Although mid back pain (MBP) is a common condition that causes significant disability, it has received little attention in research and knowledge about trajectories and prognosis of MBP is limited. The purpose of this study was to identify trajectories of MBP and baseline risk factors for an unfavorable outcome in MBP patients undergoing chiropractic treatment.This prospective-observational study analyzes outcome data of 90 adult MBP patients  during one year  after start of chiropractic treatment. Patients completed an 11-point (0 to 10) numeric pain rating scale (NRS) at baseline and one week, one month, three, six and twelve months after treatment start and the Patient’s Global Impression of Change (PGIC) questionnaire at all time points except baseline. To determine trajectories, clustering with the package kml (software R), a variant of k-means clustering adapted for longitudinal data, was performed using the NRS-data. The identified NRS-clusters and PGIC data after three months were tested for association with baseline variables using univariable logistic regression analyses, conditional inference trees and random forest plots.p = 0.002] and to report subjective improvement after twelve months , which was confirmed by the conditional inference tree and the random forest analyses.Two distinct NRS-clusters indicating a favourable  and an unfavourable trajectory  were identified. Chronic (> 3 months) pain duration at baseline significantly predicted that a patient was less likely to follow a favourable trajectory [OR = 0.16, 95% CI = 0.05–0.50, This prospective exploratory study identified two distinct MBP trajectories, representing a favourable and an unfavourable outcome over the course of one year after chiropractic treatment. Pain chronicity was the factor that influenced outcome measures using NRS or PGIC. Mid back pain (MBP) or thoracic spine pain, described as pain between the 1st and 12th thoracic vertebrae and the corresponding posterior aspect of the trunk ). ComparA recent systematic review by Johansson and colleagues identified a knowledge gap with respect to MBP recovery trajectories and prognostic factors . BecauseTo help closing the identified knowledge gaps in MBP research, the aim of this prospective observational study was to identify trajectories and risk factors for an unfavorable outcome in MBP patients undergoing chiropractic treatment.The present study analyzes data collected between June 2014 and December 2019 of an ongoing study tracking patients of a chiropractic teaching clinic affiliated with a mainly orthopedic university hospital in Switzerland. Patients over 18 years without any contra-indications to chiropractic manipulative treatment  completed an 11-point (0 to 10) numeric rating scale (NRS) for present pain intensity before the first chiropractic treatment (baseline) and after one week, one month and after three, six and twelve months. In addition, they completed the Patient’s Global Impression of Change (PGIC), a seven point Likert-scale assessing the patient’s rating of overall improvement with the extremes “much worse” and “much better” . This stPatients for whom NRS data were available from at least five out of the six time points were included. To handle missing data, the random forest package (MissForest ), a non-Repeated measures ANOVA was conducted to test for the significance of NRS changes between baseline and one year after treatment start. For the PGIC, the two highest categories (“much better” and “better”) were defined as clinically relevant improvement , 18. TheClustering with the package KmL , a variant of k-means clustering specifically designed for longitudinal data, was performed to determine trajectories , 20. TheThe obtained clusters were subsequently tested for association with baseline factors using univariable logistic regression analysis with cluster membership as the dependent variable. The independent variables were age, gender, pain duration  and long-term (≥ 3 months) outcome was shown to be comparable for these groups in NP ), previop-value of < 0.05 was considered statistically significant.Descriptive statistics, repeated measures ANOVA and logistic regression analyses were performed using SPSS 24.0 . Data imputation, determination of trajectories, the conditional inference trees and random forest plots were performed using the statistical software R . For alN = 57/64.8%), the current MBP episode was the first, while 11 patients (12.5%) had suffered from one to three previous episodes and 20 patients (22.7%) from more than three episodes . Fourty-eight (53.9%) patients were acute (pain duration ≤30 days), 8 (9.0%) subacute patients (pain duration 31–90 days) and 33 (37.1%) chronic patients (pain duration > 90 days) . Thirty-four patients (37.8%) reported concurrent LBP, NP or LBP and NP. Ten patients (11.4%) reported MBP of traumatic origin , and rib involvement was reported by the treating chiropractor in 36 patients (40.0%). Of the 52 patients without rib involvement, 25 (27.8%) were diagnosed with axial pain and 29 (32.2%) were diagnosed with somatic referred pain. Twenty-four patients (27.0%) were smokers . These patients were comparable to those who were excluded from the study because they did not provide data of at least five of the six time points and did not statistically differ in any of the variables mentioned above.Ninety patients (mean age = 37.0 ± 14.6 years) of whom 49 (54.4%) were female were included in the analysis (84 patients were excluded due to fewer than five data sets). Of these, 15 patients chose to be contacted via phone and 75 patients answered the follow-up questionnaires using the provided electronic link. For the majority of patients  = 54.16, p < 0.001]. Post-hoc tests showed significant pain reduction from baseline to all time points (p’s < 0.001) and from one week to all time points (p’s < 0.001). Afterwards, no significant pain reduction occurred up to one year after treatment start  points at baseline to 1.81 (± SD 2.21) points . Using the imputed data set, the results were comparable .The percentage of patients reporting improvement in the PGIC significantly increased from The five criteria indicated highest partition quality for a two- and six-cluster solution: three criteria were in favor of two clusters and two criteria in favor of six clusters Fig. .Fig. 2PN = 72/80%) followed trajectory 1 (N = 51/70.8% were acute/subacute), and 18 patients (20%) followed trajectory 2 (N = 5/27.8% were acute/subacute). Thus, 91.1% from the acute/subacute patients and 61.8% from the chronic patients followed trajectory 1 , moderate (Cluster D) or from severe pain (Cluster A and B) describe rapidly improving pain (‘marked decrease in pain intensity within one month’ ) followe2 = 0.09) and chronic pain (Nagelkerke R2 = 0.18) were the factors that predicted the unfavorable trajectory (trajectory 2) in the univariable logistic regression models based on NRS data (Table Traumatic onset (Nagelkerke Rp = 0.006), which was confirmed as being the most important factor (highest mean decrease accuracy) in the random forest analysis (estimate of error rate 20.0%). Similarly, pain duration longer than 3 months predicted no improvement in the PGIC 12 months after treatment start in the univariable logistic regression models (Nagelkerke R2 = 0.17) (Table p = 0.002) and in the random forest analysis (estimate of error rate 34.44%). The Fisher’s exact tests for testing pairwise associations found only one significant association, namely between the factors ‘other complaints’ and ‘rib involvement’ (p = 0.009) indicating that multicollinearity was a minor problem in the model.In the conditional inference tree analysis using the same factors as the univariable models as independent variables, chronic pain was the only significant predictor for becoming a ‘non-improver’  and the ‘non-improvers’ . The second best partition was a six-cluster solution revealing a more fine grained representation of trajectories. Pain longer than three months before treatment start significantly predicted that a patient followed the ‘non-improver’ trajectory in the two-cluster solution and reported non-improvement in the PGIC after three months.Because of the lack of information in the literature regarding MBP trajectories and prognostic factors , the traacute LBP patients, Downie and colleagues . M. Macute tensity’ . They idtensity’ ) with pe2 = 0.18 and 0.17). In accordance, MBP of longer duration (> 30 days) was associated with a higher incidence rate for sickness absence than acute MBP [Pain duration longer than three months before treatment start was associated with poor outcome in the present study reflected in the patients following an unfavorable trajectory based on NRS data and in the patients reporting no overall improvement in the PGIC, although this association was relatively low, with pain duration explaining 18% (NRS) and 17% (PGIC) of the variance in outcome (Rcute MBP . Overallcute MBP  and the cute MBP . Altogetcute MBP .Because the present study design did not include a control group, these data do not allow for drawing any conclusions about the effectiveness of chiropractic treatment. Instead, the data might depict the natural history of MPB. Furthermore, the relatively small number of MPB patients, their heterogeneity with respect to symptom duration and the fact that the MBP patients were recruited from a teaching clinic at a university hospital might limit the generalizability of the present study. Lastly, several factors possibly influencing the course and outcome of MBP, such as other concurrent therapies, medication, pre-existing comorbidities and physical activity were not included in the analysis. With regard to imaging it should be noted that approximately 90% of back problems are non-specific without any pathoanatomical cause that would be identifiable using imaging . TherefoThis study is a first step towards identifying trajectories in MBP, which were shown to be comparable to those of LBP. Pain duration longer than three months emerged as main risk factor for poor outcome. These findings support the notion that LBP and MBP belong to the same general disorder, which needs being confirmed in larger studies in the future.


A patient taking opioid maintenance therapy unintentionally injected dissolved zolpidem pills into the femoral artery and suffered acute limb ischemia. High amounts of opioids with supplemental therapies were inefficient for intractable ischemic pain, suggesting the presence of opioid‐induced hyperalgesia (OIH). Epidural analgesia efficiently relieved pain and symptoms of OIH. Intra‐arterial zolpidem injection resulted in vascular obstruction, muscle necrosis (arrowhead), acute limb ischemia, and intractable pain unresponsive to high doses of opioids. Opioid‐induced hyperalgesia (OIH) was suspected. Epidural analgesia efficiently relieved pain and symptoms of OIH in the addicted patient. High amounts of opioids with supplemental therapies were inefficient for intractable ischemic pain, suggesting the presence of opioid‐induced hyperalgesia (OIH). Epidural analgesia efficiently relieved pain and symptoms of OIH.A substantial increase in prescription opioid use was observed over the last two decades, as well as numerous patients undergoing surgery who are on maintenance therapy (OMT) with methadone or buprenorphine. These patients present a unique challenge for anesthesiologists usually requiring a complex perioperative and postoperative pain therapy.Opioid medications and nonsteroidal anti‐inflammatory drugs (NSAIDs) are the basic management of ischemic pain in acute limb ischemia. In addicted patients, unpredictable amounts of opioids could be required to effectively suppress ischemic pain demanding other ways for pain treatment. Challenging perioperative period is not a good time to start withdrawal therapy or to start rehabilitation of these patients.We will present a perioperative approach in the treatment of acute ischemic and postoperative pain in an addicted patient who suffered acute limb ischemia with intractable ischemic pain. Despite increasing doses of opioids, his pain became worse, suggesting opioid‐induced hyperalgesia (OIH).2A 33‐year‐old Caucasian man was admitted to a tertiary hospital in an agitated state with excruciating pain in his left leg. He was a former heroin user on OMT with methadone 45 mg PO daily. The patient unintentionally injected four dissolved zolpidem pills into his femoral artery on the day before the hospital admission. After the injection, he felt intractable pain and he took >100 mg of methadone PO with no effect.2.1During the hospital admission in the emergency department, patient's leg was pale and cold, but with preserved peripheral arterial pulsation. He was admitted to the vascular surgery department. His initial laboratory tests suggested disseminated intravascular coagulopathy (DIC). D‐dimer was 26 400 µg/L, and platelets and fibrinogen were low. Despite peroral and parenteral rehydration, and forced diuresis with urinary alkalization, myoglobin values were still extremely high (39 159 µg/L) with a presentation of acute compartment syndrome. Color Doppler flow imaging confirmed normal blood flow at major arteries.2.2An attending vascular surgeon has confirmed that the patient suffers acute ischemic pain that may be reduced after fasciotomy. He also suggested high doses of opioids according to the guidelines of the British National Institute for Health and Care Excellence.A psychiatry/addiction medicine consultation suggested to continue the methadone OMT at 60 mg PO daily and diazepam 10 mg PO three times a day with meperidine IV up to 60 mg boluses. Still, the patient's pain was 9 to 10 on the NRS. He became scared and disoriented, and OIH was suspected. Diclofenac was started for his pain treatment along with diazepam to suppress anxiety, but with no changes in his status.Due to the progression of compartment syndrome above the knee and severe pain, fasciotomy has been extended under general inhalational anesthesia 24 hours after hospital admission. Systemic opioid therapy (multiple fentanyl 100‐200 µg IV IV boluses) was continued after the surgery, and the OMT dose was increased to 100 mg PO daily. However, he was still extremely anxious, and unable to sleep and communicate. Diazepam was replaced with midazolam, and on the patient's request, diclofenac was replaced by metamizole. His pain was still unbearable. The diagnosis of flow obstruction at the minor blood vessels with severe acute ischemic pain and opioid‐induced hyperalgesia was confirmed.9/L). The peripheral pulsations were palpable on the dorsalis pedis and posterior tibial artery, but the patient's leg was still cold with diffuse cyanotic and livid skin areas and painful cramps. His pain became intractable, both at the rest and with movement.On the second day after the admission (third day after zolpidem injection), he suffered painful cramps and was not able to place the affected leg into a comfort position. His plasma myoglobin levels decreased (18 829 H µg/L), diuresis was preserved, with normal urea (5.1 mmol/L) and creatinine (86 µmol/L). Platelets and packed red blood cell transfusions were given due to the ongoing bleeding with laboratory signs of DIC with platelet consumption  was offered and accepted by the patient. After platelet transfusion, a lumbar epidural catheter was uneventfully placed at the L3‐L4 levels. EA with 10 mL boluses of levobupivacaine 0.25% and fentanyl 1.2 µg/mL was started, achieving excellent pain control (NRS 0). The methadone dose was reduced to his usual maintenance dose, 45 mg/daily. He had no other complaints, was able to move his leg, and had good sleep through the night.On the third day of hospitalization, physical examination revealed a cold left leg with multiple pale and cyanotic skin areas, suggestive for focal areas of microvascular thromboses and embolizations with skin and muscle necroses Figure . Posteri2.3The patient was discharged to home care on day 6 after a leg amputation. He had ordinary postoperative recovery with usual OMT dose and NSAIDs analgesia. After the rehabilitation, he got the prosthesis and was able to walk well.Histopathology specimens of his amputated leg showed multiple necrotic muscle fibers and vascular occlusions caused by the intra‐arterial injection of zolpidem. Histology slides showed severe inflammatory reactions within arteries in the areas surrounding foreign body particles Figure , as well3Perioperative pain control in OMT patients is often cumbersome and problematic for all parties involved patients, nurses, anesthesiologists, and surgeons. Interruption or discontinuation of OMT in patients with a history of opioid use disorder is not recommended.Although opioids with NSAIDs are the mainstay of pain treatment in acute limb ischemia, regional anesthesia (RA) techniques are suggested as supplemental therapy if high doses of opioids are required for pain control or if the rotation of opioids is ineffective (NICE). RA provides effective pain control but may be associated with several adverse events in acute limb ischemia. It can mask acute ischemic pain and thus lead to delay of surgical or endovascular interventions. Furthermore, RA may result in hypotension, tachycardia, bradycardia, or toxic reactions, especially in patients with cardiac comorbidities.In our patient on OMT, both increasing doses and rotation of opioids were ineffective, and the pain was getting worse with altered mental status. These clinical signs are suggestive for OIH.A choice of anesthetic technique should be discussed with the patient and surgeon before surgery. General anesthesia may be used as a rescue method in patients with intractable pain, but RA may be a preferable technique. It could easily achieve both adequate postoperative analgesia and peripheral vasodilatation. Suitable regional anesthesia/analgesia techniques may also decrease fear and increase patient's compliance.However, RA has a few disadvantages in vascular patients and must be used cautiously. It could mask ischemic pain, which is an important clinical sign in the case of limb ischemia and acute compartment syndrome. Therefore, RA techniques must be followed by proper clinical, neurological, and laboratory monitoring. Prevention of an opioid withdrawal syndrome should be considered, and opioid maintenance therapy continued in the perioperative period in addicted patients undergoing RA procedures.4According to the current guidelines, the use of OMT in patients with acute limb ischemia must not be discontinued in the perioperative period. The utilization of additional opioids may lead to the opioid hyperalgesia and should not be the first‐line perioperative pain treatment. Multimodal pain management strategies using regional anesthesia techniques and adjuvant opioid‐sparing techniques will allow for the best acceptable outcome.The authors declare that they have no conflicts of interest.IKK: treated the patient, analyzed literature, and drafted and reviewed the manuscript. SK: treated the patient, analyzed laboratory values, and wrote the manuscript. KM: performed the pathohistological examination and described figures. BM: revised the manuscript critically for English language and intellectual content. KP and TI: performed surgical procedures and critically analyzed manuscript, and both participated during the literature search. All authors: read and approved the final manuscript.Since the patient was not available to give written informed consent for manuscript publication, ethics committee approval was obtained for publication of this report and accompanying images.


The postoperative analgesic effect of transmuscular quadratus lumborum block (QLB-TM) in patients following lower abdominal surgeries has been identified; however, the efficacy of QLB using the lateral approach (QLB-L) is still in debate. Therefore, this retrospective study was conducted to investigate the effect of a single-shot block with QLB-L on postoperative analgesia for patients undergoing percutaneous nephrolithotomy (PCNL).The medical information of the patients undergoing PCNL was retrieved from the electronic charter system  in our Nanjing Drum Tower Hospital during the period of Jan/2019 to Jun/2019. Among the total of 57 patients, there are 17, 18, and 22 patients subjected to QLB-L, QLB-TM, or routine treatment, respectively. The primary observational parameter was to assess postoperative pain with visual analog scales (VAS) at rest 30 min after extubation, 24 h, and 48 h after surgery, respectively. The secondary observatory endpoints, including the consumption of intraoperative opioids, the cumulative dose of non-steroid anti-inflammatory drugs (NSAIDs) and the incidence of adverse events related to postoperative analgesia, were evaluated as well.P = 0.04). There were no significant differences in the incidence of postoperative nausea and vomit (PONV), itches, respiratory depression, the time for the first defecation, and the length of hospital stay (LOS) among the three groups.The static VAS score at 24 h after surgery and the intraoperative consumption of sufentanil were significantly lower in patients receiving either intervention of QLB-L or QLB-TM as compared with those receiving routine treatment. However, one shot of QLB had no impact on VAS scores at 30 min post-extubation, 48 h after PCNL procedure compared with the patients receiving routine treatment. The percentage of non-ambulatory patients within 24 h post-PCNL was significantly higher in the QLB-TM group compared with the routine treatment group (QLB-L procedure may exert as equivalent as QLB-TM in terms of abrogating postoperative pain within 24 h post-surgery and decreasing intraoperative sufentanil consumption in patients undergoing PCNL procedure as well. The caution should be taken to avoid lower extremities weakness in the patients after QLB-TM within the first 24 h post-PCNL procedure. Percutaneous nephrolithotomy (PCNL) is the treatment of choice for patients with multiple or complex kidney or upper urinary tract stones, which necessitates the meticulous multi-modality analgesia due to mild to moderate pain originated from renal capsule dilation or nephrostomy-tube-related stress during the first 24 h after operation . Hence, In this study, we investigated the effect of ultrasound-guided QLB, targeting anterior-laterally or transmuscularly to the QL muscle, on pain relief after PCNL. Our hypothesis in this study is that the patients who receive QLB-L procedure record as low visual analog scales (VAS) value at rest as QLB-TM.This study was approved by the ethics committee of Drum Tower Hospital Affiliated with the Nanjing University Medical School (reference number: 2019–304-01).The medical information of the patients undergoing PCNL was retrieved from the electronic charter system  in our Nanjing Drum Tower Hospital from Jan/2019 to Jun/2019. Query used the following criteria: (a) anesthesia start time within the specified date/time parameters (Jan/2019-Jun/2019); (b) surgical procedure equal to PCNL;(C) patient has a completed pain assessment procedure form indicating the performance of QLB-L or QLB-TM. This is a retrospectively comparative study comparing the analgesic effect of ultrasound-guided QLB with two different approaches  versus routine practice (control group) on postoperative pain following PCNL.Those eligible patients with age > 18 years old, American Society of Anesthesiologists (ASA) physical status classification I-III scheduled to undertake the selective PCNL procedure were included in this retrospective study. The patients with the history of severe hypertension (systolic blood pressure > 180 mmHg), diabetes mellitus with neuropathic pain, hepatic cirrhosis, renal function insufficiency, depressant condition, alcohol addiction, chronic intake of oral non-steroid anti-inflammatory drugs (NSAIDs) or analgesics, or with incomplete/loss of clinical data were excluded in this study.The decision on which type of QLB approach performed before general anesthesia or intravenous medication alone without the requirement of truncal nerve block for pain control after PCNL was made by practitioners their own according to their daily routine of anesthetic management for those PCNL patients.QLB-L technique , cisatracurium (2 microgram/kg/min) to ensure appropriate sedation (BIS at the range of 40–60), substantial analgesia and muscle relaxation, respectively. The invasive arterial pressure monitor was established via left radial artery cannulation with a transducer connected to Philips  before surgery. Intermittent sufentanil (0.1 microgram/kg) was given if the heart rate (HR), blood pressure, or both increased more than 20% of the baseline. At 10 min before the beginning of the surgical procedure, 50 mg of flurbiprofen dissolved in 100 ml saline were intravenously administered. The hemodynamic parameters and oropharyngeal temperature were recorded automatically by Medisystem electronic charter database  in our department.All patients received standard general anesthesia monitoring, and intravenous infusion commenced with Lactate Ringer’s solution at the rate of 400 ml/h to replace the fluid loss owing to 8 h fasting and no drinking. Anesthesia was induced with intermittent bolus injection of (midazolam 0.01 mg/kg), propofol (2 mg/kg), sufentanil (0.2 microgram/kg), and cisatracurium (0.2 mg/kg) facilitated in tracheal intubation. The mechanical ventilation was commenced to maintain the end-tidal PCOAt the end of the operation, the patient was transferred to the post-anesthesia care unit (PACU), and the tracheal tube was removed after full emergence from anesthesia. The patient was discharged from the PACU to the ward once Steward Scale score  was higher than five assessed by an experienced physician in PACU. The VAS method was used for postoperative pain intensity quantification with the scale ranges from 0 to10 . VAS scores were assessed by a well-trained doctor at 30 min immediately after extubation, every other 4 h thereafter till 48 h post-surgery in the ward. When the VAS score of patients was over 3, 50 mg flurbiprofen was titrated to free of pain. Given the VAS score over 5, dizocine (0.1 mg/kg) was administrated for pain control as a rescue dose. The maximal dose of flurbiprofen or dizocine is 200 mg, 0.2 mg/kg daily, respectively.2); ASA classification; underlying diseases . Intraoperative variables included the following: duration of operation (minutes); anesthesia time (defined as the time spent in the operating room in minutes); categories of drugs used for general anesthesia; intraoperative mean arterial pressure (MAP) and HR; dosage of intraoperatively administered narcotics. Postoperative variables included the following: additional analgesic requirement ; pain intensity assessed on VAS; the incidence of postoperative nausea and vomiting (PONV), itching, respiratory depression, the time for the first defecation, and the length of hospital stay (LOS).Preoperative demographic variables included the following: age (years); gender; BMI , beginning of surgery (T1), the end of surgery (T2), immediate post-extubation (T3), and leaving PACU (T4); the duration of operation, intraoperative opioid (sufentanil) consumption; LOS; postoperative additional analgesic requirement within 48 h after PCNL as well as the adverse effects  were recorded for further analysis.P value of < 0.05 was accepted as statistically significant. The analysis of the data was carried out using the IBM SPSS 21.0 statistical package software.Power analysis was based on results of the preliminary estimation of the difference in VAS at 24 h after PCNL procedure among various treatment groups from our electronic charter database; specifically, power was set at 0.8, significance criterion was set at 0.05, sigma was at 0.74. This yielded a sample size of 17 for each group. A Shapiro-Wilk test was used to evaluate whether or not the data are normally distributed; The distribution of each continuous variable was presented with s mean ± standard deviation or median with range (R)/ interquartile range (IQR). The distribution of each categorical variable was summarized in terms of its frequency and percentage. One-way analysis of variance using LSD correction for multiple comparisons of parametric variables and the Kruskal-Wallis test was used for the non-parametric variables followed by Dunn’s test for multiple comparisons. Repeated measurement analysis of variance was used to analyze repeated measurements. The test of chi-square or Fisher’s exact test was applied for the categorized data. A As is shown in Table P < 0.01; QLB-L vs Con: 0(0–1) vs 2(1.9–3.1), P < 0.01). As shown in Fig. The postoperative pain scores assessed using VAS were collected at 30 min after removal of the endotracheal tube in a PACU, 24, 48 h after surgery in the ward, respectively. The patients receiving either type of QLB had lower VAS values at rest 24 h after surgery compared with the patients under routine analgesic treatment (QLB-TM vs Con: 1(0–2) vs 2(1.9–3.1), P < 0.05). The results of each group were shown in the supplementary material . Table S2. Intraoperative Consumption of Sufentanil (microgram). Table S3. Comparison of mean arterial pressure (MAP) and heart rate (HR)


Cancer-related pain (CRP) is a major problem with a potential negative impact on quality of life of the patients and their caregivers. Methodology. A facility-based cross-sectional study design was conducted in ACSH from January to March 2019. A well-structured professional-assisted questionnaire using Brief Pain Inventory-Short Form (BPI-SF) was used to collect data concerning the severity of pain, functioning interference, and adequacy of pain management in cancer patients. Data were analyzed using SPSS v.21.  To assess the adequacy of cancer-related pain management in Ayder Comprehensive Specialized Hospital (ACSH).  Out of 91 participants, 47 (51.6%) were male and 52 (57.1%) were between the age group of 18–45, with the mean age of 44.8 ± 13.6 years. According to the pain assessment tool (BPI), 85 (93.4%) patients experienced pain and 90 (98.9%) patients had activity interference; negative pain management index (PMI) was observed in 40 (43.95%) patients, showing that 43.95% were receiving inadequate pain management. Out of 38 patients who received no analgesics, 35.2% were found to have inadequate pain management, whereas those who took strong opioids had 100% effective pain management and the majority of the patients were in stage III. Among 38 (41.76%) only 20 (52.63%) received adequate pain management, based on patients' self-report in which 18.7% of the participants stated that they got 30% pain relief and only 1.1% got 90% relief. The predictors of undertreatment were presence of severe pain, metastasis, comorbidity, and stage of the cancer and could also be due to the educational level and monthly income, as evidenced by significant association.  This study suggests that cancer pain management in ACSH was sufficient for only 56%. However, large numbers of individuals are suffering from a manageable pain. Hence, remedial action should be taken, including increasing awareness of symptom management in medical staff and incorporating existing knowledge into routine clinical practice. Cancer is a disease condition in which the body's cells begin to grow and proliferate in an uncontrollable way , 2. The According to previous studies, greater than half of the patients with cancer experience pain from moderate to severe intensity , 7. CancDespite the availability of many guidelines for the treatment of CRP, patients usually receive inadequate pain management as highlighted by studies from different parts of the world. A report in Japan shows physicians undertreated CRP in 70% of patients . In a crThis research was done at Mekelle University, Ayder Comprehensive and Specialized Hospital, located in Tigray, Northern Ethiopia. The hospital was established to provide educational and medical services in 2008 to around 9 million people from Tigray and neighboring regions such as Afar and Northeastern Amhara and Eritrea. It renders a variety of medical services for all age groups in both inpatient and outpatient departments. Ayder Comprehensive and Specialized Hospital is the second largest hospital in the country. It has about 500 inpatient beds in all departments including the oncology unit .A cross-sectional study design was conducted from January 01 to March 30, 2019, to assess CRP in the oncology unit of ACSH.Study population included all adult cancer patients visiting Ayder Comprehensive Specialized Hospital during the study period.Cancer patients who meet the following criteria were included in the study: eighteen years old and greater; patients diagnosed with any kind of cancer; and all patients in the outpatient and inpatient wards of the oncology unit at specified time duration.Terminally ill patients, patients with neurologic disorders, and individuals who refuse to participate in the study were excluded.All patients who attended the outpatient and inpatient oncology department at the specified study period were included in the study in a census manner as long as they meet the inclusion criteria.Data were collected using the Brief Pain Inventory-Short Form (BPI-SF)  and charMuch information was collected from the patient including sociodemographic variables, comorbidity status, patient diagnoses, cancer location and stages, presence or absence of metastases, treatment modality, and number of drugs given and analgesics prescribed. The questionnaire was first translated into Tigrigna  and then translated back to English to verify accuracy. Clinical data were gathered from chart review, and type and severity of pain grading, analgesic use with percentage of pain interference, and relief of pain were collected by interviewing patients using the BPI-SF data collection tool.According to the type of antipain medication(s) patient uses, scores were given as follows: 0 , 1 (nonopioid antipain drug), 2 (weak opioid), and 3 (strong opioid), and then PMI was determined. Four levels of analgesic medications were estimated by the potency: (0) no order for antipain drug, (1) nonopioid , (2) weak opioid (codeine), and (3) strong opioid (morphine), and then potency of drugs was compared with “ worst pain.” No pain was scored as “0,” mild pain “1,” moderate pain “2,” and severe pain “3.” Finally, the PMI is determined by subtracting the pain level from the analgesic level in which the values go from −3  to +3 (morphine use and no pain reported). Therefore, inadequate pain management is considered when negative PMI is scored.  Cancer-related pain management  Pain-related interferences  Age, sex, religion, ethnicity, educational status, family size, residence, income, marital status, stage of cancer, type of cancer, and site of cancer-related pain.  Antipain medication administrationp < 0.05.Statistical analysis was done using SPSS version 21. Descriptive statistics was used to summarize demographic characteristics, pain type, and number and type of analgesics given to the patient. Adequacy of cancer pain management and pain interference were cross tabulated to compare the magnitude among different variables. Association was tested between independent and dependent variables using the chi-square test. Significance level was set by fixingThe questionnaire was pretested in a total of 20 individuals at a hospital which is not a study site . The completeness of the questionnaire was checked step by step by the data collectors and supervisors and further counterchecked by the principal investigator daily.A total of ninety-one (91) participants were included in the study. Nearly half of the patients (47 (51.6%)) were male while the rest were females (48.4%). Majority of them (74 (81.3%)) were Orthodox Christians. The mean age was 44.8 ± 13.6 years ranging from 19 to 72 years, sixty-three (69.2%) were from urban areas. The mean income of a family was 3590.2 ± 2336.5, and the family size of the participants was 4.97 ± 3.06 .Of the total number of participants, 81 (89%) were admitted. Only 6 (6.6%) patients had comorbidities. As the study indicates, 22 (22%), 38 (41.8%), and 33 (36.3%) patients were in stages II, III, and IV, respectively. It was observed that 42 (46.1%) of the patients were with metastasized cancer. Nearly fifty percent of the patients (50 (54.9%)) experienced a moderate severity of pain. Most of the patients (59 (64.8%)) received chemotherapy plus surgical intervention .With regard to the type of pain, most patients experienced a mixed type of pain (44 (48.4%)) followed by nociceptive pain (16 (17.6%)) .The commonest site of CRP was in the intestinal area 31 (34.1%), followed by genitourinary (18 (19.8%)), and least at the amputated site (1 (1.1%)) .According to the information collected using the pain assessment tool (BPI), 85 (93.4%) patients experienced pain, of which 50 (54.9%) had moderate pain, while only 6 (6.6%) felt no pain. Likewise, almost all (90 (98.9%)) patients had pain functioning interference; among those, 36 (39.6%) patients faced moderate pain and 32 (35.2%) felt severe pain .While investigating the adequacy of pain treatment, negative PMI was observed in 40 (43.95%) patients showing that they were receiving inadequate pain management. Most of the patients (51 (56.04%)) had received adequate management of pain .Out of the 38 patients who received no analgesics, 32 (84%) had inadequate pain management while 100% effective pain management in patients taking strong opioids .Upon crosstab and Pearson chi-square analysis of the adequacy of CRP treatment and pain functioning interference, it was revealed that pain was more significantly adequately managed in patients with the following characteristics: age ranging from 18 to 45 years, males, orthodox, married, illiterate, urban dwellers, having >5000 monthly income, stage III and stage IV of the disease, absence of metastasis, being treated with chemotherapy plus surgery, absence of comorbidity, having moderate pain severity, and being on strong opioids + nonopioids + adjuvant. With regard to pain interference presence on functioning, moderate to severe interference of pain was most likely to be present in patients with the following characteristics: age ranging from 18 to 45 years, males, orthodox, divorced, illiterate, urban dwellers, having ≤ 2000 monthly income, stage III of the disease, presence of metastasis, being treated by combination therapy, absence of comorbidity, presence of history of pain, moderate pain severity, and being on strong opioids + nonopioids + adjuvant Tables –8.Forty-four (48.35%) patients had mixed type of pain, of which 28 (63.6%) were adequately treated and 42 (95.5%) had moderate to severe functioning interference. Regarding the staging of cancer, the majority of patients were on stage III 38 (41.76%), of which 20 (52.63%) received adequate pain management and 28 (73.7%) faced moderate to severe functioning interference .The patients were allowed to self-report their relief to the provided analgesics and only 18.7% of the patients have responded that the drugs prescribed reduced their pains by 30%. Relatively small percentage (1.1%) of the patients got 90% relief while 11% of the participants exercised 0% effective pain relief .Pain is one of the most frequent and distressing symptoms experienced by cancer patients, and it affects their quality of life . HoweverIn this study, a total of 91 cancer patients participated. It was found that 93.4% of them had cancer-related pain. This is comparable with the study result from Gondar, Ethiopia, which reported 91.6% of cancer patients experience CRP , but mucAccording to this study, 43.9% of patients received inadequate pain management, which is lower in comparison to a study result from Gondar which reported 65% of cancer patients had received inadequate pain management . HoweverThe study revealed that a significant association of inadequacy of pain management was observed with marital status, level of education, presence of comorbidity, types of pain and pain severity, and activity functioning interference. This finding was similar to the study conducted in the University of Gondar .Cancer-related pain may have interference with daily activities. This study found that almost all (98.9%) cancer patients experienced cancer pain interference in their daily activities. This figure is higher when compared to the result of a study from Northern Ethiopia in which it was found to be 89.2% .Interference of CRP with daily activities is highly affected by stage of cancer. This study found that cancer patients with stages II, III, and IV have no/mild and moderate/severe pain interferes with their daily activities . This study's result was comparable with findings of the study from Gondar . However, the severe interference of pain in stage IV was higher in our study (29.4%) relative to that of Gondar (15.7%) [In conclusion, cancer-related pain management in Ayder Comprehensive Specialized Hospital is inadequate, and some of the patient's pain was not managed appropriately as indicated by negative pain index. Assessment of the knowledge and perception of health professionals working in the oncology unit of ACSH and the availability and affordability of antipain medications should be done to find out their role in the inadequacy of CRP management. In addition, the hospital should develop guidelines and drug use policies specifically for CRP management, and in-service training regarding CRP management should be given to health care providers who are working in cancer centers.


In patients without TJR pain intensity, pF, QoL did not improve, and increased pain sensitivity to cold and a stronger loss of detection were observed. In patients after TJR, however, a reduction in mechanical pain sensitivity and allodynia occurred in accordance with a reduction of pain intensity and improvement of functionality while QoL did not improve. Additionally, an increased sensitivity to heat pain and a more pronounced loss of mechanical detection could be observed in this group. TJR seems to stop peripheral pain input leading to a reduction of pain intensity and central sensitization, but surgery-induced sensory changes such as peripheral sensitization and loss of detection occur. Furthermore, TJR has favorable effects on pain intensity and functionality but not QoL.To investigate sensory changes, physical function (pF), quality of life (QoL) and pain intensity of patients with osteoarthritis (OA) in the natural course of disease, and patients undergoing total joint replacement therapy (TJR) 31 , patients with OA were investigated with questionnaires and quantitative sensory testing (QST) in the area of referred pain at the thigh at baseline and follow-up 22–49 weeks later; changes were analyzed separately for patients with ( Osteoarthritis (OA), especially of the hip and the knee, is a frequent syndrome which leads to a considerable health problem in the afflicted patients and a substantial use of the healthcare system . AmongstThe quantitative sensory testing (QST) battery by the German research Network on Neuropathic Pain (DFNS) investigates afferent peripheral nerve fiber functions or central pathways  and can Joint replacement surgery is a common treatment for chronic osteoarthritis, has increased over the last 2–3 decades, and is suggested to increase further in the future ,14. HoweAims of this study were therefore to thoroughly investigate the changes of somatosensory profile, somatosensory characteristics and pain intensity, physical function, and quality of life in patients with OA in the natural course of disease and in patients undergoing total joint replacement surgery.Patients diagnosed with OA by orthopedic and trauma specialists were included. All patients were investigated at inclusion of the study  as well as at follow-up (visit 2) either in the natural course of disease at least 21 weeks later or at least 19 weeks after TJR, respectively. Patients without TJR, i.e., those who were followed-up on in the natural course of disease, continued the treatment  which they already perceived at visit 1 and/or were allowed to optimize treatment in the course of disease in case of insufficiency in between visits 1 and 2 (best treatment). Treatment decisions regarding conservative treatment or joint replacement were made by the independent orthopedic or trauma specialists not associated with this study. Upon both visits, average pain intensity during the previous 3 days was documented, patients completed questionnaires , the EuroQol-5D-3L (EQ-5D) and SF-12 Health Survey (SF-12) ,24,25, fThe EQ-5D is a tool to examine the subjective overall health status. It consists of two parts. The first part is a questionnaire that comprises five operational dimensions: mobility self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has three levels: no problems, some problems, and extreme problems. In the second part, patients have to mark their overall health state on a 101-point visual analogue scale  representing a subjective rating of their health .The SF-12 is a disease independent gauge to assess the health-related quality of life. It examines the general health as well as the subscores for physical and psychological/mental health status, respectively. Values > 60% are above average and values < 40% represent below average health status ,33,34.The FFbH-OA rates the physical function in patients with osteoarthritis. The score ranges from 0–100% of function. Scores from 80–100% represent normal physical function; scores from 60–80% reflect a mild impairment of physical function; scores < 60% show relevant impairment of function .The WOMAC is a tri-dimensional, disease-specific patient reported outcome measure with three subscales assessing pain intensity, stiffness, and functional limitations resulting in one overall score. The higher the (sub-) score, the more severe the subitems pain intensity, stiffness, functional limitations due to OA, respectively ,28.The HADS is used to screen for the presence of anxiety and depression in patients with chronic diseases .Two subsSince pain arising from hip OA frequently radiates to the knee, thigh, and buttocks, while knee OA is often described around the knee and on the upper tibia , QST at 2) placed on the skin in the testing area with a baseline temperature of 32 °C. The thermode increased/decreased its temperature by 1 °C/s until the patient detected the onset of the stimulus and clicked the response button causing the thermode to return to the baseline temperature of 32 °C. There were 3 stimuli in total, with a 10 s interval between single stimuli. An average threshold temperature was then calculated from the three assessments. To obtain the thermal sensory limen (TSL), the thermode constantly altered its temperature starting at 32 °C. Whenever a stimulus was detected, patients were asked to push the response button and rate the stimuli as being warm or cold. Upon pushing the response button, the thermode gradually reversed the direction of the temperature. Six stimuli were applied and the square mean was calculated. The number of paradoxical heat sensations during this procedure was recorded. Paradoxical heat sensations were present when a patient reported a stimulus as warm, hot or burning when in fact a cold stimulus was applied.Tests were always performed in the same order, starting with thermal tests. Thermal tests  were assessed using a thermode , exerting a force between 0.25 and 512 mN ,38 was uFor assessment of MPT pinprick stimuli with fixed stimulus intensities  were used. For MPT, thresholds were measured by stepwise increasing and decreasing stimulus intensity. A geometric mean (in mN) was calculated from five ascending and descending stimulus series.For the mechanical pain sensitivity (MPS) of the skin and the dynamic mechanical allodynia (DMA) pinprick, stimuli were interspersed with a paintbrush exerting a force between 200–400 mN, a Q-tip mounted on a flexible plastic ruler with a force of approximately 100 mN and a cotton wisp providing a force of approximately 3 mN stroked over 1–2 cm skin. Fifty stimuli were applied per side in a pseudo-randomized order. The patient reported the painfulness of each stimulus using a numerical rating scale . Pain elicited by stroking with normally non painful stimuli such as the Q-tip, paintbrush and cotton wisp (pain to light touch) provided evidence of dynamic mechanical allodynia .2) compared to a single pinprick stimulus of the same force.WUR was defined by the perceived magnitude of pain to a series of pinprick stimuli  placed on the patella for OA of the knee or the anterior superior iliac spine for OA of the hip. Patients indicated when they could no longer detect vibration. The vibration threshold was determined by calculating a mean of 3 repetitions.For PPT, the tip of a pressure gauge /SDdatabase). The resulting Z-scores above “0” indicate hyperfunction, i.e., patients are more sensitive to the tested parameter compared to controls (lower thresholds), whereas Z-scores below “0” indicate hypofunction and therefore a loss of or lower sensitivity of the patient compared to controls (higher thresholds). Wilcoxon-test was used for intra-individual comparison at baseline and at follow-up. p < 0.05 was considered statistically significant.QST-results were analyzed according to published guidelines  and compCharacteristics of patients are shown in p = 0.025, Both groups of patients, i.e., those with and without undergoing TJR later on, did not differ regarding age, duration of symptoms, pain intensity, BMI, positive screening for anxiety and depression, WOMAC overall score and sub scores, QoL  during visits, but patients undergoing TJR later on showed a stronger impairment upon FFbH-OA, which explains the decision for surgery in this subgroup (A follow-up visit (visit 2) was performed 21–49 weeks (mean 34.2 ± 10.7 weeks) after visit 1. A trend towards a slight reduction of average pain intensity between visit 1 and 2 could be detected . Maximum pain intensity  and quality of life  did not Upon QST, the cold pain threshold decreased and a stronger loss for mechanical detection was observed for visit 2 compared to visit 1 . On the p < 0.01) and maximum  pain intensity decreased and functionality improved from visits 1 to 2 in patients that underwent TJR, whereas no differences in QoL were observed (Follow-up visit (visit 2) was performed 19–35 weeks (mean 26.2 ± 4.1 weeks) after visit 1. In contrast to patients without TJR, mean  occurs in accordance with a reduction of pain intensity and improvement of functionality, whereas, interestingly, QoL does not improve. In contrast, an increased sensitivity to heat pain and a more pronounced loss in mechanical detection can be observed. The concomitant decrease of pain intensity and improvement of QST parameters representing central sensitization in patients who underwent TJR point towards a crucial role of pain intensity for the development and maintenance of central sensitization phenomena. Similar results have been generated by Kosek et al.  who demoFor visit 2, a stronger loss of mechanical detection and an increased sensitivity to heat pain could be demonstrated, suggesting additional pathological peripheral mechanisms that occur in consequence of TJR, e.g., a lesion of cutaneous nerve fibers as a part of tissue damage due to surgery.The main limitation of this study is the small sample size. Furthermore, treatment of patients without TJR was not documented in detail.Interestingly, despite improvement in pain intensity and functionality after TJR, no changes in QoL parameters could be detected. As shown by Gierthmühlen et al., pain and symptom intensity, functionality, and QoL are not necessarily reported in association with one another . To thisSumming up, results of this study suggest that, in contrast to conservative treatment, TJR stops peripheral pain input, resulting in a reduction of pain intensity and central sensitization phenomena. Whether TJR is therefore favorable compared to conservative treatment needs to be elucidated in future studies.


Treating pain in later life is complex, and there are significant safety risks associated with the use of analgesics, particularly opioids. This study examined preliminary results from a pilot study of a telephone-delivered collaborative care service designed for community-dwelling older adults with chronic pain receiving prescriptions for high doses of opioids . Eighty-two older adults referred by the Pennsylvania Department of Aging’s pharmaceutical assistance program for low-income seniors (PACE/PACENET) were eligible and enrolled in the program . Patients were on average 73.5 (+/-6.1) years old, and the majority were white (91%) and female (70%). Patients completed a comprehensive baseline clinical assessment capturing their mental health, cognition, pain and functional status, as well as self-reported daily opioid dose and biopsychosocial needs. Patients were considered engaged in the program if they completed 2+ additional follow-up contacts with a care manager. During these contacts, care managers offered individualized treatment planning, with the goal of opioid dose reduction to safer levels. Of the 82 patients completing the baseline, 53 (65%) engaged in the program. At their last clinical contact, 91% of engaged patients achieved dose reductions . Engaged patients also reported significant reductions in pain severity (p=0.05) and depressive symptoms (p=0.003) at the last contact relative to baseline. Findings support the feasibility of a community-based, collaborative care model for pain management and suggest the potential for positive treatment outcomes.


Chronic pain is a leading cause of disability and remains under-treated in nearly half of patients with cancer. The opioid crisis has highlighted an urgent public health need for effective nonpharmacological pain management. Electroacupuncture (EA) and Battlefield Acupuncture (BFA) represent nonpharmacological modalities used in clinical practice to manage pain; however, their effectiveness has not been rigorously evaluated in oncology settings.We describe the design of a 3-arm, parallel, single-center, multisite randomized controlled trial that investigates EA and BFA versus usual-care wait-list control (WLC) for chronic musculoskeletal pain among 360 patients with diverse cancer types across various stages. The primary aim is to compare effects of EA and BFA versus WLC on pain, physical function, and co-morbid symptoms. The secondary aim is to examine the interaction between patient outcome expectancy and acupuncture modality (EA vs BFA) on pain reduction. The tertiary aim is to evaluate the association between genetic polymorphisms and responses to acupuncture. Patients will be randomized in a 2:2:1 ratio to EA:BFA:WLC. Acupuncture groups will receive weekly treatments over 10 weeks. WLC will receive usual care over the same evaluation period as the acupuncture groups. The primary endpoint will be the change in average pain intensity score from baseline to week 12. We will collect validated patient-reported outcomes and blood/saliva samples at multiple timepoints over 24 weeks.Our findings will advance nonpharmacological pain management in oncology and inform personalized treatment approaches that integrate individuals’ expectations and genetic biomarkers to deliver “precision” acupuncture to cancer patients with chronic pain.ClinicalTrials.gov Identifier: NCT02979574 The national opioid crisis has created new challenges to pain management in the cancer population and highlighted the urgent public health need for effective nonpharmacological therapies.Chronic pain affects approximately 100 million Americans and is the leading cause of disability in the United States. It is considered safe with few side effects.,10 Acupuncture has been shown to modulate ascending and descending pain pathways in animal models,–13 and human functional neuroimaging studies have elucidated the effects of acupuncture on key brain areas involved in pain processing. A recent meta-analysis demonstrated a moderate level of evidence of acupuncture for cancer-related pain; however, there was substantial heterogeneity among the studies and the types of acupuncture techniques that were evaluated.Derived from Traditional Chinese Medicine, acupuncture is a therapeutic modality that involves insertion of thin, sterile, single-use, metallic needles into the body surface. Several trials have evaluated EA for chronic nonmalignant pain,,18 but evidence for this particular modality remains limited in cancer populations. Battlefield Acupuncture (BFA), an auricular form of acupuncture developed by Colonel (Ret) Richard C. Niemtzow, MD, has received growing interest based on preliminary reports of its effectiveness for pain.–23 Due to its standardized protocol and relative ease of administration, BFA is undergoing nationwide implementation within the Veterans Healthcare Administration (VA); however, paucity of rigorous effectiveness data remains a major barrier to successful implementation.Electroacupuncture (EA) represents a specific acupuncture modality that involves electrical stimulation of needles, and its growing use in pain management is supported by scientific research demonstrating differential modulation of endogenous opioids by electrical stimulation of varying frequencies. our trial will also seek to understand patient-level characteristics, both psychological  and biological , that can be leveraged to predict individual response to acupuncture. Our primary aim is to compare the effects of EA and BFA versus usual-care waitlist control (WLC) on patient-reported pain, physical function, and co-morbid symptoms in cancer patients with chronic musculoskeletal pain (Aim 1). Our secondary aim is to examine the interaction between patient outcome expectancy and acupuncture modality (EA vs BFA) on pain reduction (Aim 2). Our tertiary aim is to evaluate the association between genetic polymorphisms and responses to acupuncture (Aim 3). The findings will inform the evidence-based, personalized delivery of acupuncture to improve pain management for patients with cancer in the era of the opioid epidemic.We describe a randomized controlled trial that addresses these gaps in the evidence base of EA and BFA and seeks to evaluate their effectiveness compared to usual care for chronic pain in oncology settings. In light of the growing emphasis on personalized pain management,22.1This study is a 3-arm, parallel, single-center, multisite randomized controlled trial (RCT) to evaluate the comparative effects of EA and BFA versus WLC on pain and co-morbid symptoms in a heterogenous sample of 360 patients with cancer who are experiencing chronic musculoskeletal pain Fig. . Eligibl and Standards for Reporting Interventions in Clinical Trials of Acupuncture (STRICTA). The trial is funded by the U.S. Department of Defense (W81XWH-15-1-0245) and is registered at ClinicalTrials.gov (Identifier: NCT02979574). All study procedures are approved by the institutional review board at Memorial Sloan Kettering Cancer Center (MSK).To enhance the rigor and transparency of our study, we will adhere to the guidelines from Consolidated Standards of Reporting Trials (CONSORT)2.2Study participants will be recruited from MSK, a National Cancer Institute-designated comprehensive cancer center with a main campus located in Manhattan and multiple other regional sites throughout New York  and New Jersey . Recruitment will take place at a total of 6 MSK sites across diverse regions in New York and New Jersey. We will primarily use a population-based recruitment strategy by mailing letters to potentially eligible participants identified through MSK's patient registry. We will also engage oncology stakeholders to publicize the study and facilitate referrals. The target accrual goal is 360 participants. Enrollment began in March 2017 and study participant assessments are scheduled to be completed in May 2020.2.3English-speaking adult patients with a primary diagnosis of any cancer type will be eligible for the study. Patients with history of metastatic cancer are eligible if they have no current evidence of disease. Active treatment with surgery, chemotherapy, and/or radiotherapy must have been completed at least 1 month before study initiation; however, patients may continue to receive hormonal treatment or maintenance targeted therapies during the study.To be eligible, patients must also report chronic musculoskeletal pain as the primary source of pain, defined as regional  or generalized . This pain must be present for at least 3 months and for at least 15 days in the preceding 30 days. Their worst pain intensity in the preceding week must be rated as ≥4 on a 0 to 10 numerical rating scale. Nonmusculoskeletal pain syndromes  may be present as co-morbid conditions if the patient reports musculoskeletal pain as the primary source of pain.Patients will be excluded if they have inflammatory arthritis requiring disease-modifying drugs; phantom limb pain; a pending pain-related Veteran Administration, social security, or worker's compensation disability claim by self-report; or an implanted electronically charged medical device.2.4All potential participants will undergo an initial screening with a research coordinator in person or over the phone. During this initial screening, the research coordinator will communicate study goals and procedures and screen participants for eligibility. A study clinician will then review screened patients to confirm that all inclusion/exclusion criteria are met. Once eligibility is confirmed, participants will complete informed consent and undergo randomization. To encourage adherence to the study procedures, all participants will be compensated with a $30 gift card at weeks 0, 4, 10, 12, 16, and 24 for a total of $180. Additionally, participants will receive reminders to complete study assessments.Participants will complete assessments at weeks 0, 4, 10, 12, 16, and 24. These assessments will be completed electronically online using REDCap electronic data capture tools.2.5We will randomize 360 participants using MSK's Clinical Research Database, a secure system that provides full allocation concealment and ensures that treatment group assignments cannot be guessed before or modified after a patient is enrolled in the trial. Group assignment (2:2:1 for EA:BFA:WLC) will be performed using permuted block randomization, stratified by accrual site  and baseline opioid use (yes vs no). The study statisticians will be blinded to treatment assignments.2.6 The BPI includes 4 questions related to the pain intensity with response choices ranging from 0 (“no pain”) to 10 (“pain as bad as you can imagine”). The change in average pain intensity score from baseline to week 12 will be the primary endpoint for this study. Patients who report a ≥30% reduction in their pain intensity will be classified as treatment responders who demonstrated a clinically meaningful improvement. In addition to the pain intensity items, the BPI also contains 7 pain interference questions with response choices ranging from 0 (“does not interfere”) to 10 (“completely interferes”); the average of these interference scores will be a secondary outcome.The Brief Pain Inventory (BPI) is one of the most widely used instruments to quantify pain intensity and interference. It is a reliable, valid measure with Cronbach α ranging from 0.77 to 0.91 and has been shown to be responsive to interventions.2.7 The 13 items describe different thoughts and feelings that may be associated with pain symptoms. The PCS yields a total score and 3 subscales scores .The Pain Catastrophizing Scale (PCS) is a validated, reliable 13-item scale (Cronbach α = 0.93) that assesses the negative cognitive-emotional responses to pain. Patients will be asked, “How would you describe your pain since the first clinical visit?” with the following response choices: very much worse, much worse, a little worse, the same, a little improved, much improved, or very much improved. Patients reporting “much improved” and “very much improved” will be classified as treatment responders.The Patients’ Global Impression of Change is a 1-item survey that will be used to define a clinically important change from the patient's perspective.,35 and by calculating health insurance direct costs  and indirect costs . To evaluate the cost-effectiveness of acupuncture, we will collect quality-of-life data using the Patient-Reported Outcomes Measurement Information System-Global Health  and convert these into Euro-QoL (EQ-5D) index scores. For the purposes of this study, the cost of each acupuncture session will be valued at $100 for a total of $1000 over 10 treatments.The health economics of chronic pain will be measured by assessing the monetary value of patients’ resource consumption during the 12-week period after randomization. Information on resource use will be collected by medical care cost questions The physical function subscale consists of 17 questions with excellent face, content, and construct validity. For each question, patients choose the degree of functional difficulty ranging from 0 (“none”) to 4 (“extreme”). These scores are summed to yield of total score 0 to 96 with higher scores indicating greater degrees of functional difficulties.The Western Ontario and McMaster Universities Osteoarthritis (WOMAC)–Physical Function subscale will be used to assess functional limitations of the lower extremity. This WOMAC subscale has been shown to be reliable (Cronbach α ranging from 0.92 to 0.97) and responsive to therapeutic interventions. Scores range from 0 (no disability) to 100 (most severe disability). We validated this instrument in patients with musculoskeletal pain and demonstrated excellent internal consistency (Cronbach α = 0.93), test–retest reliability, and construct validity.The Quick-Disability Arm/Shoulder/Hand (quick-DASH) is an 11-item instrument that measures disability related to arm, shoulder, and hand symptoms.2.8; thus, we will use validated patient-reported outcomes to measure the effects of acupuncture on fatigue, anxiety/depression, post-traumatic stress disorder (PTSD), and sleep disturbance.Our previous study suggests that EA improves pain-associated co-morbidities, such as fatigue and psychological distress Three items ask patients to rate the severity of their worst, usual, or current fatigue during normal waking hours. Six items assess the amount that fatigue has interfered with the daily activities of the patient during the past 24 hours. A composite fatigue severity score can be found by averaging the score obtained on each test item.The Brief Fatigue Inventory is a validated 9-item instrument that provides a reliable measure of fatigue in cancer populations with Cronbach α of 0.96. The reliability, validity, and factor structure of the HADS has been established in cancer patients with Cronbach α of 0.83  and 0.79 .The Hospital Anxiety and Depression Scale (HADS) will be used to determine the effects of acupuncture on anxiety and depression. This 14-item, self-administered rating scale has 2 subscales (anxiety and depression), each containing 7 items. Scores of ≥11 on either subscale indicate clinically abnormal psychological morbidity; scores of 8 to 10 indicate borderline cases; and scores of 0 to 7 are considered normal. The total score ranges from 17 to 85 with higher scores indicating greater degree of reported stress.The PTSD Check List–Civilian (PCL-C) is a validated 17-item instrument that corresponds to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) criteria for PTSD. It has demonstrated adequate psychometric properties, including internal consistency (Cronbach α = 0.94), test–retest reliability, convergent validity, and discriminant validity. The psychometric properties of the PSQI have been established in a variety of populations with Cronbach α ranging from 0.70 to 0.83.The Pittsburgh Sleep Quality Index (PSQI) is a 19-item instrument that produces a global sleep quality score as well as specific sleep component scores: quality, latency, duration, disturbance, habitual sleep efficiency, use of sleeping medications, and daytime dysfunction. Questions are scored on a 0 to 3 scale over a period of 1 month. The sum of the 7 components yield 1 global score that will be used as a patient-reported outcome for sleep disturbance. Global scores range from 0 to 21 and reflect the number and severity of sleep problems; scores of ≥5 indicate poor sleep quality and high sleep disturbance.,48 It contains 2 domains, mental health (Cronbach α 0.86) and physical health (Cronbach α 0.81).The PROMIS-Global Health is a 10-item instrument that has demonstrated reliability and validity as a measure of health-related quality of life.2.9 The Acupuncture Expectancy Scale (AES) is a 4-item instrument developed by the principal investigator (JJM) to measure outcome expectancy in the context of acupuncture treatment. It has demonstrated reliability and validity in oncology populations with a Cronbach α of 0.95 and is sensitive to change over time in response to acupuncture treatment. It has also been shown to correlate with patient self-efficacy and treatment satisfaction. The score ranges from 4 to 20, with higher scores indicating greater patient expectation of improvement.Patient expectancy has been shown to be an important predictor of acupuncture outcomes.2.10,53 In our recent work, we have examined the genetic polymorphisms, Catechol-O-methyltransferase (COMT) and T-cell leukemia 1A (TCL1A).COMT is an enzyme that regulates dopamine catabolism and other processes associated with the placebo effect, such as reward, pain, memory, and learning. In animal models and clinical studies, acupuncture has been shown to regulate dopamine,57 and key brain regions involved in pain, memory, and learning,,59 thus providing biological plausibility for the role of COMT in responses to acupuncture. Similarly, TCL1A has been shown to be associated with musculoskeletal pain,,61 suggesting that it may modulate pain-related processes. Building on this preliminary evidence, we seek to determine whether genetic variants in COMT and TCL1A predict responses to acupuncture in patients experiencing chronic musculoskeletal pain.Genetic biomarkers represent an emerging focus of research on pain and responses to treatment.We will collect whole blood samples (4 mL) in an EDTA tube and store them at −80°C in preparation for processing. If a patient does not wish to provide a blood sample, we will offer a saliva collection kit as an alternative, and patients will be asked to collect 2 mL of saliva in Oragene•DISCOVER (OGR-500) collection kits (DNA Genotek Inc.) following the manufacturer's instructions. Saliva specimens will be kept at room temperature until extraction in batches.–64Blood and/or saliva specimens will be delivered to MSK's Molecular Epidemiology Laboratory for DNA extraction using the Qiagen QIAamp DNA Blood Kit or the PrepIT-L2P purifier according to the manufacturers’ instructions. Extracted DNA will be quantified and qualified with a Nanodrop ND-8000 to estimate the total DNA and with a Qubit 4.0 (Invitrogen) to estimate the amounts of double stranded DNA. We will conduct genotyping using custom designs and PCR-based genotyping assays , as we have done in our previous research.2.11To better characterize our population, we will collect data on sociodemographics , clinical history , and pain medication usage. We will obtain pain medication prescription information by having patients bring in their medication bottles. Additionally, patients will be asked to complete 1 week of daily pain medication diaries at weeks 0, 4, 10, 12, 16, and 24 to calculate weekly average pain medication usage throughout the study time period.2.12The study interventions (EA and BFA) will be delivered by licensed acupuncturists with >5 years of experience in oncology settings. All study acupuncturists will receive a training manual detailing the EA and BFA treatment protocols. The principal investigator (a physician-acupuncturist with extensive oncology experience) will then provide in-person training for each acupuncturist. Before delivering any treatments, all study acupuncturists will be required to be certified by the principal investigator. Acupuncture sessions will be audited bi-weekly to ensure fidelity to study protocols. For quality assurance, acupuncturists will be re-certified twice a year. New acupuncturists who join the study will need to complete the identical training and certification process. These methods to ensure the fidelity of intervention delivery have been successful in our previous acupuncture trial. The acupuncturist will choose at least 4 local points near the body area with the most severe pain. Additionally, the acupuncturist will choose at least 4 distal points to address the patient's co-morbid symptoms. After sterilizing the skin, the acupuncturist will insert needles  at appropriate angles and depths, depending on the location on the body and body type of the patient. The acupuncturist will manually manipulate the needles to achieve the “De Qi” sensation. “De Qi” is a local sensation of soreness, numbness, or distension that accompanies the insertion and manipulation of acupuncture needles. The needles at the 4 local points will be electrically stimulated at 2 Hz with a TENS unit. The acupuncturist will leave the needles in place for 30 minutes. After removing the needles, the acupuncturist will apply a sterile cotton-tipped applicator to any areas of bleeding.For the EA intervention, we will use a standardized, semi-fixed protocol developed and tested by our group. Unlike EA, the BFA protocol is not customized to specific pain locations or comorbid conditions. The acupuncturist will clean both ears with alcohol swabs and then place an ASP needle in the Cingulate Gyrus point on 1 ear. Afterwards, the acupuncturist will instruct the patient to walk for a minute, assisting as needed and assessing for any signs of dizziness or lightheadedness indicative of a vasovagal response. After the brief walk, the acupuncturist will evaluate the patient's pain severity. If the reported pain is >1 of 10 and the patient is willing to continue, the acupuncturist will then place another ASP needle in the Cingulate Gyrus point of the other ear. This process is repeated for each of the other ear points: Thalamus, Omega-2, Point Zero, then Shen Men. The acupuncturist will stop placing ASP needles if one of the following conditions is met: pain decreased to 1 or 0 of 10; patient declines further needling due to discomfort; or significant vasovagal response is observed. The total duration of BFA delivery is about 10 to 20 minutes, depending how many ASP needles  are administered. The needles remain in place for 3 to 4 days. Patients are instructed how to remove the needles safely.For the BFA intervention, the acupuncturist will follow a strictly standardized protocol developed by Niemtzow.2.13Patients in the wait-list control (WLC) group will be followed for a 12-week waiting period; during this waiting period, WLC participants will be contacted by the research coordinator at the same frequency as the acupuncture groups and complete assessments at the same timepoints as the acupuncture groups. WLC patients will continue to receive their standard pain management and medical care as prescribed by their healthcare providers, including analgesic medications. Given the ethical implications of withholding a potentially beneficial treatment, we will offer all WLC patients the option of receiving 10 acupuncture treatments after week 12 (the time of the primary endpoint assessment). The WLC patients will be able to choose whether to receive EA or BFA. The WLC will provide a usual care comparison group so that we can understand the overall magnitude of the acupuncture intervention effects. The WLC will also increase the rigor of our study by controlling for regression to the mean, Hawthorne effect, and the natural history of pain processes in the usual care setting.2.14 We will first separately compare BFA to WLC and EA to WLC using the methods described below. If both acupuncture groups are significantly superior to WLC at significance threshold P < .025 , we will compare BFA to EA using a noninferiority approach, calculating a 1-sided, 95% confidence interval.We will perform analysis according to the intention-to-treat (ITT) principle . The change in BPI pain intensity from baseline to Week 12 is the primary endpoint for this study. To maintain the overall type 1 error level at 5% for testing the primary endpoint between study arms, we will use a “gatekeeping” approach to manage the multiple statistical comparisons. to test differences between treatment arms in score changes from baseline to week 12, with randomization strata as covariates. Specifically, in addition to the randomization strata, the models will adjust for baseline score and will contain assessment time, treatment arm, and the time-by-treatment arm interaction. The interaction term will be used to test whether the treatment arms significantly differ in their changes from baseline. To determine the durability of treatment effects, we will report the change between week 12 and week 24 using ordinary least squares regression in the BFA and EA group separately. For secondary outcomes, we will use similar analytical strategies for physical functions, co-morbid symptoms , and quality of life. Additionally, we will use the weekly pain medication diaries to calculate average pain medication usage across the study time for each study participant to determine if acupuncture decreased the use of pain medication.For Aim 1, to compare the effects of acupuncture on patient-reported pain (primary outcome), physical functions, and comorbid symptoms  at week 12, we will use linear mixed models (LMMs) we will then build a multiple linear regression model with percent reduction in BPI intensity as the dependent variable, and baseline expectancy and treatment group (EA or SA) as independent variables, including the expectancy and treatment group interaction term. The regression coefficient for the interaction term represents the between-group difference of percent reduction in BPI for one unit change in the expectancy score.For Aim 2, to determine the interaction between outcome expectancy and type of needling delivery/stimulation (EA vs BFA) on pain reduction, we will define response to acupuncture therapy as a continuous outcome measured as percent change of the BPI pain intensity score from baseline to week 12. Similar to our approach in our previous study, We will perform rigorous quality control for the genotype data and will exclude genotypes that are missing for >15% subjects and subjects with >15% missing SNPs from subsequent analyses. We will tabulate genotype frequencies and perform tests of Hardy-Weinberg Equilibrium (HWE) separately for each race/ethnicity subgroup. To test our primary hypothesis that polymorphisms in COMT and TCL1A are associated with acupuncture response, we will develop multivariable linear regression models with the genotype for each SNP and treatment indictor (EA vs BFA) included as independent variables. A significant association will be claimed if the P value for the genotype variable is <0.025 (since we are testing 2 SNPs). In addition to assessing associations with binary pain response, we will also explore associations with changes in the raw scores and percent change. We will code each genotype as the count of minor alleles in all association testing.For Aim 3, we hypothesize that those participants with either AA in COMT (rs4680) or GG/AG in TCL1A (rs2369049) will be more likely than those without the genetic combination to respond to acupuncture treatments (EA or BFA). To ensure our findings can result in actionable information to guide clinical care, we will calculate percent pain intensity reduction between Week 12 and Baseline for each patient, and we will define a binary variable for clinical response to acupuncture as 30% pain reduction between week 12 and baseline. This binary response variable is consistent with that established by Farrar et al. to be a clinically important change in pain trials.2.15 Using the “power.mmrm” function from the R package “longpower,” we applied the formulas in Lu et al to derive the smallest detectable effect size for the coefficient of the time-by-arm interaction term in our LMM (see Section 2.14), which we transformed to represent the standardized mean difference  between 2 arms in changes in pain intensity from baseline to week 12. Assuming a 20% attrition rate across all arms by week 12, significance threshold of P < 0.025, a correlation between baseline and post-treatment assessments of 0.5, and power of 80%, we will be able to detect an effect size of ≥0.48 between either EA versus WLC or BFA versus WLC. This is a moderate effect size which is smaller than that found in our previous pilot trial (effect size of 0.76) and that detected by the meta-analysis conducted by Vickers et al (0.5 between acupuncture and standard care). Thus, our trial is adequately powered to detect such a difference.For our Aim 1 sample size/power considerations for comparisons between EA versus WLC and BFA versus WLC, we calculated the smallest standardized effect size  that we will be able to detect with 80% power, given our gatekeeping multiple testing strategy and sample sizes of 144 in each of the acupuncture arms and 72 in WLC. To estimate this smallest detectable effect size, we applied sample size calculations designed for LMMs in the context of RCTs with participant attrition.P < .025 threshold, then there is no need for us to evaluate whether BFA is noninferior to EA. On the contrary, if both EA and BFA have significant improvements in pain intensity compared to WLC at the P < .025 threshold, then we will proceed to evaluate whether BFA is noninferior to EA. In this gatekeeping scenario, the alphas from both of the comparisons with WLC will propogate to our noninferiority comparison and our overall type I error rate for testing our primary endpoint will be preserved at 5%. Given our sample size, we will have 80% power to find BFA non-inferior to EA with respect to change in BPI pain intensity within a margin of .33 change-score standard deviations (SDs), assuming a 1-sided significance threshold of P < .05. We expect this SD to be between 2 and 3, so this margin translates to between 0.67- and 1-point difference in BPI pain intensity reduction. If we are able to demonstrate this, the interpretation would be that BFA is as good as EA with the caveat that we cannot exclude the possibility that EA is slightly better but not to the degree of clinical importance.As part of our gatekeeping multiple testing procedure, we split our overall type I error rate of 5% evenly between the test of EA versus WLC and the test of BFA versus WLC. If neither, or only one of, EA or BFA is better than WLC at the  Using a conservative estimate of correlation (0.2) between the interaction term and the dependent variable, we need a total of 191 subjects to detect this observed interaction effect with 80% power. Thus, our proposed sample size (288 subjects in both EA and BFA groups) is sufficient to detect this observed interaction effect.Aim 2 hypothesizes that there is a significant interaction between treatment and baseline AES on percent pain intensity reduction. Our preliminary data demonstrate that the regression coefficient for the interaction term between treatment and AES is 8.31 (standard error = 4.21) using percent change in BPI-severity as the dependent variable in a linear regression model including treatment, baseline AES, and their interaction. Therefore, assuming 45% carrier rate, there will be 52 carriers (∼45% of 116 patients) and 64 noncarriers. Assuming a 45% response rate in noncarriers, as shown in the preliminary study, we will have at least 90% power at 5% significance level to detect at least 30% difference in response rates between 52 carriers and 64 noncarriers. Similar power calculation applies to comparison of response to acupuncture in carriers and noncarriers in the BFA group.For Aim 3, we performed a power calculation to compare response to acupuncture in carriers of AA in rs4680 or GG/AG in rs2369049 versus noncarriers in the EA group. In the preliminary study, 47.2% of 38 patients were carriers; the response rates were 45% in noncarriers and ∼78% in carriers.3 The opioid crisis has highlighted the devastating public health consequences of chronic pain and sparked growing interest from governmental and medical organizations to integrate nonpharmacologic options into pain management. Our study will provide timely findings in the era of the opioid epidemic to guide the evidence-based delivery of acupuncture to cancer survivors with pain.Despite advances in medical therapy, chronic pain remains inadequately treated and costs the United States >$600 billion each year in health care expenditures and lost productivity.,10,17,18; however, further research is required to determine its clinical utility for pain conditions in oncology settings. Expected to exceed 20 million by 2026, American cancer survivors represent a rapidly growing, diverse population with high symptom burden that negatively impacts their recovery and quality of life. Our study will help to understand whether two acupuncture techniques, EA or BFA, are effective nonpharmacologic treatment options for pain and common comorbid conditions in this growing population.Substantial research has established the effectiveness and safety of acupuncture for pain management in general populations and has demonstrated relatively high levels of acceptability in cancer patients compared to the general population, only an estimated 1.7% to 31% of the oncology population has tried acupuncture, highlighting that important barriers to acupuncture remain. Contrary to EA, the BFA protocol can be learned and delivered by nonacupuncturist clinicians and is notable for its relative ease of administration and scalability. In 2013, the Department of Defense/Veterans Administration Joint Incentive Fund established the Acupuncture Training Across Clinical Settings (ATACS) initiative to develop, pilot, evaluate, and implement a national education program for VA health care providers. By 2016, ATACS had successfully trained >2,700 providers to deliver BFA; of these, approximately 110 were certified to train additional providers in BFA. Despite these successes, the real-world implementation of BFA has been hindered by the lack of high-quality data on the long-term effectiveness and side effects of BFA. Our study will address this evidence gap and provide clarity on the appropriate role of BFA in pain management. If BFA is found to be safe and effective, the implementation efforts by the VA will provide a template to overcome access barriers and increase acupuncture availability across healthcare systems.Although acupuncture is available at approximately 75% of academic cancer centers in the United States,18 Third, due to ethical concerns about withholding potentially beneficial treatments from patients with moderate-severe pain, this study allows patients in the WLC to receive acupuncture treatments after the primary endpoint; although this may limit comparison of long-term effects between the acupuncture versus WLC groups, a meta-analysis of 17,922 patients with chronic nonmalignant pain previously showed approximately 90% of the pain-relieving effects of acupuncture were sustained at 12 months relative to controls. Finally, our study design does not allow for crossover between the two acupuncture groups; thus, we will not be able to evaluate whether nonresponders to one acupuncture modality may demonstrate greater improvements with the other modality.The results of our study will need to be considered in the context of several limitations. First, although the study includes diverse cancer types across various stages and is conducted at multiple sites throughout New York and New Jersey, this is a single-center trial at a tertiary cancer center; thus, the results may not be generalizable to other populations. Second, this study does not include a sham acupuncture control group, thus precluding evaluation of the specific efficacy of these interventions; however, previous research has demonstrated that acupuncture produces significantly greater pain reduction than sham controls.Despite these limitations, this study represents the largest RCT to date to evaluate the comparative effectiveness of two acupuncture techniques (EA and BFA) versus usual care for chronic pain in a diverse cancer population, presenting a unique opportunity to advance nonpharmacological pain management in the era of the opioid epidemic. Our investigation of clinical predictors of acupuncture response  will also help to inform more personalized approaches to treatment. Other strengths of our study include large sample size, rigorous design, 6-month follow-up, and inclusion of diverse cancer types across multiple stages of disease. This research has the potential to shift pain management from a one-size-fits-all paradigm towards a personalized model that integrates individuals’ expectations and genetic biomarkers to deliver “precision” acupuncture with maximal benefit to cancer survivors suffering from chronic pain.The authors thank the patients, oncologists, nurses, and clinical staff at all study sites for their contributions to this study.Kevin T. Liou: Investigation, writing – original draft, writing – review and editing. Ray Baser: Formal analysis, writing – review and editing. Sally A.D. Romero: Project administration, writing – review and editing. Jamie Green: Project administration, data curation, writing – review and editing. Q. Susan Li: Project administration, data curation, writing – review and editing. Irene Orlow: Resources, methodology, writing – review and editing. Katherine S. Panageas: Methodology, formal analysis, writing – review and editing. Jun Mao: Conceptualization, funding acquisition, investigation, supervision, writing – review and editing.