Background: Digital nerve block (DB) is a commonly utilized anesthetic procedure in ingrown toenail surgery. However, severe procedure-related pain has been reported. Although the popliteal sciatic nerve block (PB) is widely accepted in foot and ankle surgery, its use in ingrown toenail surgery has not been reported. Therefore, this study aimed to investigate the safety and effectiveness of PB in the surgical treatment of ingrown toenails. Methods: One-hundred-ten patients surgically treated for an ingrown toenail were enrolled. Sixty-six patients underwent DB, and 44 underwent PB. PB was performed under ultrasound-guidance via a 22-gauge needle with 15 mL of 1% lidocaine in the popliteal region. The visual analogue scale was used to assess pain at two-time points: pain with skin penetration and pain with the solution injection. Time to sensory block, duration of sensory block, need for additional injections, and adverse events were recorded. Results: PB group demonstrated significantly lower procedure-related pain than the DB group. Time to sensory block was significantly longer in the PB group (20.8 ± 4.6 versus 6.5 ± 1.6 minutes). The sensory block duration was significantly longer in the PB group (187.9 ± 22.0 versus 106.5 ± 19.1 minutes). Additional injections were required in 16 (24.2%) DB cases, while no additional injections were required in PB cases. Four adverse events occurred in the DB group and two in the PB group. Conclusion: PB was a less painful anesthetic procedure associated with a longer sensory block duration and fewer repeat injections compared with DB. The result of this study implicates that PB can be an alternative anesthetic option in the surgical treatment of ingrown toenails. An ingrown toenail is one of the most common painful conditions affecting the nail of the great toe. Surgical treatments are warranted when conservative treatment is not effective ,2,3,4.In the surgical treatment of ingrown toenails, digital nerve block (DB) has been the most frequently used anesthetic technique due to its simplicity and rapid onset time ,5. HowevPopliteal sciatic nerve block (PB) has been widely used in the field of foot and ankle surgery with minimal risk and excellent patient satisfaction ,12. WithThis study aimed to investigate the safety and effectiveness of PB with short-acting lidocaine in the surgical treatment of ingrown toenails compared to conventional DB. The current study hypothesized that the PB would be a safe and effective anesthetic method with lower procedure-related pain in ingrown toenail surgery.This study was conducted in the armed forces hospital and approved by the Institutional Review Board of the medical command. Informed consent was obtained from all of the patients. The medical records of 150 patients who underwent surgical treatment of ingrown toenail between 2016 and 2017 were reviewed. Patients who underwent solitary ingrown toenail surgery were included in the study cohort. Patients who (1) underwent other types of foot and ankle procedures at the time of ingrown toenail surgery and (2) used anesthetic agents other than lidocaine were excluded from the study.n = 44) group and digital block  group. The mean age of the PB group was 20.7 years , and the mean body mass index (BMI) was 23.6 kg/m2 . The mean age of the DB group was 20.9 years , and the mean body mass index (BMI) was 24.6 kg/m2 . The demographic characteristics of the study groups are tabulated in Ultimately, a total of 110 patients constituted our cohort. Patients were divided into two groups, according to the anesthetic method used for the surgical treatment; popliteal block  equipped with a 7–12 MHz linear transducer. Patients were positioned prone with the affected limb close to the practitioner. After povidone-iodine sterilization, the sciatic nerve was imaged in the short axis. Beginning from the popliteal crease, the tibial nerve was first identified just lateral and superficial to the popliteal artery, then traced proximally until it merged with the common peroneal nerve. The bifurcation point was identified where both branches  were situated contiguously ,15. The The DB was performed with patients positioned supine. After povidone-iodine sterilization, a 25-gauge needle was introduced into the dorsal aspect of the webspace aiming towards the dorsal digital nerve just distal to the metatarsophalangeal joint. Then, 1.5 ml of 2% lidocaine was administered. The needle was withdrawn and redirected to the toe’s plantar surface, where the remaining solution (1.5 mL) was injected towards the plantar digital nerve. The procedure was repeated similarly on the opposite side of the toe to achieve sufficient anesthesia.All patients involved in this study underwent partial nail extraction with matrixectomy of the hallux. After sufficient anesthesia was achieved, a distal skin incision was made over the nail sulci and then advanced to the proximal nail base. An excision of embedded part of the nail was performed. The germinal matrix was curetted and coagulated with an electrocautery device  (power 50v), then sutured with 4-0 nylon. The compressive dressing was applied, and stitches were removed two weeks postoperatively.The primary outcome measure was procedure-related pain intensity at two different time points: pain during skin penetration and pain during the solution injection. This was assessed using the visual analog scale  ranging from 0 to 10 mm, with a greater score indicating more severe pain. Secondary outcome measures were block characteristics of the two anesthetic methods: time to sensory block, duration of sensory block, additional injections required due to insufficient anesthesia, and adverse reactions to anesthesia . Once the anesthetic procedure was complete, an independent observer assessed block progression every 3 minutes for 30 minutes until the sensory block was achieved. Sensory examination was performed by the pinprick test of both the tibial and common peroneal distributions . It was assumed that the sensory block was achieved when there was no response to the pinprick stimulus. After the operation, the same observer evaluated the duration of the block, which was the time between the sensory block achievement and the point when the patient started to feel pain. All subjects were observed in the hospital for at least 4 hours after anesthesia for potential adverse reactions, such as nausea, vomiting, or dizziness.P-values less than 0.05 were considered statistically significant.Data analyses were conducted using Prism 8 for Mac . The assumption of normality in data was tested using the Shapiro–Wilk test. An independent t-test was used to compare procedures-related pain, time to sensory block, and duration of the sensory block between the two groups (DB and PB). Chi-square analysis was used to compare differences in the needs for additional injections due to insufficient anesthesia and adverse events related to anesthesia. p < 0.001). The mean VAS scores during skin penetration were 43.5 mm  and 58.3 mm (±23.6) in PB and DB, respectively. The mean VAS scores during the injection of solution were 23.6 mm (±10.6) and 58.3 mm (±13.8) in the PB and DB, respectively  application on the area of injection before DB. However, they found no clinical benefit of topical cream compared to the placebo. The authors concluded that the topical anesthesia might not infiltrate to the deeply-located digital nerve where much of the pain is thought to originate from . A studyIn addition to procedure-related pain, DB often requires multiple injections, since both medial and lateral nail folds are frequently involved in the clinical presentation of ingrown toenails. Furthermore, as seen in this study, an additional injection of anesthetic agents is sometimes required to achieve full anesthesia in a toe with severely inflamed soft tissue due to its increased tissue acidity . HoweverThe nail folds are innervated by plantar digital nerves, which are branches from the medial and lateral plantar nerve, and the plantar nerves originates from the peroneal and tibial nerve . AlthougThe safety and effectiveness of the PB in the foot and ankle surgery have been well established in the literature ,17,18,24The pain at both skin penetration and anesthetic infiltration was lower in the PB group. We suspect that this may have been originated from the difference in the pain sensitivity between two target anatomic regions. Besides, due to the relatively small surface area of the toe, the pain caused by tissue expansion during solution injection is expected to be greater in DB.In the current study, we utilized only short-acting lidocaine for PB because the surgical removal of the ingrown toenail is relatively a short procedure usually performed as a same-day outpatient surgery. In usual practice, a popliteal sciatic nerve block is completed with a mixture of rapid onset anesthetics such as lidocaine and more prolonged duration anesthetics such as ropivacaine or bupivacaine. The duration of anesthesia achieved by using this mixture is reported to be more than 10 hours ,27. AlthTo our knowledge, this is the first study to date describing the use of PB in ingrown toenail surgery. Although PB demonstrated some advantages over DB in terms of procedure-related pain and block characteristics, the result of this study is not against or in favor of the substitution of DB. Instead, this study was designed to examine the efficacy of an alternative anesthetic method for surgical treatment of ingrown toenails. In our clinical experience, patients who had a bilateral ingrown toenail and had one side first with DB had greater reluctancy in receiving the same anesthetic method again due to pain from the anesthetic procedure. In those cases, PB can be considered as this can provide less pain related to the procedure.The current study is not without limitations. First, this study was conducted in healthy males in their twenties. On average, this patient cohort’s health status may be different from the general population, which may explain for a relatively low adverse reaction rate to anesthesia. However, we believe the primary and secondary outcomes related to pain and block characteristics may be generalizable due to anatomic similarities. Another limitation is a relatively small sample size and retrospective nature of the study. However, we believe this preliminary investigation would provide a foundation for a future prospective randomized controlled trial comparing PB and DB in a larger cohort.In conclusion, our data suggest that PB is a less painful anesthetic procedure with a longer duration of anesthesia and fewer repeat injections in the surgical treatment of ingrown toenails. The result of this study implicates that PB can be an alternative anesthetic option in the surgical treatment of ingrown toenails for patients who are reluctant to undergo DB.


This study aims to explore the feasibility of the eCoach-Pain, comprising a tool measuring pain complexity, diaries, pain education sessions, monitoring options, and chat function. Feasibility was evaluated (June–December 2020) by assessing learnability, usability, desirability, adherence to the application, and experiences from patients and general practitioners, practice nurses mental health, and physiotherapists. Six primary healthcare professionals (PHCPs) from two settings participated in the study and recruited 29 patients ). PHCPs participated in a focus group. Patient data was collected by evaluation questionnaires, individual interviews, and eCoach-Pain-use registration. Patients used the eCoach during the entire treatment phase (on average 107.0 days (IQR = 46.0); 23 patients completed the pain complexity tool and used the educational sessions, and 12 patients the chat function. Patients were satisfied with the eCoach-Pain (median grade 7.0 (IQR = 2.8) on a 0–10 scale) and made some recommendations for better fit with patient-specific complaints. According to PHCPs, the eCoach-Pain is of added value to their treatment, and patients also see treatment benefits. However, the implementation strategy is important for successful use of the eCoach-Pain. It is recommended to improve this strategy and involve a case-manager per patient. Chronic musculoskeletal pain (CMP) is a significant public health problem occurring in 19–28% of the European population . The curChallenges in this change are accessibility and cost-effectiveness of rehabilitation care, for which eHealth can be a solution . eHealthFirst, current care for chronic pain is fragmented and continuity of care for the individual patient is often lacking. eHealth can improve healthcare organization as it can facilitate communication and collaboration between healthcare professionals of different disciplines . AccordiSecond, currently, healthcare professionals receive training on diagnosis and treatment, primarily focused on knowledge within their own discipline . This raThird, earlier studies indicated that eHealth improves self-care support and improves daily activities for people with chronic illnesses ,21,22. eTo study the additional value of eHealth in an interdisciplinary network of healthcare professionals for patients with CMP, we implemented an electronic Coach (eCoach-Pain) to facilitate pain rehabilitation within the South East of the Netherlands ,29. BaseThis study (June 2020 and December 2020) had a mixed-methods design. Feasibility was evaluated with a focus on learnability, usability, desirability, adherence to the application, and experiences from patients and PHCPS. These were measured by use of patient questionnaires, data about eCoach-Pain-use, a focus group with PHCPs, and interviews with patients. Ethical approval was obtained from the Medical Ethics Committee Z, the Netherlands (METCZ20190037). Patients did not have to pay for participation in Network Pain Rehabilitation Limburg or the eCoach-Pain. During a patient’s first login in the eCoach-Pain, an electronic informed consent for the use of the eCoach-Pain and consent for transferability of their contact details to the researcher were registered. Additionally, for the telephonic interview, patients were asked for informed consent and for recording the interview. PHCPs were asked for informed consent at the start of the focus group.n = 6). They all participated in the Network Pain Rehabilitation Limburg . This network within and between primary, secondary, and tertiary care aims to support a shared biopsychosocial vision regarding CMP, early recognition of patients with subacute complaints, and a person-centered referral and treatment.PHCPs  of two interdisciplinary primary care practices were recruited to participate in this feasibility study , werOnce a new patient with CMP, or with an increased risk of developing chronic pain, consulted a PHCP, the patient was asked to use the eCoach-Pain. The PHCP gave the main instructions and sent a manual by email.The eCoach-Pain has been designed by Sananet Care B.V., based on earlier developed eCoaches, such as for Inflammatory Bowel Disease and heart failure ,32,33. IEach patient has an own account for the eCoach-Pain , which cAfter login by the patient, a home screen is presented, which contains four different elements .1.The pain complexity tool:The pain complexity tool supports the PHCPs in their decision-making for problem-mapping and treatment selection. It consists of two parts:(A)The STarT MSK Tool assessing the complexity of the pain problem for referral within primary care. The patient’s first action in the eCoach-Pain is completing this questionnaire. The Dutch version of the STarT MSKTool is translated and validated ,31. The (B)To further differentiate within the range of primary, secondary and tertiary rehabilitation care an additional set of questions about the biopsychosocial complaints and background of the patient was added to be filled in by the PHCP. After completion of both parts of the complexity tool, the eCoach-Pain calculates the score and assigns the best-fitting referral option to assist the PHCP. The PHCP discusses the results with the patient and refers him/her to the most appropriate treatment via shared decision making.2.Diaries:The eCoach-Pain also contains the possibility to use diaries. The PHCP decides, together with the patient, if and how often diaries will be sent to the patient. Diaries can automatically be sent every week, every two weeks, or once a month. However, the diary option can also be neglected. The automatic setting of these diaries is once a week. The diaries exist of the pain complexity tool with additional questions. This extension exists of additional questions based on the questions in the STarT MSK tool scored with “Yes”. The answers to these additional questions could be discussed with the PHCP during consultation and used to adjust the treatment or to provide additional educational material to the patient.3.Education sessions:The educational sessions provide patients background information about topics related to pain and pain-related disability, such as the difference between acute and chronic pain, treatment of pain, biopsychosocial influences on their pain, information about work and pain, and treatment options. The educational sessions are interactive (YouTube videos and quiz questions with feedback on answers), and they are integrated to stimulate learning and improving knowledge about (chronic) pain. The educational materials are presented in 13 themes and per theme subdivided over several sessions .4.Chat function:The chat function is used to send bidirectional messages containing questions or treatment material between patient and PHCP. All communication between patient and PHCP remains accessible in the eCoach-Pain to enable patients to reread answers, advice, or treatment exercise at later moments and times.PHCPs could access the eCoach-Pain via a secured webpage on their own device. The PHCPs were instructed to monitor and analyze the patient’s situation within a few working days after the patient had completed the pain complexity tool or diary, and to respond as quickly as possible to messages from the patients. To facilitate interpretation of the pain complexity tool and diaries and to save PHCPs’ time, information within the application was supportively presented using overviews, graphs, and colored risk flags. Based on the results of the pain complexity tool, different flags appeared on the intervention list: a red flag for a high risk, an orange flag for a medium risk, and a green flag for a low risk for developing CMP .PHCPs had only access to data of patients treated by themselves. It was possible that more PHCPs, for example, a PT and GP, have access to the data of the same patient in case it was a joint patient. When the PHCP sent a message to a patient or another PHCP, respectively, the other PHCPs and patient were able to read this message in the chat function.An instruction meeting of one hour to become familiar with the possibilities of the eCoach-Pain was provided to all PHCPs before the start of the study. The software developers and research team facilitated this meeting. Afterward, a paper-copy instruction manual was provided. Moreover, during the pilot, the PHCPS could contact the service desk of the software developers when help was needed or technical issues occurred.In September 2020, when the PHCPs had used the eCoach-Pain already for approximately three months, the researcher sent a questionnaire to participating patients. The questionnaire assessed learnability (5-items), usability (5-items), and desirability (6-items) and was an adjusted version of a questionnaire used in a study by Hochstenbach et al. (2016) . UsabiliBefore data analysis, negatively-keyed items were reversed-scored using Microsoft Excel, version Professional Plus 2016, the Microsoft Corporation, Santa Rosa, CA, USA. Median scores with interquartile ranges per item and category were calculated. To identify differences between the PHCPs disciplines, a sub-analysis with discipline as dependent variable was performed.To assess the patients’ adherence, process data from the pain complexity tool, diaries , and from the educational sessions  were logged on the server. The data collected between June 2020 and September 2020 were exported in October 2020.Median scores and interquartile ranges were calculated using Microsoft Excel, for the number of days patients were active in the eCoach-Pain, number of completed pain complexity tools, diaries, educational sessions, and chat messages used.Moreover, data about the PHCPs was collected. The median and interquartile ranges of the number of log-ins of the PHCPs was registered overall and per PHCP discipline.Based on stratified probability sampling on sex, age, and PHCP, patients were contacted for a telephonic interview by the researcher to gain more insight into the experiences with the eCoach-Pain in September 2020. It was intended to ask approximately 16 patients, of which eight agreed, until data-saturation would be reached. However, as data saturation was not reached after this number of interviews, five additional interviews were performed in December 2020. Topics discussed in the semi-structured interviews included: the use and acceptance of the pain complexity tool, diaries, educational sessions, and chat function, the supportiveness of the application regarding self-management, and technological functioning of the application. Interviews were audio-recorded.https://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home (accessed on 4 November 2021) [The audio recordings of the interviews were transcribed verbatim. These written interviews were independently analyzed with inductive and deductive thematic analysis by two researchers (C.L. and M.d.M.) using QSR International Pty Ltd. (2018) NVivo (Version 12), er 2021) ,36,37. DIn September 2020, the researcher (C.L.) and observer (A.K.) held an online focus group interview with all participating PHCPs via Zoom . Technichttps://www.qsrinternational.com/nvivo-qualitative-data-analysis-software/home (accessed on 4 November 2021) [During the focus group with the PHCPs, the observer (A.K.) made notes and gave a summary per topic discussed. These summaries were asked to be confirmed by the PHCPs during the focus group. Before analysis, the audio recording was used to add additional notes to the summaries by the researchers (C.L. and M.d.M.). These summaries were independently analyzed with thematic analysis on the topics discussed by two researchers (C.L. and M.d.M.) using QSR International Pty Ltd.  (2018) NVivo (Version 12), er 2021) .Data was collected from 29 patients in total; see Twenty-three patients received the invitation for the evaluation questionnaire (September 2020), of whom 11 patients responded (48%). The responders were older (65 (IQR = 23) years old) than the non-responders (48.0 (IQR = 24) years old), and there were less females than males ; female non-responders: 83% (10 out of 12)) compared to the total sample.Six patients started using the eCoach-Pain after the questionnaire was sent and were therefore not invited. The patients who filled in the evaluation questionnaire were an average of 65 (IQR = 23) years old, 55% (6 out of 11) were female, and, on average, active in the eCoach-Pain for 109 (IQR = 41) days. Ten patients answered all questions, and one patient answered only the questions regarding learnability and usability.n = 6) scored 5.0 (IQR = 0.0) for learnability, 5.0 (IQR = 1.0) for usability, and 4.5 (IQR = 2.0) for desirability, while patients subscribed by PTs (n = 5) scored 5.0 (IQR = 1.0), 5.0 (IQR = 2.0), and 4.0 (IQR = 1.0), respectively.n = 3) or did not want to use it anymore (n = 7). The other 16 patients were still active in the eCoach-Pain at that time.At the end of October 2020, for 26 of the 29 patients (median age 53.5 years (IQR = 24.75), 69% female (18 out of 26)), the export data about adherence to the application was available. Three patients were asked to participate in the interviews in December 2020. At that moment, exports were already performed; therefore, no export data of them were available. At the moment of data export, the included 26 patients were, on average, 107.0 (IQR = 46.0) days active in the eCoach-Pain. Ten of them stopped using the eCoach-Pain prematurely because they finished treatment (n = 23).Twenty-three patients completed the pain complexity tool . For 21 patients, their PHCPs also answered the second part of the pain complexity tool. On average, the diaries were 6.0 (IQR = 3.5) times filled  educational sessions per person. On average, each separate educational session in the eCoach-Pain was started by 19.5 (IQR = 6.3) individual patients. In total, 224 unique educational sessions were opened by these patients. As there were 13 sessions, this means that some patients read (a part of) the educational sessions several times. Fourteen patients completed all education sessions.Twelve messages were sent from seven (27%) unique patients to their PHCP, and five messages were sent from the PHCPs to the patients by the chat function. The patients started all conversations. They often elaborated on their diary answers, technical dysfunction of the eCoach-Pain, or they explained why they were not able to fill in the diaries.The six PHCPs together logged in on average 6 times (IQR = 16.75), the GPs on average 16 times (IQR = 8), the PTs on average 35.5 times (IQR = 32.5), and the PNMHs on average 2.5 times (IQR = 1.5).At the end of September 2020, 16 patients were asked to participate in a telephonic interview, to which eight agreed. To reach data saturation, five additional patients had to be asked, of which three agreed to be interviewed in December 2020. This led to 11 patients participating in the telephonic interviews (mean duration 15 min). The participants had a median age of 60.0 (IQR = 2) years, 73% was female (8 out of 11), and they were active in the eCoach-Pain for 100.5 (IQR = 31.75) days.Two GPs , two PTs , and one PNMH  participated in a focus group. In addition, one other PNMH  participated in an individual telephonic interview, as she was not able to participate in the focus group.Patients stated that they were positive about the eCoach-Pain because the functionality worked well for their treatment, it was easy to use, and text was written in clear and understandable language. The content was perceived as informative concerning their pain complaints and knowledge about pain pathophysiology. The interaction between patient and PHCP in the diaries and the quiz questions in the educational sessions of the eCoach-Pain were experienced of added value. Some patients appreciated the reminders for diaries and educational sessions as it gave them structure and control. However, for other patients, these automatic reminders were perceived as somewhat stressful.n = 6) started using the eCoach-Pain, they expected the content would be more tailored to their own medical complaints and history. Furthermore, patients expected that the eCoach-Pain would motivate them for treatment compliance to improve their complaints. Although PHCPs are able to change diary frequency, six patients expected less frequent diaries and repetition of information. Besides, some patients indicated that they had preferred to receive more information (by their PHCP or a pamphlet) about the content, frequency of questions, and expected duration of the eCoach-Pain program when they started to use it. Some patients expected more feedback from the eCoach-Pain itself about their answers or an automatic end-session in the eCoach-Pain to close it. Seven patients found it frustrating that, in their opinion, “non-relevant” questions kept returning. The option to indicate a holiday leave and stop sending reminders during this leave was felt to be missing.Before patients  indicated that the repetition and frequency of the questions were too high. They also missed background information of the questions in the introduction of the eCoach-Pain.Patients indicated difficulties in distinguishing the pain complexity tool from the diaries, as the tool and the diaries both were presented as a questionnaire in the eCoach-Pain. Therefore, in this paragraph, the tool and diaries are presented together. Eight of the 11 patients perceived the usability of the pain complexity tool and diaries as good. They indicated that the pain complexity tool and diaries were easy to use, not too time-consuming, easy to understand, and that the reminders by email were of added value. In addition, patients perceived the content as easy to keep track of their pain complaints and the amount of questions as good. However, most patients . Some other patients indicated that they perceived recognition and acceptance of their CMP during the sessions due to explanations about the pathophysiology of pain. One patient indicated the sessions as confronting as she/he recognized her/himself for the first time as a patient with chronic pain.R13: “I have read all sessions and the total overview was good for me. But at the same time it was also confronting, maybe that was good, as well.”The educational sessions were most often used by the PTs, and sometimes by the PNMH. PT1 used it to guide the content of his treatment, and PT2 and both PNMHs used it as additional education material for the patient. They indicated that patients were satisfied with the content of the educational sessions and that it gave them more insight into their pain problem. However, they perceived the educational sessions as less applicable for patients with a lower IQ-score or restricted literacy.Two patients used the chat function, while nine patients indicated they did not. Those two patients were positive about its usability.Four patients indicated that they had contact with their PT about the diaries and educational sessions they performed in the eCoach-Pain and rated these of added value. For at least one patient, the physiotherapy treatment was adjusted based on the results in the eCoach-Pain. Moreover, some patients discussed the diary questions about their psychosocial status. Furthermore, patients indicated that the pain education received by their PT fitted well with the information in the educational sessions. The eCoach-Pain resulted in a better patient-PT treatment relationship. Three patients had questions about the eCoach-Pain and needed extra support from their PHCP, for example, about the content of the eCoach-Pain, when to finish using the eCoach-Pain, or extra practical tips regarding their pain complaints. Moreover, some patients mentioned that they had discussed technical issues with their PHCP, such as logging in, bugs in the sessions, or difficulties with data exchange between the PHCP and patient.The other seven patients mentioned no contact with their PHCP about their activities in the eCoach-Pain. Reasons for this ranged from patients’ holidays and sick leave periods, technical issues which limited eCoach-Pain-use, or the fact that the patient had not filled in the pain complexity tools and diaries before the next contact with the PHCP could take place.Patients did not bother with the fact that their PHCP was able to track their activity in the eCoach-Pain, while some of them did not know this option before the interview. Two patients mentioned that they felt no need to discuss their activity in the eCoach-Pain with their PHCP. Most patients indicated that the possibility to discuss their activity online with the eCoach-Pain was of added value, especially in the situation of COVID-19 they were in during the pilot period, as live contact with PHCPs was only limited to emergency consultations.PHCPs indicated that they did not use the chat function of the eCoach-Pain often as they preferred other ways to communicate with the patient, such as email, chat functions of other applications, or a real-life contact. Furthermore, the fact that they had to log in again to answer these messages was another reason not to use the chat function. GPs mentioned that they did not always communicate with the patient about the results of the eCoach-Pain themselves, but, instead, they asked the PT or PNMH to respond to the patient.GP1: “Because of our work-flow, it is the easiest way that the PT communicates with the patient and has a prominent role in the follow-up.”They checked if a patient scored a red flag, and only then did they contact the patient or the PT. PT1 discussed the results during nearly each treatment session, while PT2 and the PNMH used a less frequent basis or when the patient had questions about it.Six patients did not report any technical issues using the eCoach-Pain. Others mentioned problems in finding how to use all functions of the eCoach-Pain, bugs in sessions, or difficulties connecting their eCoach-Pain to the PHCP’s profile. Two patients perceived difficulties with logging in into the eCoach-Pain because they had to renew their password more than once or had to log in several times in a row. Two patients had help from family or friends with logging in, use of a computer, or receiving reminders. There were no problems mentioned with the instruction manual, and nobody contacted the Helpdesk of the software developer during the pilot period. Four patients registered themselves with the self-subscription option via a website without any problems. The others were registered by their PHCP; in one case, the connection between the application of the patient and the application of the PHCP failed.Overall, PHCPs indicated that the eCoach-Pain is easy to use. However, all PHCPs reported having difficulties with the two-way factor identification for logging-in, which is obligated by the General Data Protection Regulation (GDPR). They perceived a delay in receiving the codes by email or the email is marked as spam. The fact that there is an extra step for logging-in hindered them in using the eCoach-Pain more often. They also indicated that it is difficult for them to combine the eCoach-Pain with other existing applications in daily practice, as each application has its own login system, function, and layout.Most patients were satisfied with the eCoach-Pain. Some patients indicated that the eCoach-Pain supports to increase insight in how pain impacts daily activities and participation and that it answers questions about their pain complaints. Moreover, they recommend it for the use of the chat function with their PHCP. Some patients would recommend the eCoach-Pain because they were satisfied with it themselves. Most of them would recommend it to patients with other complaints than their own, as they indicated that the content did not fit perfectly based on their own situation. They would especially recommend it to patients who are recently diagnosed, have problems in daily activities and participation, are low literate, or who want to use an eCoach-Pain frequently.R16: “I would recommend it to people who get acquainted with pain complaints, or who have not so much knowledge yet, for them it is useful to get to know more about pain. But for people who have complaints for years, like me, I would not recommend it.”They would not recommend it to patients with pain complaints for years, elderly who are not familiar with eHealth, or patients who do not want to use the eCoach-Pain frequently. However, some patients who are recently diagnosed would recommend it for patients with chronic complaints.Most PHCPs indicated that they will keep on using the eCoach-Pain in the future as they find it important to offer the patient something extra besides usual care. However, due to time constraints in daily practice, GPs hope that PNMHs can get a more prominent role in the follow-up of patients and contact other PHCPs about the results in the eCoach-Pain. In this case, the PNMH has to contact the GP when expertise or referral of the patient is needed.GP1: “Because of the high work-load in primary care, it would be of added value when someone as a PNMH can get a more prominent role in follow-up of patients. They will also be able to keep track of the eCoach-Pain activities. We as GPs have not enough time to do this properly.”PTs think they will keep on using the eCoach-Pain in the same way as they did during the feasibility study. However, all PHCPs indicated that the costs of the eCoach-Pain concerning their patient volume are important indicators for future usage. During this feasibility study, these costs were covered by the project budget of NPRL.The current study provides insight into the feasibility of an eCoach-Pain for patients with CMP or a high risk of becoming chronic, and for PHCPs in interdisciplinary primary care. In general, patients and PHCPs had positive experiences using the eCoach Pain. The answers to questions/statements about learnability, usability, desirability, and adherence to the application confirm that the eCoach Pain has sufficient quality for further use. However, some further adjustments for successful implementation and use are needed.Some patients mentioned that the content of the eCoach-Pain does not fit with their situation, such as multi-morbidities and previous experiences with treatment. An explanation why patients do not find the eCoach-Pain suitable could be that patients with CMP often experience multi-morbidities, such as depression, anxiety disorders, obesity, hypertension, and diabetes ,40,41,42The eCoach-Pain is well integrated into the treatment of the PTs. All PHCPs perceived advantages of the use of the eCoach-Pain during physiotherapy treatment. Patients indicated that eCoach-Pain connects to the treatment of the PT. Positive thoughts about blended rehabilitation care for other diseases are also seen in several other studies ,48. The eCoaches can stimulate and influence interdisciplinary collaboration in primary care . Based oSome patients mentioned technical problems that limited the use of diaries or education sessions, even though they received a reminder. Although the developers could not find an explanation for this, it could have influenced the adherence rates for the diaries and education sessions. Other patients indicated that they received too many reminders for diaries. Therefore, in future use of the eCoach-Pain, attention must be given to the communication between the PHCPs and patients. The PHCPs must discuss in advance the number of diaries and reminders offered, based on the preferences of the patients. Research has shown that shared-decision making for chronic illness with treatments containing more than one session leads to treatment agreement . TherefoA major strength of this study is the use of qualitative and quantitative data (mixed-methods) alongside objective data on use of the eCoach-Pain from both patients’ and PHCPs’ perspectives. These data gave a broad overview of the usability of the eCoach-Pain, as well as the experiences. Moreover, the content of the eCoach-Pain was developed together with the PHCPs before the start of the study with a user-centered design . Higginsn = 21), and most of the patients participating in the interviews were also recruited by this practice (9 out of 11). Therefore, limited results were available about the recruitment of GPs in the interviews.Some limitations of this study need to be acknowledged. First, the small sample of patients that were available for this study and the limited use of the eCoach-Pain could have introduced selection bias. It could be that patients with, for example, low literacy or co-morbidities, were not asked for participation by the PHCPs with a risk for selection bias. However, despite the small sample, patients differed in demographic characteristics, resulting in sufficient confidence to have studied a representative group of users. Second, not all patients performed all measurements, so the completeness of available data per measurement differed. Six patients did not respond on the evaluation questionnaires, and, for three patients export data of eCoach-Pain-use is missing. This could have led to information bias which could have influenced the data. Third, the sample of primary care practices and PHCPs was small, which could have influenced the results. As for primary care practice 1, all patients are subscribed by a GP or PNMH, and, for primary care practice 2, the PT also subscribed patients, besides the GP and PNMH. Most patients were recruited by primary care practice 2 (In conclusion, the eCoach-Pain seems to be promising in primary care: the patients, as well as the PHCPs, experienced advantages for treatment of patients with CMP. However, adjustments to the content have to be made for better fit with patient-specific CMP complaints. Moreover, the implementation strategy seems to be an important factor for successful use among PHCPs. This should be improved for successful use in interdisciplinary primary care settings. The involvement of a case-manager for CMP should be further explored when implementing the eCoach-Pain. Thereby, it is important to use user-centered designs and implementation science methods to evaluate adjustments resulting in a successful implementation.


BackgroundMusculoskeletal pain is the most common complaint presented to the health practitioner. It is well-known that untreated or under-treated pain can have a significant negative impact on an individual’s quality of life (QoL).ObjectivesThe current study aimed to assess the clinical response of Nuberol Forte® (paracetamol 650 mg + orphenadrine 50 mg) to musculoskeletal pain in routine Pakistani practice and its impact on improving the patient’s QoL.MethodsA prospective, observational multicenter study (NFORT-EFFECT: Safety & Efficacy of Nuberol Forte in Pain Management). Three hundred ninety-nine patients with known prescreened musculoskeletal pain were recruited from 10 major healthcare facilities across six (6) major cities of Pakistan, as per the inclusion/exclusion criteria. After the baseline visit (Visit 1), the patients were followed up one to two weeks (Visit 2) after the treatment as per the physician's discretion. Data were collected using the Case Report Form (CRF) designed for the study, and adverse events (AEs) were also monitored to assess drug safety. Pain intensity was assessed through a visual analog scale (VAS), and QoL was assessed using the Muscle and Joint Measure (MJM) scale.ResultsOut of 399 enrolled patients, 49.4% were males and 50.6% were females with a mean age of 47.24 ± 14.20 years. Most patients were presented with knee osteoarthritis (OA), i.e., 148 (38%), followed by backache 70 (18.2%). A significant reduction in the mean pain score was observed after treatment with the combination of paracetamol and orphenadrine (p<0.05). Furthermore, an overall improvement in the patient’s QoL was also observed. During the study, only 10 patients reported mild adverse events (AEs), namely, dryness of the mouth, dizziness, gastric irritation, tachycardia, restlessness, etc.ConclusionThe combination of paracetamol and orphenadrine (Nuberol Forte) exhibited effective pain management among patients with musculoskeletal conditions and improved their QoL. Musculoskeletal conditions are challenging disorders for patients and treating doctors . It is tThe musculoskeletal pain affects the patient’s quality of life (QoL) and unusually visual analog scale (VAS), a unidimensional measure for assessing acute and chronic pain -10. It iThe two main approaches to measuring the QoL includes generic and disease-specific instruments. In generic tools, the short form 36 questionnaire (SF-36) and the Euroqol five questionnaire (EQ-5D) are the most frequently used questionnaires enabling quantification of the HRQoL in people with musculoskeletal disorders -13. HoweFrom a therapeutic perspective, a multimodal, multidisciplinary approach using fixed-dose combinations of analgesics potentiates pain relief and reduces the consequent risk of adverse events (AEs) . In the Multiple studies evaluating the clinical response of paracetamol fixed-dose with different combinations  as an analgesic have been conducted -19. DespStudy design and populationThis NFORT-EFFECT observational, prospective multicenter study was conducted in compliance with Good Clinical Practice guidelines and local regulatory requirements. The study sponsor was The Searle Company Limited, Pakistan. To maintain the GCP compliances, the sponsor assigned the CRO for the site and data management.A total of 399 patients with known, prescreened musculoskeletal conditions and pain who attended the study sites were enrolled. All consenting patients aged ≥18 and ≤70 years, inclusive of either sex, were kept in the inclusion criteria. While patients with known hypersensitivity to the Nuberol Forte product, the metabolites, or formulation excipients, those with glaucoma, prostatic hypertrophy or obstruction at the bladder neck, myasthenia gravis, oesophageal spasm, and pyloric or duodenal obstruction were excluded from the study. Also excluded were pregnant or breastfeeding women and those treated with Nuberol Forte to evaluate safety as per approved prescribing information for Nuberol Forte in Pakistan.The recruited patients were then prescribed paracetamol (650 mg) and orphenadrine (50 mg) combination (Nuberol Forte) for seven to 14 days as per the investigator's discretion based on the pain intensity. After the initial screening (Visit 1), a follow-up visit was conducted after one to two weeks of the treatment (Visit 2).Study endpointsThe primary objective was to assess the pain management response of Nuberol Forte treatment and the overall safety of the drug. VAS was used to measure pain severity. Secondary to pain, the patients' health-related quality of life (HRQoL) was also assessed using the Muscle and Joint Measure (MJM) scale. Safety was monitored on the first dose by the patients. These assessments were done at each study visit.Description of study visits and timing of assessmentsEntry Visit (V1) (Baseline)After signing informed consent, the patients were evaluated, and selection was made based on inclusion/exclusion criteria. Patient demographics, vital signs , relevant medical history, systemic examination, VAS scale scoring for pain, MJM scale for QoL, concomitant medications, and study medication was recorded in the case report form (CRF).Follow-Up Visit (V2)A follow-up visit was planned for all enrolled patients one to two weeks after the baseline visit. These subjects were evaluated for the clinical response of the study drug and pain status, QoL was re-recorded in the follow-up visit, and overall effectiveness and safety were assessed. The drug safety was determined based on the frequency of adverse event(s) (AEs), evaluated through the AE form provided within the CRF.Ethics approval and consent to participateEthical approval was obtained from Pakistan Medical Association Committee on Ethics (Reference no: OS/908/PWQ/10). The patients were enrolled after signing informed consent.Statistical analysisData analysis was done using Statistical Package for Social Sciences (SPSS) version 21.0 . All categorical variables were displayed using frequency (percentages) while all continuous variables were given as mean ± SD. Chi-square and T-test were used to compare the pre and post-treatment qualitative and quantitative values respectively. P-value ≤ 0.05 was taken as significant.In this multicenter study, the mean age of the included patients was 47.24 ± 14.20 years. The male to female ratio was nearly equal. Moreover, 62% of patients had normal BMI; vitals were also stable in most cases. The majority of the enrolled cases were non-smokers (89.7%) and non-alcoholics (99.7%). Further details regarding the baseline characteristics of the study participants are given in Table Most of the enrolled participants had knee osteoarthritis (OA) (38.4%) followed by backache 18.2%), rheumatoid arthritis , generalized muscular pain (7.3%), and frozen shoulder (6.0%) while other musculoskeletal conditions or pain conditions are mentioned in Table %, rheumaA significant decrease was observed in the pain severity after the treatment with Nuberol Forte (paracetamol 650 mg + orphenadrine 50 mg) (p<0.05), as shown in Figure At the baseline visit, 24 patients had mild pain, mainly OA (45.5%), followed by frozen shoulder, soft tissue injury, RA, backache, and generalized muscular pain. One hundred ninety-one had moderate pain, mainly with osteoarthritis (51.3%), backache (18.1%), frozen shoulder (7.3%), RA (6.2%), and others, including sciatic nerve compression, soft tissue injury, neck pain, dysmenorrhea, toothache, and operative pain. Furthermore, 164 patients complaint of the severe form of the pain, of which 29.2% was due to osteoarthritis followed by backache (18.9%), rheumatoid arthritis (9.1%), toothache (7.3%), and the remaining had frozen shoulder, dysmenorrhea, soft tissue injury, earache, and sciatic nerve compression. While on the follow-up visit, only 29 patients had severe pain.There was a significant change in the pain grade before and after treatment among patients with various musculoskeletal disorders. In case of severe and worst pain, Nuberol Forte was prescribed with diclofenac sodium or aceclofenac. See Table The results of the MJM (QoL) assessment showed that the mean score for severity of muscle cramps or spasms reduced from 7.07 ± 1.54 (baseline) to 4.75 ± 2.20 (follow-up)  associated with Nuberol Forte and seven were reported by the patients treated with Nuberol Forte and other NSAIDs. Dryness of the mouth (n=2), dizziness (n=1), gastric irritation (n=3), tachycardia (n=1), restlessness (n=1), Palpitation (n=1), and itching (n=1) were the AEs observed.This study provides real-life evidence on the effectiveness, safety, and tolerability of the paracetamol with orphenadrine combination (Nuberol Forte) for musculoskeletal pain in Pakistani practice. Internationally, multiple studies have addressed the role of the paracetamol with orphenadrine combination in pain management in different musculoskeletal conditions -25, but Hunskaar et al.'s study on mice showed increased and prolong antinociceptive effects of paracetamol in mice, and a combination of the paracetamol with orphenadrine showed a significantly improved effect as compared to either of the drugs alone -23. SimiFurthermore, 14 patients in the current study had a toothache; all of them responded well with the provided combination regime and reflected an overall improvement in the quality of life. The McGuinness trial was designed to compare the pain management response of the combination (orphenadrine citrate and paracetamol) and paracetamol alone . The stuConcerning the association between lifestyle and musculoskeletal pain, a number of studies identified various risk factors in association with musculoskeletal pain. Walsh et al. conducted a systematic review and meta-analysis to assess the association between body fat and musculoskeletal pain . The resGlobally, NSAIDs are usually prescribed analgesics although gastrointestinal (GI) complications are well-established. The associated drug adverse effects with traditional NSAIDs, cyclooxygenase-2 inhibitors (COX-2) inhibitors, and acetylsalicylic acid (ASA) ,33 have Musculoskeletal pain is the foremost problem in the psychosocial and physical wellbeing of an individual and significantly impairs the subject’s quality of life . The curLimitationOne of the significant limitations of the study was the limited sample size. Moreover, our objective was limited to safety and quality of life. Longitudinal, large-scale, multicenter studies should be conducted focusing on psychosocial and physical well-being in the future.The paracetamol and orphenadrine combination (Nuberol Forte) exhibited a positive clinical response to musculoskeletal pain and improved patients' quality of life. Overall, Nuberol Forte is a well-tolerated treatment choice with fewer adverse effects than NSAIDS or other therapeutic agents.


The objective of this study is to determine whether elevated circulating plasma catecholamine levels significantly impact opioid requirements during the first 24 hours postoperative period in individuals with acute surgical pain.We retrospectively reviewed 15 electronic medical records (EMRs) from adults 18 years and older, with confirmed elevated plasma catecholamine levels  and 15 electronic health records (EHRs) from matched-controls for age, gender, race and type of surgery, with a follow up of 24 hours postoperatively.The total morphine milligram equivalents (MMEs) requirements from the experimental group were not statistically different when compared with controls . However, the intraoperative MMEs showed a significant difference, among the two groups; . The intraoperative dosage of midazolam showed a highly significant positive correlation to the total MMEs (p 0.0005). The subjects with both elevated plasma catecholamines and hypertension used significantly higher intraoperative MMEs compared to controls . Those 51 years and younger, with elevated circulating levels of catecholamines, required significantly higher levels of both the postoperative MMEs  and total MMEs [544.05 (13 to 81) mg versus 29.42 (13 to 92.5) mg; (p 0.00018), when compared to controls with history of nicotine and alcohol use.This preliminary study evaluated a biologic factor, which have promising clinical usefulness for predicting analgesic requirements that can drive clinical decisions on acute surgical pain. Opioids are commonly used to control acute postoperative pain. However, opioids are associated with some drawbacks, including adverse side effects related to higher opioid requirements and subsequent opioid use disorders . It is eB-endorphins, dynorphins) along with catecholamines , are praised to be major components in pain perception and analgesic requirements  including medulloadrenal hyperfunction (ICD9-255.6), adrenomedullary hyperfunction (ICD10-E27.5), acute postoperative pain (ICD9-338.18), and other acute post-procedural pain (ICD10-G89.18) for identifying subjects in the experimental group. As a comparison group (controls), we selected patients who had ICD9/10 codes, including both ICD9-338.18 and ICD10-G89.18 only. We excluded all EMRs in the query that included chronic pain syndrome (ICD10-G89.4) and liver disease unspecified (ICD10-K76.9). Other demographic data included age at time of surgery, gender, height, weight, and body mass index (BMI). Other data included type of surgery and milligrams of opioid therapies converted into MMEs.Those with elevated circulating levels of catecholamines were confirmed by laboratory results, for elevated metanephrine and normetanephrine levels in the blood and compared with controls. Of note, to confirm that elevated circulating catecholamine levels were not present in the control group, the medical informatics specialist identified those subjects who included the ICD9 and ICD10 codes aforementioned above only without the ones used for the experimental group. This is to purify our control group sample. We anticipated controlling for bias using a control-matched strategy for age, sex, race, and type of surgery.We reviewed EMRs of subjects with acute surgical pain who were treated with opioid therapies during the first 24 hours of hospitalization.The primary outcome variable was total amount of opioid therapy milligrams, converted to MMEs. Opioid medication therapy data was available in the EMRs, under the nursing notes in the floor and discharge summary of each study subject.Secondary outcome variables included milligrams administered of intraoperative midazolam, propofol, and 2% lidocaine . Other variables included pre-existing medical conditions including hypertension, diabetes mellitus type 2, depression, anxiety, fibromyalgia, and nicotine and alcohol use.The analysis of the primary outcome variable, total MMEs in the first 24 hours after surgery, involved a Wilcoxon rank-sum test. In addition, intraoperative and postoperative MMEs involved the Wilcoxon rank-sum test. For the analysis of the secondary outcome variables including; milligrams of intraoperative midazolam, propofol and 2% lidocaine and pre-existing medical problems, both the linear regression analysis and the Mann–Whitney–Wilkoxon U test were used. All statistical analyses used a two-tail test at a significance level of ≤0.1. Of note, as a preliminary study designed was selected, both the sample size and the effect difference were not determined.Of the 19,341 EMRs, identified from TriNetX, we removed 10,729 duplicates. From the first screening of 8612 EMRs, we excluded 1569 EMRs. From second screening of 7043 EMRs, 83 EMRs met inclusion criteria for experimental group. In addition, 6960 EMRs met inclusion criteria in the control group. The final screening of 7013 EMRs excluded 68 EMRs in the experimental group and 6945 EMRs in the control group. Thirty subject’s EMRs were included in the analysis  kg/m2 (p 0.2891) in the controls. The proportion of pre-existing medical conditions in both the experimental group and the controls are listed in Table Among the 30 EMRs, 19 were females and 11 males. There were no significant differences in demographics between the experimental group and controls. The Median (range) age in the experimental group was 52 (23 to 82) years compared to 59 (23 to 82) years of age in the controls (p 0.8807). Median height was 164 (154 to 187) cm in the experimental group compared to 167 (154 to 193) cm in the controls (p 1.0000). Median weight in the experimental group was 83.9 (43.1 to 158) kg compared to 78.3 (52 to 117.4) kg in the controls (p 0.4413). Median BMI in the experimental group was 27.7 (16.9 to 58.7) kg/mThe median and range of midazolam was 2 (0 to 2) mg in the experimental group compared to 2 (0 to 9) mg in the control group p 0.1770). Median propofol was 199.2 (12 to 300) mg in the experimental group compared to 120 (0 to 450) mg in the control group (p 0.9521). The median of 2% lidocaine received in the operating room was 80 (0 to 100) mg for both the experimental group and control group (p 0.5485).  mg versus 15 (6.5 to 130) mg, respectively; p 0.0734]. However, the amount of postoperative MMEs and total MMEs was not significantly different between the two groups . . On the other hand, midazolam showed a highly significant positive correlation to total morphine milligram equivalents (p 0.0005). (Table N = 12), were administered with significantly higher intraoperative MMEs, compared to controls (N = 11) ). Fig.  It is wo to 163 mThe purpose of this preliminary study was to determine whether subjects with elevated circulating plasma catecholamines require higher levels of total MMEs during the first 24 hours postoperative period compared to controls. The findings in this study suggested that subjects with elevated circulating plasma catecholamines required higher intraoperative MMEs compared to controls. However, we could not find a significant difference between the two groups in the total MMEs, administered during the first 24 hours postoperative period. Moreover, most of our study population who did require higher intraoperative MMEs had pre-existing hypertension (>70%). It has been reported that ˜95% of the population with pheochromocytoma  endures some type of hypertension secondary to the elevated levels of catecholamines (PMCID: PMC3094542). Similar to the outcomes in our study, previous research has highlighted the higher intraoperative opioid requirements in those with pre-existing hypertension. For instance, in a study from the Netherlands, it was reported that higher doses of intraoperative fentanyl (130–140 µg/kg) were administered to reduce hypertension on patients who underwent cardiac surgery . Other rThere is a safety concern about daily opioid requirements and acute surgical pain management in those most vulnerable for receiving higher MMEs for pain control. This is due to the impact of the elevated therapeutic drug requirements and its potential development of opioid use disorders . TherefoOther factors have been identified for predicting the patient’s responses to surgical pain therapies  Of theseThis preliminary study evaluated a potential predictive factor to opioid analgesic responses using translational research methods. These findings have the potential to drive clinical decision-making in acute surgical pain management. Of note, predicting the responses through identification of biologic factors may potentially tailor the decision whether to use opioids as a short-term pain therapy. This is critical for mitigating opioid use disorders in the future.The findings of this study suggested that future research should focus on the correlation of catecholamines, pain perception, and responses to pain medication. In particular, larger sample size clinical studies that focus on novel strategies to develop precision pain protocols for the management of acute surgical pain. Previous reports have underscored the critical nature of such research ,26.There are several limitations to our study. Despite of the fact that we matched for several factors including type of surgery, the impact of surgical trauma, even in the same type of surgery, can significantly impact postoperative outcomes and therefore affect pain management.Pre-existing conditions were not taken into account if they appeared in the electronic health record. In addition, it must be highlighted that the assessment of severity of pre-existing conditions was not defined by parameters or surrogate outcomes. The quantitative measurement of the severity of these pre-conditions is to be accounted in future research to evaluate other factors in this regards. Other intraoperative and postoperative pain management protocols, with volatile anesthetic agents and non-opioid drugs, may create bias in pain responses in the postoperative pain responses to medications. However, the investigation of this bias was out of the scope of this study. In addition, the sample size utilized for this study was considered very small. This can significantly affect the statistical analysis. It is important to mention that it was our objective to evaluate the responses to opioid analgesics in acute surgical pain when catecholamines were circulating in elevated levels in the population, with a preliminary study design in a clinical scenario. Therefore, this approach was selected and considered feasible at this phase of investigation. Another limitation of this study was that psychosocial conditions are assumed to be associated with elevated catecholamine levels and increased incidence of hypertension in the population. In this study, psychosocial conditions including depression and stress were not assessed in the control group, which can be determinant when measuring opioid drug requirements.This preliminary study has used translational research methods to evaluate the potential impact of elevated circulating plasma catecholamines on the response to opioids in acute surgical pain management. We conclude that elevated circulating levels of catecholamines and secondary hypertension predisposed patients to receive higher intraoperative MMEs. In addition, intraoperative midazolam may potentially influence higher total MMEs during the first 24 hours postoperative period.Based on the results of this study, we conclude that individuals with elevated plasma catecholamine levels had similar trends in consumption of opioid for surgical pain management when compared to those acknowledged to have altered pain perception and pain responses, secondary to pre-existing psychosocial conditions, including depression and history of nicotine and alcohol use.Though, age was not a predictive factor considered in this study, it is important to emphasize that subjects 51 years and younger, with elevated plasma catecholamine levels, are subject to further research on total opioid consumption for acute surgical pain management.We strongly believe that this study shows the need for future investigations on catecholamines and opioid consumption, as it relates to putting patients at risk of significant long-term sequela, secondary to the short-term opioid requirements for postoperative pain management.


No difference between the groups was seen in postoperative pain intensity measured on the visual analog scale, except for the evaluation at hour 2, which was in favor of the QLB group (p = 0.03). Patients who received QLB were more satisfied with postoperative pain management than the CON group. Persistent postoperative pain was assessed with the Neuropathic Pain Symptom Inventory (NPSI) at months 1, 3, and 6, and was found to be significantly lower in the QLB group at each evaluation (p < 0.001). We also analyzed the impact of the surgery type on persistent pain severity, which was significantly lower after laparoscopic procedures than open procedures at months 1, 3, and 6. Conclusions: QLB reduces oxycodone consumption in patients undergoing open and laparoscopic nephrectomy and decreases persistent pain severity months after hospital discharge. Background: New regional techniques can improve pain management after nephrectomy. Methods: This study was a randomized controlled trial conducted at two teaching hospitals. Patients undergoing elective open and laparoscopic nephrectomy were eligible to participate in the trial. A total of 100 patients were divided into a quadratus lumborum block (QLB) group (50 patients) and a control (CON) group (50 patients). At the end of surgery, but while still under general anesthesia, unilateral QLB with ropivacaine was performed on the side of nephrectomy for patients in the QLB group. The main measured outcome of this study was oxycodone consumption via a patient-controlled anesthesia (PCA) pump during the first 24 h following surgery; other measured outcomes included postoperative pain intensity assessment, patient satisfaction with pain management, and persistent pain evaluation. Results: Patients undergoing QLB needed less oxycodone than those in the CON group (34.5 mg (interquartile range 23 to 40 mg) vs. 47.5 mg (35–50 mg);  Although a multimodal analgesia approach is recommended following nephrectomy, some individuals still suffer from severe pain after the procedure . RegionaQuadratus lumborum block (QLB) is a relatively new regional anesthesia technique; it was developed by Blanco  and has Our study aimed to evaluate the impact of QLB on postoperative oxycodone consumption in patients undergoing laparoscopic and open nephrectomies. The secondary measures included postoperative pain intensity assessment, patient satisfaction with pain management, and persistent pain evaluation. Our primary hypothesis was that a 25% reduction in oxycodone use would be observed in the QLB group.The RCT was conducted in the urology departments of two teaching hospitals. The Institutional Review Board of the Medical University of Lublin, Poland approved the study protocol (permit number KE-0254/328/2017), which was registered with ClinicalTrials.gov (NCT03529201) before patient recruitment. Written informed consent was obtained from each patient, and the study was conducted in accordance with the principles for medical research involving human subjects of the Declaration of Helsinki.Adult patients younger than 80 years who were scheduled for nephrectomy procedures (due to cancer) could volunteer to participate in the study. Patients with known coagulopathy, allergies to the studied drugs, psychiatric disorders requiring antidepressant usage, or addiction to alcohol or other recreational drugs were excluded. Before recruitment, the investigators assessed the patients’ ability to handle a patient-controlled analgesia (PCA) pump and to understand the visual analog scale (VAS) and the Neuropathic Pain Symptom Inventory (NPSI).2), a three-lead electrocardiogram (ECG), non-invasive blood pressure (NIBP), capnography, oxygen, and volatile anesthetic concentrations. The type of surgery—open or laparoscopic nephrectomy—was chosen at the surgeon’s discretion.General anesthesia was induced and maintained by an anesthesiologist who was unaware of the patient’s group allocation. To induce general anesthesia, each patient received fentanyl , propofol , and rocuronium . Anesthesia was maintained with 1.5–2.0% sevoflurane  in a mixture of oxygen and air, and additional doses of fentanyl and rocuronium were administered. Standard monitoring during the procedure included blood oxygen saturation  group and half to the QLB group. Computer-generated randomization was prepared by an investigator who was not involved in the procedure or further assessment of the participants. Both the primary investigator and the statistician were blinded to data collection throughout the study.Patients in the CON group emerged from anesthesia and were transferred to the post-anesthesia care unit (PACU). In the other group, QLB was performed before the end of anesthesia, under ultrasound guidance, and with the patient in the lateral position. Only one person in each center performed the QLBs. The anesthesiologist used a 10 cm Ultraplex 360 needle  to perform a QLB type II . The needle was introduced in the medial to posterolateral direction. Infiltration with 0.9% saline and the needle’s position were confirmed, and 2 mL/kg 0.375% ropivacaine  was then deposited (up to 40 mL) only on the side of the surgery. Patients were not aware of the group to which they had been allocated.In the PACU, oxygen was supplied and the patient’s vital signs, including respiratory rate, plethysmography, oxygen saturation, heart rate, and blood pressure, were monitored. The standard postoperative pain management in both groups included oxycodone and non-opioid drugs. The investigator began pain treatment with oxycodone administered intravenously (i.v.) via a PCA pump, 1 mg/mL with a 5-minute lockout. The attending nurse could add 5 mg of oxycodone in the case of severe pain exceeding 40 mm on the VAS. The other painkillers comprised i.v. paracetamol, 1 g every 6 h, and i.v. ketoprofen, 100 mg twice daily. The patient also received 4 mg of ondansetron, twice daily, as prophylaxis for nausea and vomiting. The nurse, who was unaware of the participants’ group allocations, reminded the patients about the pain severity assessment.The total patient consumption of oxycodone via PCA during the first 24 postoperative hours was the primary measure of the study. The other outcome measures included pain severity on the VAS at hours 2, 4, 8, 12, and 24; rescue doses of oxycodone administered by nurses in the PACU; patient satisfaction with pain management; and persistent pain evaluation. Satisfaction with pain treatment was assessed on a five-point Likert scale on which the patient and the investigator could describe the pain management as very poor (1), poor (2), moderate (3), good (4), or excellent (5). The presence and intensity of persistent postoperative pain were evaluated during a phone interview at months 1, 3, and 6 using the NPSI , which wContinuous data were compared using the Mann–Whitney U test or the Kruskal–Wallis test by ranks (for more than two comparisons). Medians (interquartile ranges) are used to present these data. Categorical variables were compared using Fisher’s exact test. Logistic regression was used to reveal the parameters that affect chronic pain presentation. The odds ratio (OR) was used to describe the predictors that were included in the model. The receiver operating characteristic (ROC) curve was calculated for the best model. All analyses were performed using Statistica 13.1 software , which was also used to generate the random group assignments.A sample size analysis was performed for the primary outcome of the study. In a pilot study, we recruited 20 patients (10 per group) and found a mean oxycodone consumption of 42 mg in the CON group and 30 mg in the QLB group, with an SD of 18. The calculated sample size for a significance level of 0.05 and power of 0.9 that would detect a hypothesized 25% reduction in oxycodone use was 49 participants per group; we therefore recruited 105 patients with a 1:1 randomization ratio.The study was conducted from May 2018 to February 2019. p < 0.001).p = 0.028), and patients in the QLB group were more satisfied with the postoperative pain management  and 6 (red arrows). Pairwise comparisons were made with the Mann–Whitney U test using a significance level of 0.008 after Bonferroni correction. CON: control group; QLB: quadratus lumborum block group.Three factors were associated with the incidence of persistent pain after nephrectomy at month 6. The severity of persistent pain at month 3 increased the risk of chronic pain prevalence at month 6 ). Conversely, a lower amount of oxycodone administered via PCA had a reduced risk of persistent pain after 6 months ). Moreover, patients after laparoscopic nephrectomy who received QLB had a lower chance of chronic pain ). The area under the ROC curve for this model was 0.91 .The primary hypothesis of our study—A 25% reduction in PCA-administered oxycodone in the QLB group—was confirmed by the results . FurtherFurther analysis showed that patients undergoing open nephrectomies had more severe chronic pain at months 1, 3, and 6 than those undergoing laparoscopic surgery . In our Our study had some methodological differences from previous RCTs examining QLB use in patients after nephrectomy. First, both open and laparoscopic procedures were studied; in previous RCTs, only laparoscopic nephrectomies were investigated ,5,12,13.Similar to our results, in all RCTs in which QLB was compared with a control, the total consumption of opioids administered via PCA was significantly lower at hour 24 following the surgery ,13; notaFew researchers have investigated the problem of persistent pain in patients following nephrectomy. Alper and Yüksel compared 27 laparoscopic nephrectomy patients with 25 open surgery patients  and founFurthermore, more severe pain was found after open nephrectomy than laparoscopic nephrectomy in our RCT 6 months after surgery, but only in the CON group. The difference between our results and those of Alper and Yüksel could be a result of the NPSI in our trial allowing more detailed identification of persistent pain. However, Owen et al. also found chronic pain in 33% of kidney donors following open surgery , and theOur study presented a significant reduction in persistent pain severity in patients following the plain block, however, the QLB was performed postoperatively. It is possible that chronic pain severity would have been even lower in the QLB group if the block had been done pre-emptively. However, the block was performed under general anesthesia. Thus, patients had reduced nociception due to opioids and anesthetics. Our study has some limitations. Patients undergoing both laparoscopic and open nephrectomies were included, and our population was thus more heterogeneous than in previous RCTs. Patients in the CON group also did not receive a sham block with saline. Although a significant difference in persistent pain severity between the QLB and the CON groups was found in our study, its impact on patient recovery and quality of life was not assessed. To conclude, QLB reduces opioid consumption and alleviates persistent pain severity in patients undergoing laparoscopic and open nephrectomies.


Results on gray matter alterations in complex regional pain syndrome (CRPS) showed heterogeneous findings. Since CRPS is a rare disease, most studies included only small and heterogeneous samples resulting in a low reliability of findings between studies. We investigated 24 CRPS patients with right upper limb affection in the chronic stage of disease using structural MRI and clinical testing. We focused on gray matter volume (GMV) alterations of the brain in comparison to 33 age matched healthy controls, their association to clinical characteristics (duration of pain syndrome and pain intensity ratings) and sensorimotor performance (finger dexterity and spatiotactile resolution). When applying an explorative whole brain analysis CRPS patients showed lower GMV in the bilateral medial thalamus. No other areas showed a relevant GMV difference for the group comparisons. When applying a region of interest driven approach using anatomical masks of the thalamus, ACC/mPFC, putamen, and insula we found relevant associations of clinical and behavioral data in ACC and insula. Whereas, the GMV in ACC showed negative associations with pain intensity and CRPS duration, the GMV of the left posterior insula was negatively associated with sensorimotor performance of the affected hand side. Overall, our results are in accordance to results of others describing a thalamic reduction of GMV in patients with neuropathic pain and are also in accordance with associations of pain intensity and duration with reduced ACC in general in patients with chronic pain syndromes. Sensorimotor performance seems to be related to posterior insula GMV reduction, which has not been described yet for other patient groups. Chronic pain has a substantial impact on quality of life of patients and their families. With a prevalence of 20%  it also Besides CLBP, neuropathic facial pain such as trigeminal neuralgia showed robust effects of GMV decrease in bilateral ACC , 10, insWhen using large samples, especially general population-based cohorts, the inter-individual random noise in the variance is significantly reduced, resulting in reliable and robust statistical testing, including correction, for e.g., multiple comparisons .Chronic pain can be differentiated into various syndromes. One of these syndromes, which has been categorized as a subtype of neuropathic pain [for an overview see ], is comContradictory findings have been reported for GMV alterations in CRPS –27. Gehap = 0.001. In addition, the authors applied a ROI-analysis for the pre- and postcentral gyrus. The results of this study were surprising since they found higher GMV for CRPS patients compared to HCs in dmPFC and M1 contralateral to the affected hand side. However, it is unknown how generalizable these findings are since some of the methods used in this study were older  and most patients (with 2 exclusions) were in the subacute stage of the disease.Pleger et al.  applied p < 0.005; resulting in t = 3.71 threshold but only reported clusters with at least 30 voxels . The study found decreased GMV in the posterior insula, left OFC and CC . However, an increase in GMV in bilateral putamen and right hypothalamus was also found. Higher pain intensity resulted in lower GMV in the dlPFC.Barad et al.  applied van Velzen et al.  did not These divergent results of the aforementioned studies might well be caused by small sample sizes, inhomogeneous patient groups , and differing or non-optimized evaluation strategies focusing on structural gray matter alterations. Overall, small sample sizes and large variances often prevent exploratory whole brain volume analyses and the necessary correction for multiple comparisons over said volume, favoring less conservative statistical approaches which are one cause of the reproducibility crisis in psychology [for the field of brain imaging see ]. By usiExplorative approach with correction over the whole brain volume and a ROI approach for those areas which already showed effects in previous investigations surviving a correction for multiple comparisons over the measurement volume: Are there GMV alterations in CRPS patients compared to healthy controls?ROI-approach for those areas which already showed effects in previous investigations surviving a correction for multiple comparisons over the measurement volume: Are there associations between GMV decrease in CRPS patients and pain severity, chronicity, and relevant performance impairment alterations in GMV?We here investigated common and specific GMV alterations in patients with CRPS from two study samples in an explorative (multiple comparison correction for the whole brain volume) and a hypothesis-driven approach . The following hypotheses were tested:via support groups in Northern Germany and via the hand surgery and Anesthesiology of the University of Greifswald. Twenty-four right hand affected CRPS-patients have been included which have been characterized in detail in Participants were recruited Twenty-four patients had been diagnosed based on the Budapest criteria  were on p < 0.05 effect for GMV decrease in the medial prefrontal cortex (mPFC). The mPFC appeared to be a robust finding in a number of different studies on associations of GMV decrease with pain chronicity; see also Kang et al.  using a 32-channel head coil. T1-weighted structural scans were acquired using the following characteristics: MP-RAGE, TR 1,690, TE 2.52 ms, flip angle 9°, matrix size 256 × 256, voxel size 1 × 1 × 1 mmp < 0.05 (voxel height) using a family wise error (FWE) correction over (1) the whole brain, and (2) in an additional ROI-correction (FWE voxel height) comprising mPFC , ACC , and bilateral ROIs . ROIs for GMV analyses were tested on the basis of prior investigations  or sensorimotor performance (Roeder and TPD) were associated with GMV.t = 3.24; p = 0.001). In addition, CRPS patients showed a decrease in spatiotactile discrimination as tested with the two-point discrimination .Pain intensity at rest, duration of CRPS symptoms, and performance were not relevantly associated with GMV alterations  than HCs . For the ANATOMY/Oxford atlas differentiation (based on connectivity information) the temporal  and the prefrontal  parts of the thalamus showed highest effects. Effects remained largely unchanged when only including patents with more than 12 months of disease persistence for the group comparisons ; t = 4.26; cluster level p = 0.008).For the exploratory GMV analyses (corrected for the whole brain volume) CRPS patients showed lower GMV in the bilateral thalamus  but not for the other ROIs selected.When using ROI-analysis  we again only observed bilateral anterior-medial thalamus GMV decrease for CRPS . Pain intensity was negatively associated with GMV in the same Area  = 0.038]. For the somatosensory testing with TPD we observed a negative association with GMV in the left posterior insula .When testing possible associations between decrease in GMV with sensorimotor performance we used those parameters which were impaired in our patients compared to healthy controls. For the motor testing with the Roeder test we found a negative association with GMV in the left posterior insula . ComparAn overlapping area in the ventroposterior thalamus has been described to be reduced in GMV before, showing reduced connectivity and reduced GABA for patients with neuropathic pain .Interestingly, Fukumato et al. used radioactive labeled iodoamphetamine in a SPECT study in 10 patients with CRPS to investigate perfusion differences between the hemispheres contra- and ipsilateral to the affected upper limb. When compared to ipsilateral, contralateral thalamus showed a reduction in perfusion and this reduction index was related to time of onset of the disease (6–36 months). In contrast, healthy controls showed symmetric thalamic perfusion. They discussed their results with the finding that chronic neuropathic pain results in a long-term thalamic inhibition whereas acute pain increases its activity. In contrast to Fukumoto, we observed a bilateral reduction in thalamic GMV. However, the effect for the contralateral hemisphere to the affected hand was stronger—especially when investigating only patients who had more than 12 months duration of CRPS.Here, the anterior cingulate cortex GMV was negatively associated with the duration of CRPS and pain intensity. This finding supports finding of others who showed associations of persistence of CRPS and GMV , showed In the rodent neuropathic pain model using nerve compression induced by surgical intervention S1, ACC, and insula GMV loss was associated with somatosensory impairment . The insThere is an ongoing debate concerning the fundamental neural substrates of GMV alterations. Underlying mechanisms for GMV decrease in patients with chronic pain have been discussed recently on the basis of ACC/mPFC GMV . One of 3) should be standard nowadays. Resampling 4 mm slice thickness with 1 mm spacing between slices (gap) into a voxel-based morphometry is not even justifiable when considering technical deficits of past decades . The patients/participants provided their written informed consent to participate in this study.SS organized patient recruitment and corrected the manuscript. MD helped with data evaluation and corrected the manuscript. JM corrected the manuscript and added ideas in data evaluation. ML managed the study, evaluated data, wrote the manuscript, and corrected and submitted the manuscript. All authors contributed to the article and approved the submitted version.ML and JM were supported by the Australian National Health and Medical Research Council (NHMRC) grant #1163149. SS was awarded a Gerhard-Domagk fellowship for undertaking this study; he also received a grant by the Else Kröner Fresenius-Stiftung 2019-A24. In addition, the investigations of GMV in chronic pain are subject to a funding of the DFG for ML (LO 795/37-1).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.