresponding to distractor onset (between 3600 and 3700 ms) and subtracted from the mean amplitudes of the baseline segment . Based on previous studies that investigated the ssVEP dynamics in response to emotional content , we haveontrasts .In addition, we extracted the time-varying inter-electrode phase-locking value, calculated as the stability of the complex phase across trials, relative to the site Oz . SpecifiSpearman = 0.39, 95% CI , p = 0.016] and depression , p = 0.004] scores, but not with sleep quality scores , p = 0.3]. Affective symptoms (depression and anxiety) were highly correlated , p < 0.001] and sleep quality correlated with depression , p < 0.04] but not with anxiety , p = 0.12] (see The mean score of the McGill pain questionnaire was 24.8 (± 10.5 SD) [no standard clinical cutoff . These r.12] see . Self-reF = 18, η2 = 0.24, 90% CI , p < 0.001] . FMS patients displayed overall reduced responsivity to task stimulus , p = 0.01] (main effect for group). Most importantly, the ANOVA model revealed a significant triple time-window*group*distractor-valence interaction , p = 0.017], indicating different dynamics of the ssVEP response. Further exploring this interaction, post hoc tests revealed that during the early time window, HC subjects (but not FMS patients) were able to discriminate between neutral and negative distractors . In the late time window, this pattern was flipped: FMS patients showed a strong attentional shift to the negative stimulus, while HC showed adaptation to this type of distractor  = 7.8, η2 = 0.12, 90% CI , p = 0.007]. Follow-up analysis revealed time-dependent differences (early/late time-window) in the FMS (PScheffe > 0.001) but not in the HC group  between early and late time-windows, indicating transient disruption of fronto-occipital synchrony upon viewing the distractor picture, corresponded to subjective sleep disturbances (PSQI score) , q = 0.03] , as well as the severity of depressive symptoms (BDI), was not correlated with any ssVEP indices .We correlated these EEG indices with the four main scales measuring symptom severity: the general scores of the McGill, STAI-T, BDI, and PSQI questionnaires. To correct for multiple comparisons, we used the FDR method . This an = 0.05] . To make = 0.03] . When coThe current study aimed to characterize the relations between abnormalities in neural processing of affect-biased attention, and somatic and affective symptoms of chronic pain. Our results regarding EEG dynamics revealed that FMS patients display altered attention toward negative emotional content compared to controls in primary visual areas as well as in higher-level modulatory circuits. Relative to controls, FMS patients displayed initially impaired discrimination between neutral and negative emotional stimuli, which was followed by sustained attention toward the negative stimuli, suggesting a reduction in normal habituation.Loss of context-dependent emotional discrimination was predictive of pain severity. Specifically, increased initial attention to the neutral relative to negative stimuli was correlated with more severe clinical pain. This is in line with the generalization pattern seen in FMS in which neutral somatic information is interpreted as aversive . InteresIn our FMS cohort, decreased fronto-occipital phase-locking values corresponded to the severity of sleep disturbance. In accordance, it was previously shown that sleep deprivation, produces similar abnormalities in EEG connectivity to those found here, and further corresponded to impaired frontal control on limbic regions . NotablyFurthermore, our findings suggest that patients with chronic pain demonstrate a similar pattern of results to the one found in previous studies with anxious and sleep-deprived individuals . HoweverIn this study, the relationship between the EEG indices and clinical symptom severity is correlational and not causal. The issue of whether the maladaptive attentional patterns of FMS patients predispose these individuals to develop chronic pain or vice versa is an issue that should be addressed using longitudinal studies. When such a longitudinal approach was implemented by We used FMS as a model of a chronic pain disorder that heavily involves affective symptoms. The results presented pose the question of whether similar relations between biases in affective attention and chronic pain, will also be present in other pain conditions that do not involve such a burden of overt affective symptoms. Testing this issue in a new patient population, for example in individuals that suffer from ongoing, but not yet chronic pain, or in other clinical chronic pain conditions, would advance our understanding of the intricate relational mechanisms underlying pain-emotion associations as well as their temporal dynamics. Accordingly, such insights might help inform treatment decisions and improve diagnostics, as suggested here for FMS. In addition, the EEG-ssVEP methods that were used here allowed us to infer about attentional processes that are impaired in FMS and their relations to disease symptoms without relying on direct patient reports. However, this is a rather limited approach in terms of tracking brain network dynamics and additional insights might be gained from using fMRI and a similar behavioral paradigm. An additional approach that might of use in this respect could involve the implementation of psychophysical tests that correspond to specific neurobiological mechanisms such as conditioned pain modulation CPM;  or quantThe results of this study emphasize the intimate involvement of affective attention, a key process of emotional construction, in chronic pain, and highlight the potential importance of quantitatively probing such processes when evaluating and treating populations suffering from complex somatic symptomatology. Moreover, these results may suggest that negative attentional bias is a core impairment in several disorders that has differential clinical manifestations stemming from additional impairments in other domains.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.This study was reviewed and approved by Tel-Aviv Sourasky Medical Center institutional review board. The patients/participants provided their written informed consent to participate in this study.NG, AK, EB, TH, and HS: conception and design. NG, YZ, LW, and AG: data collection. NG, NP, and AK: statistical analysis. JA and HS: clinical evaluation and screening producer. NG: drafting of the manuscript. AK, JA, EB, TH, and HS: reading, editing, and conceptualizing the final version of the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Pain management in the pre-hospital setting remains a particular challenge for paramedics and emergency physicians, especially in children. This study evaluates the pre-hospital use and effect of analgesics in children with trauma or pain due to other reasons.This study is a retrospective analysis of the database of a German air rescue service and was conducted over a period of 9 years (2012–2020) to assess pain in general and whether patients with trauma pain due to other reasons received treatment with analgesics. We included all patients in the registry under the age of 16 years. Patients with a Glasgow Coma Scale of 3 at hospital admission and incomplete records were excluded. The intensity of pain was determined by the emergency physician on scene at arrival and hospital admission in a ten-point rating scale (0 = no pain). Effective pain reduction was analyzed.Out of 227,458 cases, a total of 22,025 emergency cases involved pediatric patients aged 0–16 years. 20,405 cases were included in the study. 12,000 (58.8%) children had suffered a trauma, 8108 (39.7%) had pain due to other reasons and 297 (1.5%) had both. In total, 4,608 (38.4%) of the children with trauma were assessed having a numerical rating scale (NRS) > 4 at EMS arrival. These patients received mainly ketamine (34.5%) and the opioids fentanyl (38.7%) and piritramide (19.1%). The value on the NRS was significantly lower at admission to hospital (mean 1.9) compared with the EMS arrival (mean 6.9). In 4.9% the NRS at hospital admission was still > 4. 282 patients within the non-trauma group had a pre-hospital NRS of > 4. The pain therapy consisted of opioids (35.8%) and ketamine (2.8%). 28.4% patients in the non-trauma group received no pain medication. In 16.0% the NRS at hospital admission was still > 4.German emergency physicians achieved a sufficient pain therapy in pediatric patients with a NRS > 4 after trauma. In case of non-trauma, the pain management by the emergency physicians is restrained and less successful. The most common analgesic medications administered were ketamine and fentanyl, followed by piritramide.Trial registration: The study has been retrospectively registered at DRKS (DRKS00026222). The treatment of pain in pre-hospital pediatric emergencies continues to be a major challenge. In recent years, numerous studies have been conducted on this topic and the results have revealed that pre-hospital pain management in children is restrained and mostly inadequate –7. SeverIn Germany, there have been no studies on the quality of pain therapy in the pre-hospital period in childhood. However, a few studies from all over the world clearly show that there are deficits in pediatric pain therapy in the emergency medical service (EMS) and that this topic should be given more attention in scientific studies, especially in a physician staffed EMS.The objective of this study was to evaluate the management of acute pain in children in the pre-hospital setting. This study analyzed the assessment of pain in children and the effectiveness of the analgetic treatment by emergency physicians with reference to etiology of pain and pain severity.DRF Luftrettung  database was conducted. The database collects all operational data of the 29 DRF helicopters in Germany. The helicopters are alerted as part of the EMS additional to an ambulance manned by paramedics or even a rapid response car with physicians. They are care for child and adult emergencies alike. The medical crew on the rescue helicopter consists of an emergency physician  and a HEMS-TC,  moreover qualified as a paramedic. The physicians of the crew have mostly additional qualification in emergency care for children (such as European Pediatric Advanced Life Support (EPALS) course or more than 50 anesthetic procedures in children less than 5 years of age).A retrospective analysis of the German air rescue service Each EMS mission is documented in a standardized online-database . The collected data includes basic patient demographics as well as diagnostical and therapeutical actions of the emergency physician on scene. The severity of pain is assessed on a 0 (no pain) to 10 (maximum of pain) scale and was collected twice: First at arrival of the emergency physician on scene and second at admission to hospital.Various analgesics are available on the helicopters, including the opioids fentanyl, sufentanil, piritramide and morphine. Ketamine and various non-opioid analgesics, like non-steroidal anti-inflammatory drugs (NSAID), are also available. All analgesics can be administered at the discretion of the emergency physician.In the retrospective study period from 2012 to 2020 all emergency medical missions of DRF helicopters were included. Furthermore, we defined children with ages ranging from 0—16 years. The Glasgow Coma Scale (GCS) was used to distinguish between awake and anaesthetized patients. Patients with a GCS 3 at hospital admission were excluded from the study because a GCS3 is associated with general anesthesia, therefore we excluded these patients from the analysis. Furthermore, patients were excluded if the documentation was incomplete in relevant variables . Based on the major diagnosis the cases were divided into a trauma and a non-trauma (e.g. acute abdomen) group. Patients with both, trauma and non-trauma, were excluded from further analyses. A value of > 4 in NRS was regarded as being moderate-to-severe pain and analyzed more in detail. The primary outcome measure was effective pain management, defined as a reduction of >  = 2 points on the NRS. Secondary outcomes were the analysis of the given pain medication.For the descriptive analysis of numerical variables, the mean and standard deviation were computed, for categorial and dichotomous variables the frequency and proportion in percent were calculated. For comparative analysis Mann–Whitney-U or Chi-Quadrat-test  were used if applicable. Tests were two sided. A p-value of 0.05 or less was considered statistically significant. Calculations were performed with IBM SPSS Statistics 26 .The study was approved by the Ethics Committee of the Christian-Albrechts-Universität Kiel (registration: D 424/22) and registered in the German Register of Clinical Studies .Out of 227,458 emergency missions in the study period, a total of 20,405 patients were included in the study Fig. . OverallIn 4,608 out of 12,000 children (38.4%) with trauma the initial NRS was > 4. The first measured mean NRS value in this group was 6.9 (SD 1.5). For analgesic treatment sufentanil und fentanyl were used in 40.8% (fentanyl 38.7% and sufentanil 2.2%) and piritramide in 19.9%. Morphine was given in 1.6%. Ketamine was administered in 34.5%. 3.1% of the patient received a non-steroidal anti-inflammatory drug (NSAID) mono therapy and 3.9% and NSAID combination therapy. A total of 9.4% within this group received no pain medication. After the EMS therapy, the mean NRS value was 1.9 (SD 1.4) at admission to hospital, 4.9% of the children still had an NRS > 4 , 15.7% reported pain (NRS > 4) at hospital admission.282 (3.5%) patients with pain in the non-trauma group had an NRS > 4 on scene  children with trauma had a NRS > 4 at first survey (mean 6.9 (SD 1.5)). Children with acute pain due to non-trauma were less likely to have moderate to high pain scores (3.5%) but if relevant pain was present (NRS > 4), it tended to be severe (mean NRS 6.7 (SD 1.5))  than in children with non-trauma mean NRS 2.7). When NSAID mono therapy or even no analgesics were administered, the results were poor: 10.4% NSAID resp. 15.7%  of the patients reported NRS > 4 at hospital admission (Table .7. When We consider these numbers to be worrying because they clearly reflect uncertainty in the treatment of children. We can only speculate about the causes of the inadequate pain therapy in our setting, as all emergency physicians on our helicopters are required to have expertise in pediatric analgetic treatment. However, our findings are consistent with those of many other studies that have drawn attention to inadequate pain management for children in emergency medicine worldwide. Another study of pre-hospital analgesia found that although pain was noted in 446 cases, analgesia was administered in only 3.3% . In one Murphy et al. describe possible reasons such as communication problems in infants and young children, inadequate training of emergency personnel, and uncertainty and lack of experience in the assessment and care of children . ParamedThe difficulty of correctly assessing pain in children has been cited as another potential cause of inadequate pain management in children. The major problem in pain assessment appears to be subjectivity and finding an adequate scale for the age. In our study, NRS was reported for almost all children, which is possibly due to the electronic patient report form used, in which two documented NRS scores are mandatory, one at first contact on scene and one at hospital admission. A large proportion of our patients were younger than 8 years, limiting the applicability of the NRS. Certainly, some children were unable to assign a number to their pain, e.g. depending on their common status. Presumably, the reported value in these patients corresponded to the personal impression of the emergency physician. It remains unclear whether in some cases other scores were additionally collected but not documented. In several studies the NRS was validated in children aged 8 + years . The minFor children, there are further scales according to their age, including the Wong-Baker faces scale, on which children are asked to select the face that best represents their pain; this scale has been validated from the age of 3 years . The ChiOur study has several limitations starting with the retrospective character. As mentioned above, accuracy and objectiveness of the pain assessment might be a query. We were also not able to assess the influence of non-pharmacological pain management techniques such as slings and bandages. That is interesting because some patients with severe pain also showed improvement in NRS even though they did not receive analgesic medication. In these cases, conservative measures may have alleviated the pain. We were also not able to assess the influence of transport time on pain relief. Bendall et al. reported that children with a shorter care time are less likely to achieve effective pain management . WhitleyOverall, the results show that a sufficient pain therapy could be achieved especially in patients with NRS > 4. Children with trauma received more pain medication than in the context of non-trauma, even if the pain was comparably severe. In Germany the most common analgesic medications administered were ketamine and fentanyl, followed by piritramide. Ketamine was given more frequently to children under 6 years of age, while opioids were given more frequently with increasing age. To further improve sufficient pain management in children and reduce anxiety, dosing tools should be available in all settings and regular training with them should be provided.


Evidence-based services to support cancer patients with pain via clinical pharmacy services are currently lacking. Therefore, there is a need to undertake a randomized controlled trial (RCT) to explore the effectiveness of clinical pharmacists (CPs)’ input into the multidisciplinary team (MDT) in providing better therapeutic outcomes for cancer pain management.The main aim of this pilot RCT is to determine the feasibility and preliminary efficacy of integrating CPs into the MDT for cancer pain management on the clinical outcomes of cancer patients experiencing pain.This study protocol outlines two-armed multicenter pilot RCT. Cancer patients suffering from pain will be randomly allocated to receive either clinical pharmacy services, i.e., PharmaCAP trial intervention from the CP, or the usual standard care . Patients will be recruited consecutively from two hospitals in Kathmandu valley, Nepal. The outcomes will be assessed at baseline (pre-intervention) and 4 weeks post-intervention. The primary feasibility outcomes will include eligibility rate, recruitment rate, willingness to participate, acceptability of screening procedures and random allocation, possible contamination between the groups, intervention fidelity and compliance, treatment satisfaction, and patient understanding of the provided interventions. Subsequently, the primary clinical outcome, i.e., pain intensity of cancer patients, will be assessed. The secondary clinical outcomes will include health-related quality of life (HRQoL), anxiety, depression, adverse drug reactions, and patient medication compliance following the integration of CP into the healthcare team.The feasibility and potential for integrating CP involvement in MDT to improve clinical outcomes of cancer patients with pain will be evaluated through the PharmaCAP trial.Trial registration: ClinicalTrials.gov NCT05021393. Registered on 25th August 2022.The online version contains supplementary material available at 10.1186/s40545-022-00505-0. SincHealth-related quality of life [European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30)]  will be Nine common symptoms [Edmonton Symptom Assessment System Revised (ESAS-r)] , 34 willAnxiety and depression [Hospital Anxiety and Depression Scale (HADS) Nepalese Version]  will be Medication adherence [Medication Adherence Report Scale (MARS‐5)]  will be ADRs related to cancer pain treatment and analgesics will be assessed according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events  . IdentifThe secondary clinical outcomes and outcomes measures are as follows:Additional questionnaires are developed by the research team after a literature review. These additional questionnaires developed will be administered to obtain information related to (1) socio-demographic information ; (2) cancer status , metastasis and its site, medicine used for cancer treatment, family history), and (3) pain history including duration of pain, pain flares, pain management index (PMI), aggravating and relieving factors, medicines used for cancer pain management as well as ADRs due to drugs used for cancer pain management. Other information, such as resources required to conduct the trial  and the time expected to enroll the optimal number of participants, will also be documented . AdditioData collection and study implementation will be supervised via weekly meetings with the PI, research team, representatives from the study sites, research pharmacists, and project CPs to ensure that protocols of trial are reliably executed. Data collected in this study will be confidentially treated and securely stored at the School of Pharmacy, Monash University Malaysia. Only the study investigators at the School of Pharmacy, Monash University Malaysia, will access the final dataset.The research team will designate study participants with a unique code to facilitate data linkage during the follow-up. The research team members who are trained in data entry will enter all collected data. One of member from the research team will verify the data entry for all participants.An intention-to-treat (ITT) analysis will be conducted. Quantitative data will be imported into statistical package for social sciences (SPSS) version 28.0  for the data analysis. Baseline and demographic characteristics will be descriptively analyzed . Changes in the secondary outcome measures at follow-up will be assessed using paired t-tests (for continuous variables) and McNemar’s test . A p-value < 0.05 will be considered statistically significant for all analyses.All required measures will be taken to preserve the confidentiality of the study participants and protect data. Access to the data will be under strict privacy and security throughout the study duration, publication, and at any public presentation. No identifiable data will be released. The data will be stored using codes assigned by the PI and supervisor and be kept on password-protected computers. The study database will only be accessible to those people whom the lead researcher of the study has given permission.a and SSb will always supervise the study in the study sites to ensure that the study protocol is followed to maximize adherence, solve problems, and consider how to respond flexibly to the needs of each case. In continuing group supervision, research team meet fortnightly in a group format under the direction of AQB, SLT, BKC, VP and SHG. This includes exchanging case studies, discussion of problems, its solution and instructive insights with other researchers engaged in the related subjects. The entire team will handle low participation rate-related issues that arise throughout the trial. All the ethical principles provided by the Declaration of Helsinki will be followed by all the research members throughout the study. The investigators will not violate any rules and ethical codes of the Nepal Health Research Council (NHRC) and Monash University Human Research Ethics Committee (MUHREC). The investigators of this study will regulate the NHRC and MUHREC ethical principles among all research team members and research assistants involved in the study.SSCancer patients suffering from pain who meet the inclusion criteria will be provided oral and written information regarding the trial objective. Following informed written consent, patients who do not wish to participate are free to decline or withdraw from the study at any time. Confidentiality of cancer patients’ responses and data will be assured. The study has been approved by the Ethical Review Board NHRC in Nepal  and MUHREC (Project ID: 30907). Ethical approval from institutional review committee and hospital management are also taken. The protocol trial is registered in the Clinical Trials Registry .Moreover, if cancer patients feel uncomfortable with the study trial, they are allowed to withdraw at any time. No agreements or other regulations will limit access to the data collected. The study will be reported according to the guidelines of the Consolidated Standards of Reporting Trials .This PharmaCAP trial is being undertaken between May to November 2022. Data collection will proceed as initially planned. Additionally, the CPs and research team will take necessary precautions when entering practices to collect the data and for patient intervention, including wearing personal protective equipment (PPE), considering an ongoing pandemic.To the authors' knowledge, this is the first pilot multicenter RCT that is going to be conduct in Nepal that evaluates an integration of CP in MDT for managing cancer patients suffering from pain. The study will inform the development of definitive RCT and the development of evidence related to the involvement of CPs as essential members of the MDT for pain management in cancer patients.In addition to being the first study in LMICs, such as Nepal, to evaluate the feasibility and acceptability of a CP among the cancer population with pain in the country, this study will also provide preliminary insights into the impact of a CP on cancer pain-related outcomes. Moreover, integrating CP to MDT takes an inherently patient-centered approach to pain management. This study will aid in generating evidence regarding the contribution of CP in cancer pain management and incorporating them into collaborative cancer pain management practice in more extensive multi-site settings.CPs can contribute to cancer pain management by delivering pharmaceutical care, reducing pain intensity, and improving HRQoL. However, CP’s involvement in cancer pain management is new and necessitates assessment before organizing a large-scale RCT. PharmaCAP trial intervention will be a new practice in the case of LMICs, and the study will determine whether future definitive trials can be conducted. Findings will be disseminated through conference presentations and peer-review open-access publications. If the pilot RCT is feasible, acceptable to the stakeholders, and demonstrates a positive impact and cost-effectiveness, a full, pragmatic RCT will be conducted.This study is novel and innovative in low-resource settings because CP’s role in cancer pain management will contribute to the treatment outcome of cancer patients and help their integration in MDT in a rigorously designed pilot RCT. Establishing the role of a CP is essential for improving clinical and therapeutic outcomes of cancer patients suffering from pain who may benefit from skilled hospital CPs, doctors in LMICs, and CPs.The successful execution of a future full-powered RCT will be based on the current intervention delivered by the CP. Therefore, CP can potentially benefit cancer patients suffering from pain. CP can work alongside oncologists and other healthcare professionals in hospitals to help improve outcomes for cancer pain. The results of this trial will be of relevance to policy makers on the importance of CP in oncology settings.The pilot multicenter RCT is the first to be conducted in LMIC, Nepal, involving CPs who deliver a combination of pharmacological and non-pharmacological interventions to cancer patients suffering from pain. This study will help demonstrate the value of integrating CPs in MDT in an oncology setting to reduce pain intensity. Overall, it can help improve clinical outcomes in cancer patients.The duration for the 4 weeks of intervention may be too short for showing the full influence of the intervention on cancer- and drug-related outcomes. Nevertheless, as this trial is a pilot study, the findings of this study will provide preliminary results regarding the efficacy of integrating CP in the MDT being tested. Although the study sample size will be sufficient to determine the viability of running a full-scale RCT, the sample size is not large enough to formally compare the outcomes of the two treatments. It will provide an estimate of the variation on which to power a future, definitive trial. Another potential barrier to a future trial is the lack of CP in cancer hospitals in medical oncology units and cancer hospitals of Nepal, and the ability to recruit CP for future trials. Future trials can be expanded to other cancer hospitals and institutions nationwide.The PharmaCAP trial is one of the first pilot multicenter RCTs to be conducted in Nepal to evaluate the feasibility of integrating CP in MDT and their impact on the clinical outcomes of cancer patients suffering from pain. The study will inform the design, procedures, measures, interventions delivered by the CP, and data analyses for a larger, multicenter trial to generate further robust evidence in future RCTs.Additional file 1. Recommended items to address in a clinical trial protocol and related documents.