Pain score after coughing during recovery at 2, 8 and 12 h after the operation were significantly decreased.  The patient satisfaction scores in the POG were significantly higher in all times. There was a statistically significant difference between the two groups in terms of rate of postoperative nausea and vomiting (PONV), indicating that patients in the POG had significantly lower incidences of the PONV compared tothe PG. The time to first analgesic request was significantly shorterin the POG, which was statistically significant . There was no statistically significant difference between the two groups in terms of consumption of analgesics. The postoperative TAP block could offer better postoperative analgesia than preepmtive TAP block.Nowadays, there are various methods to manage pain after laparoscopic cholecystectomy. The aim of this study was to compare the effectof preemptive versus postoperative use of ultrasound-guided transversus abdominis plane (USG-TAP) block on pain relief after laparoscopic cholecystectomy. In this single-blinded randomized clinical trial, the patients who were candidates for laparoscopic cholecystectomy were randomly divided into the two groups (n = 38 per group). In the preemptive group (PG) after the induction of anesthesia and in the postoperative group (POG) after the end of surgery and before the extubation, bilateral ultrasound-guided transversus abdominis plane (TAP) block was performed on patients using 20 cc of ropivacaine 0.25%. Both groups received patient controlled IV analgesia (PCIA) containing Acetaminophen (20 mg/ml) plus ketorolac (0.6 mg/ml) as a standard postoperative analgesia and meperidine 20 mg q 4 h PRN for rescue analgesia. Using the numerical rating scales (NSR), the patients’ pain intensity was assessed at time of arrival to the PACU and in 2th, 4th, 8th, 12th, 24th h. Primary outcome of interest is NSR at rest and coughing in the PACU and in 2th, 4th, 8th, 12th, 24th h. Secondary outcomes of interests were the time to first post-surgical rescue analgesic and level of patients’ pain control satisfaction in the first 24 h. The USG-TAP block significantly decreased pain score in the POG compared to the PG, and also the pain was relieved at rest especially in 8 and 12 h ( In addition to the side effects of opioid analgesics such as dizziness, respiratory depression, ileus, nausea, vomiting and itching, it is difficult to determine the appropriate dose of these opioids and achieve a steady state concentration, so the regional analgesic techniques have received much attention recently2. Peripheral nerve block is one type of these techniques and have received much attention recently because of their effective role in reducing postoperative pain and their better tolerance3. In order to improve quality of perioperative pain, the use of multimodal analgesia including the ultrasound-guided regional nerve along with non-steroidal anti-inflammatory drugs (NSAIDs) has received much attention recently4.Nowadays, Postoperative pain management is an important issue that has received a great deal of attention in the medical community. There are several methods for postoperative pain management, including the systemic analgesia (opioids and non-opioids) and the neuraxial anesthesia6. Several studies have demonstrated the efficacy of the TAP block in reducing postoperative pain scores and increasing the patient satisfaction6. The TAP block has been used to manage the preoperative pain, but few studies have been conducted on the timing of TAP block administration for the postoperative pain control.The aim of this study was to compare the effect the effect of preemptive versus postoperative use of the USG TAP block on pain relief after LC.Post-laparoscopic cholecystectomy (LC) pain is multifactorial, and therefore multimodal analgesia has been suggested for its treatment. Visceral pain has been the primary source of postoperative pain in LC. Somatic or parietal pain in LC is less intense than visceral pain, owing to the small (1–4 cm) abdominal incisions of the trocar site and the limited damage to the abdominal wall but dealing with it could be as a part of multimodal analgesia which transversus abdominis plane (TAP) block can be an effective approach. Ultrasound-guided (USG) TAP block is one of the methods recommended for postoperative pain especially somatic pain control in the abdomenwww.irct.ir: IRCT registration number: IRCT20120814010599N26; registration date: 31/05/2020 . All methods were carried out in accordance with relevant guidelines and regulations. All the ethical considerations of the latest version of Helsinki’s declaration were met throughout the study, and patients signed the written informed consent forms after receiving a complete explanation about the study.This study was performed on the patients who were candidates for elective LC and referred to a university hospital,June 2020 to October 2020. The study protocol was approved by Ethical committee of Iran University . The study was registered with the Iranian Clinical Trial registry at The inclusion criteria were: (1) age range between 20 and 60 years, (2) ASA physical status of I-II according to American Society of Anesthesiologists classification, and (3) patients’ willingness to participate in the research. The exclusion criteria were: (1) Emergency cholecystectomy (2) history of opioid dependence or tolerance (2) conversion of laparoscopic cholecystectomy to open cholecystectomy (3) Unable to consent (4) history of allergy to ropivacaine (5) BMI > 35 (6) Coagulopathy (7) uncontrolled intraoperative bleeding. Eligible patients were randomized blindly into two groups: 38 patients in the preemptive group (PG) and 38 patients in the postoperative group (POG). For randomization, a simple randomization method is used, which is done using a table of random numbers. To use the number of random numbers, we first determine the reading path of the table numbers . Then we assume certain numbers for each group . Then we touch on one of the numbers and move in one of the predetermined directions and record the numbers and assign them to different groups. Firstly, we did allocation and then blinding was done. The participants were not blinded to the allocation group. To prevent selection bias, allocation concealment was done in which the sequence of the group was unknown exactly before intervention.With using this sequence, patients were assigned to PG or POG. Patients were anesthetized per research protocol: intravenous antibiotic prophylaxis according to the hospital's protocol, fentanyl 2 μg/kg, midazolam 0.12 mg/kg were used as premedication. Induction of anesthesia was performed by propofol 2 mg/kg and cisatracurium 0.2 mg/kg. Isoflurane1MAC (1.2%), cisatracurium 2 mg every 30 min. All patients were monitored by non-invasive blood pressure (NIBP), pulse oximetry, electrocardiography (ECG), capnography (ETCO2), and BIS. ETCO2 was kept 30 to 35 mmHg and BIS 40 to 60. There were four trocars entry points (measured 1–5 cm) were used- one at the umbilicus and three in the right upper abdominal quadrant. Intraperitoneal Co2 was insufflated to the intrabdominal with pressure of less than 15 mm Hg. Ondansetron 4 mg and paracetamol 1 gr were given in the last 20 min intravenous. After evacuating the pneumoperitoneum, patients were reversed by neostigmine and atropine and extubated. Fluid and electrolyte were managed based on the standard of care.In both group, standardized monitoring  were applied on arrival to the post anesthesia care unit (PACU). Patient controlled intravenous analgesia (PCIA) containing 20 mg/ml of Acetaminophen and 0.6 mg/ml of Ketorolac with a bolus bottom (2 ml every 15 min) was started for each patient upon arrival to the PACU.In the PG after the induction of anesthesia and in the POG after the end of surgery and before the extubation, the USG TAP block  was performed on patients rested in a supine position using linear probe (5–13 MHZ). To perform the TAP block, the ultrasound probe was placed longitudinally on the midaxillary line near umbilicus, and the transversus abdominis and internal oblique muscles were scanned and observed. The needle  was inserted in plane and after placing the needle-tip into the fascia between transversus abdominis and internal oblique muscles, 20 ml of ropivacaine 0.25% was injected bilaterally. It was all done by one Anesthetist which was expert in that area and was not in charge of collecting the data.Pain intensity assessed by numerical rating scale (NRS) during rest and requested deep coughing, providing a range scores from 0 (no pain) to 10 (severe pain), by a blind assessor at six different times including: T0: on arrival to the PACU, T2:2th h, T4:4th h, T8:8th h, T12:12th h and T24:24th h.Patients were assessed regarding pain intensity using NRS during rest and requested deep coughing, providing a range scores from 0 (no pain) to 10 (severe pain),by a blind assessor at six different times including:T0:on arrival to the PACU, T2:2th h, T4:4th h, T8:8th h, T12:12th h and T24:24th h. After using PCIA, if the patient had NRS > 3, Meperidine 20 mg was also prescribed as rescue analgesia at every time during the postoperative period for 24 h. Same blind assessor evaluated the patients satisfaction with a satisfaction score  were also reported at the end of the 24 h. Indeed, outcome assessor and the person analyzing the information were unaware of the study groups.7, using the mean difference formula for two independent groups  with power of 80% (Z1-β = 0.84), the significance level/alpha of 0.05 (Z1-α/2 = 1.96) and d  of 0.27 as following:A sample size of 76 was determined according to a study by Suseelaet alThe statistical analysis for comparing the effectiveness of two methods was conducted as follows: for comparison of gender, medical history, vomiting, and the request for narcotics between two groups (post-op and preemptive) the chi-square tests were applied. For comparison of age, height, weight, and BMI and dosage of narcotics using Mann–Whitney U test were conducted. Comparison of NRS scores and satisfaction on 0, 2, 4, 8, 12, 24 h were separately conducted using Freidman test between two groups. Graphs show the mean and SEM of NRS and satisfaction scores. All analysis was done in Matlab 2018b.www.irct.ir: IRCT registration number: IRCT20120814010599N26; Registration date: 31/05/2020; https://en.irct.ir/trial/48012.The study protocol was approved by the Ethics Committee of Iran University of Medical Sciences, Tehran, Iran (IR.IUMS.FMD.REC.1397.287). All the ethical considerations of the latest version of Helsinki’s declaration were met throughout the study, and patients signed the written informed consent forms after receiving a complete explanation about the study. The study was registered with the Iranian Clinical Trial registry at Informed consent was obtained from the patients.A total of 85 patients who were candidates for elective LC were enrolled in this study. Nine patients  were excluded from the study. As shown in consort flow diagram Fig. . Finallyp = 0.089), there was no statistically difference between the two groups in terms of Postoperative Meperidine Consumption (p = 0.518)  Table .Table 1Dp value = 0.04 and = 0.00 respectively)   Fig. .Figure 3Patient satisfaction scores were significantly increased in both groups in all times Fig. . No comp10. Given that in patients undergoing LCsurgery, the maxim level of pain was in the first 24 h after surgery that was in trocar sites8, determining the optimal time to perform TAP blockeven before or at the end of surgery to increase blockefficiency is of clinical importance.However, few studies have been conducted on the comparison of analgesic effect between preepmtive and postoperative USG TAP blocks on pain relief after LC. In the current study, USG TAP block was performedin PG after the induction of anesthesia and in the POG at the end of surgery and before the extubation. Our results demonstrated that the USG TAP block decreased NRS scores both at rest and during coughing in the PG compared to the POG up to 24 h after the operation, especially in the first 8 h after the operation, which were not consistent with previous studies. In the Rashid study11 no significant difference was observed between the two groups in term of the amount of analgesia when performing dual TAP block and port site local anesthetic infiltration. Richard Kalu12 compared the effect of preoperative versus postoperative use of TAP on postoperative opioid use and the results showed that TAP block reduced the postoperative pain in both groups, but there was no significant difference between the groups with respect to the opioid use which was similar in our results. Our findings were consistent with those of the study of Tikuisis et al.13 demonstrating that TAP block reduced the pain scores both at rest in 2, 4, and 12 h after the operation and during coughing 2 and 4 h after the operation. A regional block of the abdominal wall, when used as a part of multimodal analgesia, can significantly relieve postoperative pain. Theblind TAP block technique based on an anatomical landmark can cause the complications and even injury to the abdominal viscera such as liver injury and intestinal puncture14. In the present study, there were no complications attributable to the TAP block because we performed real-time ultrasound guidance for TAP block in the patients. There was also no vital anatomical structure in this area. Our results showed thatthe USG-TAP block reduced the use of pethidinein the POG as compared with the PG, which in turn decreased the side effects of opioid analgesics such as dizziness, nausea, vomiting, itching, etc. In the present study, there were no complications attributable to block, indicating that by selecting the appropriate local anesthetic dose for TAP block, it could be used safely to reduce postoperative pain.Some studiesalso reported a beneficial effect of USG-TAP block on pain 48 h after surgery, which may be due to the relatively small presence of vascular structures in the neurovascular plane of the abdominal wall, as these structures play an important role in the drug clearance. Accordingly, systemic toxicity from local anesthetics has decreased significantly usingthe USG-TAPblock16. Patient satisfaction scores at all times during the first 24 h after surgery was statistically significant. This result was consistent with the study of Huang et al.17 comparinganalgesic efficacy of trocar sites local anesthetic infiltration with and without transversus abdominis plane block after laparoscopic hysterectomy and the results showed that patient satisfaction score was significantly higher in the TAP group. In the current study, the USG-TAP block reduced the opioid use and its side effects, especially PONV, but this reduction was statistically significant in the POG. Our Study showed postoperative TAP block appeared to be more efficacious than preoperative one in longer analgesia and lower pain scores.Several studies have shown that the USG TAP blockas a part of multimodal analgesia for postoperative pain management, results in better analgesia, higher satisfaction, and greater opioid sparing effects18. Another limitation of our study was the lack of Sensory assessment of theTAP block because the appropriate sensory level caused by the USG-TAP block is important for its efficiency and the evaluation of the patient's pain20. Another limitation of the study is the small sample size and single center study.However, this studyhas some limitations. One of the limitations of the study was the lack of evaluation of the effects of local anestheticswith the different doses and concentrations as some studies have shown that the use of higher doses relieves the pain and reducesopioid use in the parentsThe USG-TAP block, as a part of multimodal analgesia for postoperative pain management, resulted in better analgesia and higher satisfaction in the POG compared to the PG. The opioid sparing effect of the TAP block reduced the side effects of opioid use, including nausea and vomiting. TAP block could be considered as an integral part of multimodal analgesic strategy that is an inexpensive, simple and easily performed procedure.


A clinical conundrum can occur when a patient with active opioid use disorder (OUD) or at elevated risk for the condition presents with cancer and related painful symptoms. Despite earlier beliefs that cancer patients were relatively unaffected by opioid misuse, it appears that cancer patients have similar risks as the general population for OUD but are more likely to need and take opioids. Treating such patients requires an individualized approach, informed consent, and a shared decision-making model. Tools exist to help stratify patients for risk of OUD. While improved clinician education in pain control is needed, patients too need to be better informed about the risks and benefits of opioids. Patients may fear pain more than OUD, but opioids are not always the most effective pain reliever for a given patient and some patients do not tolerate or want to take opioids. The association of OUD with mental health disorders  can also complicate delivery of care as patients with mental health issues may be less adherent to treatment and may use opioids for “chemical coping” as much as for pain control. Pain is prevalent in oncology patients. A population-based study of cancer patients using the Brief Pain Inventory (BPI) found that 55% had experienced pain in the prior week and this pain was moderate to severe BPI ≥ 4) in 44% . Even in in 44% .Pain in cancer patients differs from pain in other groups. For one thing, cancer pain changes its characteristics, locations, and intensity frequently; postoperative pain, treatment-associated pain, and chronic forms of persistent pain. Cancer pain can worsen abruptly, may be characterized by abrupt and terrible flares, and is both psychologically as well as physically distressing . WorseniOpioids are generally effective analgesics but are associated with known and potentially treatment-limiting side effects as well as risks for opioid use disorder (OUD) . Pain trThis is a narrative review in which the authors used the PubMed, the Medline database of the National Library of Medicine, to search for literature using keywords of “cancer pain opioid risk” (658 results), “cancer pain opioid use disorder” (345 results), “cancer pain OUD” (23 results), and “cancer pain risk of addiction opioids” (105 results). The delimiter of 5 years was used since opioid prescribing has changed in the past 5 years and older articles would be less relevant to current medical understanding of opioid use and misuse. Articles not about cancer pain or opioids were excluded. The bibliographies of these articles were also used to retrieve relevant background or supplemental information.n = 482,688) found 6.6% of cancer patients had a comorbid diagnosis of substance use disorder and these veterans had a greater rate of medical and psychiatric disorders than those with cancer alone , to help stratify patients . Risk faAssessing so-called drug-seeking aberrant behaviors in cancer patients can be challenging, because many common “red flags” have alternate explanations. Patients who actively seek opioids, particularly by product name and specific dose, may be misusing these drugs, but this action can likewise be explained by patients who live with severe pain and know exactly what works for them. While asking for higher doses of opioids to manage pain may be an aberrant drug-seeking behavior, it may also be the result of tolerance where the patient needs higher opioid doses in order to control the same amount of pain. Unusual requests, such as claiming to have lost or accidentally disposed of an opioid prescription, urgent demands for an immediate appointment, or requests for the last appointment of the day, may be signs of OUD, particularly if they occur frequently. However, an occasional request of this nature may not mean anything at all in a stressed cancer patient with a lot of cancer-related medical appointments and treatments to manage.By the same token, these risks must be taken seriously. In a study of 1,554 cancer patients receiving opioid therapy from outpatient care at a single center from 2016 to 2018, it was reported that 19% exhibited non-medical opioid use within 8 weeks after their intake consultation. Being single or divorced, having a score on the SOAPP tool >7, experiencing greater pain severity, and taking higher doses of opioids were all risk factors for non-medical opioid use, defined as taking opioids in ways other than exactly as prescribed  found their most frequently reported barriers to adequate cancer pain management were: poor pain assessment, reluctance to prescribe opioids, and regulations surrounding opioid prescribing  . ProlongWhen cancer patients present with both moderate to severe pain plus risk factors for OUD, referral to a pain specialist may be warranted. OUD is characterized by intense drug cravings, reduced understanding or appreciation of one's own behavior, dysfunctional emotional response, lack of behavioral controls, and an inability to stop taking the drugs . PatientSome people who are in recovery from OUD refuse opioids, preferring to deal with pain rather than risk relapse. If non-opioid medications can control pain effectively or at least sufficiently, this may be an excellent solution. In some cases, combination therapy with a non-opioid analgesic plus adjuvants may be appropriate. Cancer pain can sometimes be managed with a procedural intervention or other technique, such as an implantable intrathecal drug pump , 50. LefThe population of people with OUD have a high consumption of healthcare services and disproportionately high healthcare costs , 52. As Clinicians may have implicit biases and suspect that a cancer patient with OUD or at risk for OUD may be manipulative and deceptive about reporting pain . PrescriIt may not be automatically assumed that cancer patients with OUD desire opioid rehabilitation . In the Although clinicians are increasingly confronted with cases of managing moderate to severe pain in cancer patients with OUD or at high risk for OUD, there is a paucity of literature, clinical studies, or guidance as to how to best manage treatment.Opioids are not always effective against pain in cancer patients; indeed, some types of pain do not respond to opioids . DespiteWhile opioids are effective analgesics, they can paradoxically cause pain to increase over time. Opioid-induced hyperalgesia is a condition in which prolonged exposure to opioids actually lowers the pain threshold and increases pain levels; pain is better controlled when opioids are discontinued . High doRisk stratification may be less clinically relevant in palliative care at end of life. They differ from the burgeoning group of cancer patients actively living with managed disease and concomitant pain. In general, non-pharmacological and non-opioid pain treatments should be considered as first-line therapy for most, if not all, cancer patients, regardless of the risk of OUD with the recognition that they may be ineffective for certain types of pain. For postsurgical patients and patients undergoing anticancer treatment or suffering tumor-related or other cancer pain, there may be few if any viable alternatives to opioids. Cancer patients cannot simply be relegated to deal with intolerable pain, decreased function, and a diminished quality of life, so the clinician and patient may have to determine if the benefits of opioid use outweigh the risks and how those risks can be managed. Such management strategies include close clinical monitoring, periodic patient interviews, regular urine drug monitoring, use of the prescription monitoring program, periodic pill counts, limited refills and small-quantity prescriptions. Referral to a pain specialist, an addiction medicine specialist, or psychiatric professional may be appropriate .In some cases, combination drug therapy may be beneficial. There are numerous fixed-dose combination products on the market, such as acetaminophen and oxycodone or tramadol plus diclofenac, and loose-dose combinations may be selected in the form of multiple drugs  to allow for greater dosing flexibility , 70. In Clinicians must be alert to the possibility for opioid diversion as, regrettably, cancer patients are often targeted by drug seekers among their friends and family, because they are potential steady sources of prescription opioids . Opioid Cancer patients should only be considered for opioid therapy after frank discussions of risks, benefits, and side effects. A plain-language patient agreement can be helpful to describe the treatment goals, the therapy, and the conditions that apply to the patient; such agreements require the prescriber to provide realistic pharmacological options to manage pain and the patient agrees not to abuse or divert these medications . In thisOpioids should be administered in the lowest possible effective dose for a short time in order to trial the results. Patients should be thoroughly informed about possible side effects and therapeutic objectives should be discussed with the patient. For most patients outside palliation, an exit plan for opioid therapy rather than open-ended prescriptions is appropriate.Pain, a biopsychosocial phenomenon, is one of the oldest and most commonly described symptom, but pain as a medical subspecialty is in its infancy. Efforts to treat pain aggressively, even calling for analgesia as a fundamental human right , have shPrescribers may need to engage in frequent conversations with cancer patients to best understand their frequently changing pain characteristics and analgesic needs. Increasing pain intensity, new pain locations, or other changes in pain can signal cancer progression. Pain can also change with many aspects of the patient's living situation, familial support, financial concerns, mental health, and overall outlook, all of which may be disrupted by the cancer treatments. A clinician treating pain in a cancer patient must use a differential approach: how can the pain be effectively managed and, balanced against that, what are the risks of opioid-associated side effects, tolerance, OUD, chemical coping, hyperalgesia? .Substance use disorder and mental illness are strongly associated –81. EmotCancer is associated with mental illness as well. Major depressive disorder is up to four times more prevalent among cancer patients than in the general population . The psyAnxiety is likewise prevalent among cancer patients and may affect patients at any point in the course of their cancer. Benzodiazepines are sometimes prescribed for anxiety , but then = 1,001) and without  schizophrenia, and determined that schizophrenic cancer patients used less opioids in the month before death  but reasons for this remain unclear , aberrant drug-seeking behaviors occurred in 12% and of those patients, and 91% had at least one risk factor for substance use disorder. This study found that in young patients, the use of multiple opioids was significantly associated with aberrant opioid-associated behaviors (p = 0.003)  . The ratMental illness and substance use disorder are often comorbid in a condition described earlier as dual diagnosis, but not all mentally ill patients who present with cancer will have OUD. Treating a mentally ill patient with cancer may be particularly challenging, in part because the mentally ill have a truncated life expectancy of about 10 years earlier than the general population . In factGeriatric patients without a history of substance use disorder are at reduced risk for OUD, but care must be taken to avoid drug-drug interactions as many geriatric patients with cancer routinely take multiple drugs . Opioid Opioids should not be considered, even in cancer patients, without evaluating the patient's risk for OUD, assessing their pain, and discussing with them the risks and benefits of opioid therapy. While pain control is important, even a fundamental human right , providiPeople with OUD or at high risk for OUD may develop cancer and are worthy of professional compassion and excellent care. To the greatest extent possible, prescribers and patients should have a frank discussion about pain control. Patients with OUD who present with cancer are as diverse as any other patient population: some may want to overcome their addiction and some may remain more interested in opioid use than conquering cancer. Clinicians may encounter cancer patients who, for a variety of reasons, refuse opioids, even when they are the best analgesic choice, while other cancer patients with OUD may be reluctant to even entertain any other options except opioids, even when there are other effective analgesics available.Even when a cancer patient at elevated risk for OUD is a candidate for opioid therapy, prescribers must approach opioid analgesia with caution. On the one hand, safe and effective therapy is based on trust, so patients must have faith their clinical team will not abandon them to live with excruciating pain. On the other hand, clinicians cannot simply dispense opioids to certain patients without exposing them to risks that may be worse than pain. For instance, cancer patients with active OUD who are prescribed opioids may neglect their health, be non-adherent with cancer treatments, engage in unhealthy behaviors, and have overall worse quality of life. People with active OUD have often made opioids the overwhelming focus of their life, and this may distract them from their fight against cancer.Cancer patients with a history of OUD on current opioid agonist therapy, typically with buprenorphine or methadone, are complex cases. An initial consultation with the other prescriber is appropriate and possibly an addiction medicine specialist should be added to the clinical team. In some situations, the dose of the agonist (opioid) can be temporarily increased; in other cases, non-opioid analgesics should be considered first to synergistically supplement the opioid for analgesic benefit. Some patients may be able to maintain the opioid reocvery program and take short-acting oral opioids to manage acute pain. It is difficult to set forth a one-size-fits-all strategy in that much depends on the patient's personality and mental health, age, the type and extent of cancer, the cancer treatments, the prognosis, and the patient's family and social situation.As more and more cancer patients survive the disease or live well for many years with managed disease, the issue of long-term analgesia becomes important. Cancer patients may be at risk for OUD; indeed, some people with cancer present with active use of illicit opioids. Managing these patients requires an individualized approach. There are tools to help stratify patients at risk for OUD. At that point, the type of cancer, prognosis, pain treatment options, and the patient's individual characteristics must be incorporated in the evaluation. It is crucial that cancer patients, even with active OUD, not be abandoned to suffer excruciating pain or be denied good medical care, but opioid prescribing is not appropriate in all patients. For some cancer patients, opioids may actually increase pain and suffering, lower quality of life, and cause more suffering. On the other hand, there are cancer patients with OUD who may need opioids to manage their cancer-related pain. Clinicians should establish good rapport with patients, frankly discuss the risks and benefits of opioid therapy, re-evaluate these patients regularly, and individualize analgesic strategies on a case-by-case basis.JP was invited to prepare this article and provided the concepts, the structure, and clinical recommendations, reviewed the article, and provided bibliographic support. PM reviewed the manuscript and provided critical analysis of the articles and how the content was organized. JL is a medical writer who did the literature searches, prepared the bibliography, and edited the manuscript for publication. FB reviewed the articles, selected particularly relevant articles for inclusion, and reviewed the final manuscript. PC and KM reviewed the manuscript and offered critical comments on how to organize the text. GV worked on the paper concepts and bibliographic search strategies, reviewed the literature, helped interpret the body of work, and reviewed the final manuscript in detail. All authors contributed to the article and approved the submitted version.JP and KM were employed by company NEMA Research, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background and Aims: Chronic pain is a complex clinical condition, often devastating for patients and unmanageable with pharmacological treatments. Converging evidence suggests that transcutaneous spinal Direct Current Stimulation (tsDCS) might represent a complementary therapy in managing chronic pain. In this randomized, double-blind and sham-controlled crossover study, we assessed tsDCS effects in chronic pain patients.Methods: Sixteen patients  with chronic pain of different etiology underwent sham and anodal tsDCS . As outcomes, we considered the Visual Analog Scale (VAS), the Neuropathic Pain Symptom Inventory (NPSI), and the components of the lower limb flexion reflex (LLFR), i.e., RIII threshold, RII latency and area, RIII latency and area, and flexion reflex (FR) total area. Assessments were conducted before (T0), immediately at the end of the treatment (T1), after 1 week (T2) and 1 month (T3).Results: Compared to sham, anodal tsDCS reduced RIII area at T2 (p = 0.0043) and T3 (p = 0.0012); similarly, FR total area was reduced at T3 (p = 0.03). Clinically, anodal tsDCS dampened VAS at T3 (p = 0.015), and NPSI scores at T1 (p = 0.0012), and T3 (p = 0.0015), whereas sham condition left them unchanged. Changes in VAS and NPSI scores linearly correlated with the reduction in LLFR areas (p = 0.0004).Conclusions: Our findings suggest that tsDCS could modulate nociceptive processing and pain perception in chronic pain syndromes. Chronic pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients . CentralSeveral non-invasive brain stimulation (NIBS) techniques have given evidence to improve pain; cerebellar transcranial direct current stimulation (tDCS), a recent technique of stimulation, has shown promising results for pain reduction , 8, whilLLFR is a polysynaptic and multi-segmental spinal reflex that induces a complex flexion synergy of the stimulated limb; it has two main components, formally named RII and RIII, which derive from the activation of the cutaneous A-beta and nociceptive A-delta fibers, respectively –28. GuidTo the best of our knowledge, no study has evaluated to date whether tsDCS modulates the RIII reflex, as a measure of the central nociceptive processing in chronic pain patients. Our aim was to evaluate the use of tsDCS, applied over the spinal cord  and primary somatosensory cortex , as non-pharmacological treatment in patients with chronic pain of different etiologies, by monitoring the effects on the LLFR and clinical scales, as assessed by the Visual Analog Scale (VAS) and the Neuropathic Pain Symptom Inventory (NPSI).Sixteen patients  with chronic pain have been enrolled in our study. Demographic features are summarized in In this randomized, double-blind, sham-controlled crossover study, each patient underwent sham and anodal tsDCS . Participants were assigned randomly to either group A (active tsDCS first) or group B (sham tsDCS first), using a random number generator. At the next treatment, patients were crossed over to the opposite treatment. Due to the potential carryover effect from crossover design, a washout period of at least 4 weeks was provided between treatments. Clinical (VAS and NPSI) and neurophysiological (LLFR) outcome were assessed before (T0) and at the end (T1) of the 5-day treatment and 1 week (T2) and 1 month (T3) after the completion of the stimulation protocol see . Both su2). We applied a current density of 0.035 mA/cm2 and delivered a total charge density of 42.8 mC/cm2, below the threshold values reported for tissue damage  of the main components of the FR (RII and RIII) were assessed. Stimuli with increased intensities were delivered with an interval of 2.5 mA at a time to obtain a repeatable response in three consecutive recordings, with a minimum width of at least 50 μV. The RII response, originated from the sensory activation of the nerve fibers, usually appeared with a lower stimulus intensity compared to RIII, with latency between 40 and 80 ms. Once the RII response was obtained, the intensity of the stimulus was increased until the RIII response appeared. Five responses of FR were recorded with a stimulus intensity set at the threshold 20% higher than RIII. Since the FR is variable, the recording was kept in a constant time of day for all the evaluation time points . The voluntary EMG activity at rest was monitored by video-audio feedback to ensure the lack of significant muscle contraction during experimental sessions.Lower limb flexion reflex (LLFR) was recorded from the left lower limb with patients in a prone position on a bed in a prepared room, with the ankle flexed at 90°. Ag/AgCl surface-capping electrodes placed with patches were used to guarantee the signal was recorded at the same position during all the experiments and ensure a reliable registration. Furthermore, an electro-conductive gel was used under the stimulating electrodes to optimize the passage of the currents and increase patient compliance. The RIII reflex was evoked and recorded from the left lower limb, as described in detail elsewhere , 40. BriThe Visual Analog Scale (VAS)  and Neurp < 0.05); Mann–Whitney test for each variable was performed on raw data to exclude significant differences at baseline (sham vs. active tsDCS). tsDCS-induced changes in each variable were then assessed by using the Friedman test  with the main factor “time” . In order to disclose significant changes at each time point between anodal and sham tsDCS, a Wilcoxon matched-pairs signed test was then applied. Both the electrophysiological measures and clinical scores were normalized to T0 score before entering the analysis [according to the formula (T1 – T0)/T0 * 100 + 100]. Finally, the Spearman's rank correlation coefficient was used to compare changes in electrophysiological parameters (LLFR) with the clinical outcome. Statistical significance was set at p < 0.05. The data were analyzed using SPSS v. 21.0 for Windows (SPSS Inc.). Neurophysiological and clinical data are expressed as mean ± Standard Error (S.E.).Non-parametric analyses were used, as all data sets did not pass the Shapiro–Wilk test for normality (p > 0.05). The statistical analysis disclosed that changes both in RIII and FR total area between the two groups were found over time, with anodal tsDCS leading to a marked reduction of both parameters and sham condition eliciting opposite effects   and T3 (p = 0.0012); FR total area significantly decreased in the anodal compared to sham tsDCS at T3 (Wilcoxon's test: p = 0.03). The sham group showed a significant increase in RII latency from T0 to T3  and in RIII area from T0 to T2  . Regardip > 0.05). The active group significantly changed over time in VAS (Friedman test: p < 0.05) and NPSI (Friedman test: p < 0.0001) scores, with post-hoc pairwise comparison showing a significant reduction for NPSI from T0 to T1 (p < 0.0001) and from T0 to T2 (p < 0.0001). In sham condition, VAS showed significant changes over time, with scores increasing from T2 to T3 , paralleled by a worsening of NPSI scores  , whereas NPSI scores improved both at T1 (p = 0.0012) and T3 (p = 0.0015). Changes in VAS and NPSI scores linearly correlated with the reduction in LLFR areas. Indeed, patients with greater clinical improvement showed a more robust modulation of neurophysiological responses .Mann–Whitney test for each raw clinical variable  at baseline revealed no statistical difference between the two groups ( < 0.01) . When coOur results demonstrated that the use of tsDCS for chronic pain subjects is safe and feasible. All subjects tolerated the stimulation well without dropouts. Anodal tsDCS dampened both RIII and FR total area and improved NPSI scores over time, thus resulting in an overall analgesic effect.Anodal tsDCS modulates the nociceptive component (RIII) of the LLFR. These findings are in line with the results reported by Cogiamanian et al. , showingMoreover, it is important to note the high variability in our estimates (expressed by large standard errors). This is partially explained by our small sample size, and also due to the mixed etiologies of chronic pain we included. The overall neurophysiological results reported on neuropathic and chronic pain tend to be heterogeneous, which might suggest RIII changes to be pathophysiology dependent . AnotherIt has been suggested that RIII reflex variables are correlated with pain-related measurements. For instance, the threshold of the RIII reflex has been shown to correspond to the pain threshold and the area of the reflex to be related to the level of pain perception , 56. OurFinally, the lack of changes in RII parameters is not surprising, as this component reflects the activation of non-nociceptive, large-diameter fibers, although recent studies have suggested that Aβ terminals are also engaged in the pathophysiology of paroxysmal pain , 61.The pain modulation mechanism of tsDCS remains open to questions. It has been suggested that anodal spinal tsDCS may produce a combination of spinal and supraspinal effects . FurtherMoreover, Truini et al.  showed aThis study has some limitations. First, the small sample size might have underpowered the study, even though we found neurophysiological and clinically significant results. Second, we included a heterogenous chronic pain population, with multiple neuropathic pain etiologies. The different degree of central nociceptive signal transmission affectation underlying such conditions might have affected the results and reduced the external validity of our findings. Similarly, our patients had stable but different (or even no) pharmacological therapies in place during the study. The different biochemical effects induced by the medications may have affected tsDCS effects, as previously suggested , 52.In conclusion, our findings on anodal tsDCS-induced reduction of nociceptive reflex (RIII reflex area) and pain intensity  in chronic pain subjects confirm that a non-invasive spinal neuromodulatory technique could modulate central nociceptive signal transmission and pain perception. Thus, tsDCS represents a promising intervention to reduce chronic pain by targeting pain-maladaptive plasticity. Further studies are needed with larger sample sizes, including a more homogenous population, and with optimized study design  and stimulation protocols .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 Ethics Committee of the IRCCS Ca' Granda Foundation - Maggiore Policlinico Hospital of Milan. The patients/participants provided their written informed consent to participate in this study.MV and SB: concept and design. MV, GA, AN, and SV: acquisition of data. MV and TB: interpretation of data. MG, RF, KP-B, SG-L, and TB: drafting of the manuscript. AP: critical revision of the manuscript. All authors contributed to the article and approved the submitted version.RF, MV, SB, and AP are founders and shareholders of Newronika Spa. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Significance of total ischemic time (TIT) in the context of ST-segment elevation myocardial infarction (STEMI) is still controversial. Therefore, in this study, we have evaluate the association of TIT with immediate outcomes in STEMI patients in whom recommended door to balloon (DTB) time of less than 90 min was achieved.p = 0.022), number of diseased vessels (p = 0.002), use of intra-aortic balloon pump (p = 0.003), and in-hospital mortality (p = 0.002). Mortality rate was 4.5%, 5.7%, and 7.8% for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively. Thirty days’ risk of mortality on TIMI score was 4.97 ± 7.09%, 5.01 ± 6.99%, and 7.12 ± 8.64% for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively.A total of 5730 patients were included in this study, out of which 80.9% were male and median age was 55 [61–48] years. The median DTB was observed to be 60 [75–45] min and onset of chest pain to emergency room (ER) arrival time was 180 [300–120] min. Prolonged TIT was associated with poor pre-procedure thrombolysis in myocardial infarction (TIMI) flow grade (Prolonged total ischemic was associated with higher in-hospital mortality. Therefore, TIT can also be considered in the matrix of focus, along with DTB time and other clinical determinants to improve the survival from STEMI. Both American College of Cardiology (ACC)/American Heart Association (AHA)/Society for Cardiovascular Angiography and Interventions (SCAI) and European Society of Cardiology (ESC) guidelines recommend primary percutaneous coronary intervention (PCI) for early reperfusion of the ST-segment elevation myocardial infarction (STEMI) for patients presenting to emergency room (ER) within 12 h of onset of chest pain . PercutaHowever, less attention was given to the other delays in the timeline of STEMI such as time between onset of chest and PCI capable hospital arrival . The totConsequently, it is well established that DTB time is very important in identifying in-hospital outcomes and long term morbidity and mortality in the STEMI; however, significance of total ischemic time in STEMI patients is still debatable. Moreover, there is paucity of local data which further enlightened its significance for further research. Therefore, the aim of this study was to evaluate the association of TIT with immediate outcomes in STEMI patients in whom recommended DTB time of less than 90 min was achieved.This study was conducted on selected patients from a prospectively collected institutional data registry. A single center hospital-based registry was established in January 2015 at the National Institute of Cardiovascular Diseases (NICVD), Karachi, Pakistan. Prior to inclusion, informed consent was taken explaining purpose and benefits of the study. Collected data were accessible to authorized personnel only and confidentiality was maintained at all stage of extraction of data and results. NICVD is one of the largest public sector tertiary care cardiac hospital and training center in Pakistan where primary PCI is being offered as the standard treatment 24/7 since 2010. All the procedures were performed as per the ACC/AHA guidelines by consultant cardiologist with experience of more than 5 years. Any contraindication to dual antiplatelet therapy was ruled out by taking brief history of the patient and an echocardiographic screening was done to assess any potential mechanical complications.Study was commenced after approval of the institutional ethical review committee. In this study, we included patients presented within 12 h of onset of chest pain, diagnosed with STEMI and underwent primary PCI during 1st June 2015 to 28th February 2018. Patients with prior history of any cardiac related surgery or intervention and patients with DTB time of > 90 min, due to any reason, were also excluded from the study. The TIT was measured on hospital arrival and was defined as the duration (in minutes) between onset of chest pain and ER arrival plus the duration (in minutes) between ER arrival and device activation. The DTB time was defined as the duration (in minutes) between ER arrival and device activation. Variables extracted from the registry were patient’s demography, risk profile, intra procedural characteristics, post procedural components, presenting KILLIP class, time variables, and in-hospital mortality.p ≤ 0.05 was the criteria for statistical significance.Patients were grouped into three based on TIT: Group 1, TIT ≤ 120 min; Group 2, TIT between 121 to 240 min; and Group 3, TIT > 240 min. All the variables were entered into the IBM SPSS Statistics for Windows, Version 21.0.  for data analysis. Frequency and percentages were calculated for all the categorical variables. Continuous variables were assessed for normality of distribution by applying Kolmogorov–Smirnov normality test and appropriate summary measure such as mean ± standard deviation (SD) or median [interquartile range (IQR)] were computed. Records with missing information regarding disease anatomy, in-hospital outcome, and other study variables were excluded from the analysis. The receiver operating characteristic (ROC) curve analysis was performed and area under the curve (AUC), optimal prognostic cutoff value of TIT and its sensitivity and specificity were calculated. Chi-square test was performed to assess the differences in various characteristics and outcomes by different TIT groups. Multivariable logistic regression analysis was performed to assess the predictors of mortality taken demographic characteristics (such as gender and age), co-morbid conditions , and TIT as explanatory variables based on results of univariate comparison and clinical judgment and odds ratio (OR) and 95% confidence interval (CI) were reported. Throughout the analysis, p < 0.001), gender (p < 0.001), diabetes (p = 0.039), and hypertension (p = 0.021). Baseline clinical and demographic characteristics stratified by the total ischemic time are presented in Table A total of 5730 patients were selected, of them 4637 (80.9%) were males and median age was 55 61–48) years. The median of DTB was observed to be 60 (75–45) min and chest pain ER arrival time was 180 (300–120) min. A total of 2978 (52%) patients were hypertensive, 1712 (29.9%) diabetic, 1636 (28.6%) smokers, and 263 (4.6%) had family history of CAD. Prolonged TIT was found to be associated with age (–48 yearsp = 0.022), number of diseased vessels (p = 0.002), use of IABP (p = 0.003), and side branch involvement (p = 0.008).Angiographic and procedural characteristics stratified by the TIT are presented in Table Post-procedure TIMI flow grade 0 was observed in 94 1.6%), I in 47 (0.8%), II in 228 (4.0%), and III in 5361 (93.6%) patients. In-hospital mortality rate was 388 (6.8%) and mortality rate was 4.5%, 5.7%, and 7.8% for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively. Thirty days risk of mortality on TIMI score was 2.2% (4.4–1.6%), 2.2% [4.4–1.6%], and 4.4% [7.3–2.2%] for the patients with TIT of ≤ 120 min, 121 to 240 min, and > 240 min, respectively. The optimal cutoff value of TIT based on ROC curve analysis was found to be 297 min (rounded of to 300 min), with sensitivity of 50.26% and specificity of 63.33%. ROC curve and in-hospital mortality rate stratified by the TIT are presented in Fig. .6%, I inp = 0.046), age , diabetes , and TIT  were significant predictors of in-hospital mortality.Multivariable logistic regression analysis for in-hospital mortality is presented in Table In this study, our aim was to assess the effect of TIT on mortality of STEMI patients in whom the recommended DTB time of < 90 min was achieved. We found that TIT is a good prognostic marker, mortality rate is linearly associated with TIT and every delay of an hour after onset of chest pain increases risk of mortality nearly by 5% (OR = 1.05). The optimal prognostic cutoff value for the TIT was 300 min, after which the risk of mortality increases exponentially. In our setup, more than half (54.3%) of the STEMI patients had TIT of more than 4 h. Prolonged TIT was observed to be associated with age and female gender, and patients with prolonged TIT had low TIMI flow grades, multivessel involvement, and increased use of IABP.p < 0.05) as compared to alive patients. Results from a Korean nationwide registry by Kim et al. [The prognostic importance of TIT is well documented by various studies in the past. De Luca et al.  reportedm et al.  observedm et al. , utilizaHence, most of the studies addressing the impact of TIT in STEMI management, including our study, agreed to the fact that TIT holds prognostic utility. In fact, in a number of cases, it proved to be a better predictor of mortality  than DTB time , 13–16. Single center registry-based study and non-randomized nature of the design are key limitations of this study. Secondly, time of onset of chest pain was noted in the ER based on patient or attendants recall, which may have some over or understating. Even though TIT was observed to be an independent predictor of in-hospital mortality, but low predictive value of ischemic time warranted further investigation for the potential effect of confounding factors.Prolonged TIT was associated with higher in-hospital mortality of STEMI patients in whom the recommended DTB was achieved. Although predictive value of TIT was low, but it was found to be an independent predictor of mortality and risk of mortality increases nearly by 5% with every passing hour of TIT. This could be achieved through a rigorous Emergency Management System (EMS) and meticulous patient awareness programs in developing countries.


In neuropathic postural tachycardia syndrome, peripheral sympathetic dysfunction leads to excessive venous blood pooling during orthostasis. Up to 84% of patients report leg pain and weakness in the upright position. To explore possible pathophysiological processes underlying these symptoms, the present study examined muscle excitability depending on body position in patients with neuropathic postural tachycardia syndrome and healthy subjects.In ten patients with neuropathic postural tachycardia syndrome and ten healthy subjects, muscle excitability measurements were performed repeatedly: in the supine position, during 10 min of head-up tilt and during 6 min thereafter. Additionally, lower leg circumference was measured and subjective leg pain levels were assessed.In patients with neuropathic postural tachycardia syndrome, muscle excitability was increased in the supine position, decreased progressively during tilt, continued to decrease after being returned to the supine position, and did not completely recover to baseline values after 6 min of supine rest. The reduction in muscle excitability during tilt was paralleled by an increase in lower leg circumference as well as leg pain levels. No such changes were observed in healthy subjects.This study provides evidence for the occurrence of orthostatic changes in muscle excitability in patients with neuropathic postural tachycardia syndrome and that these may be associated with inadequate perfusion of the lower extremities. Insufficient perfusion as a consequence of blood stasis may cause misery perfusion of the muscles, which could explain the occurrence of orthostatic leg pain in neuropathic postural tachycardia syndrome. Postural tachycardia syndrome (POTS) is a chronic disorder of the autonomic nervous system. Typical orthostatic symptoms in POTS include light-headedness, palpitations, blurred vision, cognitive dysfunction, generalized weakness, dyspnoea and headache. Many patients also experience non-orthostatic symptoms such as bowel and bladder dysfunction, fatigue, sleep disturbance and exercise intolerance , 2. The The recording of muscle velocity recovery cycles (MVRCs) is an electrophysiological method that allows us to investigate the function and properties of muscle fibre membranes in vivo , 9. ThisTo the best of our knowledge, the aetiology of muscle weakness and pain experienced by patients with neuropathic POTS has not been further investigated. The aim of the present study was to examine possible changes in muscle membrane properties in patients with neuropathic POTS as a function of body position and to compare the results to healthy subjects in order to investigate position-dependent leg symptoms in neuropathic POTS.Ten patients with confirmed neuropathic POTS and ten healthy subjects participated in this study. All subjects had to be older than 18 years of age, and patients had to have a positive history of orthostatic leg pain. Exclusion criteria for all participants included pregnancy and breastfeeding, and additionally for control subjects vasovagal syncope in the medical history, intake of vasoactive medication, and venous insufficiency. For the diagnosis of neuropathic POTS, medical history, physical and neurological examination, cardiovascular autonomic function testing, thermoregulatory sweat test and/or quantitative testing of sudomotor axon reflexes, measurement of plasma norepinephrine levels, determination of autoantibodies against G-protein-coupled receptors, and in some cases skin biopsies were considered . The meaThis case–control study investigated muscle membrane properties as a function of body position. To this end, MVRCs were recorded repeatedly during tilt table testing in patients with neuropathic POTS and healthy control subjects. The study protocol is illustrated in Fig. All participants were placed comfortably in the supine position on a tilt table. During the experimental procedure, beat-to-beat blood pressure and heart rate were measured with the Portapres device  on the left hand. In addition, intermittent brachial blood pressure and heart rate were measured on the right arm in the supine position and during HUT using an automated Dinamap Pro 100 sphygmomanometer . Furthermore, a standard three-lead electrocardiogram was recorded throughout testing. All participants underwent standard screening autonomic function tests in the supine position before HUT. The autonomic function screening included a pressure-controlled Valsalva manoeuvre (40 mmHg for 15 s) in the supine position, the investigation of the pressor response to a cutaneous cold stimulus at the wrist, and assessment of the heart rate variability in response to deep breathing . HUT wasMVRC recordings were performed from the participant’s tibialis anterior muscle of the left leg as described in detail in prior studies , 23. ThiMuscle action potentials were recorded with a concentric electromyography (EMG) needle electrode , which was positioned approximately 20 mm proximal to the stimulating needle electrode. A non-polarizable surface electrode  placed on the skin at the lateral malleolus or the patella served as ground electrode. The stimulation and recording electrodes were inserted to a depth of about 7–10 mm and repositioned until a stable muscle action potential could be recorded. The electrode leads were taped to the skin to avoid displacement, especially during HUT. The position of the electrodes was checked regularly throughout testing. Signals were amplified  and digitized  using a sampling rate of 20 kHz. For stimulation and recording, the QtracW software  was used. Every 2 s, test stimuli were delivered. The interval between the preceding conditioning stimulus and the test stimulus was varied in 34 steps between 1000 and 2 ms. Hence, the duration of one full MVRC recording was 3 min. The following parameters were measured from each MVRC recording: (1) MRRP, defined as the shortest interpolated interstimulus interval at which the latencies of the unconditioned and conditioned test response were identical, (2) ESN, measured as the peak percentage reduction in latency at interstimulus intervals shorter than 15 ms and (3) LSN, measured as the average percentage reduction in latency at interstimulus intervals between 50 and 150 ms. The first MVRC was recorded in the supine position before HUT, three during 10 min of HUT and two during recovery after HUT in the supine position.The circumference of the right lower leg was measured 15 cm proximally to the lateral malleolus in the supine position just before HUT and at 3, 6 and 9 min of HUT. The circumference was measured with a measuring tape that was attached to the participant’s leg throughout the examination. At the same time, subjects and patients were asked to rate any leg pain they experienced on a scale from 0 to 10 (where 0 corresponds to no pain and 10 corresponds to severest pain). The rating of leg pain was explained to all participants before the beginning of the examination.t test. For the analysis of MVRC data, 2 × 6 analyses of variance (ANOVA) for repeated measures with post hoc Bonferroni correction for multiple comparisons were applied. The factors consisted of (i) group  and (ii) position . For leg pain, leg circumference and heart rate, 2 × 4 repeated-measures ANOVAs with post hoc Bonferroni correction for multiple comparisons were applied. The factors consisted of (i) group  and (ii) position . Pearson correlations were calculated for relative values of MVRC parameters and relative values of leg circumference and leg pain (differences between the baseline supine and 9-min HUT position). Data are reported as mean ± standard deviation (SD). A P value < 0.05 was defined as statistically significant.MVRC data were analysed using QtracP software as described previously . For staTable F = 4.07, p = 0.022) and no significant interaction. Post hoc pairwise comparisons showed a reduction in MRRP from the supine to the 3-min recovery position (p = 0.023) in patients only. The same analysis for ESN showed a significant effect of position  and a significant interaction . Post hoc pairwise comparisons showed an increased ESN in the baseline supine recording in patients compared to healthy subjects (p = 0.044). Furthermore, ESN decreased in patients from the supine to the 3-min HUT (p < 0.001), 6-min HUT (p < 0.001), 9-min HUT (p < 0.001), 3-min recovery (p < 0.001) and 6-min recovery position (p < 0.001). Additionally, from the 3-min HUT, ESN continued to decrease to the 6-min HUT (p = 0.015), 9-min HUT (p = 0.002), 3-min recovery (p = 0.002) and 6-min recovery position (p = 0.012) in patients only. In the control group no significant changes were found. The analysis for LSN did not reveal a significant effect for position or a significant interaction, but showed a significant effect for group (p = 0.047). Post hoc pairwise comparisons did not show any significant differences between or within the two groups.In all participants, six consecutive MVRCs were successfully recorded. In Fig. F = 7.11, p = 0.005). Pairwise comparisons showed that in patients, the circumference increased from the supine to the 6-min (p = 0.011) and the 9-min HUT position (p = 0.001). Looking at the HUT phase only, the circumference also increased from the 3-min to the 9-min HUT position (p = 0.004) and from the 6-min to the 9-min HUT position (p = 0.024). No such changes were found for the control group. The analysis for leg pain revealed a significant effect for position  and group (p = 0.006), as well as a significant interaction . Pairwise comparisons showed that at 6 and 9 min of HUT, the pain levels were higher in patients than in healthy subjects . Furthermore, the pain levels significantly increased in patients from the supine to the 6-min and 9-min HUT position, and from the 3-min to the 6-min and 10-min HUT position . Again, no such changes were found for the control group. The decrease in ESN from the supine to the 9-min HUT position correlated negatively with the increase in leg pain during the same time period . All other correlations between MVRC parameters and leg circumference and pain were not significant. During HUT, patients experienced a mean heart rate increase of 28 bpm, and healthy subjects an increase of 15 bpm (p < 0.001).Regarding the biological parameters, the repeated-measures ANOVA for circumference of the lower leg showed a significant effect for position . Furthermore, the aim of this study was to investigate muscle membrane properties depending on the patient’s body position, and therefore we were primarily interested in the within-subject changes occurring during HUT. Within-subject differences could not be influenced by medication; such an influence would only be possible for between-subject differences. For these reasons we conclude that a possible confounding effect of medication is unlikely and, most importantly, the main research question could be investigated unaffected by the intake of the listed medications. Finally, as patients experience a delayed recovery of muscle excitability parameters after being upright, and the baseline MVRC measurement in the supine position was recorded after a 20- to 30-min supine rest period, we cannot fully exclude the possibility that this measurement may have been affected by too short a rest period before the start of the recordings.In summary, our results show that in patients with neuropathic POTS, muscle fibres are hyperpolarized in the supine position and depolarize progressively during HUT with delayed recovery. Depolarization of muscle fibres during HUT was paralleled by an increase in the circumference of the lower leg and leg pain levels. Hence, the altered perfusion as a consequence of blood stasis may cause an ischemia-like state of the muscles, which could explain the occurrence of orthostatic leg pain in patients with neuropathic POTS.


Neuropathic pain (NP) is one of the main complications of leprosy, and its management is challenging. Infrared thermography (IRT) has been shown to be effective in the evaluation of peripheral autonomic function resulting from microcirculation flow changes in painful syndromes. This study used IRT to map the skin temperature on the hands and feet of leprosy patients with NP.This cross-sectional study included 20 controls and 55 leprosy patients, distributed into 29 with NP (PWP) and 26 without NP (PNP). Thermal images of the hands and feet were captured with infrared camera and clinical evaluations were performed. Electroneuromyography (ENMG) was used as a complementary neurological exam. Instruments used for the NP diagnosis were visual analog pain scale (VAS), Douleur Neuropathic en 4 questions (DN4), and simplified neurological assessment protocol. The prevalence of NP was 52.7%. Pain intensity showed that 93.1% of patients with NP had moderate/severe pain. The most frequent DN4 items in individuals with NP were numbness (86.2%), tingling (86.2%) and electric shocks (82.7%). Reactional episodes type 1 were statistically significant in the PWP group. Approximately 81.3% of patients showed a predominance of multiple mononeuropathy in ENMG, 79.6% had sensory loss, and 81.4% showed some degree of disability. The average temperature in the patients’ hands and feet was slightly lower than in the controls, but without a significant difference. Compared to controls, all patients showed significant temperature asymmetry in almost all points assessed on the hands, except for two palmar points and one dorsal point. In the feet, there was significant asymmetry in all points, indicating a greater involvement of the lower limbs.IRT confirmed the asymmetric pattern of leprosy neuropathy, indicating a change in the function of the autonomic nervous system, and proving to be a useful method in the approach of pain. Pain has been shown to be a significant problem for leprosy patients and may be of nociceptive origin due to tissue inflammation, which occurs during reactional episodes mediated by the immune system, or neuropathic due to leprosy affecting the somatosensory system. It is important to differentiate neuropathic pain from chronic neuritis pain because the clinical implications and treatment are different. Multidrug therapy does not seem to prevent the occurrence of neuropathic pain, which is associated with low indices of quality of life and the general state of health. Infrared thermography is a complementary imaging test that is still growing and can be used in monitoring and determining the prognosis of patients in the health area. The thermographic examination records the abnormal thermal distribution and temperature differences in circulation alterations, which are not noticeable in the subjective evaluation of pain. We believe that the use of thermography as a complementary exam in the study of pain in leprosy neuropathy can assist in the definition of conduct protocols, which will enable the tracking and referral of patients to specific sectors in specialized health units, thereby changing the direction of the disease. Mycobacterium leprae [Leprosy is a chronic infectious disease caused by the bacillus m leprae , which, m leprae . Periphem leprae . This nem leprae . Leprosym leprae .Pain has been shown to be a significant problem in leprosy neuropathy, and may be of nociceptive origin due to neuritis, which occurs during reactional episodes, neuropathic due to the involvement of the somatosensory system, or mixed (nociceptive and neuropathic) ,7. AccorIn the absence of biomarkers or other gold standard examination, the diagnosis is initially clinical . ValidatThere are some quantitative assessment methods available that can assist in the approach of NP, such as infrared thermography (IRT), which allows the mapping of the skin surface temperature, capturing changes in the microcirculation blood flow . AccordiThe present study used IRT to assess the function of the peripheral autonomic nervous system by mapping the skin temperature of the hands and feet of leprosy patients who were undergoing treatment for relapses or treatment failure. Considering the magnitude of neuropathic pain in leprosy, this study aims to describe thermographic findings in leprosy patients, evaluating the association of these findings with the presence of neuropathic pain, as autonomic impairment may accompany this clinical condition.The Committee of Ethics in Research from the Federal University of Uberlandia (UFU)/MG approved this study (CAAE: 60427816.4.0000.5152). The researchers explained the aim of the study to the participants, and those who agreed to participate in the study signed the free and informed consent form.This cross-sectional study was conducted from January 2018 to December 2019 at the National Reference Center for Sanitary Dermatology and Leprosy (CREDESH), Clinical Hospital, Federal University of Uberlandia, located in Uberlandia/MG, Brazil. Patients (>18 years old) diagnosed with leprosy relapse or failure of previous treatment were eligible for this study. Clinical criteria were used for the diagnosis of leprosy relapse or treatment failure as follows: 1) Presence of active skin lesions; 2) New areas with change in sensitivity; 3) Neurological abnormalities, persistent neuritis, or reactional outbreak unresponsive to clinical treatment. Laboratory criteria used included: 1) Presence and characteristics of bacillus according to the bacilloscopic index in dermal scraping and skin biopsy; 2) Presence and quantification of bacillary DNA by qPCR (threshold cycle result) in dermal scraping and skin biopsy; 3) Maintenance or increase of the ELISA IgM anti-PGL-I index. Regarding the time to relapse, it was considered as greater than or equal to five years from the time of discharge from the last treatment. Regarding treatment failure, patients who had no clinical and laboratory improvement were defined as stated above, at the time of discharge from MDT for 24 months or alternative ROM regimen (rifampicin 600 mg + ofloxacin 400 mg + minocycline 100 mg) in monthly supervised doses for 24 months [To compare epidemiologic data and thermal measurements, 22 healthy individuals who had no contact with leprosy patients were invited to participate in this study as a control group. Their health status was confirmed by physical exam, and those with a normal sensory and motor assessment were included, while individuals with suspected systemic or localized diseases were excluded. The final sample consisted of 20 healthy individuals .The thermal images of the hands and feet of healthy individuals and leprosy patients were captured using a thermal camera. To perform the IRT, the patients were instructed to prepare according to the protocol of the American Academy of Thermology , which cOn the day of the examination, the individuals were placed in an air-conditioned room without air currents or a heat source. The lighting of the room was made with fluorescent lamps to prevent the heating of the room. The temperature and humidity were monitored using the digital thermo-hygrometer Incoterm model: 7666.02.0.00. The room temperature was kept at 23°C ± 1°C and relative humidity at 55.5% ± 3.5%, and the participants remained seated and barefoot, resting in this environment for 15 minutes for acclimatization. A qualified physician captured the images using an infrared camera, with high spatial resolution of 320 x 240 pixels, calibrated with thermal sensitivity from 0.045°C to 30°C, frequency of 60 Hz, and having the ability to adjust the emissivity to 0.98. The camera was positioned on a tripod at a distance of 67–70 cm from the participant, and IT was captured from the hands  and feet (dorsum and sole) bilaterally. The IT obtained were saved in Joint Photographic Experts Group (JPEG) format and analyzed using thermography software.Regions of interest (ROIs) were defined for quantitative temperature evaluation, 24 in the hands, back, and palm, and 17 in the feet, plant, and back . The ROIThe ROIs defined in each neural area were: 1) Median nerve: P1, P2, P3, P4, P5, P6, AP1, D1, D3, and D5; 2) Ulnar nerve: P9, P10, AP2, D9, D10, and AD2; 3) Radial nerve: D2, D4, D6, and AD1; 4) Tibial nerve: PL1, PL2, PL3, PL4, PL5, PL6, PL7, PPL8, PL9, and PL10; 5) Fibular nerve: D1, D2, D3, D4, D5, F, AD1, and AD2 . Points For statistical comparison, the average temperatures of the ROIs (isolated and grouped) and the temperature difference (ΔT = Tright—Tleft) between the contralateral hands and feet were calculated. The ΔT was used to assess asymmetry and detect possible dysfunctions.The patients underwent clinical evaluation during which sociodemographic  and clinical data were collected: World Health Organization (WHO) and the Ridley-Jopling classification , previouDouleur Neuropathique en 4 Questions (DN4) [Participants in the PWP group were asked to locate the anatomical region of their pain, and the degree of pain intensity was assessed using the visual analog pain scale (VAS), where 0 = no pain and 10 = maximum pain . The intns (DN4) , a univens (DN4) , composeThe leprosy patients were submitted to the assessment of the peripheral sensory-motor function by the physiotherapy team at the CREDESH. In the motor assessment, functional tests were performed in the muscle groups of abductor pollicis brevis and lumbricals (first and second) for the median nerve; first dorsal interosseous, abductor digiti minimi, and lumbricals (third and fourth).for the ulnar nerve; common extensor of the fingers and radial carpal for the radial nerve; and the muscles tibial anterior, extensor digitorum longus, and extensor hallucis longus innervated by the deep fibular nerve. The Medical Research Council Scale was used with a graduation of 0–5, considered as grade 0 = paralysis and 5 = normal strength, and any change in function < 4 in one or more muscle groups was considered abnormal .The sensory evaluation was performed using the six Semmes-Weinstein filaments, which exert forces of 0.05 g, 0.2 g, 2g, 4g, 10g, and 300 g when applied to the skin, and the tested points coincided with the ROIs evaluated. Sensory loss was considered as the absence of positive response to filaments of 0.2 g in the hands and 2g in the feet .Electroneuromyography was performed on the participants in the PWP and PNP groups to assess neuropathy, by the neurophysiologist of CREDESH. The device used in the examination was the MEB 4200K (NIHON-KODHEN) and the techniques and configurations of the examination were standardized in the previous study. The sensory nerves evaluated were the median, ulnar, dorsal cutaneous of the hand, radial, sural, superficial fibular, and medial plantar bilaterally, and the motor nerves were the median, ulnar, deep fibular, and tibial bilaterally. The electroneuromyography was classified according to the neurophysiological pattern in mononeuropathy: presence of only one altered nerve or asymmetric multiple mononeuropathy and presence of two or more altered nerves .It was calculated the sample size of this study using the software G*Power . One-way ANOVA fixed effects were performed by means of priori analysis with the effect size of 0.37, obtained from a pilot study concerning thermography (not published), alpha err probability of 5% (0.05), power of test (1-β err probability) 0.80 (80%) and the number of 3 groups. Thus, the total sample size, considering the above parameters, was 75 individuals.D’Agustino-Pearson test was used to evaluate the normality of the values referring to the temperatures of each cutaneous region and the values of ΔT. The nonparametric distribution variables were normalized by the Log 10 transformation when necessary. The Binomial test evaluated the association between clinical/sociodemographic variables and patient groups with or without pain.The The student’s t-test, for paired samples, was used in the comparison between the average temperatures of the upper limbs right and left. Mann-Whitney test was used in the comparisons between the sum of the average of the stations for each ΔT referring to the differences in temperatures by cutaneous region obtained for different groups.The statistical program used was the Statistical Package for Social Sciences version 22 , with a significance level of 5% for all analyses.Fifty-five leprosy patients were evaluated, with 29 patients in the PWP group and 26 patients in the PNP group. There was no statistical difference between the PWP group  male), PNP group (48 ± 13.44 years: 61.5% (16/26) male), and healthy subjects  male) in relation to age and gender (p>0.05). The control group presented normal sensory-motor function, being the inclusion criteria for this group. The clinical data of the PWP and PNP groups are shown in The previous reactional episodes type 1 were statistically significant in the PWP group (p = 0.020). The ENMG showed a predominance of multiple mononeuropathy in the patient groups, with a significant difference in the PWP and PNP groups (p < 0.045). Most individuals presented sensory loss and some degree of disability, but there was no significant difference between the PWP and PNP groups. There was a greater loss of motor function in the PWP group (p = 0.001) .In the PWP group, 93.1% (27/29) of patients had NP and 6.9% (2/29) mixed pain. The prevalence of NP was 52.7% (29/55), considering individuals who had mixed pain. The most frequent DN4 items in individuals with NP were numbness and tingling 86.2% each (25/29), electric shocks 82.7% (24/29), hypoesthesia to touch 75.8% (22/29), pins and needles 72.4% (21/29), and burning 68.9% (20/29), and the least frequent were brushing/painful cold with 37.9% each (11/29), hypoesthesia to prick 34.5% (10/29), and Itching 27.6% (8/29). All patients with NP had chronic pain, and as for the periodicity of pain, 62.1% (18/29) of the individuals reported that the pain was intermittent and 37.9% (11/29) reported that the pain was continuous.The patients reported NP in the innervation territory of the following nerves: 89.6% (26/29) left tibial, 75.9% (22/29) left fibular, 58.6% (17/29) right tibial, 62.1% (18/29) right fibular, 55.2% (16/29) left ulnar, 41.4% (12/29) right ulnar, 34.5% (10/29) left radial and median, and 31.03% (9/29) right radial and median. Only 13.8% (4/29) of the patients with NP reported pain in only one nerve, and 86.2% (25/29) had two or more nerve involvement. Pain intensity assessed by VAS showed that 93.1% (27/29) of patients with NP had moderate/severe pain. The intensity of peripheral nerve topography is represented in Comparisons of the mean temperature of each individual with that of the contralateral side was performed, and the ΔT measurements were compared between the group of patients (PWP and PNP) and healthy controls. The average temperatures of the ROIs and the neural areas ranged from 31.69°C to 33.74°C in the hands and 29.5°C to 32.06°C in the feet, in the group of patients (PWP and PNP). There was a significant mean temperature difference in P4, P5 and P10 in the hands and PL7, PL8, D2, and D3 in the feet of the group of leprosy patients. In the healthy controls, the average temperature was between 32.34°C to 33.71°C in the hands and 30.38°C to 32.15°C in the feet, but only ROI P5 had a significant difference in this group . In all When the groups of patients were compared to each other, the average temperature in the hands of the PWP group ranged from 31.38°C to 33.63°C and in the PNP group from 31.71°C to 33.6°C. In the feet, it varied from 29.62°C to 32.01°C in the PWP group and 29.35°C to 32.11°C in the PNP group. In the PWP group, there was a significant difference in the mean temperature on the right side with the left in two ROIs (P2 and AD2) in the hands and two ROIs (PL2 and PL7) in the feet (p < 0.05). In the PNP group, there was no significant difference between the average temperatures (p > 0.05) . There wNP in leprosy has been underdiagnosed and poorly treated. Therefore, new tools are needed to help in the correct approach to the diagnosis of pain, because the presence of pain greatly impacts the quality of life of patients . PatientIn the present study, 92.7% (51/55) of patients had previous reactional episodes, and the PWP group had a higher number of type 1 reactions than the PNP group (p = 0.02). Multibacillary patients have a higher chance of developing leprosy reactions regardless of the type . Type 1 It has been described that sensory and autonomic fibers  are the first to be affected in leprosy , therefoM leprae antigens [In this study, the prevalence of NP was 52.7% 29/55). The high prevalence of NP in patients with relapse and treatment failure could be caused by chronic inflammation around the nerve, the existence of persistent antigens , or resi/55. The antigens .Regarding pain localization, this study showed a higher incidence in the tibial and fibular nerves, a fact that differed from other studies that reported a higher incidence in the ulnar nerves ,40. TibiThe IRT has been used as an auxiliary tool in the triage and monitoring of neuropathic painful syndromes, but its use should be judicious because it reflects the emission of heat determined by physiological and pathological neural processes or not . The skiIn this study, the average temperature of the ROIs showed almost no significant difference between the control group and leprosy patients (PWP and PNP), which due to the subtle variation in the temperature distribution  or becauIn this study, the method used was the static method, where the temperature measurement was performed in a single moment and the main way of evaluating the temperatures in this method was by ΔT, which evaluates the temperature difference on one side of the body compared to its contralateral side . There iThere was no statistical difference in the ΔT between the PWP and PNP groups in the ROIs and neural areas evaluated, probably because most patients were already presenting an advanced neural disease. The static thermography was able to diagnose autonomic dysfunction in leprosy, which is not always accompanied by NP; therefore, thermal images should always be analyzed based on clinical evaluation. It should be considered that thermography captures acute or chronic sympathetic nervous system dysfunction, and as chronic neurological disease progresses, sympathetic thermal dysfunction becomes bilateral . ThermogIRT seems to be a promising method to approach pain, as it is safe and non-invasive. By tracking changes in the microcirculation of the hands and feet of patients with leprosy, sensorimotor neural assessments can be correlated with the dysautonomia demonstrated by the skin’s thermal pattern.The creation of a database with individual thermograms can assist in monitoring the progression of neuropathies through temperature changes. These repeated accompanying measures during treatment will clarify the link between asymmetric temperature distributions and pathophysiological changes on the skin surface and the extent of the neural injury.Given its limitations, IRT cannot be considered as a substitute for clinical examination and motor-sensory evaluation, but it complements this peripheral neural evaluation and can assist in therapeutic approaches to pain, impacting measures to prevent leprosy deficiencies.PN in leprosy needs to be better understood to be treated properly, as it directly impacts the individual’s quality of life. Further IRT studies are needed, evaluating the patient early before the installation of permanent neural damage and using dynamic methods associated with thermal stress tests that can increase sensitivity for the detection of NP dysautonomia in leprosy, thereby allowing for the better understanding and applicability of thermal tests.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


Physicians do not prescribe opioid analgesics for pain treatment equally across groups, and such disparities may pose significant public health concerns. Although research suggests that institutional constraints and cultural stereotypes influence doctors’ treatment of pain, prior quantitative evidence is mixed. The objective of this secondary analysis is therefore to clarify which institutional constraints and patient demographics bias provider prescribing of opioid analgesics.We used electronic medical record data from an emergency department of a large U.S hospital during years 2008–2014. We ran multi-level logistic regression models to estimate factors associated with providing an opioid prescription during a given visit while controlling for ICD-9 diagnosis codes and between-patient heterogeneity.A total of 180,829 patient visits for 63,513 unique patients were recorded during the period of analysis. Overall, providers were significantly less likely to prescribe opioids to the same individual patient when the visit occurred during higher rates of emergency department crowding, later times of day, earlier in the week, later years in our sample, and when the patient had received fewer previous opioid prescriptions. Across all patients, providers were significantly more likely to prescribe opioids to patients who were middle-aged, white, and married. We found no bias towards women and no interaction effects between race and crowding or between race and sex.Providers tend to prescribe fewer opioids during constrained diagnostic situations and undertreat pain for patients from high-risk and marginalized demographic groups. Potential harms resulting from previous treatment decisions may accumulate by informing future treatment decisions.The online version contains supplementary material available at 10.1186/s12889-021-11551-9. Physicians do not prescribe opioid analgesics for pain treatment equally across groups. Latino and African Americans, for example, are significantly less likely than whites to receive opioid analgesics following a major surgical procedure –4, and oUndertreatment for pain results from many factors that operate in combination including pain’s ambiguous diagnostic criteria, cultural stereotypes around particular groups’ experience of pain, and institutional constraints that affect doctors’ ability to diagnose pain. Because pain often lacks clear physical markers, doctors are forced to elicit information directly from patients to determine whether opioid analgesic treatment is necessary –13. HoweAlthough there are many studies about how institutional constraints and cultural stereotypes influence doctors’ treatment of pain, quantitative evidence is mixed. Recent research suggests that doctors are biased towards over-treating patients during periods of time constraint and hospital crowding , 23, butSociological research suggests that some discrepant findings may be due to overlooked mediators and moderators of other cultural and institutional constraints , 20, 28.To understand how institutional constraints and patient demographics influence pain treatment, this paper examines a large longitudinal dataset of electronic medical records gathered at an emergency department of a large private hospital in the United States. We study how opioid treatment for pain is simultaneously influenced by multiple factors and how this may bias pain treatment. Specifically, we examine how pain treatment is influenced by the intersection of emergency department crowding and race, the time patients visited the emergency department, patients’ medical histories, patients’ diagnoses, age, sex, marital status, and year of analysis. This is one of the largest and most comprehensive longitudinal studies of demographic and institutional predicates of opioid pain treatment in the literature, and it is one of only a few studies that examine multiple factors associated with pain treatment in tandem and over time. Our findings inform dominant hypotheses about provider bias, clarify prior mixed evidence, and provide evidence for under-explored avenues of bias in pain treatment.n = 180,829 patient visits; 63,513 unique individuals). Roughly 54.1%  patients are seen only once in the ED, while 18.6%  visit the ED twice, 8.9% (5669) visit the ED three times, 5.0% (3180) visit the ED four times, and 67.4% (8459) visit the ED five or more times over the sample period. Consistent with prior work on doctor biases in pain treatment, we focus on EDs because the majority of patients who visit EDs  system of a large university hospital in the United States. We focus our analysis on EMR data collected from 2008 to 2014 at the hospital’s emergency department (ED) (h as 70% ) do so fTo determine factors associated with provider bias in opioid pain treatment, we estimate a series of three generalized linear mixed models with a logit link function that predict whether a patient was prescribed opioids during a given ED visit based on a variety of contextual and demographic variables. Our models are ordered by complexity. Our first model includes patient-level random intercepts to account for repeated observations for individual patients. Our second model includes both patient-level random intercepts and fixed effects for each of 484 common International Classification of Diseases  (ICD-9) prescribed any opioids during the patient visit. Because our data include detailed patient records, we are able to observe and measure whether the patient received a prescription. This is a binary measure that tracks whether a patient received at least one of the following generic opioid prescriptions (listed in order of frequency): oxycodone, morphine, hydromorphone, fentanyl, hydrocodone, codeine, methadone, tapentadol, or meperidine.1The dependent variable in all models is whether individuals were ED crowding, our most central contextual measure, as the number of patients who visited in the last 4 hours. This variable accounts for the degree to which providers are under time pressure. We chose 4 hours as our cutoff in order to leverage available data and account for the fact that many EDs set four-hours as their target maximum wait time [ED crowding and respondent race (ED crowding x black). Third, we include several indicators for time of day to adjust for different patient counts throughout the day: 12 am-5:59 am , 6 am-11:59 am (morning), 12 pm-5:59 pm (afternoon), and 6 pm-11:59 pm (evening). Fourth, we include an indicator that the ED visit occurred on a weekend (Saturday or Sunday) to control for lower patient numbers during the weekend. Finally, we include an indicator for year of visit from 2008 (reference) to 2014. The year variable accounts for a cautioning effect of the opioid crisis on prescribing opioids. After controlling for routine variations in ED visits based on time of day, week, and year, the ED crowding variable captures the quasi-random fluctuation in ED visits that are unexpected and not likely to be correlated with patient characteristics or other patient-level determinants of physicians’ opioid prescribing.We use five variables to measure ED context. First, we measure ait time . Second,age coded as 10-year age indicator variables  to test whether providers are more hesitant to prescribe opioid analgesics to younger or older citizens. We measure race using indicator variables for white (reference), black, Latino, Asian, and other race to test for racial biases against prescribing opioids to people of color. We include an indicator for sex  and we include four race-sex interaction terms to test whether women or women of color have distinct disadvantages when seeking pain treatment. We include indicators for marital status  to test whether doctors prescribe opioid analgesics more often to individuals who have familial ties than to individuals who are single. Finally, we account for patient medical histories by modeling the number of times patients had received any opioid prescriptions during prior ED visits (previously prescribed number). Because our coverage of patients’ medical histories increases over time, we also include year interactions with patient prescription counts and exclude the first year of our available data (2007) from analysis.We also control for demographic factors that are known to be associated with opioid prescriptions. We include measures of patient Table Figure Table b = − 0.002 in Model 3; 95% CI = − 0.005 to − 0.002), suggesting that providers are less likely to prescribe opioids during crowded hours. The coefficient for ED crowding implies that patients who visited the ED during mean rates of crowding (13.92 patients) had a 2.78% reduced probability to receive an opioid prescription than patients who visited the ED while it was empty. There was no significant association for the interaction between ED crowding and black patients across models (b = 0.000 in Model 3), indicating no significant difference in how ED crowding affected provider prescribing towards black and other patients. The parameter estimate for events from 6 pm-11:59 pm (b = − 0.026 in Model 3) is negative, indicating that providers were less likely to prescribe opioids in the evening compared to overnight (12 am to 6 am). In contrast, the estimate for events on the weekend (b = 0.029 in Model 3) is positive, indicating that providers were more likely to prescribe opioids on weekends. The coefficient for year is negative (b = − 0.028 in Model 3), implying that providers have become less likely to prescribe opioids over this sample period. Moreover, the models imply that providers were substantially more likely to prescribe opioids to patients that had been previously prescribed opioids at the ED .Parameter estimates for contextual variables are similar across models. ED crowding was associated with a reduced probability for providers to prescribe opioids (b = − 0.063 in Model 2). Patients that are married (b = 0.014) and widowed (b = 0.012) have an increased probability to be prescribed opioids compared to the unmarried. Although black and Latino females were less likely to be prescribed opioids in Model 1 , there are no differences after controlling for ICD-9 diagnosis. Without controlling for ICD-9 diagnosis (as illustrated in Model 1), providers have a lower probability to prescribe opioids to patients that are black (b = − 0.033) and Asian (b = − 0.049), and a higher probability to prescribe opioids to individuals who are Latino (b = 0.024). However, controlling for diagnosis in Model 2 resulted in negative parameter estimates for black and Asian patients but no difference for Latinos relative to white patients. Together, these changes indicate a negative association between non-white race and receiving opioid analgesics once we control for racial differences in health conditions.Parameter estimates for demographic variables are unavailable for Model 3 due to their time-invariance but are mostly consistent between Model 1 and Model 2. In these models, individuals’ probability to receive opioids decreases after age 70  prevent us from determining whether patients in these conditions were truly undertreated. Factors that we found to have a downward association with opioid pain treatment may have actually served to prevent overtreatment.We found that within-patient differences in the receipt of an opioid prescription during a visit to the ED was negatively associated with visiting the ED at higher rates of crowding, later times of day, earlier days of the week, at later years, and with having received few opioid prescriptions during previous ED visits. Across patients, we found that providers were more likely to prescribe opioids to patients who were middle-aged, white, and married. These results reaffirm previous findings that institutional constraints and racial demographics can significantly bias how providers prescribe opioid analgesics and suggest new paths that may bias providers in analgesic treatment. Given the current state of the opioid epidemic in America, our findings that providers tend to err towards more cautious treatment for pain during constrained diagnostic situations may seem encouraging. However, it is critical that we do not forget the costs of undertreatment as well. To identify the consequences of undertreatment, future research should estimate the direct effects of provider biases in opioid analgesic prescribing on patients’ long-term health. It is essential that the field continues to work towards identifying institutional policies that can lead to consistent and appropriate treatment for pain.Additional file 1. Full logistic regression results for Models 1–3 in log odds.Additional file 2. Logistic regression results for non-opioid prescriptions.Additional file 3. Histogram for previous opioid prescriptions.