Aims of the study were to evaluate the reliability and validity of the Italian version of the Majeed and Iowa questionnaires and to investigate the long-term surgical outcomes following sacroiliac joint arthrodesis. Twenty one patients who underwent a sacroiliac joint arthrodesis and 21 healthy subjects were evaluated. The experimental procedure consisted of gait analysis and a physical activity assessment (in both groups) and of administration of outcome questionnaires and pain assessment (in the patient group). The Majeed and Iowa questionnaires showed excellent reliability, excellent (for the Majeed questionnaire) and good (for the Iowa questionnaire) construct validity, and poor convergent validity (for both questionnaires) relative to walking speed. Most of the patients reported no pain and minimum pain-related disability and their physical activity profile was comparable to healthy controls. Patients showed an impaired walking performance  compared with healthy controls. Long-term walking pattern abnormalities following sacroiliac joint arthrodesis may occur despite excellent clinical results. Given their excellent reliability and construct validity, the Majeed and Iowa questionnaires can be used in combination with the assessment of spatiotemporal gait parameters for the prognostic assessment and/or follow-up of surgical patients. Sacroiliac joint fusion, also referred to as arthrodesis, is a surgical procedure that fuses the iliac bone (pelvis) to the sacrum (spine). It is performed for a variety of orthopedic conditions including fractures and spinal instability.Sacroiliac joint fusion may be performed as a minimally invasive procedure or as an open surgical procedure requiring relatively large incisions, significant bone harvesting, and lengthy hospital stays . The recDespite various treatments, patients with pelvic injuries still have a spectrum of poor to excellent outcomes ,4,5,6,7 2) who underwent a sacroiliac joint arthrodesis after fracture were identified and volunteered to participate in the study. The surgical procedure consisted of either open reduction internal fixation (performed in 9 patients) or percutaneous iliosacral screw fixation (performed in 12 patients). Post-operative assessment of fracture reduction was performed on the basis of the maximal displacement measured on the anteroposterior, inlet, and outlet pelvic views according to the following previously described criteria: excellent (≤4 mm), good (4–10 mm), fair (10–20 mm), and poor (>20 mm) [Patients were randomly selected from postoperative lists and medical files of the “Centro Traumatologico Ortopedico (C.T.O.)” hospital . Twenty one patients  age: 49.0 (41.0–60.0) years; body mass index: 26.9 (26.0–29.4) kg/m(>20 mm) . In our 2) was also tested.A control group of 21 healthy subjects matched for gender, age, and body mass index  age: 49.0 (42.0–58.0) years; body mass index: 23.6 (21.8–26.0) kg/mAll subjects received a detailed explanation of the study and gave written informed consent prior to participation. The study conformed with the guidelines in the Declaration of Helsinki and was approved by the University of Turin ethics committee (protocol n. 133282).The experimental procedure consisted of gait analysis (see below) and physical activity assessment  ) in bothThe original English versions of the Majeed and Iowa questionnaires were first cross-culturally adapted so as to be used for evaluating Italian-speaking subjects (see below). According to the COSMIN checklist ,18, reliThe cross-cultural adaptation process of the Majeed and Iowa questionnaires was performed according to previously published guidelines  ,20 and cThe IPAQ short comprises seven items investigating different physical activity intensities (vigorous or moderate), the time spent walking and sitting (as a proxy for sedentary behavior) during the last 7 days . Based oThe Majeed pelvic score  compriseThe Iowa pelvic score  compriseThe Oswestry Disability Index questionnaire, that examines the perceived level of disability in ten everyday activities of daily living ,22, was Patients were asked to rate their pelvic pain intensity using a 11-point numerical rating scale (NRS), with 0 corresponding to “no pain” and 10 corresponding to “the worst imaginable pain”. Resting pain intensity was assessed prior to any study procedures, while movement pain was assessed during walking. Pain intensity was classified as mild for NRS scores between 1 and 3, moderate for scores between 4 and 6, and severe for scores between 7 and 10.Spatiotemporal parameters of gait were measured in both groups with the use of the OptoGait photoelectric cell system , which has been shown to provide reliable and valid data ,24,25. TParticipants, who were barefoot for the experiment, were asked to walk at two different speeds: self-selected comfortable  and fast . At each speed, one familiarization trial always preceded three experimental trials and a rest interval of 60 s was observed between each trial. For each velocity, the following gait parameters were quantified as the average of the three walking trials: walking speed (m/s), cadence (steps/min), stride and step lengths (cm), stance and swing phase durations (ms), and double and single support durations (percentage of gait cycle). Moreover, the following other variables were compared concerning the operated limb of the patients, contralateral non-operated limb, and healthy subjects data : step length, stance and swing phase durations, and single support duration.The Shapiro-Wilk test for normal distribution of the data failed, and non-parametric statistical tests were therefore used. The Mann–Whitney test, the Fisher’s test, and the Kruskall-Wallis ANOVA  were adopted for data comparison between healthy subjects and patients.Changes in the questionnaire scores between the 1st and 2nd administration were analyzed with the Wilcoxon test to assess the presence of systematic bias.Reliability  of the Majeed and Iowa scores was assessed as test-retest reliability and measurement error ,18.Test-retest reliability  was evaluated using the intra-class correlation coefficient . A sample size of at least 20 patients was considered necessary for the test-retest reliability analysis, using the approximate method developed by Walter et al.  based onMeasurement error  was evaluated using: (i) the standard error of measurement (SEM) that was calculated as follows: √mean square error term from the ANOVA ; (ii) thThe validity of the Majeed and Iowa questionnaires was assessed as construct validity  by comparing their scores with the Oswestry Disability Index score and it was also assessed as convergent validity  by correlation analysis with walking speed, which is a well-established indicator of lower limb function in orthopedic patients ,13.Floor and ceiling effects of the questionnaires were considered to be present if the lowest or the highest score was achieved by more than 15% of the cases.The Spearman’s test was adopted for correlation analyses. The criteria used for the interpretation of ICC and Spearman’s correlation coefficient were as follows: 0.00–0.25: no correlation; 0.26–0.49: low correlation; 0.50–0.69: moderate correlation; 0.70–0.89: high correlation; and 0.90–1.00: very high correlation .p = 0.05. Statistical tests were performed with the IBM SPSS Statistics  software package.Data were expressed in the text as median and 1st–3rd quartile or range (as indicated) and were reported in the tables as mean (±standard deviation). The threshold for statistical significance was set to No pain (NRS = 0) was reported by most of the patients (15 of 21 in resting conditions and 12 of 21 during movement). Median (1st–3rd quartile) values of NRS for pain were 0 (0–2) in both resting and movement conditions.Median (1st–3rd quartile) values of Oswestry Disability Index score were 8 (6–22)%: pain-related disability was minimum for most of the patients (14 of 21 patients showed Oswestry Disability Index scores below 20%).Surgical results could be considered excellent in most of the patients : consistently, 13 of 21 patients showed Majeed scores above 85%.p = 0.65) values for patients (IPAQ score: 840 (420–1260) MET*min/week) and healthy controls (IPAQ score: 840 (420–900) MET*min/week). Consistently, the proportions of sedentary subjects (6 of 21 patients vs. 8 of 21 controls), moderately active subjects (13 of 21 patients vs. 12 of 21 controls), and active subjects (2 of 21 patients vs. 1 of 21 controls) were comparable  between the two groups.The comparison of physical activity estimates between the two groups of subjects showed comparable  between patients (median (1st–3rd quartile) increase: +66 (47–77)%) and controls (median increase: +47 (37–66)%). Such an ability to increase the walking speed resulted from increases in cadence and stride length. The cadence increase was comparable (p = 0.97) between patients (+29 (16–32)%) and controls (+26 (17–38)%), while the stride length increase observed in patients (+22 (17–33)%) was significantly (p = 0.03) greater than that observed in controls (+18 (11–22)%).Both groups of subjects were able to increase their walking speed when they were asked to walk at a faster-than-normal velocity, with no differences (p = 0.18) and Iowa (1st administration: 90 (78–98) vs. 2nd administration: 92 (74–97); p = 0.53) questionnaires.No significant outcome differences were observed between the two administrations of both the Majeed (median (1st–3rd quartile)-1st administration: 85 (67–96) vs. 2nd administration: 92 (65–96); The ICC values were 0.95 (95% confidence limits: 0.88–0.98) and 0.94 (95% confidence limits: 0.86–0.96) for the Majeed and Iowa questionnaires, respectively. The SEM (SDC) values were 4.6 (12.8) and 3.7 (10.4) for the Majeed and Iowa questionnaires, respectively.R = −0.91, p < 0.0001) scores and between the Iowa and Oswestry  scores, while a significant positive correlation was observed between the Majeed and Iowa  scores. Significant positive correlations were also obtained both between Majeed score and walking speed  and between Iowa score and walking speed .Significant negative correlations were observed both between the Majeed and Oswestry , while a ceiling effect was observed . No floor or ceiling effects were identified for the Iowa score .This study investigated pain intensity, perceived pain disability, physical activity, and spatiotemporal parameters of gait in patients after post-traumatic sacroiliac joint arthrodesis and tested the reliability and validity of the cross-culturally adapted Italian versions of the Majeed and Iowa questionnaires. The main findings of this study were that: (i) several years after surgery, most of the patients reported no pain and minimum pain-related disability; (ii) the physical activity profile was comparable between patients and healthy controls; (iii) patients showed an impaired walking performance compared with healthy controls; (iv) the Majeed and Iowa questionnaires showed excellent reliability, excellent (for the Majeed questionnaire) and good (for the Iowa questionnaire) construct validity, and poor convergent validity (for both questionnaires) relative to walking speed.The use of a valid tool  for the assessment of walking performance and the recruitment of similar  populations of subjects are the notable strengths of this study. Another study strength is represented by the long-term follow-up. In fact, the experimental procedures were conducted after several years from surgery, at a time when muscle damage repair and bone healing had occurred, to minimize their influence on pain, physical activity and walking performance.We found that several years after sacroiliac joint arthrodesis, most of the patients reported no pain and minimum pain-related disability and their physical activity profile was comparable with healthy controls. The excellent surgical results we observed  are in agreement with the recent study by Baron et al.  who repoHowever, the assessment of spatiotemporal parameters of gait showed that patients walked slower and used shorter steps compared with healthy controls. These walking pattern abnormalities have also been previously reported in patients after total knee  and hip Although the measurement properties  of the Majeed and Iowa scores have previously been investigated ,31, to oThere are several limitations of this study worth highlighting. First, the cross-sectional design does not allow causal inference. Second, physical activity was estimated through the IPAQ, which is a quick, simple, and inexpensive evaluation tool, although it is well-known that objective measures of physical activity demonstrate less variability in properties of methodological effectiveness than self-reported measures . Third, This study documented long-term walking pattern abnormalities following sacroiliac joint arthrodesis despite excellent clinical results. The study also showed excellent reliability and construct validity of the Italian version of the Majeed and Iowa questionnaires. We propose that these questionnaires can be used in combination with the assessment of spatiotemporal gait parameters for the prognostic assessment and/or follow-up of surgical patients.


Sustained Acoustic Medicine (SAM) is an emerging, non-invasive, non-narcotic, home-use ultrasound therapy for the daily treatment of joint pain. The aim of this multi-site clinical study was to examine the efficacy of long-duration continuous ultrasound combined with a 1% diclofenac ultrasound gel patch in treating pain and improving function in patients with knee osteoarthritis.2, 1.3 W) and 6 grams of 1% diclofenac were applied with a wearable device for 4 hours daily for 1 week, delivering 18,720 Joules of ultrasound energy per treatment. The primary outcome was the daily change in pain intensity using a numeric rating scale (NRS 0–10), which was assessed prior to intervention , before and after each daily treatment, and after 1 week of daily treatment (day 7). Rapid responders were classified as those patients exhibiting greater than a 1-point reduction in pain following the first treatment. Change in Western Ontario McMaster Osteoarthritis Questionnaire (WOMAC) score from baseline to day 7 was the secondary functional outcome measure. Additionally, a series of daily usability and user experience questions related to devising ease of use, functionality, safety, and effectiveness, were collected. Data were analyzed using t-tests and repeated measure ANOVAs.The Consolidated Standards of Reporting Trials (CONSORT) were followed. Thirty-two (32) patients  54 years of average age with moderate to severe knee pain and radiographically confirmed knee osteoarthritis (Kellgren-Lawrence (KL) grade II/III) were enrolled for treatment with the SAM device and diclofenac patch applied daily to the treated knee. SAM ultrasound  for all subjects  and 2.96-points (70%) for rapid responders . The WOMAC functional score significantly improved by 351 points for all subjects , and 510 points for rapid responders . Over 95% of patients found the device safe, effective and easy to use, and would continue treatment for their knee OA symptoms.Sustained Acoustic Medicine combined with 1% topical diclofenac rapidly reduced pain and improved function in patients with moderate to severe osteoarthritis-related knee pain. The clinical findings suggest that this treatment approach may be used as a conservative, non-invasive treatment option for patients with knee osteoarthritis. Additional research is warranted on non-weight bearing joints of the musculoskeletal system as well as different topical drugs that could benefit from improved localized delivery.NCT04391842).Clinical Trial Registry Number: ( OA deveNonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most common treatments of OA and have been used to manage OA associated pain for decades. Long-term use of systemic NSAIDs have adverse effects on the kidney, liver, and gastrointestinal system , 16 – 18et al. (2005) showed the effectiveness of ultrasound  as adjunct OA therapy improving physical activity. Patients showed an increase in knee range of motion (ROM) and a decrease in pain on the visual analog scale (VAS) after 8 weeks of treatment [Ultrasound has been considered a potential therapy to alleviate pain associated with OA progression  – 29. Threatment .et al. (2006) reported a significant increase in VAS scores after 28 days for ultrasound treatment for OA [et al. (2014) reported that daily SAM treatment for 12 to 60 days significantly reduced pain by 52% (2 to 4 -points improvement on the VAS), and demonstrated a 20% improvement in joint function for the active versus placebo treatment group. The authors concluded that the SAM studies were underpowered for the determination of clinical significance and that a larger clinical trial was warranted [et al. (2015) reported in a 47 patient, randomized placebo-controlled study (28 active and 19 placebo) on SAM treatment of radiographic mild to moderate clinical knee OA  scale), and demonstrated that patients with moderate to severe pain had a 2.5-point reduction in pain on the VAS over 42 days of treatment which was statistically significant over the placebo 1.23-point decrease. The authors concluded that reduction in OA pain was clinically meaningful and exceeded The Initiative on Methods, Measurements, and Pain Assessment in Clinical Trials (IMMPACT) guidelines [et al. (2018), 93 patients with moderate to severe pain and mild radiographic knee OA (Kellgren-Lawrence grade I/II) had a significant 1.96-point pain reduction for active versus 0.85 point reduction for placebo on a numeric rating scale (NRS). Patients receiving active SAM treatment also had significant improvement in pain, stiffness, and function on the Western Ontario and McMaster Universities (WOMAC) scale compared with placebo . The authors concluded that SAM treatment significantly reduced pain and improved joint function in patients with moderate to severe OA knee pain and could be used as a conservative treatment option for patients with knee OA [Similarly, Yang t for OA . In two arranted . Langer idelines . In a do knee OA . A recen knee OA , 41. The2.ClinicalTrials.gov identifier NCT04391842. Patient enrollment was accomplished through referrals from Cayuga Medical Center and the Yale-New Haven Health System community hospitals, to Medical Pain Consultants and Sport and Orthopaedic Physical Therapy, affiliated outpatient care practices, respectively. The practices served as the setting for enrollment, training on the use of the device, visits of the patients with research staff, and pre/post functional measurements. The patient’s home/work setting served as the setting at which the device was self-administered and where pain measurements were recorded. The study was approved by the institutional review board of the Integ Review, and all patients provided informed consent to participate. The procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 [The study and methods followed the Consolidated Standards of Reporting Trials (CONSORT) . The proIncluded patients were 45 to 85 years of age, reported moderate to severe knee OA pain negatively affecting their life, were radiologically confirmed to have mild to moderate OA (Kellgren-Lawrence (KL) grade II-III score) in one or both knees, had baseline day-1 pain Numerical Rate Score (NRS 0–10) pain between 3 and 7, had no intraarticular injection to the treated knee in the last 6 months, had no trauma to the treated knee, and had no implants or surgeries to the treated knee. In cases of bilateral knee OA, the more painful knee was selected for treatment; if equal pain, a flip of a coin was used to select the knee for treatment. Participants were excluded if they had KL score greater than III, showed an inability to apply the device, were currently using a steroid-based medication, had a recent history of trauma to the knee or having osteoarthritis develop secondary to a metabolic disorder.Patients meeting inclusion criteria were enrolled for a 7-day treatment with SAM ultrasound device and 1% diclofenac ultrasound coupling patch. Patients subsequently self-applied the respective treatment 4 hours per day for 1 week to the lateral and medial arthritic knee, as shown in et al. (2018) using the mean knee OA pain reduction from SAM treatment for the first 2 weeks of the study (active mean 3.61 ± 2.53) and mean baseline pain of the study group (mean 5.53 ± 2.37); A sample size of 23 patients provided over 95% power for the primary outcome measure NRS pain reduction. We conservatively targeted enrollment of 30 patients anticipating insignificant (less than 5%) dropouts for the 1-week study. We also anticipated a stronger treatment effect size for pain reduction in our study since SAM was to be applied for 4-hours with topical diclofenac per treatment versus only SAM in Draper et al. (2018). Total participants completing the study was slightly above target (+2).The clinical sample size for the study was determined from Draper 2.1.2 intensity per transducer and overall energy delivery of 18,720 Joules over 4 hours of treatment. The device is attached to the body with a disposable adhesive patch which was pre-filled with 3g ultrasonic coupling gel with 1% diclofenac provided by the manufacturer  scores were recorded at the outpatient care facilities on Day 1 of the study. Patients were trained to use the Sustained Acoustic Medicine (SAM) device along with diclofenac patch and record NRS pain scores before the treatment and post 4-hour treatment in daily diaries for 7 days. SAM® Pro 2.0  is a portable, wearable, US Food and Drug Administration FDA-approved Class II medical device for prescription home-use ultrasound treatment. The SAM device delivers ultrasound at 3 MHz, 100% duty cycle, 1.3 W with 132 mw/cmfacturer .At the clinics, patients were shown how to apply the disposable adhesive patches/transducers to the medial and lateral sides of the arthritic knee and set the medical devices treatment timer for 4 hours of continuous ultrasound . PatientPatients recorded the primary outcome NRS  at pre-treatment and post-treatment over 7 days. The secondary outcome WOMAC was recorded at the outpatient care practices at the beginning of the study and after 7 days of treatment, evaluating activity, stiffness, and function of the treated knee.2.2.i.e., a serious unanticipated injury or death) or reactions  from the device.Once enrolled in the study, patients completed outpatient care facility visits on day 1  and day 7 (study completion). During the week, the research staff talked with the patient once on the phone to review the daily pain diary, addressed any questions the patient had about using the device or being involved in the study, and monitored for any adverse events  was evaluated on day 1 and day 7. Demographic and outcomes data were analyzed using t-tests and repeated measure ANOVAs. Based on the primary outcome measure, rapid responders were considered to have greater than a 1-point reduction in pain on the first treatment. Chi-squared proportional assessment was used to assess gender demographics between groups. Data analysis was conducted in the R software environment for statistical computing . Data are expressed as means ± SDs (standard deviations). The p-values of less than 0.05 were considered statistically significant.3.A total of 38 patients were screened. Thirty-four  patients3.1.Knee osteoarthritis pain was significantly reduced daily and over the course of the 7-day treatment regimen for both the entire study cohort  and rapid responders . For the entire patient cohort, the pretreatment day 1 baseline pain was 4.06 ± 2.39, and after 7 days of treatment, pain decreased to 2.00 ± 2.41, 2.06-point change 7 days  over 7 days of treatment . Pain re3.2.The WOMAC score measuring the change in pain, stiffness, and functionality of the knee was significantly improved for SAM with diclofenac patch by 351 points for all subjects  is a progressive disease of the joints, resulting in the degradation of cartilage and bone, leading to a reduction of joint space and increased inflammatory response over time , 7, 44. et al. (2020) demonstrated SAM increased transdermal diclofenac delivery 3.8 fold greater than topical application alone [et al. (2013) [The wearable SAM device and 1% diclofenac ultrasound gel patch could be successfully self-applied by patients for use in the home, providing significant pain relief of KL grade II/III knee OA. No adverse events were noted in the study population, and 94% of participants completed the study. Participants in the study had between a 50% (2.06-point) to a  pain reduction on the NRS scale. The NRS pain data show an incremental decrease in pain throughout the 7-day treatment with the highest rate of reduction in pain during the first two days. This outcome may be explained by increased penetration of diclofenac into the joint space leading to inhibition of COX1 and COX2 pathways , 38, thuon alone , which w. (2013) . The suset al. (2018) demonstrated a 1.96-point pain reduction on NRS and improvement in total WOMAC score by 505 points comparing the application of SAM active continuous long-duration ultrasound to the placebo group in a 93-subject double-blind, randomized controlled study [et al.  reported a 40% and 48% reduction in knee OA pain after 6 weeks of daily SAM treatment in two pilot case series and one placebo-controlled study, including 66 subjects in total. The current study did not include a placebo group but had similar inclusion criteria, baseline pain, the severity of knee OA (KL grade II/III), and patient demographics. Therefore, the more rapid and robust pain reduction can be attributed to the addition of the 1% diclofenac ultrasound gel coupling patch. Yang et al. (2006) has also reported on the efficacy of ultrasound in the reduction of pain with a combination of NSAIDs [Ultrasound has been shown to be an effective pain management method for arthritis-associated knee pain , 52 – 56ed study . This ref NSAIDs .et al. (2018) has reported that the application of continuous therapeutic ultrasound in 30 patients showed a significant reduction in visual analog scale (VAS) and WOMAC scores, and improved cartilage thickness in medial femoral condyle after 10 sessions of treatment in a double-blinded trial [et al. (2012) also reported encouraging effects of ultrasound application in managing mild to moderate knee OA in a double-blinded randomized study in 27 patients with a significant increase in cartilage thickness after 20 sessions [Sustained therapeutic ultrasound has also been shown to contribute to improved cartilage thickness. Özgönenel ed trial . Loyola-sessions . Additiosessions , 45, 55.The FDA approved non-invasive prescription home-use SAM device has little to no adverse effects reported and the contraindications are similar to traditional therapeutic ultrasound , 40, 58.Recent preclinical and clinical studies have shown that ultrasound therapy has chondroprotective effects by inhibiting inflammatory factors , 70 – 72The SAM device is one of two prescription home-use (1 to 3MHz) ultrasound devices available in the USA. The other device  was approved by the FDA in the early 1990s for non-thermal application and used a pulsed 20-minute daily ultrasound treatment at a low energy level (140 Joules per 20-minute treatment) , 74. TheSustained Acoustic Medicine with diclofenac patch rapidly reduced pain and improved joint function in patients with knee osteoarthritis pain. The clinical findings suggest the long-duration continuous ultrasound therapy with diclofenac can provide significant rapid pain reduction for patients with osteoarthritis. The use of SAM device and diclofenac should be considered for patients with moderate pain, requiring a fast-acting intervention in the home setting.


The general consensus is that surgical treatment is advised when conservative methods fail in patients with lumbosacral radicular syndrome (LRS). Preliminary evidence from our pilot study indicates that combination therapy  can prevent surgical treatment in patients on the waiting list for surgery. The pilot study lacked a control group, and therefore, firm conclusions pertaining to effects could not be made. This study aims to determine if combination therapy, performed while being on the waiting list for lumbar herniated disc surgery, is effective and cost‐effective compared with usual care  among patients with a magnetic resonance imaging (MRI)‐confirmed indication for a lumbar herniated disc surgery.A randomized controlled trial will be conducted with an economic evaluation. Patients aged 18 and above with incapacitating LRS, with leg pain and an MRI confirmed indication for lumbar disc hernia surgery, will be recruited from seven Dutch hospitals. While being on the waiting list for lumbar herniated disc surgery, patients will be randomized to either the combination therapy or usual care group. The primary outcome measure is the number of patients undergoing lumbar disc surgery during 12‐month follow‐up. Secondary outcomes include back and leg pain intensity , physical functioning (Roland Morris Disability Questionnaires‐23), self‐perceived recovery , and health‐related quality of life  and 12‐Item Short Form Health Survey (SF‐12)). For the economic evaluation, societal and health care costs will be measured. Measurements moments are baseline, 1, 2, 4, 6, 9, and 12 months. Data will be analysed according to the intention‐to‐treat principle.No randomized controlled trials have evaluated the effectiveness and cost‐effectiveness of combination therapy compared with usual care in patients with an indication for lumbar herniated disc surgery, which emphasizes the importance of this study. Characteristics of LRS include radiating lower limb pain into a particular dermatome, which may be accompanied by sensory and or motor deficits  and transforaminal epidural steroid injections (TESIs) are reported to be individually effective in reducing pain and improving function among LRS patients  that had lasted for a minimum of 6 weeks with or without mild neurological deficit ; and a magnetic resonance imaging that confirms a hernia nuclei pulposi that compromises the spinal nerve and can explain the clinical symptoms of the patient.2.2.2Exclusion criteria are as follows: spine surgery and or transforaminal injections at the same level during the previous 6 months; bony stenosis; cauda equina syndrome; spondylolisthesis; pregnancy; complicated disc herniation requiring more than one operation; severe coexisting disease ; patient with contraindications for steroid injections; insufficient knowledge of the Dutch language; emergency surgery as determined by the neurosurgeon; and being allergic for Iohexol 240 mg/ml .2.2.3Figure 2.2.4Participants will be recruited from seven hospitals in the Netherlands. The hospitals were chosen due to their proximity to the four primary care‐based outpatient clinics  where the combination therapy will be provided.2.32.3.1Prognostic factors measured at baseline using an online questionnaire include duration and severity of complaints before operation, various psychosocial variables , and known confounding factors such as age, gender, educational level, and treatment expectation  to 10 (“representing worst pain imaginable”). The numerical pain rating scale is reliable, valid, and has good sensitivity  to 23 . It has been extensively used in radiculopathy and stenosis research as a standardized measure and is widely used to assess disability specific to back and leg pain making it suitable people with LRS  items were removed and four new items were added from the initial source of RMDQ items, to create RMDQ‐23  to “completely recovered” (7). Being recovered will be defined as being “completely recovered” or “much improved”; other responses will be defined as not recovered. The test reliability of the global perceived effect scale is said to be good  and presenteeism . Health care costs will only include costs accruing to the formal Dutch health care sector.Intervention costs will be microcosted. For this purpose, information about the combination therapy will be gathered using a case report form, including information on patient classification, number of sessions, discharge, and referral to a network MDT or to the surgeon. All other cost categories will be measured using cost questionnaires administered at baseline 2, 4, 6, 9, and 12 months after randomization. Resource use will be valued in accordance with the Dutch manual of costing , and we will use one randomization list per hospital. The randomization key will be safeguarded by an independent researcher. Patients allocated to the intervention group will be called for an appointment within 48 hr of randomization and will attend their first appointment within the first week following randomization.2.4.2While being on the waiting list to receive lumbar disc surgery, intervention group participants will receive the combination therapy. The combination therapy has two parts (a) MDT and (b) TESIs and is delivered by teams of pain interventionists and physiotherapists. The pain interventionist is responsible for the TESIs and the physiotherapists for the MDT. Prior to receiving the combination therapy, patients are seen by a pain interventionist who checks for contraindications for injections and medications including steroid use. During the same appointment, participants are classified as “centralizers” or “noncentralizers” using MDT principles, that is, assessment of the patients' pain pattern responses on repeated movement tests.Centralizers are defined as patients with centralization  or directional preference . Testing for centralization is done according to MDT principles as described in the textbook of McKenzie and May . SearchiNoncentralizers are defined as patients with peripheralization  or no effect . The hypothesis is that in these patients, the pain is a result of the inflammation. Noncentralizers will receive a transforaminal epidural injection in accordance with the procedure described below.The patient lies in prone position. Under fluoroscopic guidance with contrast medium (Iohexol 240 mg/ml 0.5 cc), a very thin needle will be placed next to the compressed nerve. The contrast medium is then used to control if fluid will come to the compressed nerve. After which a combination of a local anaesthetic (lidocaine 20 mg/ml 0.5 cc) with an anti‐inflammatory agent (dexamethasone 20 mg/ml 0.5 cc) is injected. Half an hour after the injection, the pain interventionist checks the effects of the injection. The duration of pain absence is dependent on the working of the anti‐inflammatory drug on the inflammation. Two weeks after the injection, the patient is seen back by the MDT therapist to check for classification in the described subgroups and to decide if a second injection is necessary in shared decision making with patient and the pain interventionist. If pain reduction is less than 80%, then usually, a second injection will be administered with patient consent. A maximum of three injections are given to optimize pain relief.resolved symptoms ;centralizing and significantly less pain ;noncentralizing and significantly less pain ; andnoncentralizing with high levels of pain and disability .In the first three subgroups mentioned here, patients will get specific MDT exercises and advice. These three subgroups will be treated by an MDT therapist in one to six sessions in on average 4 weeks. If more sessions are required, patients are referred to accredited MDT therapists within the Rugpoli network. Network therapists are in close contact with the Rugpoli centres and are located all over the Netherlands.After the injections, participants will be reclassified using the same MDT principles, into four subgroups. The subgroups are as follows:Only the patients in Subgroup 4 will be referred back to the neurosurgeon who will assess whether patients still require surgery. Throughout the combination therapy, there is shared decision making.2.4.3Control group participants will solely be placed on a waiting list and scheduled to receive lumbar disc surgery if still required. The aim of surgery is to remove the symptomatic disc herniation by a minimal unilateral transflaval approach with magnification, with the patient under general or spinal anaesthesia.2.4.4Use of cointerventions by patients is allowed and will be monitored. Patients will be requested to complete questionnaires in which medication usage and any health care utilization is recorded throughout the follow‐up period.2.4.5We will not attempt to blind the patients to the intervention or control condition, as this is practically impossible in this study due to the nature of the intervention. The outcomes assessor will not be blinded, because all outcomes are self‐reported. Treatment providers  will not be blinded due the nature of the intervention they will provide to patients.2.4.6n = 73 per treatment group; Pocock, We expect that 90–95%  of the patients in the usual care group will receive surgery, and we hypothesize that in the combination group, this rate will be reduced by 30% (or more). To detect this difference of 30% with an alpha of 0.05 (two sided), a power of 95%, anticipating a 20% drop‐out rate and taking into account the multilevel structure (with an Intraclass Correlation Coefficient (ICC) of 0.15), we need to include a total of 146 patients  to assess if balanced groups were obtained after randomization .2.4.8The primary analysis will be an intention‐to‐treat analysis. The primary study parameter  will be analysed in a logistic mixed model with responses at 2, 4, 6, 9, and 12 months. In this analysis, we will take into account the levels of hospital, patient, and time of measurement. An odds ratio with 95% confidence interval between the combination therapy group and usual care group will be calculated. If necessary, the analysis will be adjusted for important prognostic characteristics.2.4.9The secondary study parameters  will be analysed in the same way as the primary study parameter . However, for continuous outcomes, we will use a linear mixed model with the same multilevel structure.2.4.10An economic evaluation will be performed from a societal and a health care perspective. When the societal perspective is applied, all costs and consequences relevant to the intervention will be taken into account irrespective of whom pays or benefits, whereas only those accruing to the formal Dutch health care sector will be considered when the health care perspective is applied .3Prior to this study, only our pilot study has evaluated the effectiveness of a combination therapy (MDT and TESIs) in patients presenting with lumbar disc herniation (van Helvoirt et al., The importance of this study is further emphasized by the fact that there are huge discrepancies in the treatment and management of lumbar disc herniation regionally and internationally (Weinstein et al., To our knowledge, this is the first randomized controlled trial investigating the effectiveness and cost‐effectiveness of the combination therapy in patients with LRS compared with usual care. Therefore, the present study aims to determine if a combination therapy, while being on the waiting list for a lumbar herniated disc surgery, is effective and cost‐effective compared with usual care among patients with an indication for a lumbar herniated disc surgery. Hence, this research will help bridge the knowledge gap in the treatment and management of patients with LRS.


To evaluate the effectiveness of a multidisciplinary, nonpharmacological, integrative approach that uses shared medical appointments to improve health-related quality of life and reduce opioid medication use in patients with chronic pain.This is a retrospective, pre–post review of “Living Well with Chronic Pain” shared medical appointments (August 2016 through May 2018).The appointments included eight 3-hour-long visits held once per week at an outpatient wellness facility.Patients with chronic, non–cancer-related pain.Patients received evaluation and evidence-based therapies from a team of integrative and lifestyle medicine professionals, as well as education about nonpharmacological therapeutic approaches, the etiology of pain, and the relationship of pain to lifestyle factors. Experiential elements focused on the relaxation techniques of meditation, yoga, breathing, and hypnotherapy, while patients also received acupuncture, acupressure, massage, cognitive behavioral therapy, and chiropractic education. Patients self-reported data via the Patient-Reported Outcomes Measurement Information System (PROMIS-57) standardized questionnaire. Use of opioid medications was evaluated in morphine milligram equivalents.P < 0.001) between the pre-intervention (visit 1) and post-intervention (visit 8) scores. Average opioid use decreased nonsignificantly over the 8-week intervention, but the lower rate of opioid use was not sustained at 6 and 12 months’ follow-up.A total of 178 participants completed the PROMIS-57 questionnaire at the first and the last visits. Statistically significant improvements in all domains  were observed (Patients suffering from chronic pain who participated in a multidisciplinary, nonpharmacological treatment approach delivered via shared medical appointments experienced reduced pain and improved measures of physical, mental, and social health without increased use of opioid pain medications. Chronic pain affects more than 100 million Americans each year, more than are affected by heart disease, stroke, cancer, and diabetes combined. An estimated $635 billion each year is spent on direct medical costs, lost productivity, and disability programs for patients suffering from chronic pain. Almost 20 million adults suffer from high-impact pain severe enough to interfere with life or work activities on most days .all aspects of a patient’s situation while focusing on symptomatic relief.In 2018, the Joint Commission provided guidance for evidence-based, non-opioid treatment options that can be considered for treating pain, including behavioral therapies, meditation techniques, acupuncture, spinal manipulation, massage, and music therapy . Recent Shared medical appointments (SMAs) are increasingly used to improve the health and daily living of patients with common chronic diseases, such as cardiovascular disease, obesity, diabetes, and breast cancer . It has The present investigation was conducted from August 2016 through May 2018 at an outpatient facility of the Cleveland Clinic, at the Centers for Integrative and Lifestyle Medicine. It was reviewed and approved by the Institutional Review Board (IRB#16–671).The Cleveland Clinic “Living Well with Chronic Pain” SMAs occurred over 8 weeks (with a single 3-hour visit per week) and were facilitated by a physician and a holistic psychotherapist. Providers of a particular integrative modality participated in and facilitated individual group appointments when their therapeutic approach was featured. The SMA format (8–13 participants) allows for social reintegration and community building and is a safe environment in which to practice new skills. The goals of these SMAs were to help individuals learn and develop techniques to aid in decreasing the sensations of pain in the physical body and to help manage the emotional effects of living with chronic pain. We used tools to assist participants with pain and stress relief, lifestyle modifications, and positive behavioral changes. The group visits enabled participants to determine the tools that worked best for them, eliminate or limit negative thoughts and behaviors, and create their own specialized plan of care on the basis of the 8 weeks of practice and exposure to new ways of managing pain.In this study, each 3-hour weekly session included measurement of patient vitals and physical assessment, individual check-in with the physician and the group, a topic lecture, self-massage, gentle chair yoga, auricular acupuncture, and hypnotherapy/meditation. Topic lectures were focused on acupuncture and acupressure for pain reduction, massage, nutrition and supplementation, chiropractic education about proper techniques for performing activities of daily living, mechanisms of action of pain, art therapy or guided imagery for emotional wellness, goal setting, and Chinese herbal medicine. Patients were encouraged to pursue individual follow-up appointments in an integrative or lifestyle medicine area they found beneficial. Additionally, monthly group follow-up sessions were held to support lifestyle changes and encourage healthy habits.Patients included in this study were referred by their primary care physicians as anyone self-reporting as living with chronic pain, independent of the specific diagnosis or prior treatment involvement. This study accepted patients who may have undergone different forms of treatment, including opioid prescription medication. The SMA providers were informed of but did not manage, initiate, or discontinue pain medications, nor were they involved in the diagnostic work-up for the source of pain sensations. Patients were included in this study if they completed both pre-evaluation  and post-evaluation  Patient Reported Outcome Measurement Information System (PROMIS-57) surveys. Patients starting the SMAs after August 1, 2018, were not considered because they would not have had a full year of follow-up with regard to their opioid use evaluation. As such, a total of 178 patients (out of 312 patients enrolled) met these criteria . Among tAn overview of the group visit structure of the “Living Well with Chronic Pain” SMAs is depicted in SMA providers performed a brief physical assessment of each patient, which included measurement of heart rate and blood pressure, a brief examination, and an evaluation of general mental and physical well-being.The holistic psychotherapist–led check-in was an essential component of the program. Through a series of weekly questions, the aim of check-in was to see which tools each person was using and finding helpful. Check-in was a time for the holistic psychotherapist to listen deeply to the language of the participants and assist with cognitive restructuring and reframing of negative thought patterns . The focus of check-in was to shift thoughts to a more positive outlook and to learn that the mind and body are connected.Each week, a specific topic was presented as part of the SMA visit. Topics were designed and specifically chosen to reflect the tools to which patients would be exposed during the 8 weeks, including Korean Sujok-style acupressure for pain reduction, massage, nutrition and supplementation, chiropractic education, education about the mechanisms of action of pain, art therapy or guided imagery for emotional wellness, goal setting, and Chinese herbal medicine.Participants were taught trigger-point release, gentle stretching, relaxation, effleurage, hot and cold applications, and cross-fiber friction.The program offered gentle chair yoga, which allows the participants to move their bodies in a simple way, learning to stretch and to become more aware of their physical sensations in the moment. The yoga was adapted for people of all abilities, and no prior yoga experience was necessary. Breathing and mindfulness techniques were an important part of this yoga practice.All participants received prescribed auricular acupuncture in a group setting at the end of each weekly session. While participants were treated with acupuncture, a holistic psychotherapist guided them in a hypnotherapy process to induce a state of relaxation in the body and decreased discomfort.Affirmations and journaling prompts were provided to encourage positive self-talk, self-reflection, and healthy emotional expression.The goal was to offer participants a wide variety of tools from which to choose. At the end of 8 weeks, participants were able to share their overall experience, both good and bad, but importantly of how the diverse skills and techniques learned throughout all SMA sessions had contributed to a higher quality of life and functionality. Participants were also encouraged to engage in individual holistic psychotherapy sessions throughout the program to gain additional support for what they had learned in the group visits, as well as to address social/emotional challenges.Primary study end points included the PROMIS-57 Profile v2.0, which contains a separate eight-question scale for each of seven domains: 1) Physical Function, 2) Anxiety, 3) Depression, 4) Fatigue, 5) Sleep Disturbance, 6) Ability to Participate in Social Roles and Activities, and 7) Pain Interference. Mean population scoring of each PROMIS domain is defined as having a value of 50 , with larger scores indicating greater amounts of each health element . In question 57 of the questionnaire, patients were also asked to rate their pain intensity on a 0 to 10 Likert pain scale that denotes 0 as representing “no pain” and 10 representing “the worst pain possible.”® 9.1.20, Vanderbilt University).Patient demographic data were collected at baseline, and all medications, including opioid prescription use in morphine milligram equivalents (MME), were recorded weekly throughout the 8-week intervention period. Data were collected either manually via paper forms or digitally via iPad and were entered into a protected, digital database  multiple imputation (five sets) for all missing values and 2) multiple imputation for pre-SMA missing values and last observation carried forward for post-SMA missing values; the latter (#2 above) assumes no change for all subjects who did not complete the post-SMA questionnaire and reflects the minimal average change. All tests were two-tailed and performed at a significance level of 0.05 in SAS 9.4 software .Patient groups were described with medians and quartiles or mean ± SD for continuous variables and counts and percentages for categorical variables. PROMIS-57 raw scores were standardized to a mean of 50 and an SD of 10. Normality of data was assessed by evaluating QQ plots and model residuals for analysis of variance (ANOVA) and analysis of covariance (ANCOVA) analyses. Statistical analysis of the change in opioid MME dosage and PROMIS-57 standardized scores before and after SMAs was performed with paired The description of the study cohort (n = 178) is shown in The baseline measurements in seven domains of the PROMIS-57 questionnaire and Pain Intensity for all study participants (N = 178) are shown in P < 0.001) and in Pain Intensity (P < 0.001). In two PROMIS domains, Fatigue and Pain Interference, the changes in t score were above 3  are shown in  above 3 , while iAs part of their pain management, 44% of patients used prescribed opioid medication(s) at any time during the study period. We have determined the changes in opioid use in MMEs before and after participation in the SMAs. The average monthly MMEs decreased nonsignificantly from baseline  to 6 months and 7–12 months after the completion of the eighth/final SMA  . HoweverOverall, this investigation showed that evidence-based, integrative, nonpharmacological therapies delivered via SMAs are an alternative, health-promoting approach to treating patients with chronic pain. Although the focus of this study was not to evaluate individual or specific therapeutic approaches , it may be argued that comprehensive use of such therapies contributed to self-reported improvements across multiple PROMIS domains without an increased use of opioid medications. Rather, we report a trend of decreased use of opioid medications by participants in these SMAs.The findings in our study provide additional support for previous reports  that delThe most pronounced degree of beneficial pre–post changes for all evaluated patients was in the PROMIS Pain Interference (PI) and Fatigue domains  . The meaThe PROMIS-PI domain is used to assess how pain might compromise daily activities and to evaluate the negative effects of pain on function in the range experienced by most patients with pain. The PROMIS-PI domain is highly correlated with coping strategies , similarAlthough the pre–post changes reported by our patients indicate statistically significant improvements in all PROMIS-57 domains see , uncertaSimilarly, the PROMIS Fatigue and Social domains for all patients improved, with a mean decrease of 3.1 and a mean increase of 2.9, respectively, while even larger changes were seen among patients who did not use opioid medications . This did not change when adjusted for pre-SMA PROMIS-57 domain subscores . Such a For patients with chronic musculoskeletal pain and comorbid depression and/or anxiety, the mean estimated minimally clinically important difference for the PROMIS eight-item Anxiety scale ranged from 1.7 to 5.0 , whereasImprovements in multiple domains of PROMIS-57 in our patients occurred in spite of the trend toward decreased use of opioid medications . The losIntensive inpatient (about 140 hours over 4 weeks) and outpatient (120 to 180 hours over 3 to 4 weeks) programs for patients with chronic non–cancer-related pain reported sustained decreases in opioid use at 6 and 12 months, whereas shorter outpatient programs (24 hours over 8 weeks) were less effective . A recenOur study has several limitations. First, this is a pre–post study rather than a controlled study. Without a control group, we cannot know how the observed outcomes would compare with usual care. It is possible that potential patients in a control group would improve without any of the nonpharmacological interventions used in our studies as a result of simply being in the group setting and possibly as a result of the placebo effect , 36, 37.We cannot know whether several of the observed statistically significant improvements are a direct result of patients’ participation in the SMAs, whether the degree of positive improvements is clinically meaningful, or whether those would translate into improvements in clinical outcomes that would be sustained in the long term. Considering data from the literature, we suggest that the PROMIS scores of our patients with chronic pain were worse than those of similar populations.For example, when the baseline PROMIS-57 domains of patients with chronic pain in our study were compared with those reported in the literature, it seems that we had a population of patients with worse scores in the PROMIS-57 Physical Function (PF) and Pain Interference (PI) domains than postoperative PROMIS scores reported in the orthopedic literature  and the Second, our study focused only on the evaluation of patients who completed a PROMIS-57 questionnaire at the first and last group appointments; thus, we did not consider those who did not complete the questionnaires but who could have nevertheless benefited from their participation in the SMAs. Regardless, sensitivity analyses incorporating the excluded subjects were consistent across all scenarios, with the magnitude of change being smaller but remaining significant when last observation carried forward was used .Third, we did not specifically correlate PROMIS-57 domain score changes with specific chronic pain diagnosis because our aim was not to evaluate outcomes for a specific pain condition. We also did not consider the influence of comorbid conditions our patients suffering from chronic pain may have had that could affect the interpretation of the PROMIS domains. A larger number of patients would be needed for a meaningful evaluation of that kind.No PROMIS-57 evaluations were conducted at 6 and 12 months after the completion of the SMAs, and thus it is not clear whether the multiple benefits of the comprehensive intervention were sustained or whether they followed the trend observed for the opioid medication use. Opioid use was obtained from physician prescription orders rather than from filled prescriptions as documented in the electronic medical records and was not verified by blood or urine testing.This study was conducted in a community-based ambulatory setting in the United States, and we cannot know whether the results are generalizable to other health care settings. The system, however, is similar to many health care delivery systems in the nation in terms of payer mix and provider reimbursement; thus, these outcomes would likely translate to other similar settings. Considering the limited demographic and clinical factors for our quite homogenous study population, we did not evaluate the associations of sociodemographic and health characteristics with clinical improvement within specific PROMIS subscores. A larger and more diverse population would be needed to obtain meaningful findings and avoid missing key predictors.In conclusion, implementation of a comprehensive, multimodality, evidence-based, integrative and self-care nonpharmacological intervention is beneficial for patients with chronic pain in reducing pain and in improving multiple domains of their lives without increased use of opioid pain medications. Our study adds to a growing body of evidence that a combination of several complementary nonpharmacological therapies can be effectively delivered via SMAs. In the ongoing movement toward value-based health care, this type of intervention may enhance the transition away from the current, largely medication-based treatment options for patients with chronic pain.Statistical analysis and interpretation of data were conducted by AT, JD, SMD, MG, and RL. Critical revision of the manuscript for important intellectual content was performed by JZ, KNK, MFR, AT, DS, SMD, MG, and RL..http://painmedicine.oxfordjournals.org.pnaa418_Supplementary_DataClick here for additional data file.


Primary dysmenorrhea (PDM) is a common complaint in women throughout the menstrual years. Acupuncture has been shown to be effective in dysmenorrhea; however, there are large interindividual differences in patients’ responses to acupuncture treatment. Fifty-four patients with PDM were recruited and randomized into real or sham acupuncture treatment groups . Pain-related functional connectivity (FC) matrices were constructed at baseline and post-treatment period. The different neural mechanisms altered by real and sham acupuncture were detected with multivariate analysis of variance. Multivariate pattern analysis (MVPA) based on a machine learning approach was used to explore whether the different FC patterns predicted the acupuncture treatment response in the PDM patients. The results showed that real but not sham acupuncture significantly relieved pain severity in PDM patients. Real and sham acupuncture displayed differences in FC alterations between the descending pain modulatory system (DPMS) and sensorimotor network (SMN), the salience network (SN) and SMN, and the SN and default mode network (DMN). Furthermore, MVPA found that these FC patterns at baseline could predict the acupuncture treatment response in PDM patients. The present study verified differentially altered brain mechanisms underlying real and sham acupuncture in PDM patients and supported the use of neuroimaging biomarkers for individual-based precise acupuncture treatment in patients with PDM. Primary dysmenorrhea (PDM), cyclic menstrual pain in the absence of pelvic anomalies, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women . DespiteAlthough acupuncture has been shown to be effective in PDM, patients’ responses to acupuncture treatment vary widely between individuals . In addiPDM has been proposed to be part of the central sensitization syndromes together with several chronic pain conditions, including fibromyalgia, irritable bowel syndrome, idiopathic low back pain, headache and migraine . In receIn this study, we used a longitudinal study design to investigate brain plasticity following acupuncture treatment. Our main aim was to explore whether particular pretreatment functional connectivity (FC) patterns  would predict the real and sham acupuncture response in PDM patients. First, we assessed FC alterations after acupuncture over the course of three menstrual cycles. Second, the different FC alterations between real and sham acupuncture treatment were explored. Third, we used multivariate pattern analyses (MVPA) based on a machine learning approach  to explore whether the different FC patterns predicted the acupuncture treatment response in PDM patients. We hypothesized that there were different neural mechanisms underlying real and sham acupuncture treatment that could predict the treatment response in PDM patients.Fifty-four patients with PDM were recruited from advertisements and word of mouth to participate in a dysmenorrhea study, and all participants were screened using telephone and in-person structured interviews. The Research Ethics Committee of Chengdu university of Traditional Chinses Medicine (CDUTCM) approved this study, and all participants gave written informed consent. The inclusion criteria for patients with PDM were (1) a regular menstrual cycle (27–32 days); (2) a history of PDM longer than 1 year; (3) no exogenous hormones or centrally acting medication in the last 6 months; (4) lower quadrant abdominal pain  during menstruation in the last 6 months rated higher than 4 on a visual analog scale (VAS) ; and (5) right-handedness, as confirmed by the Edinburgh Handedness Inventory . The excThe primary outcome assessed in this trial was abdominal pain severity, as measured by the 0–10 VAS rom “no pain at all” to “unbearable pain . In addiPatients were randomized using a computer-generated, random-allocation sequence and then assigned to either the real acupuncture group or the sham acupuncture group. All patients and study staff were blinded to the treatment groups. Only the acupuncturist, who had to know whether to deliver real or sham treatment, was not blinded.sanyinjiao (SP6) was selected based on data mining from our previous review and expert opinions. SP6 is located on the tibial aspect of the leg, posterior to the medial border of the tibia and 3 cun , above the medial malleolus . Needles were retained at the acupoints for 30 min, and the above manipulation was repeated twice every 10 min for 30 s each time.For the real acupuncture treatment group, alleolus . The acuxuanzhong (GB39) was selected in the sham group  in the Department of Radiology at the Affiliated Hospital of CDUTCM at baseline and the forth periovulatory phase after each clinical assessment. Tight, but comfortable, foam padding was used to minimize head motion, and earplugs were used to reduce scanner noise. Sagittal 3D T1-weighted images were acquired using a brain volume sequence with the following parameters: repetition time (TR) = 8.16 ms; echo time (TE) = 3.18 ms; flip angle (FA) = 7°; field of view (FOV) = 256 × 256 mm; matrix = 256 × 256; slice thickness = 1 mm, no gap; and 188 sagittal slices. The resting-state functional fMRI (rs-fMRI) datasets were obtained in 7 min with a gradient-recalled echo-planar imaging pulse sequence. The rs-fMRI imaging parameters were TR = 2000 ms, TE = 30 ms, FA = 90°, acquisition matrix = 64 × 64, FOV = 240 × 240 mm, thickness = 4.0 mm, voxel size = 3.5 × 3.5 × 4.02 mm1 implemented in MATLAB 8.0 . Structural images were coregistered with resting-state functional images. Conventional preprocessing steps were performed, which included (1) removing the first 5 time points; (2) slice timing correction; (3) realignment  or 1.5° of angular motion were excluded); (4) normalization of images with a T1 template in the Montreal Neurological Institute (MNI) atlas space and resampling to 3? × 3 × 3mm3 cubic voxels; (5) linear detrending; (6) nuisance covariate regression including six motion parameters, average signals of cerebrospinal fluid and white matter, and time points having spike motion of framewise displacement (FD) > 0.5; (7) temporal filtering (bandpass 0.01–0.1 Hz); and (8) spatial smoothing using a Gaussian kernel of 6-mm full-width at half-maximum (FWHM). The images with all preprocessing steps were used for region of interest (ROI) to ROI functional connectivity analysis, while the images after the first four preprocessing steps were used for group independent component analysis (GICA). There were no differences in head motion parameters (FD) within or between groups.MRI data were preprocessed and analyzed using the SPM8 toolboxFirst, GICA analysis was conducted using group ICA of the fMRI toolbox  implemented in MATLAB 8.0 and SPM8. A set of independent components (ICs) were identified as intrinsic resting-state networks in all subjects at both the baseline and post-treatment periods . The optt-test by using SPM8. The subcortical ROI of the thalamus in the SMN was acquired from automated anatomical labeling, and the PAG and RVM masks were acquired from the DPMS network mask in standard space , sensorimotor network (SMN), and salience network (SN) were chosen as components of interest to be evaluated from the resting-state data. ten ROIs in these resting-state networks (RSNs) were manually chosen from the 66 extracted ICs, which were identified as anatomically and functionally classical RSNs by two experienced neuroimaging researchers (YJ and YSY) . Four ROrd space .2. The averaged time series in each ROI were extracted, and the Pearson correlations with time series in other ROIs were calculated. Then, the FCs were transformed to Z values . Pearson correlation analyses were employed to explore associations between duration of disease, baseline VAS, SDS, and SAS scores, and changes of the VAS scores. The significance level was set at P < 0.05.Two independent t-tests were performed to detect the FC matrix alterations after treatment in each treatment group. In addition, we employed a 2 × 2 (group × time) multivariate analysis of covariance (MANCOVA) on the FC matrix to detect whether there were different neural mechanisms underlying the different treatments, with age and duration of disease as covariates  approach. The in-house script was write in MATLAB to conduct the MANCOVA in the study. The codes for MANCOVA of ROI-wise functional connectivity can be downloaded from https://github.com/cdutcmysy/ROIwise_FC_mancova.The paired variates . Traditi3) (R2) as well as the mean absolute error (MAE) to evaluate the SVR predictive ability   was empl3) . We calc ability . FurtherP > 0.05; see t-tests showed that the VAS change in the real acupuncture treatment group was significant , while the VAS change in the sham acupuncture group was not significant . In addition, there were no significant associations between duration of disease and baseline VAS, SDS, and SAS scores and post-treatment VAS score changes in either group . Conversely, the traditional bivariate correlation analyses did not find any significant associations between these differences in FC and VAS changes after acupuncture treatment in the patients with PDM  as the acupuncture target based on data mining from our previous review  acupuncture could reduce pain ratings in patients with low back pain (LBP), but the reduced pain intensity was associated with reduced FC between the mPFC and posterior insula in the real acupuncture group, while the decreased pain intensity was associated with enhanced FC between the PCC and aINS . The resWe found eight functional couplings that showed differences in alterations after real and sham treatment of PDM. As illustrated in Our research is in line with the growing interest in predictive modeling using neuroimaging and machine learning methods . Most maP = 0.06), and further studies with larger sample sizes are needed to address this point. Second, as the PDM is a cyclic chronic pain, the present study only explored the “trait pain” (average pain experienced over time) in the patients with PDM, and future studies should also explore the mechanism of the acupuncture-related analgesic effect on “state pain”  in PDM patients (The present study also has several limitations. First, the sample size in this study was small, especially in the sham acupuncture group, and previous studies have also found a significant analgesic effect of sham acupuncture . Our stupatients . Third, The present study verified the different brain mechanisms underlying real and sham acupuncture in PDM patients. In addition, the pain-related FC patterns at baseline could predict the acupuncture treatment response for patients with PDM. The findings supported the use of neuroimaging biomarkers for individual-based precise acupuncture treatment in patients with PDM.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the Research Ethics Committee of Chengdu University of Traditional Chinses Medicine. The patients/participants provided their written informed consent to participate in this study.JY and FL designed the study. SL, WW, XG, JT, QZ, and MX collected the data. SY and MX analyzed the data. SY contributed to the original draft. JY, FZ, and FL reviewed and edited 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.


Aneurysmal subarachnoid hemorrhage (SAH) as a serious type of stroke is frequently accompanied by a so-called initial thunderclap headache. However, the occurrence of burdensome long-term headache following SAH has never been studied in detail so far. The aim of this study was to determine the prevalence and characteristics of long-term burdensome headache in good-grade SAH patients as well as its relation to health-related quality of life (HR-QOL).All SAH cases treated between January 2014 and December 2016 with preserved consciousness at hospital discharge were prospectively interviewed regarding burdensome headache in 2018. Study participants were subsequently scrutinized by means of a standardized postal survey comprising validated pain and HR-QOL questionnaires. A retrospective chart review provided data on the initial treatment.p < .01) as well as more favorable neurological conditions  in HA+ cases. The mean average headache of the HA+ group was 3.7 ± 2.3 , and the mean maximum headache intensity was 5.7 ± 2.9. Pain and HR-QOL scores demonstrated profound alterations in HA+ compared to HA- patients.A total of 93 out of 145 eligible SAH patients participated in the study . A total of 41% (38/93) of subjects indicated burdensome headache at follow-up (mean 32.6 ± 9.3 months). Comparison between patients with (HA+) and without long-term headache (HA-) revealed significantly younger mean age  contains supplementary material, which is available to authorized users. A dd so far , 41, 56.Protocol and patient consent forms of this prospective single-center cross-sectional investigation were approved by the Ethics Committee of the Hamburg Medical Council (reference number PV5584). The study was conducted in accordance with the Declaration of Helsinki adopted by the World Medical Association General Assembly in 1964 and its later amendments. Study conception, data collection, and presentation strictly adhere to the principles of good practice in the conduct and reporting of survey research proposed by Kelley et al. in 2003 .GOS) ≥ 3 at hospital discharge [1, questionnaires including detailed study descriptions and informed consent forms were sent by mail to all 93 patients  willing to take part in the survey in 2018 (mean follow-up after SAH 32.6 months ±9.3 SD).A total of 145 patients treated for newly diagnosed SAH at our tertiary referral center between January 2014 and December 2016 fulfilled the beforehand specified eligibility criteria of an age of 18 years or older and favorable neurological status defined as Glasgow Outcome Scale Score (ischarge . All cas(SF-12) as a well-established generic measure of physical and mental health [(DSF) of the German Society for the Study of Pain containing among other tools a 10-point numeric pain rating scale (NRS) ranging from 0 (=no pain) to 10 (maximum pain) and the depression, anxiety, and stress scale (DASS) [(SF-MPQ), and the German version of the Henry Ford Hospital Headache Disability Inventory (HDI-G) [We used the German version of the 12-Item Short-Form Health Survey l health . Multidie (DASS) , 47, 49, (HDI-G) , 32, 44. or without  burdensome headache.All patients were initially asked whether they suffered from continuous or recurrent burdensome headache for 6 months or longer at the time of the interview. This kind of headache differs from the so-called headache attributed to SAH  which develops, by definition, simultaneously with the bleeding and resolves within 1 month thereafter . Accordi(WFNS) [(ICU) length of stay as well as functional outcome (GOS). Fisher, Graeb, and Hijdra Scores were utilized to quantify the amount of subarachnoid and intraventricular blood [Additionally, clinical and radiographic data concerning the initial inpatient course was obtained from the electronic medical records of our institution. Clinical information comprises the epidemiological data, aneurysm features including size and location , SAH severity was defined using the World Federation of Neurological Surgeons Grading (WFNS) , the lat(WFNS) , treatmear blood , 23, 27.p value < 1 in the univariate analysis  with regard to headache occurrence at follow-up. Results are displayed in the form of odds ratios (OR) with 95% confidence intervals (CI). All statistical procedures were carried out with GraphPad Prism  and SPSS , Armonk, USA). A p value < 05 was considered to indicate statistical significance. A biostatistician was involved in the planning and realization of all statistical procedures.All clinical and radiographic parameters as well as questionnaire-derived scores were calculated separately for both collectives and group comparisons were performed. Variables are presented utilizing descriptive statistics, inter alia, fractions, central tendency (mean/median), and appropriate dispersion measures ). Fisher’s exact test was applied with regard to categorical variables, and Mann-Whitney test as well as unpaired t-test was utilized depending on whether non-parametric or parametric data was available for comparison. Multivariate logistic regression was performed to determine the predictive value of epidemiological and clinical variables showing a n = 93), and non-responders (n = 52). HA+ (n = 38) and HA- (n = 55) patients presented without significant gender disparities, whereas the headache group was of markedly younger average age in comparison to their counterparts (mean ± SD (years): 47.9 ± 11.8 versus 55.6 ± 10.3; p < .01). WFNS grade distribution was notably divergent in both collectives with HA+ showing better WFNS scores (WFNS I/II in 95% (HA+) and 75% (HA-); p = .03). No significant differences between both cohorts could be determined regarding body mass index, initial transient loss of consciousness, maximum intracranial pressure (<24 h post bleeding) a hyperactive delirium during ICU treatment period, as well as GOS at discharge (GOS IV/V in 100% (HA+) versus 76% (HA-); p = .08). Considering Fisher, Graeb, and Hijdra scores as well recognized SAH radiographic features, none of them revealed significant differences between both categories. Comprehensive information on all epidemiological, clinical, and radiographic data discussed here is provided by Table Mean age, sex, and clinical WFNS scores of SAH patients did not differ significantly between the study participants . Mean SF-MPQ total pain index was significantly different between HA+ (10.7 ± 8.3) and HA- cases . Regular intake of non-opioid and opioid analgesics was more commonly seen in HA+ (42%) than in HA- patients . Correspondingly, HDI-G emotional and functional scores of the HA+ cohort indicated markedly higher values compared to the HA- group representing more pronounced degrees of limitation . The HA+ patients complained about an average number of 9.2 ± 18.0 days with considerable pain-related restrictions of daily living activities (ADL) during the last 3 months, while the HA- cohort was almost unaffected . Besides the ADL, also recreational and working activities as well as general mood were significantly impaired in HA+ patients, as shown in addition to other relevant pain-related measures in Table A total of 40.9% (38/93) of all investigated good-grade SAH patients were affected by burdensome headache. In total, 47% of the 38 HA+ patients suffered from pain attacks free of continuing background headache, whereas 53% indicated persistent cephalalgia with or without additional pain attacks. A total of 23% of HA+ cases had one or more headache attacks per day, and half of HA+ patients reported on diurnal patterns in respect of the headache. The subjective perception of headache by means of the pain description list of the DSF can be obtained from Table p < .01), substantial significant differences between both cohorts could not be determined with respect to SF-12 mental composite scores . Depression, anxiety, and stress levels evaluated by means of the DASS were increased in HA+ in relation to HA- cases. Results were significant for the anxiety  and stress subscores . In accordance with the described mental tension, 41.7% of the HA+ patients suffered from insufficient night sleep, whereas only 14.6% of the HA- collective reported on sleep disturbances (p = .01). A total of 49.3% of SAH cases (GOS ≥ 3) were recognized by the pension offices as having a degree of disability, and 29.2% of SAH patients became incapacitated for work at follow-up without significant differences in view of headache occurrence. All group comparisons regarding quality of life, psychosocial, and functional interferences are set out in detail in Table HA+ patients showed reduced HR-QOL measures in comparison to HA- cases at follow-up. While mean SF-12 physical composite scores were pronouncedly lower in the HA+ group  and initial WFNS grade  as the only factors which were independently associated with headache in the long run following SAH. GOS scores at hospital discharge demonstrated no significant predictive value.Multivariate logistic regression of parameters with significant group differences revealed age at bleeding onset  from an extensive catchment area, a long follow-up period , and the utilization of a comprehensive multidimensional set of validated pain and physical as well as mental health measures. Standardized pain questionnaires are not designed to establish a specific headache diagnosis, and therefore, we are incapable of making clear statements regarding the distribution of different headache entities with respect to the International Classification of Headache Disorders of the International Headache Society. We are aware of the potential bias due to the refusal to participate of a fraction of patients and the per-protocol exclusion of poor-grade SAH patients. Another possible limitation, which should be mentioned here, is the monocentric study design.Data on the incidence and impact of chronic headache after SAH is sparse. Here, we demonstrate that a significant number of the SAH patients suffer from burdensome headaches with a profound negative impact on the HR-QOL. Our SAH study collective presented with a mean age of 52.5 years and two out of three cases were of female gender. Previous studies on SAH reported on average patient ages between 50 and 57 years with males in general being affected earlier , 66, 69.Our results suggest that a considerable proportion of good-grade SAH patients suffers from sustained burdensome headache at long-term follow-up with significant pain-related impairment of everyday activities. Furthermore, persistent headache seems to be associated with increased weariness, sleep disturbance, cognitive dysfunction, as well as anxiety and stress levels, which may altogether contribute to a relevant reduction in the quality of life in SAH cases. Consequently, there is an urgent need for further basic and clinical research in this field to elucidate the underlying pathophysiological and psychophysiological mechanisms, characterize the specific phenotype of long-term post-SAH headache, and also develop preventive as well as therapeutic pain reduction strategies following SAH.ESM 1(DOCX 27.9 kb)


To develop a novel digital intervention to optimise cancer pain control in the community. This paper describes intervention development, content/rationale and initial feasibility testing.n = 39); and two HCP focus groups (n = 12). Intervention mapping was used to translate results into theory-based content, creating the app “Can-Pain”. Patients with/without a linked caregiver, their general practitioners and community palliative care nurses were recruited to feasibility test Can-Pain over 4 weeks.Determinants of suboptimal cancer pain management were characterised through two systematic reviews; patient, caregiver and healthcare professional (HCP) interviews  contains supplementary material, which is available to authorized users. Cancer incidence and prevalence rates are increasing . Pain afThere is increasing political interest in novel interventions that support individuals to be cared for safely, effectively and efficiently within the community , 9. It hTwo systematic reviews showed that PROM feedback can improve patient satisfaction with care and increase the number of symptoms discussed during consultations , 14. AnoAllsop et al.  reviewedDigital interventions tend to have multiple interacting components . The MedThe aim of this research was to develop a theory and evidence-based intervention to optimise cancer pain management in the community. The objectives were to fully understand the problem and to design an intervention that addressed the needs of those experiencing and managing cancer pain. This paper describes intervention development, intervention content and components, expected mechanisms of action and early feasibility testing.An intervention mapping (IM) approach guided this research project , 20. IM n = 14), their linked caregivers (n = 6) and HCPs (n = 19). Two multidisciplinary HCP focus groups were conducted [Step 1 involves fully characterising the problem and the behaviours involved in suboptimal cancer pain management. Existing literature was reviewed , 21, andonducted . Resultsonducted . FindingEffective cancer pain management relies on multiple interacting patient and professional behaviours, including interpretation and reporting of pain by patients/accessing help, pain assessment/communicating about pain, analgesic prescribing and patients utilising analgesics optimally.Patients experiencing problematic cancer pain tended to be prescribed strong opioids . BreakthManaging cancer was highly burdensome for patients and their caregivers, and pain management was one of many competing considerations. A desirable intervention would add value to current management approaches without significantly adding to patient, caregiver or professional workload.The model of the problem derived in step 1 . Individuals interacted with the mock app and offered verbal feedback, which was used to refine wording and presentation. Can-Pain was programmed using Ruby on Rails Web application framework. The current version requires Internet connectivity.A feasibility study was designed, in which data from four to six patients would be used to test usability, functionality, acceptability to patients/carers/clinicians and feasibility in clinical practice. Several of the planning group had experience of successful feasibility testing digital interventions with a small number of users , 24. It The World Health Organization suggest between 10 and 100 individuals should be involved in feasibility testing digital health interventions . A more Recruitment to feasibility testing took place in four stages: first, Macmillan nurses  were recruited by the research team via local networks. Second, the Macmillan nurse identified patients from their caseload who had cancer pain and were using/starting strong opioids. Third, the nurse approached the patient’s general practitioner (GP) to gauge interest in participation. Fourth, eligible patients of GPs who were interested in participating were given study invitation packs by their nurses and invited to reply directly to the research team if they wished to participate. Patients were asked to invite a caregiver to participate alongside them if they wished. Thus, Macmillan nurses, their linked patients and the patient’s linked GPs were recruited in triads, with or without a linked caregiver (at the discretion of the patient).Patients were asked to use Can-Pain over a 4-week period. Can-Pain automatically logged patient breakthrough and diary entries and sent them immediately to a pre-programmed email address. During the study period, the reports were sent by email to the lead researcher, who forwarded data on a weekly basis to patients’ linked GP and Macmillan nurse. The Macmillan nurse was asked to schedule at least one clinical encounter with the patient.The lead researcher (RA) gave participants a brief, user-led introduction to the app, and participants were provided with a Samsung Galaxy A7 tablet onto which the app had been loaded. Can-Pain was designed to be intuitive, but usability data were collected during feasibility testing to inform the need for additional training. Participants were given unique logins and passwords.Patient participants were telephoned by the lead researcher each week to check for any problems and collect verbal feedback (brief telephone interview) about Can-Pain. An in-depth interview was performed at the end of the study with all patient/caregiver and professional participants. All interviews were conducted according to schedules. Brief interviews covered participants’ experiences of using the app and any problems experienced, particularly burden or technical issues. End-of-study patient/caregiver interviews probed experiences of using Can-Pain, any barriers to interacting with it and how the app influenced pain management, help-seeking and interactions with healthcare professionals. Professional interviews covered experiences of using the weekly pain/symptom reports, how they influenced care and pros/cons of integrating PROMS within clinical care. All participants were asked for suggestions about how to improve the intervention. All interviews were audio-recorded, transcribed verbatim and analysed using Framework and thematic analysis . QuantitAll participants gave informed consent to participate in qualitative research and feasibility testing. Approvals were granted by North of Scotland Regional ethics committee  for feasibility testing from 6 to 4 months. Macmillan nurses had minimal contact with patients who were stable. Nurses were not asked to record patients to whom they informally mentioned the study but noted that unpredictable or rapidly deteriorating health status and admission to hospital were significant barriers to recruitment. Nurses also reported not inviting patients whom they judged might be uninterested in digital technology or the intervention. One patient returned his reply slip and had a GP who consented to participate but deteriorated clinically such that he was unable to participate.The demographics of both patient participants are presented in Table bothersome between 5 and 7 out of 10 and analgesic side effects between 5 and 7 out of 10. She used breakthrough analgesia twice to three times every day, routinely taking a breakthrough dose around 11 pm.Patient 1 had little variation in her self-reported pain and side effect ratings over the study period, rating overall pain levels between 6 and 7 out of 10, pain becoming Patient 2 also had stable pain ratings, with overall pain between 4 and 5 points out of 10, and reported considering pain bothersome at 6 out of 10. His pain ratings never crossed this threshold. He used on average three breakthrough opioid doses per week. Stress, movement and activity were pain triggers.n = 7)  generated around 4 hours of audio-recorded interview data over 4 weeks. Weekly telephone interviews with patients/caregiver had an average duration of 15 min. End-of-study interviews with patients/caregiver had an average duration of 38 min, with HCP interviews averaging 17 min.Qualitative interviews with all participants  “I don’t really want to increase my painkillers”. And we would explore you know, are you worried about them or anything like that, and not really, (…) I think actually what’s going on there is perhaps a larger thing about how she thinks about her illness (…) it’s caught up a bit more in her coping mechanisms”. (Patient 1’s GP)Patient 1’s reports of consistently high pain scores led to discussions with her HCPs about increasing her analgesic dose, which she was not keen to do. The perceived discordance between problematic pain and patient reluctance to increase analgesia led her professionals to explore the reasons for this, including any concerns about strong opioids.hard facts during time-limited consultations. Reports of patient 2 were used by his GP to start conversations about mood and stress.“I could easily identify what causes, what triggers him to take a breakthrough, (…) which in his case was mainly stress and it also really highlighted, which perhaps we hadn’t identified just quite how he was feeling in himself about the low mood and feeling hopeless at times and worthless, which I was able to use as a cue to discuss those feelings in more detail with him, so I thought that was really beneficial”. (Patient 2’s GP)Patient 2 logged low mood in his diary and reported that stress was a trigger for breakthrough analgesic use, explaining in his study interview that his emotions strongly influenced his perception of pain, but that doctors were more interested in These conversations and references to the app reports were evident in the electronic medical record.None of the patient or professional participants found the intervention burdensome or onerous. Patient 1’s caregiver took charge of app administration, logging her breakthrough doses, asking her to rate pain, reading diary questions to her and entering data on her behalf. The app seemed to be a natural extension to the roles and tasks that he had already adopted as a caregiver.The main limitation of the intervention from a patient/caregiver perspective was difficulty summarising a complex phenomenon like pain within a diary that utilised numerical ratings. Word clouds with qualitative descriptions of the pain, and the body map for pain location, helped to an extent, but patients pointed out that several types of pain could co-exist and were difficult to summarise.fiddly. Participants gave suggestions for additional triggers for breakthrough pain that might be included in the next version of the app. Participants would also have liked the ability to log breakthrough doses retrospectively.There were technical issues during feasibility testing: the app ran slowly at times, there were issues with screen sizing, there were two episodes of a patient being routed to a blank screen after logging an analgesic dose and predictive text features were found to be App usage data are presented . Other recognised problems with healthcare apps include lack of scientific/clinician input into content and failure to involve patients in design [A scoping review of publicly available apps for cancer survivors found that many apps offered symptom tracking and graphing capabilities along with educational information about cancer . None fon design . Failuren design , 30.Other digital interventions exist that support PROM feedback for individuals with symptomatic cancer , 31–33. Patients and clinicians were involved in intervention development. Intervention components were selected based on behavioural principles, supported by behavioural theories. This should make Can-Pain easy to replicate and protect core intervention components from becoming outdated as technology evolves .The target population for Can-Pain is at risk of unpredictable deterioration and is difficult to recruit into clinical research –41. Our In feasibility testing, both patients had stable pain due to bony metastases, were white Scottish, lived in urban environments and were on similar analgesic regimens. It will be essential to gather further data about how Can-Pain performs in patients with diverse demographic characteristics. Preliminary findings also suggest that caregivers play a key role in supporting loved ones to manage cancer and pain management. In this study, caregivers were recruited optionally via patients. An alternative strategy would be to recruit caregivers directly, via cancer support organisations for example. Further research is required to fully delineate the role of caregivers in promoting engagement with the intervention and whether caregivers influence the PROM data collected.A commercial partner will be engaged to optimise the app technically and to make it compatible with major app stores. In eHealth research, there is an argument that software should be continually improved and updated based on user feedback and that every version is a “beta version” . This caOutcomes will likely relate to patient-centred care, perceived control and satisfaction. It could also be possible to embed short, validated measurements of pain, quality of life and performance status into the intervention. Numerical 0 to 10-point pain rating scales were unpopular with both patients who took part in feasibility testing, whereas descriptive words were more intuitive. It would be prudent to consider embedding categorical measures of pain with verbal descriptors in addition to numerical ratings.Burden was a major theme in formative research. Treatment burden  is emerging as a major concern globally, particularly for individuals with multimorbidity. There are now several validated measurement tools to assess treatment burden  which cUltimately, it will be important to test the efficacy and cost-effectiveness of Can-Pain. An advantage of digital technology is that it is rapidly scalable. A randomised step-wedged implementation trial with embedded economic evaluation could be an efficient design through which Can-Pain could be simultaneously implemented and evaluated in the community.Can-Pain has been designed systematically with input from key stakeholders. Core components are underpinned by theories from behavioural science. Can-Pain could be a promising way of using PROMs to enhance the management of patients with symptomatic cancer within the community setting. We anticipate that Can-Pain could help professionals to recognise problems and could help patients and professionals communicate efficiently about subtler aspects of pain control, without causing unacceptable burden. We will design the next stages of testing to take account of a target population who are seriously unwell and to exploit the accessible and scalable nature of digital technology.ESM 1(DOCX 21.5 kb)ESM 2(DOCX 15.6 kb)ESM 3(DOCX 66.9 kb)